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Wang S, Li C, Dong Y, Dong W. Approaches for posaconazole therapeutic drug monitoring and their clinical benefits. Eur J Clin Pharmacol 2024; 80:1845-1855. [PMID: 39249114 DOI: 10.1007/s00228-024-03756-9] [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: 05/14/2024] [Accepted: 08/31/2024] [Indexed: 09/10/2024]
Abstract
OBJECTIVE This review examines the progress of research on posaconazole therapeutic drug monitoring (TDM) that has focused on differences in the TDM of posaconazole after clinical application in different formulations and in different populations, the factors that affect posaconazole concentrations, the advantages of posaconazole TDM in terms of clinical efficacy and cost savings, and measurement methods. METHODS A literature search (2006 to 2024) was performed in PubMed and Embase with the following search terms: noxafil, posaconazole hydrate, posaconazole, drug monitoring, therapeutic drug monitoring, and TDM. Abstracts of review articles, prospective studies, and retrospective studies were reviewed. RESULTS TDM should be implemented earlier for posaconazole tablets and injections than for oral posaconazole suspensions. Posaconazole TDM is beneficial for improving clinical efficacy, and the incidence of breakthrough invasive fungal infections (IFIs) can be significantly reduced by gradually adjusting the posaconazole dose in response to TDM in patients with inadequate trough concentrations. Early TDM allows more patients to achieve target therapeutic posaconazole concentrations. TDM can also facilitate dose adjustments, which reduce the cost of this expensive drug. Different assay techniques, including chromatography, microbiological detection, chemofluorimetry, paper spray mass spectrometry, and capillary electrophoresis, can be used for posaconazole TDM. CONCLUSIONS Posaconazole TDM has potential clinical utility and cost-saving benefits and could improve the outcomes of IFI treatment.
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Affiliation(s)
- Silu Wang
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Changkun Li
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yalin Dong
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Weihua Dong
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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2
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Xia W, Chen S, Yun Y, Cui L, Wang Z, Hou J, Tang M, Bu C, Gao S, Shao R, Tao X. A general and rapid LC-MS/MS method for simultaneous determination of voriconazole, posaconazole, fluconazole, itraconazole and hydroxyitraconazole in IFI patients. J Pharmacol Toxicol Methods 2024; 130:107565. [PMID: 39321943 DOI: 10.1016/j.vascn.2024.107565] [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: 05/27/2024] [Revised: 07/29/2024] [Accepted: 09/22/2024] [Indexed: 09/27/2024]
Abstract
OBJECTIVE To establish a rapid and universal quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) method for measuring the exposure levels of five triazole antifungal drugs in human plasma, including voriconazole, fluconazole, posaconazole, itraconazole, and hydroxyitraconazole. METHODS A triple quadrupole mass spectrometer operating in positive ionization mode was used to detect the analyte, and multiple reaction monitoring mode was employed to gather data. The mobile phase included 0.05 % formic acid in water (phase A) and acetonitrile (phase B). The analytes were separated on an Agilent EclipsePlusC18 RRHD column (30 × 50 mm, 1.8 μm) using gradient elution. The flow rate was 0.3 mL/min with the column temperature set at 35 °C. The acetonitrile was used to pretreat the plasma sample, and the itraconazole-D5 and hydroxyitraconazole-D5 were utilized as the internal standards. RESULTS The calibration range was from 100 to 10,000 ng/mL for posaconazole, itraconazole, and hydroxyitraconazole, from 200 to 20,000 ng/mL for fluconazole and from 50 to 5000 ng/mL for voriconazole, with linear correlation coefficients more than 0.99 for all regression curves. The intra- and inter-day accuracy and precision of the method were within ±15 %. The mean extraction recovery of all the analytes ranged from 74.32 % to 117.83 %, and the matrix effect was from 72.54 % to 111.2 %. The results of stability fell into the scope of ±15 % deviation. CONCLUSION This newly developed method is sensitive, simple, and robust, and successfully applied in determining triazole antifungal drugs in plasma from 66 IFI patients to provide reference for safe and effective drug administration in clinical practice.
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Affiliation(s)
- Wenwen Xia
- College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming City, Yunnan Province 650500, China; Department of Pharmacy, Second Affiliated Hospital of Naval Medical University(Shanghai Changzheng Hospital), Shanghai 200003, China
| | - Shun Chen
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University(Shanghