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Jaitner N, Safraou Y, Anders M, Schattenfroh J, Meyer T, Huang B, Jordan J, Boehm O, Caiazzo A, Schaeffter T, Mura J, Guo J, Sack I. Noninvasive assessment of portal pressure by combined measurement of volumetric strain and stiffness of in vivo human liver. Acta Biomater 2025; 197:312-325. [PMID: 40081554 DOI: 10.1016/j.actbio.2025.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 02/25/2025] [Accepted: 03/10/2025] [Indexed: 03/16/2025]
Abstract
Liver metabolism depends on the mechanical interplay between the solid tissue matrix and blood vessels, making shear modulus and pressure important variables of hepatic homeostasis. While shear modulus can be quantified by magnetic resonance elastography (MRE), pressure is not available through noninvasive imaging. We propose combined determination of liver deformation and shear modulus using volumetric MRI and MRE for noninvasive portal pressure assessment. Volumetric MRI and multifrequency MRE were performed in five ex vivo rat livers at different portal pressures. A similar imaging protocol was used to examine eleven healthy volunteers after overnight fasting in two respiratory states and after ingestion of 1.5 L of water. Models derived from ex vivo rat data served to scale human liver volumetric strain multiplied by differential shear modulus obtained from MRE to portal pressure. After water intake, liver volume expanded by 3 % (Interquartile range [IQR], 1.3-6.0; p < 0.001) and shear modulus increased by 0.12 kPa (IQR, 0.08-0.26; p = 0.001), while deep inhalation had mixed effects (p > 0.05). Positive and negative volumetric strains were associated with stiffening and softening, respectively, leading to a consistent increase in portal pressure of 0.2 to 0.3 kPa (IQR, 0.07-0.41) for inhalation and water ingestion. In conclusion, volumetric strain analysis combined with MRE in different scenarios of in vivo liver deformation and calibration with controlled ex vivo experiments allowed assessment of portal pressure changes. In clinical applications, combined MRE and volumetric MRI after inspiration or water ingestion could provide mechanical contrast for assessing hepatic pressure-related diseases. STATEMENT OF SIGNIFICANCE: Using 3D MRI and MR elastography, this study introduces trained image segmentation and registration based quantification of liver volumetric strain in combination with shear modulus measurement for non invasive assessment of portal venous pressure. Volumetric strain and tissue stiffening due to altered portal venous pressure are quantified in ex vivo rat livers and under physiological conditions in healthy volunteers. It is shown that the new method is sensitive to subtle changes in in vivo portal pressure in the range of 0.2 to 0.3 kPa due to deep inspiration or water intake. Our method offers a diagnostic tool for liver pressure related diseases by providing a better understanding of the liver shear modulus and its relationship to portal venous pressure.
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Affiliation(s)
- Noah Jaitner
- Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany
| | - Yasmine Safraou
- Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany
| | - Matthias Anders
- Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany
| | - Jakob Schattenfroh
- Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany
| | - Tom Meyer
- Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany
| | - Biru Huang
- Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany
| | - Jakob Jordan
- Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany
| | - Oliver Boehm
- Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany
| | - Alfonso Caiazzo
- Weierstrass Institute for Applied Analysis and Stochastics (WIAS) Berlin, Berlin, Germany
| | - Tobias Schaeffter
- Physikalisch-Technische Bundesanstalt, Berlin, Germany; Technical University Berlin, Berlin, Germany
| | - Joaquin Mura
- Department of Mechanical Engineering, Universidad Técnica Federico Santa María, Santiago, Chile
| | - Jing Guo
- Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany
| | - Ingolf Sack
- Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany.
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Ezuruike U, Curry L, Hatley O, Gardner I. Exploring the impact of ethnicity on drug pharmacokinetics using PBPK models: A case study with lansoprazole in Japanese subjects. Br J Clin Pharmacol 2025; 91:1016-1030. [PMID: 38072775 DOI: 10.1111/bcp.15982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 11/14/2023] [Accepted: 11/16/2023] [Indexed: 01/17/2024] Open
Abstract
AIMS The aim of this study is to demonstrate the use of PBPK modelling to explore the impact of ethnic differences on drug PK. METHODS A PBPK model developed for lansoprazole was used to predict the clinical PK of lansoprazole in Japanese subjects by incorporating the physiological parameters of a Japanese population into the model. Further verification of the developed Japanese population with clinical studies involving eight other CYP substrates-omeprazole, ticlopidine, alprazolam, midazolam, nifedipine, cinacalcet, paroxetine and dextromethorphan-was also carried out. RESULTS The PK of lansoprazole in both Caucasian and Japanese subjects was well predicted by the model as the observed data were within the 5th and 95th percentiles across all the clinical studies. In age- and sex-matched simulations in both the Caucasian and Japanese populations, the predicted PK (mean ± SD) of a single oral dose of 30-mg lansoprazole was higher in the Japanese population in all cases, with more than twofold higher AUC of 5.98 ± 6.43 mg/L.h (95% CI: 4.72, 7.24) vs. 2.46 ± 2.45 mg/L.h (95% CI: 1.98, 2.94) in one scenario. In addition, in two out of the nine clinical DDIs of lansoprazole and the additional CYP substrates simulated using the Japanese population, the predicted DDI in Japanese was more than 1.25-fold that in Caucasians, indicating an increased DDI liability. CONCLUSIONS By accounting for various physiological parameters that characterize a population in a PBPK model, the impact of the different identified interethnic differences on the drug's PK can be explored, which can inform the adoption of drugs from one region to another.
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Affiliation(s)
| | - Liam Curry
- Certara UK Limited (Simcyp Division), Sheffield, UK
| | | | - Iain Gardner
- Certara UK Limited (Simcyp Division), Sheffield, UK
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Olafuyi O, Michelet R, Garle M, Allegaert K. Exploring the Impact of Developmental Clearance Saturation on Propylene Glycol Exposure in Adults and Term Neonates Using Physiologically Based Pharmacokinetic Modeling. J Clin Pharmacol 2025; 65:272-284. [PMID: 39404076 PMCID: PMC11867916 DOI: 10.1002/jcph.6150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 09/25/2024] [Indexed: 03/01/2025]
Abstract
Propylene glycol (PG) is a pharmaceutical excipient which is generally regarded as safe (GRAS), though clinical toxicity has been reported. PG toxicity has been attributed to accumulation due to saturation of the alcohol dehydrogenase (ADH)-mediated clearance pathway. This study aims to explore the impact of the saturation of ADH-mediated PG metabolism on its developmental clearance in adults and neonates and assess the impact of a range of doses on PG clearance saturation and toxicity. Physiologically based pharmacokinetic (PBPK) models for PG in adults and term neonates were developed using maximum velocity (Vmax) and Michaelis-Menten's constant (Km) of ADH-mediated metabolism determined in vitro in human liver cytosol, published physicochemical, drug-related and ADH ontogeny parameters. The models were validated and used to determine the impact of dosing regimen on PG clearance saturation and toxicity in adults and neonates. The Vmax and Km of PG in human liver cytosol were 1.57 nmol/min/mg protein and 25.1 mM, respectively. The PG PBPK model adequately described PG PK profiles in adults and neonates. The PG dosing regimens associated with saturation and toxicity were dependent on both dose amount and cumulative in standard dosing frequencies. Doses resulting in saturation were higher than those associated with clinically observed toxicity. In individuals without impaired clearance or when PG exposure is through formulations that contain excipients with possible interaction with PG, a total daily dose of 100-200 mg/kg/day in adults and 25-50 mg/kg/day in neonates is unlikely to result in toxic PG levels or PG clearance saturation.
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Affiliation(s)
- Olusola Olafuyi
- Division of Physiology, Pharmacology and Neuroscience, School of Life SciencesUniversity of NottinghamNottinghamUK
| | - Robin Michelet
- Department of Clinical Pharmacy and BiochemistryInstitute of PharmacyFreie Universität BerlinBerlinGermany
- qharmetra LLCBerlinGermany
| | - Michael Garle
- Division of Physiology, Pharmacology and Neuroscience, School of Life SciencesUniversity of NottinghamNottinghamUK
| | - Karel Allegaert
- Department of Development and RegenerationKU LeuvenLeuvenBelgium
- Department of Pharmaceutical and Pharmacological SciencesKU LeuvenLeuvenBelgium
- Department of Hospital PharmacyErasmus Medical CenterRotterdamThe Netherlands
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Piccolo P, Brunetti-Pierri N. Current and Emerging Issues in Adeno-Associated Virus Vector-Mediated Liver-Directed Gene Therapy. Hum Gene Ther 2025; 36:77-87. [PMID: 39714937 DOI: 10.1089/hum.2024.179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2024] Open
Abstract
Adeno-associated virus (AAV) vectors have demonstrated safety and efficacy for gene transfer to hepatocytes in preclinical models, in various clinical trials and from a clinical experience with a growing number of approved gene therapy products. Although the exact duration is unknown, the expression of therapeutic genes in hepatocytes remains stable for several years after a single administration of the vector at clinically relevant doses in adult patients with hemophilia and other inherited metabolic disorders. However, clinical applications, especially for diseases requiring high AAV vector doses by intravenous administrations, have raised several concerns. These include the high prevalence of pre-existing immunity against the vector capsid, activation of the complement and the innate immunity with serious life-threatening complications, elevation of liver transaminases, liver growth associated with loss of transgene expression, underlying conditions negatively affecting AAV vector safety and efficacy. Despite these issues, the field is rapidly advancing with a better understanding of vector-host interactions and the development of new strategies to improve liver-directed gene therapy. This review provides an overview of the current and emerging challenges for AAV-mediated liver-directed gene therapy.
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Affiliation(s)
| | - Nicola Brunetti-Pierri
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy
- Genomics and Experimental Medicine Program, Scuola Superiore Meridionale (SSM, School of Advanced Studies), Naples, Italy
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Yellepeddi VK, Hunt JP, Green DJ, McKnite A, Whelan A, Watt K. A physiologically-based pharmacokinetic modeling approach for dosing amiodarone in children on ECMO. CPT Pharmacometrics Syst Pharmacol 2024; 13:1542-1553. [PMID: 39033462 PMCID: PMC11533098 DOI: 10.1002/psp4.13199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 05/27/2024] [Accepted: 06/21/2024] [Indexed: 07/23/2024] Open
Abstract
Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device commonly used to treat cardiac arrest in children. The American Heart Association guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care recommend using amiodarone as a first-line agent to treat ventricular arrhythmias in children with cardiac arrest. However, there are no dosing recommendations for amiodarone to treat ventricular arrhythmias in pediatric patients on ECMO. Amiodarone has a high propensity for adsorption to the ECMO components due to its physicochemical properties leading to altered pharmacokinetics (PK) in ECMO patients. The change in amiodarone PK due to interaction with ECMO components may result in a difference in optimal dosing in patients on ECMO when compared with non-ECMO patients. To address this clinical knowledge gap, a physiologically-based pharmacokinetic model of amiodarone was developed in adults and scaled to children, followed by the addition of an ECMO compartment. The pediatric model included ontogeny functions of cytochrome P450 (CYP450) enzyme maturation across various age groups. The ECMO compartment was parameterized using the adsorption data of amiodarone obtained from ex vivo studies. Model predictions captured observed concentrations of amiodarone in pediatric patients with ECMO well with an average fold error between 0.5 and 2. Model simulations support an amiodarone intravenous (i.v) bolus dose of 22 mg/kg (neonates), 13 mg/kg (infants), 8 mg/kg (children), and 6 mg/kg (adolescents). This PBPK modeling approach can be applied to explore the dosing of other drugs used in children on ECMO.
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Affiliation(s)
- Venkata K. Yellepeddi
- Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of MedicineUniversity of UtahSalt Lake CityUtahUSA
- Department of Molecular PharmaceuticsCollege of Pharmacy, University of UtahSalt Lake CityUtahUSA
| | - John Porter Hunt
- Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of MedicineUniversity of UtahSalt Lake CityUtahUSA
| | - Danielle J. Green
- Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of MedicineUniversity of UtahSalt Lake CityUtahUSA
- Division of Pediatric Critical Care, Department of PediatricsUniversity of UtahSalt Lake CityUtahUSA
| | - Autumn McKnite
- Department of Pharmacology and ToxicologyCollege of Pharmacy, University of UtahSalt Lake CityUtahUSA
| | - Aviva Whelan
- Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of MedicineUniversity of UtahSalt Lake CityUtahUSA
- Division of Pediatric Critical Care, Department of PediatricsUniversity of UtahSalt Lake CityUtahUSA
| | - Kevin Watt
- Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of MedicineUniversity of UtahSalt Lake CityUtahUSA
- Division of Pediatric Critical Care, Department of PediatricsUniversity of UtahSalt Lake CityUtahUSA
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Curry L, Alrubia S, Bois FY, Clayton R, El‐Khateeb E, Johnson TN, Faisal M, Neuhoff S, Wragg K, Rostami‐Hodjegan A. A guide to developing population files for physiologically-based pharmacokinetic modeling in the Simcyp Simulator. CPT Pharmacometrics Syst Pharmacol 2024; 13:1429-1447. [PMID: 39030888 PMCID: PMC11533108 DOI: 10.1002/psp4.13202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 06/20/2024] [Accepted: 07/02/2024] [Indexed: 07/22/2024] Open
Abstract
The Simcyp Simulator is a software platform widely used in the pharmaceutical industry to conduct stochastic physiologically-based pharmacokinetic (PBPK) modeling. This approach has the advantage of combining routinely generated in vitro data on drugs and drug products with knowledge of biology and physiology parameters to predict a priori potential pharmacokinetic changes in absorption, distribution, metabolism, and excretion for populations of interest. Combining such information with pharmacodynamic knowledge of drugs enables planning for potential dosage adjustment when clinical studies are feasible. Although the conduct of dedicated clinical studies in some patient groups (e.g., with hepatic or renal diseases) is part of the regulatory path for drug development, clinical studies for all permutations of covariates potentially affecting pharmacokinetics are impossible to perform. The role of PBPK in filling the latter gap is becoming more appreciated. This tutorial describes the different input parameters required for the creation of a virtual population giving robust predictions of likely changes in pharmacokinetics. It also highlights the considerations needed to qualify the models for such contexts of use. Two case studies showing the step-by-step development and application of population files for obese or morbidly obese patients and individuals with Crohn's disease are provided as the backbone of our tutorial to give some hands-on and real-world examples.
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Affiliation(s)
- Liam Curry
- Certara Predictive Technologies (CPT), Simcyp DivisionSheffieldUK
| | - Sarah Alrubia
- Centre for Applied Pharmacokinetic Research (CAPKR)The University of ManchesterManchesterUK
- Pharmaceutical Chemistry Department, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
| | - Frederic Y. Bois
- Certara Predictive Technologies (CPT), Simcyp DivisionSheffieldUK
| | - Ruth Clayton
- Certara Predictive Technologies (CPT), Simcyp DivisionSheffieldUK
| | - Eman El‐Khateeb
- Certara Predictive Technologies (CPT), Simcyp DivisionSheffieldUK
- Clinical Pharmacy Department, Faculty of PharmacyTanta UniversityTantaEgypt
| | | | - Muhammad Faisal
- Certara Predictive Technologies (CPT), Simcyp DivisionSheffieldUK
| | - Sibylle Neuhoff
- Certara Predictive Technologies (CPT), Simcyp DivisionSheffieldUK
| | - Kris Wragg
- Certara Predictive Technologies (CPT), Simcyp DivisionSheffieldUK
| | - Amin Rostami‐Hodjegan
- Certara Predictive Technologies (CPT), Simcyp DivisionSheffieldUK
- Centre for Applied Pharmacokinetic Research (CAPKR)The University of ManchesterManchesterUK
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Johnson TN, Batchelor HK, Goelen J, Horniblow RD, Dinh J. Combining data on the bioavailability of midazolam and physiologically-based pharmacokinetic modeling to investigate intestinal CYP3A4 ontogeny. CPT Pharmacometrics Syst Pharmacol 2024; 13:1570-1581. [PMID: 38923249 PMCID: PMC11533100 DOI: 10.1002/psp4.13192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 06/06/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Pediatric physiologically-based modeling in drug development has grown in the past decade and optimizing the underlying systems parameters is important in relation to overall performance. In this study, variation of clinical oral bioavailability of midazolam as a function of age is used to assess the underlying ontogeny models for intestinal CYP3A4. Data on midazolam bioavailability in adults and children and different ontogeny patterns for intestinal CYP3A4 were first collected from the literature. A pediatric PBPK model was then used to assess six different ontogeny models in predicting bioavailability from preterm neonates to adults. The average fold error ranged from 0.7 to 1.38, with the rank order of least to most biased model being No Ontogeny < Upreti = Johnson < Goelen < Chen < Kiss. The absolute average fold error ranged from 1.17 to 1.64 with the rank order of most to least precise being Johnson > Upreti > No Ontogeny > Goelen > Kiss > Chen. The optimal ontogeny model is difficult to discern when considering the possible influence of CYP3A5 and other population variability; however, this study suggests that from term neonates and older a faster onset Johnson model with a lower fraction at birth may be close to this. For inclusion in other PBPK models, independent verification will be needed to confirm these results. Further research is needed in this area both in terms of age-related changes in midazolam and similar drug bioavailability and intestinal CYP3A4 ontogeny.
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Affiliation(s)
| | - Hannah K. Batchelor
- Strathclyde Institute of Pharmacy and Biomedical SciencesUniversity of StrathclydeGlasgowUK
| | - Jan Goelen
- Centre for Neonatal and Paediatric Infection, Antimicrobial Resistance Research Group, St George'sUniversity of LondonLondonUK
| | - Richard D. Horniblow
- School of Biomedical Sciences, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUK
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Chen Z, Taubert M, Chen C, Boland J, Dong Q, Bilal M, Dokos C, Wachall B, Wargenau M, Scheidel B, Wiesen MHJ, Schaeffeler E, Tremmel R, Schwab M, Fuhr U. A Semi-Mechanistic Population Pharmacokinetic Model of Noscapine in Healthy Subjects Considering Hepatic First-Pass Extraction and CYP2C9 Genotypes. Drugs R D 2024; 24:187-199. [PMID: 38809387 PMCID: PMC11315837 DOI: 10.1007/s40268-024-00466-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/07/2024] [Indexed: 05/30/2024] Open
Abstract
INTRODUCTION Noscapine is a commonly used cough suppressant, with ongoing research on its anti-inflammatory and anti-tumor properties. The drug has a pronounced pharmacokinetic variability. OBJECTIVE This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability. METHODS Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately. RESULTS Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662-0.929) and 0.827 (0.762-0.925) for peak plasma concentrations and area under the plasma concentration-time curve, respectively. Significant differences in p values (< 0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration-time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3). CONCLUSION The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at "Deutsches Register Klinischer Studien" under registration no. DRKS00017760.
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Affiliation(s)
- Zhendong Chen
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany.
| | - Max Taubert
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany
| | - Chunli Chen
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, 150030, People's Republic of China
| | - Jana Boland
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany
| | - Qian Dong
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany
| | - Muhammad Bilal
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany
| | - Charalambos Dokos
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany
| | - Bertil Wachall
- InfectoPharm Arzneimittel und Consilium GmbH, Heppenheim, Germany
| | | | | | - Martin H J Wiesen
- Pharmacology at the Laboratory Diagnostics Centre, Therapeutic Drug Monitoring, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Baden-Württemberg, Germany
- University of Tuebingen, Tuebingen, Germany
| | - Roman Tremmel
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Baden-Württemberg, Germany
- University of Tuebingen, Tuebingen, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Baden-Württemberg, Germany
- Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Baden-Württemberg, Germany
- Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Baden-Württemberg, Germany
| | - Uwe Fuhr
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany
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Haddad A, Lendoire M, Maki H, Kang HC, Habibollahi P, Odisio BC, Huang SY, Vauthey JN. Liver volumetry and liver-regenerative interventions: history, rationale, and emerging tools. J Gastrointest Surg 2024; 28:766-775. [PMID: 38519362 DOI: 10.1016/j.gassur.2024.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 01/26/2024] [Accepted: 02/08/2024] [Indexed: 03/24/2024]
Abstract
BACKGROUND Postoperative hepatic insufficiency (PHI) is the most feared complication after hepatectomy. Volume of the future liver remnant (FLR) is one objectively measurable indicator to identify patients at risk of PHI. In this review, we summarized the development and rationale for the use of liver volumetry and liver-regenerative interventions and highlighted emerging tools that could yield new advancements in liver volumetry. METHODS A review of MEDLINE/PubMed, Embase, and Cochrane Library databases was conducted to identify literature related to liver volumetry. The references of relevant articles were reviewed to identify additional publications. RESULTS Liver volumetry based on radiologic imaging was developed in the 1980s to identify patients at risk of PHI and later used in the 1990s to evaluate grafts for living donor living transplantation. The field evolved in the 2000s by the introduction of standardized FLR based on the hepatic metabolic demands and in the 2010s by the introduction of the degree of hypertrophy and kinetic growth rate as measures of the FLR regenerative and functional capacity. Several liver-regenerative interventions, most notably portal vein embolization, are used to increase resectability and reduce the risk of PHI. In parallel with the increase in automation and machine assistance to physicians, many semi- and fully automated tools are being developed to facilitate liver volumetry. CONCLUSION Liver volumetry is the most reliable tool to detect patients at risk of PHI. Advances in imaging analysis technologies, newly developed functional measures, and liver-regenerative interventions have been improving our ability to perform safe hepatectomy.
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Affiliation(s)
- Antony Haddad
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Mateo Lendoire
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Harufumi Maki
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Hyunseon Christine Kang
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Peiman Habibollahi
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Bruno C Odisio
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Steven Y Huang
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
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Sierra T, Achour B. In Vitro to In Vivo Scalars for Drug Clearance in Nonalcoholic Fatty Liver and Steatohepatitis. Drug Metab Dispos 2024; 52:390-398. [PMID: 38423789 DOI: 10.1124/dmd.123.001629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/02/2024] Open
Abstract
In vitro-in vivo extrapolation (IVIVE) allows prediction of clinical outcomes across populations from in vitro data using specific scalars tailored to the biologic characteristics of each population. This study experimentally determined scalars for patients with varying degrees of nonalcoholic fatty liver disease (NAFLD), ranging from fatty liver to nonalcoholic steatohepatitis (NASH) and cirrhosis. Microsomal, S9, and cytosol fractions were extracted from 36 histologically normal and 66 NAFLD livers (27 nonalcoholic fatty liver [NAFL], 13 NASH, and 26 NASH with cirrhosis). Corrected microsomal protein per gram liver (MPPGL) progressively decreased with disease severity (26.8, 27.4, and 24.3 mg/g in NAFL, NASH, and NASH/cirrhosis, respectively, compared with 35.6 mg/g in normal livers; ANOVA, P < 0.001). Homogenate, S9, and cytosolic protein showed a consistent trend of decline in NASH/cirrhosis relative to normal control (post-hoc t test, P < 0.05). No differences across the groups were observed in homogenate, S9, cytosolic, and microsomal protein content in matched kidney samples. MPPGL-based scalars that combine protein content with liver size revealed that the reduction in MPPGL in NAFL and NASH was compensated by the reported increase in liver size (relative scalar ratios of 0.96 and 0.99, respectively), which was not the case with NASH/cirrhosis (ratio of 0.63), compared with healthy control. Physiologically based pharmacokinetics-informed global sensitivity analysis of the relative contribution of IVIVE scalars (hepatic CYP3A4 abundance, MPPGL, and liver size) to variability in exposure (area under the curve) to three CYP3A substrates (alprazolam, midazolam, and ibrutinib) revealed enzyme abundance as the most significant parameter, followed by MPPGL, whereas liver volume was the least impactful factor. SIGNIFICANCE STATEMENT: Nonalcoholic fatty liver disease-specific scalars necessary for extrapolation from in vitro systems to liver tissue are lacking. These are required in clearance prediction and dose selection in nonalcoholic fatty liver and steatohepatitis populations. Previously reported disease-driven changes have focused on cirrhosis, with no data on the initial stages of liver disease. The authors obtained experimental values for microsomal, cytosolic, and S9 fractions and assessed the relative impact of microsomal scalars on predicted exposure to substrate drugs using physiologically based pharmacokinetics.
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Affiliation(s)
- Teresa Sierra
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island
| | - Brahim Achour
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island
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11
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Kinoshita K, Moore G, Murakami M. Body Weight as a Preferred Method for Normalizing the Computed Tomography-Derived Liver Volume in Dogs without Hepatic Disease. Vet Sci 2024; 11:153. [PMID: 38668420 PMCID: PMC11054289 DOI: 10.3390/vetsci11040153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/13/2024] [Accepted: 03/25/2024] [Indexed: 04/29/2024] Open
Abstract
The assessment of liver size is usually performed using radiography in dogs. However, due to wide variations in patients' sizes and body conformations, accurate diagnosis of hepatomegaly or microhepatia is difficult. Computed tomographic (CT) volumetry can quantitatively and accurately measure liver volume. However, a reliable method for the standardization or normalization of volume in dogs without hepatic disease using CT has not yet been established. The purpose of this study was to assess seven different anatomic measures for normalizing liver volume in dogs and determine the tentative range of liver volume in dogs without hepatic disease. We retrospectively searched medical records from 1 January 2017 through to 1 June 2020 and included dogs with abdominal computed tomography without hepatic disease. The liver volume, lengths of four vertebrae (T11, T12, L2, L3), diameter of the abdominal aorta, body weight, and body condition scores (BCSs) of the dogs were recorded. Forty-one client-owned dogs without evidence of hepatic disease were included. The CT-derived liver volume was 813.8 ± 326.5 cm3 (mean ± SD). Body weight was determined to be the most reliable single-variable method for normalizing liver volume, with a raw CT-derived liver-volume-to-body-weight ratio of 22.1 cm3/kg (95% CI: 12.9-31.3 cm3/kg) and regression prediction model of volume = 19 × BWkg + 97. However, a better normalizing factor would likely be provided by the fat-free mass if it can be accurately measured.
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Affiliation(s)
- Kosuke Kinoshita
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA
| | - George Moore
- Department of Veterinary Administration, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA
| | - Masahiro Murakami
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA
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12
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Dar FS, Abbas Z, Ahmed I, Atique M, Aujla UI, Azeemuddin M, Aziz Z, Bhatti ABH, Bangash TA, Butt AS, Butt OT, Dogar AW, Farooqi JI, Hanif F, Haider J, Haider S, Hassan SM, Jabbar AA, Khan AN, Khan MS, Khan MY, Latif A, Luck NH, Malik AK, Rashid K, Rashid S, Salih M, Saeed A, Salamat A, Tayyab GUN, Yusuf A, Zia HH, Naveed A. National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma. World J Gastroenterol 2024; 30:1018-1042. [PMID: 38577184 PMCID: PMC10989497 DOI: 10.3748/wjg.v30.i9.1018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/03/2024] [Accepted: 01/29/2024] [Indexed: 03/06/2024] Open
Abstract
A consensus meeting of national experts from all major national hepatobiliary centres in the country was held on May 26, 2023, at the Pakistan Kidney and Liver Institute & Research Centre (PKLI & RC) after initial consultations with the experts. The Pakistan Society for the Study of Liver Diseases (PSSLD) and PKLI & RC jointly organised this meeting. This effort was based on a comprehensive literature review to establish national practice guidelines for hilar cholangiocarcinoma (hCCA). The consensus was that hCCA is a complex disease and requires a multidisciplinary team approach to best manage these patients. This coordinated effort can minimise delays and give patients a chance for curative treatment and effective palliation. The diagnostic and staging workup includes high-quality computed tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography. Brush cytology or biopsy utilizing endoscopic retrograde cholangiopancreatography is a mainstay for diagnosis. However, histopathologic confirmation is not always required before resection. Endoscopic ultrasound with fine needle aspiration of regional lymph nodes and positron emission tomography scan are valuable adjuncts for staging. The only curative treatment is the surgical resection of the biliary tree based on the Bismuth-Corlette classification. Selected patients with unresectable hCCA can be considered for liver transplantation. Adjuvant chemotherapy should be offered to patients with a high risk of recurrence. The use of preoperative biliary drainage and the need for portal vein embolisation should be based on local multidisciplinary discussions. Patients with acute cholangitis can be drained with endoscopic or percutaneous biliary drainage. Palliative chemotherapy with cisplatin and gemcitabine has shown improved survival in patients with irresectable and recurrent hCCA.
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Affiliation(s)
- Faisal Saud Dar
- Department of Hepatopancreatic Biliary Surgery & Liver Transplant, Pakistan Kidney and Liver Institute & Research Centre, Lahore 54000, Pakistan
| | - Zaigham Abbas
- Department of Hepatogastroenterology and Liver Transplantation, Dr. Ziauddin University Hospital, Karachi 75600, Sindh, Pakistan
| | - Irfan Ahmed
- Department of Hepatopancreatic Biliary Surgery & Liver Transplant, Pakistan Kidney and Liver Institute & Research Centre, Lahore 54000, Pakistan
- University of Aberdeen, Aberdeen B24 3FX, United Kingdom
| | - Muhammad Atique
- Department of Pathology, Pakistan Kidney and Liver Institute & Research Centre, Lahore 54000, Pakistan
| | - Usman Iqbal Aujla
- Department of Gastroenterology & Hepatology, Pakistan Kidney and Liver Institute & Research Centre, Lahore 54000, Pakistan
| | | | - Zeba Aziz
- Department of Oncology, Hameed Latif Hospital, Lahore 54000, Pakistan
| | - Abu Bakar Hafeez Bhatti
- Division of Hepatopancreatic Biliary Surgery & Liver Transplantation, Shifa International Hospital, Islamabad 44000, Pakistan
| | - Tariq Ali Bangash
- Department of Hepatopancreatic Biliary Surgery & Liver Transplant, Shaikh Zayed Hospital and Post Graduate Medical Institute, Lahore 54000, Pakistan
| | - Amna Subhan Butt
- Department of Medicine, Aga Khan University Hospital, Karachi 74800, Pakistan
| | - Osama Tariq Butt
- Department of Gastroenterology & Hepatology, Pakistan Kidney and Liver Institute & Research Centre, Lahore 54000, Pakistan
| | - Abdul Wahab Dogar
- Department of Liver Transplant, Pir Abdul Qadir Shah Jeelani Institute of Medical Sciences, Gambat 66020, Pakistan
| | - Javed Iqbal Farooqi
- Department of Medicine & Gastroenterology, Lifecare Hospital and Research Centre, Peshawar 25000, Khyber Pakhtunkhwa, Pakistan
| | - Faisal Hanif
- Department of Hepatopancreatobiliary & Liver Transplant, Bahria International Hospital, Lahore 54000, Pakistan
| | - Jahanzaib Haider
- Department of Surgery, Hepatopancreatobiliary & Liver Transplant, Dow University of Health Sciences, Karachi 74800, Pakistan
| | - Siraj Haider
- Department of Surgery, Hepatopancreatobiliary & Liver Transplant, Dow University of Health Sciences, Karachi 74800, Pakistan
| | - Syed Mujahid Hassan
- Department of Gastroenterology, Hepatology & Nutrition, Pir Abdul Qadir Shah Jeelani Institute of Medical Sciences, Gambat 66020, Pakistan
| | | | - Aman Nawaz Khan
- Department of Radiology, Rehman Medical Institute, Peshawar 25000, Pakistan
| | - Muhammad Shoaib Khan
- Army Liver Transplant Unit, Pak Emirates Military Hospital, Rawalpindi 46000, Pakistan
| | - Muhammad Yasir Khan
- Department of Hepatopancreatic Biliary Surgery & Liver Transplant, Pakistan Kidney and Liver Institute & Research Centre, Lahore 54000, Pakistan
| | - Amer Latif
- Department of Hepatopancreatic Biliary Surgery & Liver Transplant, Shaikh Zayed Hospital and Post Graduate Medical Institute, Lahore 54000, Pakistan
| | - Nasir Hassan Luck
- Department of Gastroenterology, Sindh Institute of Urology and Transplantation, Karachi 75500, Pakistan
| | - Ahmad Karim Malik
- Department of Gastroenterology & Hepatology, Pakistan Kidney and Liver Institute & Research Centre, Lahore 54000, Pakistan
| | - Kamran Rashid
- Rashid Nursing Home and Cancer Clinic, Rashid Nursing Home and Cancer Clinic, Rawalpindi 46000, Pakistan
| | - Sohail Rashid
- Department of Hepatopancreatic Biliary Surgery & Liver Transplant, Pakistan Kidney and Liver Institute & Research Centre, Lahore 54000, Pakistan
| | - Mohammad Salih
- Department of Gastroenterology and Hepatology, Shifa International Hospital, Islamabad 44000, Pakistan
| | - Abdullah Saeed
- Department of Radiology, Pakistan Kidney and Liver Institute & Research Centre, Lahore 54000, Pakistan
| | - Amjad Salamat
- Department of Gastroenterology and Hepatology, Quaid-e-Azam International Hospital, Rawalpindi 44000, Pakistan
| | - Ghias-un-Nabi Tayyab
- Department of Gastroenterology and Hepatology, Post Graduate Medical Institute, Lahore 54000, Pakistan
| | - Aasim Yusuf
- Department of Internal Medicine, Division of Gastroenterology, Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore 54000, Pakistan
| | - Haseeb Haider Zia
- Division of Hepatopancreatic Biliary Surgery & Liver Transplantation, Shifa International Hospital, Islamabad 44000, Pakistan
| | - Ammara Naveed
- Department of Gastroenterology & Hepatology, Pakistan Kidney and Liver Institute & Research Centre, Lahore 54000, Pakistan
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Maria H, Valentino PL, Healey PJ, Kwon YK. Small-for-size syndrome in a 9.7 kg pediatric recipient with a whole liver graft. Pediatr Transplant 2024; 28:e14716. [PMID: 38420659 DOI: 10.1111/petr.14716] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/07/2023] [Accepted: 02/01/2024] [Indexed: 03/02/2024]
Abstract
BACKGROUND Small-for-size syndrome (SFSS) in pediatric liver transplant recipients, particularly those weighing less than 10 kg, is rare. This report describes a case of a 15-month-old whole liver transplant recipient who suffered SFSS, and systematic literature review was performed to identify outcomes of such cases and potential risk factors for SFSS. CASE PRESENTATION A 15-month-old toddler with a history of biliary atresia underwent a deceased donor whole liver transplant. The graft weighed 160 g, resulting in a graft-to-recipient weight ratio (GRWR) of 1.6%. The post-operative course was complicated by SFSS, characterized by massive ascites causing hemodynamic instability and compromised hepatic artery flow. Pharmacological intervention with octreotide was initiated, and the patient eventually recovered. CONCLUSION In small pediatric recipients, especially those weighing less than 10 kg, the native liver body weight ratio (LBWR) is significantly higher. When selecting an appropriately sized graft for these recipients, this higher ratio should be taken into consideration. The literature review suggests that a GRWR of less than 2% is associated with a higher incidence of small-for-size syndrome in small pediatric recipients weighing less than 10 kg.
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Affiliation(s)
- Haytham Maria
- Division of Transplantation, Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Pamela L Valentino
- Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, Washington, USA
| | - Patrick J Healey
- Division of Transplantation, Department of Surgery, University of Washington, Seattle, Washington, USA
- Division of Transplantation, Seattle Children's Hospital, Seattle, Washington, USA
| | - Yong K Kwon
- Division of Transplantation, Department of Surgery, University of Washington, Seattle, Washington, USA
- Division of Transplantation, Seattle Children's Hospital, Seattle, Washington, USA
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14
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Adiwidjaja J, Spires J, Brouwer KLR. Physiologically Based Pharmacokinetic (PBPK) Model Predictions of Disease Mediated Changes in Drug Disposition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD). Pharm Res 2024; 41:441-462. [PMID: 38351228 DOI: 10.1007/s11095-024-03664-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 01/18/2024] [Indexed: 03/13/2024]
Abstract
PURPOSE This study was designed to verify a virtual population representing patients with nonalcoholic fatty liver disease (NAFLD) to support the implementation of a physiologically based pharmacokinetic (PBPK) modeling approach for prediction of disease-related changes in drug pharmacokinetics. METHODS A virtual NAFLD patient population was developed in GastroPlus (v.9.8.2) by accounting for pathophysiological changes associated with the disease and proteomics-informed alterations in the abundance of metabolizing enzymes and transporters pertinent to drug disposition. The NAFLD population model was verified using exemplar drugs where elimination is influenced predominantly by cytochrome P450 (CYP) enzymes (chlorzoxazone, caffeine, midazolam, pioglitazone) or by transporters (rosuvastatin, 11C-metformin, morphine and the glucuronide metabolite of morphine). RESULTS PBPK model predictions of plasma concentrations of all the selected drugs and hepatic radioactivity levels of 11C-metformin were consistent with the clinically-observed data. Importantly, the PBPK simulations using the virtual NAFLD population model provided reliable estimates of the extent of changes in key pharmacokinetic parameters for the exemplar drugs, with mean predicted ratios (NAFLD patients divided by healthy individuals) within 0.80- to 1.25-fold of the clinically-reported values, except for midazolam (prediction-fold difference of 0.72). CONCLUSION A virtual NAFLD population model within the PBPK framework was successfully developed with good predictive capability of estimating disease-related changes in drug pharmacokinetics. This supports the use of a PBPK modeling approach for prediction of the pharmacokinetics of new investigational or repurposed drugs in patients with NAFLD and may help inform dose adjustments for drugs commonly used to treat comorbidities in this patient population.
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Affiliation(s)
- Jeffry Adiwidjaja
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Simulations Plus, Inc, Lancaster, CA, USA
| | | | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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15
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Barten TRM, Atsma F, van der Meer AJ, Gansevoort R, Nevens F, Drenth JPH, Gevers TJG. Higher need for polycystic liver disease therapy in female patients: Sex-specific association between liver volume and need for therapy. Hepatology 2024; 79:551-559. [PMID: 37725713 DOI: 10.1097/hep.0000000000000602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 08/23/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND AND AIMS Prognostic tools or biomarkers are urgently needed in polycystic liver disease (PLD) to monitor disease progression and evaluate treatment outcomes. Total liver volume (TLV) is currently used to assess cross-sectional disease severity, and female patients typically have larger livers than males. Therefore, this study explores the sex-specific association between TLV and volume-reducing therapy (VRT). APPROACH AND RESULTS In this prospective cohort study, we included patients with PLD from European treatment centers. We explored sex-specific differences in the association between baseline TLV and initiation of volume-reducing therapy and determined the cumulative incidence rates of volume-reducing therapy in our cohort.We included 358 patients, of whom 157 (43.9%) received treatment. Treated patients had a higher baseline TLV (median TLV 2.16 vs. 4.34 liter, p < 0.001), were more frequently female (69.7% vs. 89.8%, p < 0.001), and had a higher risk of liver events (HR 4.381, p < 0.001). The cumulative volume-reducing therapy rate at 1 year of follow-up was 21.0% for females compared to 9.1% for males. Baseline TLV was associated with volume-reducing therapy, and there was an interaction with sex (HR females 1.202, p < 0.001; HR males 1.790, p < 0.001; at 1.5 l). CONCLUSION Baseline TLV is strongly associated with volume-reducing therapy initiation at follow-up in patients with PLD, with sex-specific differences in this association. Disease staging systems should use TLV to predict the need for future volume-reducing therapy in PLD separately for males and females.
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Affiliation(s)
- Thijs R M Barten
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network RARE-LIVER, Germany
| | - Femke Atsma
- Scientific Institute for Quality of Healthcare, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Ron Gansevoort
- Department of Nephrology, University Medical Centre Groningen, University Hospital Groningen, Groningen, Netherlands
| | - Frederik Nevens
- European Reference Network RARE-LIVER, Germany
- Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network RARE-LIVER, Germany
| | - Tom J G Gevers
- European Reference Network RARE-LIVER, Germany
- Department of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands
- Nutrim School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
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16
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Rosenthal BE, Abt PL, Schaubel DE, Reddy KR, Bittermann T. Living Donor Liver Transplantation for Adults With High Model for End-stage Liver Disease Score: The US Experience. Transplantation 2024; 108:713-723. [PMID: 37635282 PMCID: PMC10899524 DOI: 10.1097/tp.0000000000004767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
BACKGROUND Outcomes after living-donor liver transplantation (LDLT) at high Model for End-stage Liver Disease (MELD) scores are not well characterized in the United States. METHODS This was a retrospective cohort study using Organ Procurement and Transplantation Network data in adults listed for their first liver transplant alone between 2002 and 2021. Cox proportional hazards models evaluated the association of MELD score (<20, 20-24, 25-29, and ≥30) and patient/graft survival after LDLT and the association of donor type (living versus deceased) on outcomes stratified by MELD. RESULTS There were 4495 LDLTs included with 5.9% at MELD 25-29 and 1.9% at MELD ≥30. LDLTs at MELD 25-29 and ≥30 LDLT have substantially increased since 2010 and 2015, respectively. Patient survival at MELD ≥30 was not different versus MELD <20: adjusted hazard ratio 1.67 (95% confidence interval, 0.96-2.88). However, graft survival was worse: adjusted hazard ratio (aHR) 1.69 (95% confidence interval, 1.07-2.68). Compared with deceased-donor liver transplant, LDLT led to superior patient survival at MELD <20 (aHR 0.92; P = 0.024) and 20-24 (aHR 0.70; P < 0.001), equivalent patient survival at MELD 25-29 (aHR 0.97; P = 0.843), but worse graft survival at MELD ≥30 (aHR 1.68, P = 0.009). CONCLUSIONS Although patient survival remains acceptable, the benefits of LDLT may be lost at MELD ≥30.
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Affiliation(s)
| | - Peter L. Abt
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Douglas E. Schaubel
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - K. Rajender Reddy
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Therese Bittermann
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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17
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Picher EA, Wahajuddin M, Barth S, Chisholm J, Shipley J, Pors K. The Capacity of Drug-Metabolising Enzymes in Modulating the Therapeutic Efficacy of Drugs to Treat Rhabdomyosarcoma. Cancers (Basel) 2024; 16:1012. [PMID: 38473371 DOI: 10.3390/cancers16051012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma (STS) that predominantly affects children and teenagers. It is the most common STS in children (40%) and accounts for 5-8% of total childhood malignancies. Apart from surgery and radiotherapy in eligible patients, standard chemotherapy is the only therapeutic option clinically available for RMS patients. While survival rates for this childhood cancer have considerably improved over the last few decades for low-risk and intermediate-risk cases, the mortality rate remains exceptionally high in high-risk RMS patients with recurrent and/or metastatic disease. The intensification of chemotherapeutic protocols in advanced-stage RMS has historically induced aggravated toxicity with only very modest therapeutic gain. In this review, we critically analyse what has been achieved so far in RMS therapy and provide insight into how a diverse group of drug-metabolising enzymes (DMEs) possess the capacity to modify the clinical efficacy of chemotherapy. We provide suggestions for new therapeutic strategies that exploit the presence of DMEs for prodrug activation, targeted chemotherapy that does not rely on DMEs, and RMS-molecular-subtype-targeted therapies that have the potential to enter clinical evaluation.
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Affiliation(s)
- Enric Arasanz Picher
- Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
| | - Muhammad Wahajuddin
- Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
| | - Stefan Barth
- Medical Biotechnology and Immunotherapy Research Unit, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7700, South Africa
| | - Julia Chisholm
- Children and Young People's Unit, Royal Marsden Hospital, Institute of Cancer Research, Sutton SM2 5PR, UK
| | - Janet Shipley
- Sarcoma Molecular Pathology Group, Division of Molecular Pathology, The Institute of Cancer Research, Sutton SM2 5NG, UK
| | - Klaus Pors
- Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
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18
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Thanaj M, Basty N, Cule M, Sorokin EP, Whitcher B, Bell JD, Thomas EL. Liver shape analysis using statistical parametric maps at population scale. BMC Med Imaging 2024; 24:15. [PMID: 38195400 PMCID: PMC10775563 DOI: 10.1186/s12880-023-01149-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 10/31/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND Morphometric image analysis enables the quantification of differences in the shape and size of organs between individuals. METHODS Here we have applied morphometric methods to the study of the liver by constructing surface meshes from liver segmentations from abdominal MRI images in 33,434 participants in the UK Biobank. Based on these three dimensional mesh vertices, we evaluated local shape variations and modelled their association with anthropometric, phenotypic and clinical conditions, including liver disease and type-2 diabetes. RESULTS We found that age, body mass index, hepatic fat and iron content, as well as, health traits were significantly associated with regional liver shape and size. Interaction models in groups with specific clinical conditions showed that the presence of type-2 diabetes accelerates age-related changes in the liver, while presence of liver fat further increased shape variations in both type-2 diabetes and liver disease. CONCLUSIONS The results suggest that this novel approach may greatly benefit studies aiming at better categorisation of pathologies associated with acute and chronic clinical conditions.
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Affiliation(s)
- Marjola Thanaj
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK.
| | - Nicolas Basty
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK
| | | | | | - Brandon Whitcher
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK
| | - Jimmy D Bell
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK
| | - E Louise Thomas
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK
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19
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Sas DJ, Mara K, Mehta RA, Seide BM, Banks CJ, Danese DS, McGregor TL, Lieske JC, Milliner DS. Natural history of urine and plasma oxalate in children with primary hyperoxaluria type 1. Pediatr Nephrol 2024; 39:141-148. [PMID: 37458799 PMCID: PMC11044200 DOI: 10.1007/s00467-023-06074-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/13/2023] [Accepted: 06/22/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND Primary hyperoxaluria type 1 (PH1) is a rare, severe genetic disease causing increased hepatic oxalate production resulting in urinary stone disease, nephrocalcinosis, and often progressive chronic kidney disease. Little is known about the natural history of urine and plasma oxalate values over time in children with PH1. METHODS For this retrospective observational study, we analyzed data from genetically confirmed PH1 patients enrolled in the Rare Kidney Stone Consortium PH Registry between 2003 and 2018 who had at least 2 measurements before age 18 years of urine oxalate-to-creatinine ratio (Uox:cr), 24-h urine oxalate excretion normalized to body surface area (24-h Uox), or plasma oxalate concentration (Pox). We compared values among 3 groups: homozygous G170R, heterozygous G170R, and non-G170R AGXT variants both before and after initiating pyridoxine (B6). RESULTS Of 403 patients with PH1 in the registry, 83 met the inclusion criteria. Uox:cr decreased rapidly over the first 5 years of life. Both before and after B6 initiation, patients with non-G170R had the highest Uox:cr, 24-h Uox, and Pox. Patients with heterozygous G170R had similar Uox:cr to homozygous G170R prior to B6. Patients with homozygous G170R had the lowest 24-h Uox and Uox:cr after B6. Urinary oxalate excretion and Pox tend to decrease over time during childhood. eGFR over time was not different among groups. CONCLUSIONS Children with PH1 under 5 years old have relatively higher urinary oxalate excretion which may put them at greater risk for nephrocalcinosis and kidney failure than older PH1 patients. Those with homozygous G170R variants may have milder disease. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- David J Sas
- Division of Pediatric Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
| | - Kristin Mara
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA
| | - Ramila A Mehta
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA
| | - Barbara M Seide
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Carly J Banks
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | | | | | - John C Lieske
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Dawn S Milliner
- Division of Pediatric Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
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20
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Machry M, Ferreira LF, Lucchese AM, Kalil AN, Feier FH. Liver volumetric and anatomic assessment in living donor liver transplantation: The role of modern imaging and artificial intelligence. World J Transplant 2023; 13:290-298. [PMID: 38174151 PMCID: PMC10758682 DOI: 10.5500/wjt.v13.i6.290] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/17/2023] [Accepted: 10/17/2023] [Indexed: 12/15/2023] Open
Abstract
The shortage of deceased donor organs has prompted the development of alternative liver grafts for transplantation. Living-donor liver transplantation (LDLT) has emerged as a viable option, expanding the donor pool and enabling timely transplantation with favorable graft function and improved long-term outcomes. An accurate evaluation of the donor liver's volumetry (LV) and anatomical study is crucial to ensure adequate future liver remnant, graft volume and precise liver resection. Thus, ensuring donor safety and an appropriate graft-to-recipient weight ratio. Manual LV (MLV) using computed tomography has traditionally been considered the gold standard for assessing liver volume. However, the method has been limited by cost, subjectivity, and variability. Automated LV techniques employing advanced segmentation algorithms offer improved reproducibility, reduced variability, and enhanced efficiency compared to manual measurements. However, the accuracy of automated LV requires further investigation. The study provides a comprehensive review of traditional and emerging LV methods, including semi-automated image processing, automated LV techniques, and machine learning-based approaches. Additionally, the study discusses the respective strengths and weaknesses of each of the aforementioned techniques. The use of artificial intelligence (AI) technologies, including machine learning and deep learning, is expected to become a routine part of surgical planning in the near future. The implementation of AI is expected to enable faster and more accurate image study interpretations, improve workflow efficiency, and enhance the safety, speed, and cost-effectiveness of the procedures. Accurate preoperative assessment of the liver plays a crucial role in ensuring safe donor selection and improved outcomes in LDLT. MLV has inherent limitations that have led to the adoption of semi-automated and automated software solutions. Moreover, AI has tremendous potential for LV and segmentation; however, its widespread use is hindered by cost and availability. Therefore, the integration of multiple specialties is necessary to embrace technology and explore its possibilities, ranging from patient counseling to intraoperative decision-making through automation and AI.
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Affiliation(s)
- Mayara Machry
- Department of Hepato-Biliary-Pancreatic Surgery and Liver Transplantation, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
| | - Luis Fernando Ferreira
- Postgraduation Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Angelica Maria Lucchese
- Department of Hepato-Biliary-Pancreatic Surgery and Liver Transplantation, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
| | - Antonio Nocchi Kalil
- Department of Hepato-Biliary-Pancreatic Surgery and Liver Transplantation, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
- Postgraduation Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Flavia Heinz Feier
- Department of Hepato-Biliary-Pancreatic Surgery and Liver Transplantation, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
- Postgraduation Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
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21
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Dinh J, Johnson TN, Grimstein M, Lewis T. Physiologically Based Pharmacokinetics Modeling in the Neonatal Population-Current Advances, Challenges, and Opportunities. Pharmaceutics 2023; 15:2579. [PMID: 38004559 PMCID: PMC10675397 DOI: 10.3390/pharmaceutics15112579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/24/2023] [Accepted: 10/29/2023] [Indexed: 11/26/2023] Open
Abstract
Physiologically based pharmacokinetic (PBPK) modeling is an approach to predicting drug pharmacokinetics, using knowledge of the human physiology involved and drug physiochemical properties. This approach is useful when predicting drug pharmacokinetics in under-studied populations, such as pediatrics. PBPK modeling is a particularly important tool for dose optimization for the neonatal population, given that clinical trials rarely include this patient population. However, important knowledge gaps exist for neonates, resulting in uncertainty with the model predictions. This review aims to outline the sources of variability that should be considered with developing a neonatal PBPK model, the data that are currently available for the neonatal ontogeny, and lastly to highlight the data gaps where further research would be needed.
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Affiliation(s)
- Jean Dinh
- Certara UK Limited, Sheffield S1 2BJ, UK; (J.D.); (T.N.J.)
| | | | - Manuela Grimstein
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20903, USA
| | - Tamorah Lewis
- Pediatric Clinical Pharmacology & Toxicology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
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22
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Munk DE, Vendelbo MH, Kirk FT, Rewitz KS, Bender DA, Vase KH, Munk OL, Vilstrup H, Ott P, Sandahl TD. Distribution of non-ceruloplasmin-bound copper after i.v. 64Cu injection studied with PET/CT in patients with Wilson disease. JHEP Rep 2023; 5:100916. [PMID: 37886434 PMCID: PMC10597763 DOI: 10.1016/j.jhepr.2023.100916] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/31/2023] [Accepted: 08/31/2023] [Indexed: 10/28/2023] Open
Abstract
Background & Aims In Wilson disease (WD), copper accumulation and increased non-ceruloplasmin-bound copper in plasma lead to liver and brain pathology. To better understand the fate of non-ceruloplasmin-bound copper, we used PET/CT to examine the whole-body distribution of intravenously injected 64-copper (64Cu). Methods Eight patients with WD, five heterozygotes, and nine healthy controls were examined by dynamic PET/CT for 90 min and static PET/CT up to 20 h after injection. We measured 64Cu activity in blood and tissue and quantified the kinetics by compartmental analysis. Results Initially, a large fraction of injected 64Cu was distributed to extrahepatic tissues, especially skeletal muscle. Thus, across groups, extrahepatic tissues accounted for 45-58% of the injected dose (%ID) after 10 min, and 45-55% after 1 h. Kinetic analysis showed rapid exchange of 64Cu between blood and muscle as well as adipose tissue, with 64Cu retention in a secondary compartment, possibly mitochondria. This way, muscle and adipose tissue may protect the brain from spikes in non-ceruloplasmin-bound copper. Tiny amounts of cerebral 64Cu were detected (0.2%ID after 90 min and 0.3%ID after 6 h), suggesting tight control of cerebral copper in accordance with a cerebral clearance that is 2-3-fold lower than in muscle. Compared to controls, patients with WD accumulated more hepatic copper 6-20 h after injection, and also renal copper at 6 h. Conclusion Non-ceruloplasmin-bound copper is initially distributed into a number of tissues before being redistributed slowly to the eliminating organ, the liver. Cerebral uptake of copper is extremely slow and likely highly regulated. Our findings provide new insights into the mechanisms of copper control. Impact and implications Maintaining non-ceruloplasmin-bound copper within the normal range is an important treatment goal in WD as this "free" copper is considered toxic to the liver and brain. We found that intravenously injected non-ceruloplasmin-bound copper quickly distributed to a number of tissues, especially skeletal muscle, subcutaneous fat, and the liver, while uptake into the brain was slow. This study offers new insights into the mechanisms of copper control, which may encourage further research into potential new treatment targets. Clinical trial number 2016-001975-59.
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Affiliation(s)
- Ditte Emilie Munk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Mikkel Holm Vendelbo
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Frederik Teicher Kirk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Karina Stubkjær Rewitz
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Dirk Andreas Bender
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Karina Højrup Vase
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Ole Lajord Munk
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Peter Ott
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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23
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Valentino LA, Ozelo MC, Herzog RW, Key NS, Pishko AM, Ragni MV, Samelson-Jones BJ, Lillicrap D. A review of the rationale for gene therapy for hemophilia A with inhibitors: one-shot tolerance and treatment? J Thromb Haemost 2023; 21:3033-3044. [PMID: 37225021 DOI: 10.1016/j.jtha.2023.05.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/09/2023] [Accepted: 05/14/2023] [Indexed: 05/26/2023]
Abstract
The therapeutic landscape for people living with hemophilia A (PwHA) has changed dramatically in recent years, but many clinical challenges remain, including the development of inhibitory antibodies directed against factor VIII (FVIII) that occur in approximately 30% of people with severe hemophilia A. Emicizumab, an FVIII mimetic bispecific monoclonal antibody, provides safe and effective bleeding prophylaxis for many PwHA, but clinicians still explore therapeutic strategies that result in immunologic tolerance to FVIII to enable effective treatment with FVIII for problematic bleeding events. This immune tolerance induction (ITI) to FVIII is typically accomplished through repeated long-term exposure to FVIII using a variety of protocols. Meanwhile, gene therapy has recently emerged as a novel ITI option that provides an intrinsic, consistent source of FVIII. As gene therapy and other therapies now expand therapeutic options for PwHA, we review the persistent unmet medical needs with respect to FVIII inhibitors and effective ITI in PwHA, the immunology of FVIII tolerization, the latest research on tolerization strategies, and the role of liver-directed gene therapy to mediate FVIII ITI.
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Affiliation(s)
- Leonard A Valentino
- National Hemophilia Foundation, New York, New York, USA; Rush University, Chicago, Illinois, USA.
| | | | - Roland W Herzog
- Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nigel S Key
- University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
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24
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Johnson TN, Abduljalil K, Pan X, Emoto C. Development and Verification of a Japanese Pediatric Physiologically Based Pharmacokinetic Model with Emphasis on Drugs Eliminated by Cytochrome P450 or Renal Excretion. J Clin Pharmacol 2023; 63:1156-1168. [PMID: 37496106 DOI: 10.1002/jcph.2317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 07/23/2023] [Indexed: 07/28/2023]
Abstract
Physiologically based pharmacokinetic (PBPK) models are useful in bridging drug exposure in different ethnic groups, and there is increasing regulatory application of this approach in adults. Reported pediatric PBPK models tend to focus on the North European population, with few examples in other ethnic groups. This study describes the development and verification of a Japanese pediatric PBPK population. The development of the model was based on the existing North European pediatric population. Japanese systems and clinical data were collated from public databases and the literature, and the underlying demographics and equations were optimized so that physiological outputs represented the Japanese pediatric population. The model was tested using 14 different small molecule drugs, eliminated by a variety of pathways, including cytochrome P450 3A4 (CYP3A4) metabolism and renal excretion. Given the limitations of the clinical data, the overall performance of the model was good, with 44/62 predictions for PK parameters (area under the plasma drug concentration-time curve, AUC; maximum serum concentration, Cmax ; clearance, CL) being within 0.8- to 1.25-fold, 56/62 within 0.67- to 1.5-fold, and 61/62 within 0.5- to 2.0-fold of the observed values. Specific results for the 5 CYP3A4 substrates showed 20/31 cases were predicted within 0.8- to 1.25-fold, 27/31 within 0.67- to 1.5-fold, and all were within 0.5- to 2.0-fold of the observed values. Given the increased regulatory use of pediatric PBPK in drug development, expanding these models to other ethnic groups are important. Considering qualifying these models based on the context of use, there is a need to expand on the current research to include a larger range of drugs with different elimination pathways. Collaboration among academic, industry, model providers, and regulators will facilitate further development.
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Affiliation(s)
| | | | - Xian Pan
- Simcyp Division, Certara UK Limited, Sheffield, UK
| | - Chie Emoto
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan
- Translational Research Division, Chugai Pharmaceutical Co., Ltd, Tokyo, Japan
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25
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Nguyen NH, Jarvi NL, Balu-Iyer SV. Immunogenicity of Therapeutic Biological Modalities - Lessons from Hemophilia A Therapies. J Pharm Sci 2023; 112:2347-2370. [PMID: 37220828 DOI: 10.1016/j.xphs.2023.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 05/17/2023] [Accepted: 05/17/2023] [Indexed: 05/25/2023]
Abstract
The introduction and development of biologics such as therapeutic proteins, gene-, and cell-based therapy have revolutionized the scope of treatment for many diseases. However, a significant portion of the patients develop unwanted immune reactions against these novel biological modalities, referred to as immunogenicity, and no longer benefit from the treatments. In the current review, using Hemophilia A (HA) therapy as an example, we will discuss the immunogenicity issue of multiple biological modalities. Currently, the number of therapeutic modalities that are approved or recently explored to treat HA, a hereditary bleeding disorder, is increasing rapidly. These include, but are not limited to, recombinant factor VIII proteins, PEGylated FVIII, FVIII Fc fusion protein, bispecific monoclonal antibodies, gene replacement therapy, gene editing therapy, and cell-based therapy. They offer the patients a broader range of more advanced and effective treatment options, yet immunogenicity remains the most critical complication in the management of this disorder. Recent advances in strategies to manage and mitigate immunogenicity will also be reviewed.
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Affiliation(s)
- Nhan H Nguyen
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA; Currently at Truvai Biosciences, Buffalo, NY, USA
| | - Nicole L Jarvi
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Sathy V Balu-Iyer
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
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26
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Omata K, Nomura I, Hirata A, Yonezuka Y, Muto H, Kuriki R, Jimbo K, Ogasa K, Kato T. Isolation and evaluation of erythroid progenitors in the livers of larval, froglet, and adult Xenopus tropicalis. Biol Open 2023; 12:bio059862. [PMID: 37421150 PMCID: PMC10399205 DOI: 10.1242/bio.059862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 06/28/2023] [Indexed: 07/09/2023] Open
Abstract
Xenopus liver maintains erythropoietic activity from the larval to the adult stage. During metamorphosis, thyroid hormone mediates apoptosis of larval-type erythroid progenitors and proliferation of adult-type erythroid progenitors, and a globin switch occurs during this time. In addition, the whole-body mass and the liver also change; however, whether there is a change in the absolute number of erythroid progenitors is unclear. To isolate and evaluate erythroid progenitors in the Xenopus liver, we developed monoclonal ER9 antibodies against the erythropoietin receptor (EPOR) of Xenopus. ER9 recognized erythrocytes, but not white blood cells or thrombocytes. The specificity of ER9 for EPOR manifested as its inhibitory effect on the proliferation of a Xenopus EPOR-expressing cell line. Furthermore, ER9 recognition was consistent with epor gene expression. ER9 staining with Acridine orange (AO) allowed erythrocyte fractionation through fluorescence-activated cell sorting. The ER9+ and AO-red (AOr)high fractions were highly enriched in erythroid progenitors and primarily localized to the liver. The method developed using ER9 and AO was also applied to larvae and froglets with different progenitor populations from adult frogs. The liver to body weight and the number of ER9+ AOrhigh cells per unit body weight were significantly higher in adults than in larvae and froglets, and the number of ER9+ AOrhigh cells per unit liver weight was the highest in froglets. Collectively, our results show increased erythropoiesis in the froglet liver and demonstrate growth-dependent changes in erythropoiesis patterns in specific organs of Xenopus.
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Affiliation(s)
- Kazuki Omata
- Department of Biology, School of Education, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan
- Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan
| | - Ikki Nomura
- Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan
| | - Akito Hirata
- Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan
| | - Yuka Yonezuka
- Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan
| | - Hiroshi Muto
- Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan
| | - Ryo Kuriki
- Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan
| | - Kirin Jimbo
- Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan
| | - Koujin Ogasa
- Department of Biology, School of Education, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan
| | - Takashi Kato
- Department of Biology, School of Education, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan
- Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan
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27
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Knott EA, Partovi S, McBride A, Levitin A, Gadani S. Liver Venous Deprivation Using Amplatzer Vascular Plug-Assisted N-Butyl Cyanoacrylate Embolization of the Portal and Hepatic Veins: How Do I Do it? Semin Intervent Radiol 2023; 40:197-211. [PMID: 37333744 PMCID: PMC10275680 DOI: 10.1055/s-0043-1768610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Affiliation(s)
- Emily A. Knott
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Sasan Partovi
- Section of Vascular and Interventional Radiology, Imaging Institute, Cleveland Clinic, Cleveland, Ohio
| | - Aaron McBride
- Section of Vascular and Interventional Radiology, Imaging Institute, Cleveland Clinic, Cleveland, Ohio
| | - Abraham Levitin
- Section of Vascular and Interventional Radiology, Imaging Institute, Cleveland Clinic, Cleveland, Ohio
| | - Sameer Gadani
- Section of Vascular and Interventional Radiology, Imaging Institute, Cleveland Clinic, Cleveland, Ohio
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28
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Muschol N, Koehn A, von Cossel K, Okur I, Ezgu F, Harmatz P, de Castro Lopez MJ, Couce ML, Lin SP, Batzios S, Cleary M, Solano M, Nestrasil I, Kaufman B, Shaywitz AJ, Maricich SM, Kuca B, Kovalchin J, Zanelli E. A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B. J Clin Invest 2023; 133:165076. [PMID: 36413418 PMCID: PMC9843052 DOI: 10.1172/jci165076] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022] Open
Abstract
BackgroundSanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS levels, prevent brain atrophy, and potentially delay cognitive decline.MethodsIn this phase I/II open-label study, patients with MPS type IIIB (n = 22) were treated with tralesinidase alfa administered i.c.v. The patients were monitored for drug exposure; total HS and HS nonreducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma; anti-drug antibody response; brain, spleen, and liver volumes as measured by MRI; and cognitive development as measured by age-equivalent (AEq) scores.ResultsIn the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV.ConclusionAdministration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy.Trial registrationClinicaltrials.gov NCT02754076.FUNDINGBioMarin Pharmaceutical Inc. and Allievex Corporation.
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Affiliation(s)
- Nicole Muschol
- University Medical Center Hamburg-Eppendorf, International Center for Lysosomal Disorders (ICLD), Hamburg, Germany
| | - Anja Koehn
- University Medical Center Hamburg-Eppendorf, International Center for Lysosomal Disorders (ICLD), Hamburg, Germany
| | - Katharina von Cossel
- University Medical Center Hamburg-Eppendorf, International Center for Lysosomal Disorders (ICLD), Hamburg, Germany
| | - Ilyas Okur
- Gazi University Faculty of Medicine, Departments of Pediatric Metabolism and Genetics, Ankara, Turkey
| | - Fatih Ezgu
- Gazi University Faculty of Medicine, Departments of Pediatric Metabolism and Genetics, Ankara, Turkey
| | - Paul Harmatz
- UCSF Benioff Children’s Hospital Oakland, Oakland, California, USA
| | - Maria J. de Castro Lopez
- Hospital Clínico Universitario de Santiago, University of Santiago de Compostela, IDIS, CIBERER, MetabERN, A Coruña, Spain
| | - Maria Luz Couce
- Hospital Clínico Universitario de Santiago, University of Santiago de Compostela, IDIS, CIBERER, MetabERN, A Coruña, Spain
| | | | | | | | | | - Igor Nestrasil
- Division of Clinical Behavioral Neuroscience, Department of Pediatrics, and Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, Minnesota, USA
| | - Brian Kaufman
- CLB Consulting, Falls of Neuse, Raleigh, North Carolina, USA
| | | | | | - Bernice Kuca
- Allievex Corporation, Marblehead, Massachusetts, USA
| | | | - Eric Zanelli
- Allievex Corporation, Marblehead, Massachusetts, USA
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29
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Entezari P, Toskich BB, Kim E, Padia S, Christopher D, Sher A, Thornburg B, Hohlastos ES, Salem R, Collins JD, Lewandowski RJ. Promoting Surgical Resection through Future Liver Remnant Hypertrophy. Radiographics 2022; 42:2166-2183. [PMID: 36206182 DOI: 10.1148/rg.220050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
An inadequate future liver remnant (FLR) can preclude curative-intent surgical resection for patients with primary or secondary hepatic malignancies. For patients with normal baseline liver function and without risk factors, an FLR of 20% is needed to maintain postsurgical hepatic function. However, the FLR requirement is higher for patients who are exposed to systemic chemotherapy (FLR, >30%) or have cirrhosis (FLR, >40%). Interventional radiologic and surgical methods to achieve FLR hypertrophy are evolving, including portal vein ligation, portal vein embolization, radiation lobectomy, hepatic venous deprivation, and associating liver partition and portal vein ligation for staged hepatectomy. Each technique offers particular advantages and disadvantages. Knowledge of these procedures can help clinicians to choose the suitable technique for each patient. The authors review the techniques used to develop FLR hypertrophy, focusing on technical considerations, outcomes, and the advantages and disadvantages of each approach. Online supplemental material is available for this article. ©RSNA, 2022.
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Affiliation(s)
- Pouya Entezari
- From the Department of Radiology, Section of Interventional Radiology (P.E., B.T., E.S.H., R.S., R.J.L.), and Department of Surgery, Division of Transplant Surgery (D.C.), Northwestern University, 676 N Saint Clair St, Chicago, IL 60611-2927; Department of Radiology, Section of Interventional Radiology, Mayo Clinic Florida, Jacksonville, Fla (B.B.T.); Department of Radiology, Section of Interventional Radiology, Mount Sinai University Hospitals, New York, NY (E.K., A.S.); Department of Radiology, Section of Interventional Radiology, University of California-Los Angeles, Los Angeles, Calif (S.P.); and Department of Radiology, Mayo Clinic Rochester, Rochester, Minn (J.D.C.)
| | - Beau B Toskich
- From the Department of Radiology, Section of Interventional Radiology (P.E., B.T., E.S.H., R.S., R.J.L.), and Department of Surgery, Division of Transplant Surgery (D.C.), Northwestern University, 676 N Saint Clair St, Chicago, IL 60611-2927; Department of Radiology, Section of Interventional Radiology, Mayo Clinic Florida, Jacksonville, Fla (B.B.T.); Department of Radiology, Section of Interventional Radiology, Mount Sinai University Hospitals, New York, NY (E.K., A.S.); Department of Radiology, Section of Interventional Radiology, University of California-Los Angeles, Los Angeles, Calif (S.P.); and Department of Radiology, Mayo Clinic Rochester, Rochester, Minn (J.D.C.)
| | - Edward Kim
- From the Department of Radiology, Section of Interventional Radiology (P.E., B.T., E.S.H., R.S., R.J.L.), and Department of Surgery, Division of Transplant Surgery (D.C.), Northwestern University, 676 N Saint Clair St, Chicago, IL 60611-2927; Department of Radiology, Section of Interventional Radiology, Mayo Clinic Florida, Jacksonville, Fla (B.B.T.); Department of Radiology, Section of Interventional Radiology, Mount Sinai University Hospitals, New York, NY (E.K., A.S.); Department of Radiology, Section of Interventional Radiology, University of California-Los Angeles, Los Angeles, Calif (S.P.); and Department of Radiology, Mayo Clinic Rochester, Rochester, Minn (J.D.C.)
| | - Siddharth Padia
- From the Department of Radiology, Section of Interventional Radiology (P.E., B.T., E.S.H., R.S., R.J.L.), and Department of Surgery, Division of Transplant Surgery (D.C.), Northwestern University, 676 N Saint Clair St, Chicago, IL 60611-2927; Department of Radiology, Section of Interventional Radiology, Mayo Clinic Florida, Jacksonville, Fla (B.B.T.); Department of Radiology, Section of Interventional Radiology, Mount Sinai University Hospitals, New York, NY (E.K., A.S.); Department of Radiology, Section of Interventional Radiology, University of California-Los Angeles, Los Angeles, Calif (S.P.); and Department of Radiology, Mayo Clinic Rochester, Rochester, Minn (J.D.C.)
| | - Derrick Christopher
- From the Department of Radiology, Section of Interventional Radiology (P.E., B.T., E.S.H., R.S., R.J.L.), and Department of Surgery, Division of Transplant Surgery (D.C.), Northwestern University, 676 N Saint Clair St, Chicago, IL 60611-2927; Department of Radiology, Section of Interventional Radiology, Mayo Clinic Florida, Jacksonville, Fla (B.B.T.); Department of Radiology, Section of Interventional Radiology, Mount Sinai University Hospitals, New York, NY (E.K., A.S.); Department of Radiology, Section of Interventional Radiology, University of California-Los Angeles, Los Angeles, Calif (S.P.); and Department of Radiology, Mayo Clinic Rochester, Rochester, Minn (J.D.C.)
| | - Alex Sher
- From the Department of Radiology, Section of Interventional Radiology (P.E., B.T., E.S.H., R.S., R.J.L.), and Department of Surgery, Division of Transplant Surgery (D.C.), Northwestern University, 676 N Saint Clair St, Chicago, IL 60611-2927; Department of Radiology, Section of Interventional Radiology, Mayo Clinic Florida, Jacksonville, Fla (B.B.T.); Department of Radiology, Section of Interventional Radiology, Mount Sinai University Hospitals, New York, NY (E.K., A.S.); Department of Radiology, Section of Interventional Radiology, University of California-Los Angeles, Los Angeles, Calif (S.P.); and Department of Radiology, Mayo Clinic Rochester, Rochester, Minn (J.D.C.)
| | - Bartley Thornburg
- From the Department of Radiology, Section of Interventional Radiology (P.E., B.T., E.S.H., R.S., R.J.L.), and Department of Surgery, Division of Transplant Surgery (D.C.), Northwestern University, 676 N Saint Clair St, Chicago, IL 60611-2927; Department of Radiology, Section of Interventional Radiology, Mayo Clinic Florida, Jacksonville, Fla (B.B.T.); Department of Radiology, Section of Interventional Radiology, Mount Sinai University Hospitals, New York, NY (E.K., A.S.); Department of Radiology, Section of Interventional Radiology, University of California-Los Angeles, Los Angeles, Calif (S.P.); and Department of Radiology, Mayo Clinic Rochester, Rochester, Minn (J.D.C.)
| | - Elias S Hohlastos
- From the Department of Radiology, Section of Interventional Radiology (P.E., B.T., E.S.H., R.S., R.J.L.), and Department of Surgery, Division of Transplant Surgery (D.C.), Northwestern University, 676 N Saint Clair St, Chicago, IL 60611-2927; Department of Radiology, Section of Interventional Radiology, Mayo Clinic Florida, Jacksonville, Fla (B.B.T.); Department of Radiology, Section of Interventional Radiology, Mount Sinai University Hospitals, New York, NY (E.K., A.S.); Department of Radiology, Section of Interventional Radiology, University of California-Los Angeles, Los Angeles, Calif (S.P.); and Department of Radiology, Mayo Clinic Rochester, Rochester, Minn (J.D.C.)
| | - Riad Salem
- From the Department of Radiology, Section of Interventional Radiology (P.E., B.T., E.S.H., R.S., R.J.L.), and Department of Surgery, Division of Transplant Surgery (D.C.), Northwestern University, 676 N Saint Clair St, Chicago, IL 60611-2927; Department of Radiology, Section of Interventional Radiology, Mayo Clinic Florida, Jacksonville, Fla (B.B.T.); Department of Radiology, Section of Interventional Radiology, Mount Sinai University Hospitals, New York, NY (E.K., A.S.); Department of Radiology, Section of Interventional Radiology, University of California-Los Angeles, Los Angeles, Calif (S.P.); and Department of Radiology, Mayo Clinic Rochester, Rochester, Minn (J.D.C.)
| | - Jeremy D Collins
- From the Department of Radiology, Section of Interventional Radiology (P.E., B.T., E.S.H., R.S., R.J.L.), and Department of Surgery, Division of Transplant Surgery (D.C.), Northwestern University, 676 N Saint Clair St, Chicago, IL 60611-2927; Department of Radiology, Section of Interventional Radiology, Mayo Clinic Florida, Jacksonville, Fla (B.B.T.); Department of Radiology, Section of Interventional Radiology, Mount Sinai University Hospitals, New York, NY (E.K., A.S.); Department of Radiology, Section of Interventional Radiology, University of California-Los Angeles, Los Angeles, Calif (S.P.); and Department of Radiology, Mayo Clinic Rochester, Rochester, Minn (J.D.C.)
| | - Robert J Lewandowski
- From the Department of Radiology, Section of Interventional Radiology (P.E., B.T., E.S.H., R.S., R.J.L.), and Department of Surgery, Division of Transplant Surgery (D.C.), Northwestern University, 676 N Saint Clair St, Chicago, IL 60611-2927; Department of Radiology, Section of Interventional Radiology, Mayo Clinic Florida, Jacksonville, Fla (B.B.T.); Department of Radiology, Section of Interventional Radiology, Mount Sinai University Hospitals, New York, NY (E.K., A.S.); Department of Radiology, Section of Interventional Radiology, University of California-Los Angeles, Los Angeles, Calif (S.P.); and Department of Radiology, Mayo Clinic Rochester, Rochester, Minn (J.D.C.)
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Okur I, Ezgu F, Giugliani R, Muschol N, Koehn A, Amartino H, Harmatz P, de Castro Lopez MJ, Couce ML, Lin SP, Batzios S, Cleary M, Solano M, Peters H, Lee J, Nestrasil I, Shaywitz AJ, Maricich SM, Kuca B, Kovalchin J, Zanelli E. Longitudinal Natural History of Pediatric Subjects Affected with Mucopolysaccharidosis IIIB. J Pediatr 2022; 249:50-58.e2. [PMID: 35709957 DOI: 10.1016/j.jpeds.2022.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 05/31/2022] [Accepted: 06/08/2022] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To characterize the longitudinal natural history of disease progression in pediatric subjects affected with mucopolysaccharidosis (MPS) IIIB. STUDY DESIGN Sixty-five children with a confirmed diagnosis of MPS IIIB were enrolled into 1 of 2 natural history studies and followed for up to 4 years. Cognitive and adaptive behavior functions were analyzed in all subjects, and volumetric magnetic resonance imaging analysis of liver, spleen, and brain, as well as levels of heparan sulfate (HS) and heparan sulfate nonreducing ends (HS-NRE), were measured in a subset of subjects. RESULTS The majority of subjects with MPS IIIB achieved an apex on both cognition and adaptive behavior age equivalent scales between age 3 and 6 years. Development quotients for both cognition and adaptive behavior follow a linear trajectory by which subjects reach a nadir with a score <25 for an age equivalent of 24 months by age 8 years on average and by 13.5 years at the latest. All tested subjects (n = 22) had HS and HS-NRE levels above the normal range in cerebrospinal fluid and plasma, along with signs of hepatomegaly. Subjects lost an average of 26 mL of brain volume (-2.7%) over 48 weeks, owing entirely to a loss of cortical gray matter (32 mL; -6.5%). CONCLUSIONS MPS IIIB exists along a continuum based on cognitive decline and cortical gray matter atrophy. Although a few individuals with MPS IIIB have an attenuated phenotype, the majority follow predicted trajectories for both cognition and adaptive behavior. TRIAL REGISTRATION ClinicalTrials.gov identifiers NCT02493998, NCT03227042, and NCT02754076.
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Affiliation(s)
- Ilyas Okur
- Department of Pediatric Metabolism, Gazi University Faculty of Medicine, Ankara, Turkey; Department of Genetics, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Fatih Ezgu
- Department of Pediatric Metabolism, Gazi University Faculty of Medicine, Ankara, Turkey; Department of Genetics, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Roberto Giugliani
- Medical Genetics Service and DR Brasil, HCPA, Department of Genetics, UFRGS, DASA, and INAGEMP, Porto Alegre, Brazil
| | - Nicole Muschol
- International Center for Lysosomal Disorders, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anja Koehn
- International Center for Lysosomal Disorders, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Paul Harmatz
- UCSF Benioff Children's Hospital Oakland, Oakland, CA
| | - Maria J de Castro Lopez
- Hospital Clínico Universitario de Santiago, University of Santiago de Compostela, IDIS, CIBERER, MetabERN, A Coruña, Spain
| | - Maria Luz Couce
- Hospital Clínico Universitario de Santiago, University of Santiago de Compostela, IDIS, CIBERER, MetabERN, A Coruña, Spain
| | | | | | | | | | | | - Joy Lee
- Royal Children's Hospital, Melbourne, Australia
| | - Igor Nestrasil
- Division of Clinical Behavioral Neuroscience and Masonic Institute for the Developing Brain, Department of Pediatrics, University of Minnesota, Minneapolis, MN
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31
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Shulan Estimation Model: A New Formula for Estimation of Standard Liver Volume In Chinese Adults. Transplant Proc 2022; 54:2236-2242. [PMID: 36114045 DOI: 10.1016/j.transproceed.2022.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 07/07/2022] [Accepted: 08/02/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND To establish a new and accurate model for standard liver volume (SLV) estimation and graft size prediction in liver transplantation for Chinese adults. METHODS In this study, the data of morphologic indices and liver volume (LV) were retrospectively obtained on 507 cadaveric liver transplantation donors between June 2017 and September 2020 in Shulan (Hangzhou) Hospital. Linear regression analysis was performed to evaluate the impact of each parameter and develop a new SLV formula. The new formula was then validated prospectively on 97 donors between October 2020 and June 2021, and the prediction accuracy was compared with previous formulas. RESULTS The average LV in all subjects was 1445.68 ± 309.94 mL. Body weight (BW) showing the strongest correlation (r = 0.453, P < .001). By stepwise multiple linear regression analysis, BW and age were the only 2 independent correlation factors for LV. Shulan estimation model derived: SLV (mL) = 13.266 × BW (kg) - 4.693 × age + 797.16 (R2 = 0.236, P < .001). In the validation cohort, our new model achieved no significant differences between the estimated SLV and the actual LV (P > .05), and showed the lowest mean percentage error of 0.33%. The proportions of estimated SLV within the actual LV ± 20%, ± 15%, and ± 10% percentage errors were 69.1%, 55.7%, and 40.2%, respectively. DISCUSSION The Shulan SLV estimation model predicted LV more accurately than previous formulas on Chinese adults, which could serve as a simple screening tool during the initial assessment of graft volume for potential donors.
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32
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Munk DE, Lund Laursen T, Teicher Kirk F, Vilstrup H, Ala A, Gormsen LC, Ott P, Damgaard Sandahl T. Effect of oral zinc regimens on human hepatic copper content: a randomized intervention study. Sci Rep 2022; 12:14714. [PMID: 36038585 PMCID: PMC9424214 DOI: 10.1038/s41598-022-18872-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/22/2022] [Indexed: 11/26/2022] Open
Abstract
Zinc inhibits intestinal copper uptake, an effect utilized for treating Wilson’s disease (WD). We used copper-64 (64Cu) PET/CT to examine how much four weeks of treatment with different zinc regimens reduced the hepatic 64Cu content after oral 64Cu administration and test if alternative regimens were noninferior to the standard regimen of zinc acetate 50 mg × 3 daily. Forty healthy persons were randomized to four different zinc protocols. The WD standard treatment zinc acetate 50 mg × 3 reduced the hepatic 64Cu content from 26.9 ± 7.5% to 13.3 ± 5.6% of the administered 64Cu. Zinc gluconate 50 mg × 3 was noninferior (P = 0.02) (35.8 ± 9.0% to 17.4 ± 7.5%). Zinc acetate 150 mg × 1 (33.1 ± 9.9% to 17.4 ± 7.5%) and zinc gluconate 150 mg × 1 (28.1 ± 6.7% to 22.0 ± 6.7%) were less effective. These effects were intra- and inter-individually highly variable, and 14% had no effect of any zinc regimen, which may explain disparities in zinc treatment efficacy in WD patients.
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Affiliation(s)
- Ditte Emilie Munk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark.
| | - Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark
| | - Frederik Teicher Kirk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark
| | - Aftab Ala
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK
| | - Lars Christian Gormsen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, Denmark
| | - Peter Ott
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark
| | - Thomas Damgaard Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark
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33
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Dai HR, Liu Y, Lu KY, He X, Guo HL, Hu YH, Xu J, Ding XS, Chen F, Cheng R, Jiao Z. Population pharmacokinetic modeling of caffeine in preterm infants with apnea of prematurity: New findings from concomitant erythromycin and AHR genetic polymorphisms. Pharmacol Res 2022; 184:106416. [PMID: 36029933 DOI: 10.1016/j.phrs.2022.106416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 08/04/2022] [Accepted: 08/21/2022] [Indexed: 11/26/2022]
Abstract
Current standard-dose caffeine therapy results in significant intersubject variability. The aims of this study were to develop and evaluate population pharmacokinetic (PPK) models of caffeine in preterm infants through comprehensive screening of covariates and then to propose model-informed precision dosing of caffeine for this population. A total of 129 caffeine concentrations from 96 premature neonates were incorporated into this study. Comprehensive medical record and genotype data of these neonates were collected for analysis. PPK modeling was performed by a nonlinear mixed effects modeling program (NONMEM). Final models based on the current weight (CW) or body surface area (BSA) were evaluated via multiple graphic and statistical methods. The model-informed dosing regimen was performed through Monte Carlo simulations. In addition to CW or BSA, postnatal age, coadministration with erythromycin (ERY), and aryl hydrocarbon receptor coding gene (AHR) variant (rs2158041) were incorporated into the final PPK models. Multiple evaluation results showed satisfactory prediction performance and stability of the CW- and BSA-based models. Monte Carlo simulations demonstrated that trough concentrations of caffeine in preterm infants would be affected by concomitant ERY therapy and rs2158041 under varying dose regimens. For the first time, ERY and rs2158041 were found to be associated with the clearance of caffeine in premature infants. Similar predictive performance and stability were obtained for both CW- and BSA-based PPK models. These findings provide novel insights into caffeine precision therapy for preterm infants.
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Affiliation(s)
- Hao-Ran Dai
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Yun Liu
- Neonatal Intensive Care Unit, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Ke-Yu Lu
- Neonatal Intensive Care Unit, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Xin He
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Hong-Li Guo
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Ya-Hui Hu
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Jing Xu
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Xuan-Sheng Ding
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Feng Chen
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
| | - Rui Cheng
- Neonatal Intensive Care Unit, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
| | - Zheng Jiao
- Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
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Heinke P, Rost F, Rode J, Trus P, Simonova I, Lázár E, Feddema J, Welsch T, Alkass K, Salehpour M, Zimmermann A, Seehofer D, Possnert G, Damm G, Druid H, Brusch L, Bergmann O. Diploid hepatocytes drive physiological liver renewal in adult humans. Cell Syst 2022; 13:499-507.e12. [PMID: 35649419 DOI: 10.1016/j.cels.2022.05.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 02/19/2022] [Accepted: 05/09/2022] [Indexed: 12/12/2022]
Abstract
Physiological liver cell replacement is central to maintaining the organ's high metabolic activity, although its characteristics are difficult to study in humans. Using retrospective radiocarbon (14C) birth dating of cells, we report that human hepatocytes show continuous and lifelong turnover, allowing the liver to remain a young organ (average age <3 years). Hepatocyte renewal is highly dependent on the ploidy level. Diploid hepatocytes show more than 7-fold higher annual birth rates than polyploid hepatocytes. These observations support the view that physiological liver cell renewal in humans is mainly dependent on diploid hepatocytes, whereas polyploid cells are compromised in their ability to divide. Moreover, cellular transitions between diploid and polyploid hepatocytes are limited under homeostatic conditions. With these findings, we present an integrated model of homeostatic liver cell generation in humans that provides fundamental insights into liver cell turnover dynamics.
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Affiliation(s)
- Paula Heinke
- Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany
| | - Fabian Rost
- Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany; Max Planck Institute for the Physics of Complex Systems, 01187 Dresden, Germany; Centre for Information Services and High Performance Computing, Technische Universität Dresden, 01187 Dresden, Germany
| | - Julian Rode
- Centre for Information Services and High Performance Computing, Technische Universität Dresden, 01187 Dresden, Germany
| | - Palina Trus
- Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany
| | - Irina Simonova
- Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany
| | - Enikő Lázár
- Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Joshua Feddema
- Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany
| | - Thilo Welsch
- Visceral-, Thoracic- and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Kanar Alkass
- Department of Oncology-Pathology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Mehran Salehpour
- Department of Physics and Astronomy, Applied Nuclear Physics, Ion Physics, Uppsala University, 75120 Uppsala, Sweden
| | - Andrea Zimmermann
- Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, 04103 Leipzig, Germany; Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany
| | - Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, 04103 Leipzig, Germany; Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany
| | - Göran Possnert
- Department of Physics and Astronomy, Applied Nuclear Physics, Ion Physics, Uppsala University, 75120 Uppsala, Sweden
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, 04103 Leipzig, Germany; Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany
| | - Henrik Druid
- Department of Oncology-Pathology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Lutz Brusch
- Centre for Information Services and High Performance Computing, Technische Universität Dresden, 01187 Dresden, Germany
| | - Olaf Bergmann
- Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
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35
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Lian D, Wang W, Liu L, Wang J, Rao S, Zhou J. CT volumetry helps predict prognosis of large hepatocellular carcinoma after resection. Clin Radiol 2022; 77:e599-e605. [PMID: 35483982 DOI: 10.1016/j.crad.2022.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 03/23/2022] [Indexed: 11/03/2022]
Abstract
AIM To determine whether the tumour volume measurement on preoperative contrast-enhanced computed tomography (CT) could be used to predict the overall survival patients with large hepatocellular carcinoma (>5 cm) after resection. MATERIALS AND METHODS This study included 171 patients with surgically confirmed hepatocellular carcinoma who underwent preoperative CT. The largest diameter, the product of the axial dimension, tumour volume, and tumour-to-liver volume ratio (TTLVR) on CT images were measured and calculated. The univariate and multivariate Cox proportional hazard ratio regression models were used to identify the impact of the tumour burden-related risk factors on overall survival. RESULTS In multivariate analysis, TTLVR (p=0.042) and major vascular invasion (p=0.006) were independently associated with overall survival of patients with hepatocellular carcinoma after the resection. The group in which the patients had a low TTLVR showed higher cumulative survival rates than patients with a TTLVR (p=0.004). Patients with a low TTLVR (≤26.23%) and absence of major vascular invasion had significantly higher cumulative survival rates compared to those patients with hepatocellular carcinoma with either or both the risk factors (p=0.001). CONCLUSION A higher TTLVR in combination with the presence of major vascular invasion was associated with poorer overall survival in patients with large hepatocellular carcinoma after resection.
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Affiliation(s)
- D Lian
- Department of Radiology, Xiamen Branch, Zhongshan Hospital, Fudan University, No. 668 Jinhu Road, Huli District, Xiamen 361015, China
| | - W Wang
- Department of Radiology, Cancer Center, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - L Liu
- Department of Radiology, Cancer Center, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - J Wang
- Department of Radiology, Cancer Center, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - S Rao
- Department of Radiology, Cancer Center, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China.
| | - J Zhou
- Department of Radiology, Xiamen Branch, Zhongshan Hospital, Fudan University, No. 668 Jinhu Road, Huli District, Xiamen 361015, China.
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Barten TRM, Bökkerink RMP, Venderink W, Gevers TJG, ten Broek RPG, Drenth JPH. Abdominal wall hernia is a frequent complication of polycystic liver disease and associated with hepatomegaly. Liver Int 2022; 42:871-878. [PMID: 35129293 PMCID: PMC9307001 DOI: 10.1111/liv.15177] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND AIM Polycystic liver disease (PLD) is related to hepatomegaly which causes an increased mechanical pressure on the abdominal wall. This may lead to abdominal wall herniation (AWH). We set out to establish the prevalence of AWH in PLD and explore risk factors. METHODS In this cross-sectional cohort study, we assessed the presence of AWHs from PLD patients with at least 1 abdominal computed tomography or magnetic resonance imaging scan. AWH presence on imaging was independently evaluated by two researchers. Data on potential risk factors were extracted from clinical files. RESULTS We included 484 patients of which 40.1% (n = 194) had an AWH. We found a clear predominance of umbilical hernias (25.8%, n = 125) while multiple hernias were present in 6.2% (n = 30). Using multivariate analysis, male sex (odds ratio [OR] 2.727 p < .001), abdominal surgery (OR 2.575, p < .001) and disease severity according to the Gigot classification (Type 3 OR 2.853, p < .001) were identified as risk factors. Height-adjusted total liver volume was an independent PLD-specific risk factor in the subgroup of patients with known total liver volume (OR 1.363, p = .001). Patients with multiple hernias were older (62.1 vs. 55.1, p = .001) and more frequently male (22.0% vs. 50.0%, p = .001). CONCLUSION AWHs occur frequently in PLD with a predominance of umbilical hernias. Hepatomegaly is a clear disease-specific risk factor.
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Affiliation(s)
- Thijs R. M. Barten
- Department of Gastroenterology and HepatologyRadboud University Medical CenterNijmegenthe Netherlands
| | - Roos‐Anne M. P. Bökkerink
- Department of Gastroenterology and HepatologyRadboud University Medical CenterNijmegenthe Netherlands
| | - Wulphert Venderink
- Department of Radiology and Nuclear MedicineRadboud University Medical CenterNijmegenthe Netherlands
| | - Tom J. G. Gevers
- Department of Gastroenterology and HepatologyRadboud University Medical CenterNijmegenthe Netherlands
- Department of Gastroenterology and HepatologyMaastricht University Medical CenterMaastrichtthe Netherlands
| | | | - Joost P. H. Drenth
- Department of Gastroenterology and HepatologyRadboud University Medical CenterNijmegenthe Netherlands
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Hosey CM, Halpin K, Shakhnovich V, Bi C, Sweeney B, Yan Y, Leeder JS. Pediatric growth patterns in youth-onset type 2 diabetes mellitus: Implications for physiologically-based pharmacokinetic models. Clin Transl Sci 2022; 15:912-922. [PMID: 35297172 PMCID: PMC9010268 DOI: 10.1111/cts.13207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/04/2021] [Accepted: 11/10/2021] [Indexed: 11/27/2022] Open
Abstract
An accurate understanding of the changes in height and weight of children with age is critical to the development of models predicting drug concentrations in children (i.e., physiologically‐based pharmacokinetic models). However, curves describing the growth of a typical population of children may not accurately characterize growth of children with various conditions, such as obesity. Therefore, to develop height and weight versus age growth curves for youth who were diagnosed with type 2 diabetes, we extracted data from electronic medical records. Robust nonlinear models were parameterized to the equations describing height and weight versus age as defined by the Centers for Disease Control and Prevention (CDC). CDC z‐scores were calculated using an internal program. The growth curves and z‐scores were compared to CDC norms. Youth with type 2 diabetes were increasingly heavier than CDC norms from early childhood. Except for a period around puberty, youth with type 2 diabetes were, on average, shorter than CDC norms, resulting in shorter average adult height. Deviations in growth were apparent in youth who develop type 2 diabetes; such deviations may be expected for other conditions as well, and disease‐specific growth curves should be considered during development of model‐informed drug development for pediatric conditions.
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Affiliation(s)
| | - Kelsee Halpin
- Children's Mercy Kansas City, Kansas City, Missouri, USA.,University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Valentina Shakhnovich
- Children's Mercy Kansas City, Kansas City, Missouri, USA.,University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.,University of Kansas Medical Center, Kansas City, Kansas, USA.,Center for Children's Healthy Lifestyles & Nutrition, Kansas City, Missouri, USA
| | - Chengpeng Bi
- Children's Mercy Kansas City, Kansas City, Missouri, USA
| | - Brooke Sweeney
- Children's Mercy Kansas City, Kansas City, Missouri, USA.,University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.,Center for Children's Healthy Lifestyles & Nutrition, Kansas City, Missouri, USA
| | - Yun Yan
- Children's Mercy Kansas City, Kansas City, Missouri, USA.,University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - J Steven Leeder
- Children's Mercy Kansas City, Kansas City, Missouri, USA.,University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.,University of Kansas Medical Center, Kansas City, Kansas, USA
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38
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Chhavi N, Ojha S, Awasthi A, Shalimar, Goel A. Serum Level of Alanine- and Aspartate-Aminotransferase Levels in Newborns in India. J Clin Exp Hepatol 2022; 12:306-311. [PMID: 35535103 PMCID: PMC9077228 DOI: 10.1016/j.jceh.2021.08.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤40 IU/L is normal. This cutoff, although determined in adults, is widely used for newborns. We studied the reference ranges for ALT and AST in newborns in India. METHODS We prospectively included babies with gestational age (GA) between 34 and 41weeks and birth weight (BW) ≥ 1500 g. We excluded the babies who either themselves or their mother had risk factors, which could cause elevation of serum levels of liver enzymes. Serum ALT and AST were measured in venous cord blood. The estimated percentile curves for ALT and AST, for BW and GA covariates, were drawn with General Additive Model for Location Scale and Shape (GAMLSS) with Box-Cox Power Exponential (BCPE). RESULTS Five-hundred thirty-seven babies (Boys 53.3%; GA 34-36 wks 19.7%; appropriate for GA 74.9%; BW < 2500 g 20.5%) were included. Overall, mean [SD] serum ALT and AST were 4412 IU/L and 5218 IU/L, respectively. The serum AST was significantly higher than the ALT level, regardless of gender, BW, GA, or fetal growth categories. The percentile curve against GA remained flat for ALT, although it showed a slight rise for AST. Serum levels of ALT and AST plotted against BW were also similar and showed an increase up to 2000 g and then remained stationary after that. CONCLUSION The serum levels of ALT and AST up to 44 IU/L and 52 IU/L, respectively, can be taken as normal in newborns with BW ≥ 2000 g or GA ≥34 weeks.
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Key Words
- AFD, Appropriate for date
- ALT, Alanine aminotransferase
- AST, Aspartate aminotransferase
- BCPE, Box–Cox Power Exponential
- BW, Birth weight
- GA, Gestational age
- GAMLSS, General Additive Model for Location Scale and Shape
- LFD, Large for date
- SFD, Small for date
- ULN, Upper limit of normal
- alanine aminotransferase
- aspartate aminotransferase
- liver enzymes
- liver injury
- newborns
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Affiliation(s)
- Nanda Chhavi
- Department of Pediatrics, Era’s Lucknow Medical College, Lucknow, India
| | - Sachi Ojha
- Department of Pediatrics, Era’s Lucknow Medical College, Lucknow, India
| | - Ashish Awasthi
- Centre for Chronic Conditions and Injuries, Public Health, Foundation of India, Gurgaon, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Amit Goel
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Umehara K, Cleary Y, Fowler S, Parrott N, Tuerck D. Accelerating Clinical Development of Idasanutlin through a Physiologically Based Pharmacokinetic Modeling Risk Assessment for CYP450 Isoenzyme-Related Drug-Drug Interactions. Drug Metab Dispos 2022; 50:214-223. [PMID: 34937801 DOI: 10.1124/dmd.121.000720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/20/2021] [Indexed: 11/22/2022] Open
Abstract
Idasanutlin is a potent inhibitor of the p53-MDM2 interaction that enables reactivation of the p53 pathway, which induces cell cycle arrest and/or apoptosis in tumor cells expressing functional p53. It was investigated for the treatment of solid tumors and several hematologic indications such as relapsed/refractory acute myeloid leukemia, polycythemia vera, or non-Hodgkin lymphoma. For safety reasons, it cannot be given in healthy volunteers for drug-drug interaction (DDI) explorations. This triggered the need for in silico explorations on top of the one available CYP3A clinical DDI study with posaconazole in solid tumor patients. Idasanutlin's clearance is dependent on CYP3A4/2C8 forming its major circulating metabolite M4, with contributions from UGT1A3 and biliary excretion. Idasanutlin and M4 have low permeability, very low clearance, and extremely low unbound fraction in plasma (<0.001), which makes in vitro data showing inhibition on CYP3A4/2C8 enzymes challenging to translate to clinical relevance. Physiologically-based pharmacokinetic models of idasanutlin and M4 have been established to simulate perpetrator and victim DDI scenarios and to evaluate whether further DDI studies in oncology patients are necessary. Modeling indicated that idasanutlin and M4 would show no or weak clinical inhibition of selective CYP3A4/2C8 substrates. Co-administered strong CYP3A and CYP2C8 inhibitors might lead to weak or moderate idasanutlin exposure increases, and the strong inducer rifampicin might cause moderate exposure reduction. As the simulated idasanutlin systemic exposure changes would be within the range of observed intrinsic variability, the target population can take co-medications that are either CYP2C8/3A4 inhibitors or weak/moderate CYP2C8/3A4 inducers without dose adjustment. SIGNIFICANCE STATEMENT: Clinical trials for idasanutlin are restricted to cancer patients, which imposes practical, scientific, and ethical challenges on drug-drug interaction investigations. Furthermore, idasanutlin and its major circulating metabolite have very challenging profiles of absorption, distribution, metabolism and excretion including high protein binding, low permeability and a combination of different elimination pathways each with extremely low clearance. Nonetheless, physiologically-based pharmacokinetic models could be established and applied for drug-drug interaction risk assessment and were especially useful to provide guidance on concomitant medications in patients.
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Affiliation(s)
- Kenichi Umehara
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Yumi Cleary
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Stephen Fowler
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Neil Parrott
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Dietrich Tuerck
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
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40
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Physiologically Based Pharmacokinetic Modelling and Simulation to Predict the Plasma Concentration Profile of Doxorubicin. Pharmaceutics 2022; 14:pharmaceutics14030541. [PMID: 35335919 PMCID: PMC8949582 DOI: 10.3390/pharmaceutics14030541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/19/2022] [Accepted: 02/23/2022] [Indexed: 02/05/2023] Open
Abstract
Doxorubicin (DOX) is still an important anticancer agent despite its tricky pharmacokinetics (PK) and toxicity potential. The advent of systems pharmacology enables the construction of PK models able to predict the concentration profiles of drugs and shed light on the underlying mechanisms involved in PK and pharmacodynamics (PD). By utilizing existing published data and by analysing two clinical case studies we attempt to create physiologically based pharmacokinetic (PBPK) models for DOX using widely accepted methodologies. Based on two different approaches on three different key points we derived eight plausible models. The validation of the models provides evidence that is all performing as designed and opens the way for further exploitation by integrating metabolites and pharmacogenomic information.
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41
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Leeder JS, Dinh JC, Gaedigk A, Staggs VS, Prasad B, Pearce RE. Ontogeny of Scaling Factors for Pediatric Physiology-Based Pharmacokinetic Modeling and Simulation: Microsomal Protein Per Gram of Liver. Drug Metab Dispos 2022; 50:24-32. [PMID: 34686522 PMCID: PMC8969199 DOI: 10.1124/dmd.121.000623] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/20/2021] [Indexed: 01/03/2023] Open
Abstract
Microsomal protein per gram of liver (MPPGL) is an important scaling factor for bottom-up physiology-based pharmacokinetic modeling and simulation, but data in pediatrics are limited. Therefore, MPPGL was determined in 160 liver samples from pediatric (n = 129) and adult (n = 31) donors obtained from four sources: the University of Maryland Brain and Tissue Bank (UMBTB), tissue retrieval services at the University of Minnesota and University of Pittsburgh, and Sekisui-Xenotech. Tissues were homogenized and subjected to differential centrifugation to prepare microsomes, and cytochrome c reductase activities in tissue homogenates and microsomes were used to estimate cytochrome P450 reductase (POR) activity as a marker of microsomal recovery; microsomal POR content was also assessed by quantitative proteomics. MPPGL values varied 5- to 10-fold within various age groups/developmental stages, and tissue source was identified as a contributing factor. Using a "trimmed" dataset comprised of samples ranging from 3 to 18 years of age common to the four sources, POR protein abundance and activity in microsomes and POR activity in homogenates was lower in UMBTB samples (autopsy) compared with other sources (perfused/flash-frozen). Regression analyses revealed that the UMBTB samples were driving an apparent age effect as no effect of age on log-transformed MPPGL values was observed when the UMBTB samples were excluded. We conclude that a mean±SD MPPGL value of 30.4±1.7 mg/g is representative between one month postnatal age and early adulthood. Potential source effects should be considered for studies involving tissue samples from multiple sources with different procurement and processing procedures. SIGNIFICANCE STATEMENT: Microsomal protein per gram of liver (MPPGL) is an important scaling factor for bottom up PBPK modeling and simulation, but data in pediatrics are limited. Although MPPGL varies 5- to 10-fold at a given developmental stage, a value of 30.4 ± 1.7 mg/g (mean ± SD) is representative between one month postnatal age and early adulthood. However, when tissue samples are obtained from multiple sources, different procurement and processing procedures may influence the results and should be taken into consideration.
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Affiliation(s)
- J Steven Leeder
- Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children's Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
| | - Jean C Dinh
- Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children's Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
| | - Andrea Gaedigk
- Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children's Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
| | - Vincent S Staggs
- Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children's Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
| | - Bhagwat Prasad
- Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children's Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
| | - Robin E Pearce
- Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children's Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
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Jung EH, Cho CK, Kang P, Park HJ, Lee YJ, Bae JW, Choi CI, Jang CG, Lee SY. Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients. Arch Pharm Res 2021; 44:1109-1119. [PMID: 34817825 DOI: 10.1007/s12272-021-01363-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 11/06/2021] [Indexed: 12/18/2022]
Abstract
Candesartan cilexetil is an angiotensin II receptor blocker and it is widely used to treat hypertension and heart failure. This drug is a prodrug that rapidly converts to candesartan after oral administration. Candesartan is metabolized by cytochrome P450 2C9 (CYP2C9) enzyme or uridine diphosphate glucurinosyltransferase 1A3, or excreted in an unchanged form through urine, biliary tract and feces. We investigated the effect of genetic polymorphism of CYP2C9 enzyme on drug pharmacokinetics using physiologically based pharmacokinetic (PBPK) modeling. In addition, by introducing the age and ethnicity into the model, we developed a model that can propose an appropriate dosage regimen taking into account the individual characteristics of each patient. To evaluate the suitability of the model, the results of a clinical trial on twenty-two healthy Korean subjects and their CYP2C9 genetic polymorphism data was applied. In this study, PK-Sim® was used to develop the PBPK model of candesartan.
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Affiliation(s)
- Eui Hyun Jung
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Chang-Keun Cho
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Pureum Kang
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Hye-Jung Park
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Yun Jeong Lee
- College of Pharmacy, Dankook University, Cheonan, 31116, Republic of Korea.
| | - Jung-Woo Bae
- College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea
| | - Chang-Ik Choi
- College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea
| | - Choon-Gon Jang
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Seok-Yong Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
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43
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Hamimed M, Gattacceca F, André N, Tresch-Bruneel E, Probst A, Chastagner P, Pagnier A, De Carli E, Entz-Werlé N, Grill J, Aerts I, Frappaz D, Bertozzi-Salamon AI, Solas C, Leblond P. Pharmacokinetics of oral vinorelbine in French children with recurrent or progressive primary low-grade glioma. Br J Clin Pharmacol 2021; 88:2096-2117. [PMID: 34709655 DOI: 10.1111/bcp.15131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/29/2021] [Accepted: 10/21/2021] [Indexed: 11/30/2022] Open
Abstract
AIM There is a crucial need for pharmacokinetic (PK) data of oral vinorelbine (VNR) in pediatric population. The aim of this work was to assess the PK profile of orally administered VNR in children with recurrent/progressive primary low-grade glioma (LGG). METHODS A multicentric, open-label, single-arm intervention phase II study was conducted. Patients, aged between 6 and 18 years, with histologically confirmed recurrent or progressive primary LGG or non-documented typical optic pathway tumors, were included. PK parameters were estimated by non-compartmental analysis using Phoenix WinNonlin® software (version 8.0, Certara, Inc.). The Influence of demographic and biological covariates on VNR PK parameters was investigated using a multivariate linear regression analysis. RESULTS PK analysis included 36 patients with a median age (range) of 11 (6-17) years. Estimates of apparent oral clearance (CL/F), apparent volume of distribution (V/F), half-life (t1/2 ) and their between-subject variability (CV%) at 60 mg.m-2 dose level, were 472 L.h-1 (51.8%), 7002 L (57.9%) and 10 h (21.0%), respectively. Negligible accumulation of VNR between C1 and C2 was observed. CL/F and V/F were found to increase with body surface area (BSA) (p = 0.004). Lower area under the concentration-time curve (AUC) levels were observed among children in comparison to adults. CONCLUSION Higher doses may be necessary for children with LGG. BSA showed a significant impact on VNR systemic exposure. We believe that our findings will serve as a basis for further studies to better characterize the concentration-response relationships of VNR among pediatric patients.
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Affiliation(s)
- Mourad Hamimed
- SMARTc Unit, Cancer Research Center of Marseille, Inserm U1068 - CNRS UMR 7258 - Aix-Marseille University U105, Marseille, France.,Inria - Inserm COMPO team, Centre Inria Sophia Antipolis - Méditerranée, Inserm U1068 - CNRS UMR 7258 - Aix-Marseille University U105, Marseille, France
| | - Florence Gattacceca
- SMARTc Unit, Cancer Research Center of Marseille, Inserm U1068 - CNRS UMR 7258 - Aix-Marseille University U105, Marseille, France.,Inria - Inserm COMPO team, Centre Inria Sophia Antipolis - Méditerranée, Inserm U1068 - CNRS UMR 7258 - Aix-Marseille University U105, Marseille, France
| | - Nicolas André
- SMARTc Unit, Cancer Research Center of Marseille, Inserm U1068 - CNRS UMR 7258 - Aix-Marseille University U105, Marseille, France.,Department of Pediatric Oncology, La Timone University Hospital of Marseille, APHM, Marseille, France
| | | | - Alicia Probst
- Département de la Recherche Clinique et Innovation,Oscar Lambret Cancer Center, Lille, France
| | - Pascal Chastagner
- Service d'hémato-oncologie pédiatrique, Nancy University Hospital, Nancy, France
| | - Anne Pagnier
- Service d'hémato-oncologie pédiatrique, Grenoble University Hospital, Grenoble, France
| | - Emilie De Carli
- Service d'hémato-oncologie pédiatrique, Angers University Hospital, Angers, France
| | - Natacha Entz-Werlé
- Pédiatrie Onco-Hématologie Université de Strasbourg, CHRU Hautepierre- - UMR CNRS 7021, Strasbourg, France
| | - Jacques Grill
- Département de Cancérologie de l'Enfant et de l'Adolescent et UMR CNRS 8203 Université Paris Saclay, Gustave Roussy, Villejuif, France
| | - Isabelle Aerts
- SIREDO Centre (Care, innovation and research in paediatric, adolescent and young adult oncology), Institut Curie- Oncology Center, Paris, France
| | - Didier Frappaz
- Institute of Pediatric Hematology and Oncology IHOPe, Léon Bérard Cancer Center, Lyon, France
| | | | - Caroline Solas
- Unité des Virus Émergents (UVE), Aix-Marseille Univ-IRD 190-Inserm 1207, Marseille, France.,Clinical Pharmacokinetics and Toxicology Laboratory, La Timone University Hospital of Marseille, APHM, Marseille, France
| | - Pierre Leblond
- Institute of Pediatric Hematology and Oncology IHOPe, Léon Bérard Cancer Center, Lyon, France.,Department of Pediatric Oncology, Oscar Lambret Cancer Center, Lille, France
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van Beek SW, Svensson EM, Tiono AB, Okebe J, D'Alessandro U, Gonçalves BP, Bousema T, Drakeley C, Ter Heine R. Model-based assessment of the safety of community interventions with primaquine in sub-Saharan Africa. Parasit Vectors 2021; 14:524. [PMID: 34627346 PMCID: PMC8502297 DOI: 10.1186/s13071-021-05034-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/23/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Single low-dose primaquine (SLD-PQ) is recommended in combination with artemisinin-based combination therapy to reduce Plasmodium falciparum transmission in areas threatened by artemisinin resistance or aiming for malaria elimination. SLD-PQ may be beneficial in mass drug administration (MDA) campaigns to prevent malaria transmission but uptake is limited by concerns of hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The aim of this study was to improve the evidence on the safety of MDA with SLD-PQ in a sub-Saharan African setting. METHODS A nonlinear mixed-effects model describing the pharmacokinetics and treatment-induced hemolysis of primaquine was developed using data from an adult (n = 16, G6PD deficient) and pediatric study (n = 38, G6PD normal). The relationship between primaquine pharmacokinetics and hemolysis was modeled using an established erythrocyte lifespan model. The safety of MDA with SLD-PQ was explored through Monte Carlo simulations for SLD-PQ at 0.25 or 0.4 mg/kg using baseline data from a Tanzanian setting with detailed information on hemoglobin concentrations and G6PD status. RESULTS The predicted reduction in hemoglobin levels following SLD-PQ was small and returned to pre-treatment levels after 25 days. G6PD deficiency (African A- variant) was associated with a 2.5-fold (95% CI 1.2-8.2) larger reduction in hemoglobin levels. In the Tanzanian setting where 43% of the population had at least mild anemia (hemoglobin < 11-13 g/dl depending on age and sex) and 2.73% had severe anemia (hemoglobin < 7-8 g/dl depending on age and sex), an additional 3.7% and 6.0% of the population were predicted to develop at least mild anemia and 0.25% and 0.41% to develop severe anemia after 0.25 and 0.4 mg/kg SLD-PQ, respectively. Children < 5 years of age and women ≥ 15 years of age were found to have a higher chance to have low pre-treatment hemoglobin. CONCLUSIONS This study supports the feasibility of MDA with SLD-PQ in a sub-Saharan African setting by predicting small and transient reductions in hemoglobin levels. In a setting where a substantial proportion of the population had low hemoglobin concentrations, our simulations suggest treatment with SLD-PQ would result in small increases in the prevalence of anemia which would most likely be transient.
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Affiliation(s)
- Stijn W van Beek
- Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Elin M Svensson
- Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Pharmacy, Uppsala University, Uppsala, Sweden
| | - Alfred B Tiono
- National Center for Research and Training on Malaria (CNRFP), Ouagadougou, Burkina Faso
| | - Joseph Okebe
- Department of International Public Health, Liverpool School of Tropical Medicine, Liverpool, UK
| | - Umberto D'Alessandro
- Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, Faraja , The Gambia
| | | | - Teun Bousema
- Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Chris Drakeley
- London School of Hygiene & Tropical Medicine, London, UK.
| | - Rob Ter Heine
- Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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45
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Hosey‐Cojocari C, Chan SS, Friesen CS, Robinson A, Williams V, Swanson E, O’Toole D, Radford J, Mardis N, Johnson TN, Leeder JS, Shakhnovich V. Are body surface area based estimates of liver volume applicable to children with overweight or obesity? An in vivo validation study. Clin Transl Sci 2021; 14:2008-2016. [PMID: 33982422 PMCID: PMC8504846 DOI: 10.1111/cts.13059] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/13/2021] [Accepted: 04/14/2021] [Indexed: 11/26/2022] Open
Abstract
The liver is the primary organ responsible for clearing most drugs from the body and thus determines systemic drug concentrations over time. Drug clearance by the liver appears to be directly related to organ size. In children, organ size changes as children age and grow. Liver volume has been correlated with body surface area (BSA) in healthy children and adults and has been estimated by functions of BSA. However, these relationships were derived from "typical" populations and it is unknown whether they extend to estimations of liver volumes for population "outliers," such as children with overweight or obesity, who today represent one-third of the pediatric population. Using computerized tomography or magnetic resonance imaging, this study measured liver volumes in 99 children (2-21 years) with normal weight, overweight, or obesity and compared organ measurements with estimates calculated using an established liver volume equation. A previously developed equation relating BSA to liver volume adequately estimates liver volumes in children, regardless of weight status.
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Affiliation(s)
| | - Sherwin S. Chan
- Children’s Mercy Kansas CityKansas CityMissouriUSA
- University of MissouriKansas City School of MedicineKansas CityMissouriUSA
| | | | | | | | - Erica Swanson
- University of MissouriKansas City School of MedicineKansas CityMissouriUSA
| | - Daniel O’Toole
- University of MissouriKansas City School of MedicineKansas CityMissouriUSA
| | - Jansynn Radford
- Kansas City University of Medicine and BiosciencesKansas CityMissouriUSA
| | - Neil Mardis
- Children’s Mercy Kansas CityKansas CityMissouriUSA
- University of MissouriKansas City School of MedicineKansas CityMissouriUSA
- University of Kansas School of MedicineKansas CityKansasUSA
| | | | - J. Steven Leeder
- Children’s Mercy Kansas CityKansas CityMissouriUSA
- University of MissouriKansas City School of MedicineKansas CityMissouriUSA
- University of Kansas School of MedicineKansas CityKansasUSA
| | - Valentina Shakhnovich
- Children’s Mercy Kansas CityKansas CityMissouriUSA
- University of MissouriKansas City School of MedicineKansas CityMissouriUSA
- University of Kansas Medical CenterKansas CityKansasUSA
- Center for Children’s Healthy Lifestyles & NutritionKansas CityMissouriUSA
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46
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Olafuyi O, Abbasi MY, Allegaert K. Physiologically based pharmacokinetic modelling of acetaminophen in preterm neonates-The impact of metabolising enzyme ontogeny and reduced cardiac output. Biopharm Drug Dispos 2021; 42:401-417. [PMID: 34407204 DOI: 10.1002/bdd.2301] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/14/2021] [Accepted: 07/19/2021] [Indexed: 12/20/2022]
Abstract
In preterm neonates, physiologically based pharmacokinetic (PBPK) models are suited for studying the effects of maturational and non-maturational factors on the pharmacokinetics of drugs with complex age-dependent metabolic pathways like acetaminophen (APAP). The aim of this study was to determine the impact of drug metabolising enzymes ontogeny on the pharmacokinetics of APAP in preterm neonates and to study the effect of reduced cardiac output (CO) on its PK using PBPK modelling. A PBPK model for APAP was first developed and validated in adults and then scaled to paediatric age groups to account for the effect of enzyme ontogeny. In preterm neonates, CO was reduced by 10%, 20%, and 30% to determine how this might affect APAP PK in preterm neonates. In all age groups, the predicted concentration-time profiles of APAP were within 5th and 95th percentile of the clinically observed concentration-time profiles and the predicted Cmax and AUC were within 2-folds of the reported parameters in clinical studies. Sulfation accounted for most of APAP metabolism in children, with the highest contribution of 68% in preterm neonates. A reduction in CO by up to 30% did not significantly alter the clearance of APAP in preterm neonates. The model successfully incorporated the ontogeny of drug metabolising enzymes involved in APAP metabolism and adequately predicted the PK of APAP in preterm neonates. A reduction in hepatic perfusion as a result of up to 30% reduction in CO has no effect on the PK of APAP in preterm neonates.
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Affiliation(s)
- Olusola Olafuyi
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | | | - Karel Allegaert
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium.,Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.,Department of Hospital Pharmacy, Erasmus MC University Medical Center, Rotterdam, the Netherlands
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Deepika D, Sharma RP, Schuhmacher M, Kumar V. Risk Assessment of Perfluorooctane Sulfonate (PFOS) using Dynamic Age Dependent Physiologically based Pharmacokinetic Model (PBPK) across Human Lifetime. ENVIRONMENTAL RESEARCH 2021; 199:111287. [PMID: 34000270 DOI: 10.1016/j.envres.2021.111287] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 05/03/2021] [Accepted: 05/04/2021] [Indexed: 06/12/2023]
Abstract
The widespread use of Perfluorooctane sulfonate (PFOS) in everyday life, its long half-life, and the lipophilicity that makes it easily accumulate in the body, raises the question of its safe exposure among different population groups. There are currently enough epidemiological studies showing evidence of PFOS exposure and its associated adverse effects on humans. Moreover, it is already known that physiological changes along with age e.g. organ volume, renal blood flow, cardiac output and albumin concentrations affect chemicals body burden. Human biomonitoring cohort studies have reported PFOS concentrations in blood and autopsy tissue data with PFOS present in sensitive organs across all human lifespan. However, to interpret such biomonitoring data in the context of chemical risk assessment, it is necessary to have a mechanistic framework that explains show the physiological changes across age affects the concentration of chemical inside different tissues of the human body. PBPK model is widely and successfully used in the field of risk assessment. The objective of this manuscript is to develop a dynamic age-dependent PBPK model as an extension of the previously published adult PFOS model and utilize this model to predict and compare the PFOS tissue distribution and plasma concentration across different age groups. Different cohort study data were used for exposure dose reconstruction and evaluation of time-dependent concentration in sensitive organs. Predicted plasma concentration followed trends observed in biomonitoring data and model predictions showed the increased disposition of PFOS in the geriatric population. PFOS model is sensitive to parameters governing renal resorption and elimination across all ages, which is related to PFOS half-life in humans. This model provides an effective framework for improving the quantitative risk assessment of PFOS throughout the human lifetime, particularly in susceptible age groups. The dynamic age-dependent PBPK model provides a step forward for developing such kind of dynamic model for other perfluoroalkyl substances.
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Affiliation(s)
- Deepika Deepika
- Environmental Engineering Laboratory, Departament d' Enginyeria Quimica, Universitat Rovira i Virgili, Av. Països Catalans 26, 43007, Tarragona, Catalonia, Spain
| | - Raju Prasad Sharma
- Environmental Engineering Laboratory, Departament d' Enginyeria Quimica, Universitat Rovira i Virgili, Av. Països Catalans 26, 43007, Tarragona, Catalonia, Spain
| | - Marta Schuhmacher
- Environmental Engineering Laboratory, Departament d' Enginyeria Quimica, Universitat Rovira i Virgili, Av. Països Catalans 26, 43007, Tarragona, Catalonia, Spain
| | - Vikas Kumar
- Environmental Engineering Laboratory, Departament d' Enginyeria Quimica, Universitat Rovira i Virgili, Av. Països Catalans 26, 43007, Tarragona, Catalonia, Spain; IISPV, Hospital Universitari Sant Joan de Reus, Universitat Rovira I Virgili, Reus, Spain.
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48
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Lisowski L, Staber JM, Wright JF, Valentino LA. The intersection of vector biology, gene therapy, and hemophilia. Res Pract Thromb Haemost 2021; 5:e12586. [PMID: 34485808 PMCID: PMC8410952 DOI: 10.1002/rth2.12586] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 07/01/2021] [Accepted: 07/27/2021] [Indexed: 12/17/2022] Open
Abstract
Gene therapy is at the forefront of the drive to bring the potential of cure to patients with genetic diseases. Multiple mechanisms of effective and efficient gene therapy delivery (eg, lentiviral, adeno-associated) for transgene expression as well as gene editing have been explored to improve vector and construct attributes and achieve therapeutic success. Recent clinical research has focused on recombinant adeno-associated viral (rAAV) vectors as a preferred method owing to their naturally occurring vector biology characteristics, such as serotypes with specific tissue tropisms, facilitated in vivo delivery, and stable physicochemical properties. For those living with hereditary diseases like hemophilia, this potential curative approach is balanced against the need to provide safe, predictable, effective, and durable factor expression. While in vivo studies of rAAV gene therapy have demonstrated amelioration of the bleeding phenotype in adults, long-term safety and effectiveness remain to be established. This review discusses vector biology in the context of rAAV-based liver-directed gene therapy for hemophilia and provides an overview of the types of viral vectors and vector components that are under investigation, as well as an assessment of the challenges associated with gene therapy delivery and durability of expression.
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Affiliation(s)
- Leszek Lisowski
- Translational Vectorology Research UnitFaculty of Medicine and HealthChildren's Medical Research InstituteThe University of SydneyWestmeadAustralia
- Laboratory of Molecular Oncology and Innovative TherapiesMilitary Institute of MedicineWarsawPoland
| | - Janice M. Staber
- Stead Family Department of PediatricsUniversity of IowaIowa CityIAUSA
- Carver College of MedicineUniversity of IowaIowa CityIAUSA
| | - J. Fraser Wright
- Department of PediatricsDivision of Hematology, OncologyStem Cell Transplantation and Regenerative MedicineCenter for Definitive and Curative MedicineStanford University School of MedicineStanfordCAUSA
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Yim DS, Bae SH, Choi S. Predicting human pharmacokinetics from preclinical data: clearance. Transl Clin Pharmacol 2021; 29:78-87. [PMID: 34235120 PMCID: PMC8255549 DOI: 10.12793/tcp.2021.29.e12] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 06/18/2021] [Indexed: 11/19/2022] Open
Abstract
We have streamlined known in vitro methods used to predict the clearance (CL) of small molecules in humans in this tutorial. There have been many publications on in vitro methods that are used at different steps of human CL prediction. The steps from initial intrinsic CL measurement in vitro to the final application of the well-stirred model to obtain predicted hepatic CL (CLH) are somewhat complicated. Except for the experts on drug metabolism and PBPK, many drug development scientists found it hard to figure out the entire picture of human CL prediction. To help readers overcome this barrier, we introduce each method briefly and demonstrate its usage in the chain of related equations destined to the CLH. Despite efforts in the laboratory steps, huge in vitro (predicted CLH)-in vivo (observed CLH) discrepancy is not rare. A simple remedy to this discrepancy is to correct human predicted CLH using the ratio of in vitro-in vivo CLH obtained from animal species.
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Affiliation(s)
- Dong-Seok Yim
- Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.,PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | | | - Suein Choi
- Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.,PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
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50
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A Physiologically Based Pharmacokinetic and Drug-Drug Interaction Model for the CB2 Agonist Lenabasum. Eur J Drug Metab Pharmacokinet 2021; 46:513-525. [PMID: 34143391 DOI: 10.1007/s13318-021-00693-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/22/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND AND OBJECTIVES Lenabasum is a synthetic agonist of the cannabinoid receptor type 2 (CB2) with anti-inflammatory and antifibrotic properties. Utilizing Simcyp, we developed a physiologically based pharmacokinetic (PBPK) model based on physicochemical properties, cell culture data, and cytochrome P450 (CYP) phenotyping, inhibition, and induction data. METHODS Clinical data from healthy volunteers treated with 20 mg of lenabasum in a single ascending dose (SAD) study were used for model development. The model was verified using lenabasum SAD (10 and 40 mg) data as well as multiple dose (20 mg three times per day) data. Lenabasum is a CYP substrate, and the model predicted lenabasum clearance of 51% by CYP2C9, 37% by CYP2C8, and 12% by CYP3A4. Lenabasum is also an inhibitor of these isozymes. RESULTS The model accurately described the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) for lenabasum within 1.19-fold and 1.25-fold accuracy, respectively, of the observed clinical values. The simulations of CYP inducers predicted that the strongest interaction would occur with rifampin, with the AUC decreasing to 0.36 of the control value, whereas the simulations of CYP inhibitors predicted that the greatest effect would occur with fluconazole, with a 1.43-fold increase in AUC. CONCLUSIONS Our model is a useful tool for predicting the pharmacokinetics of lenabasum and adjustments to its dosing in possible drug-drug interaction scenarios.
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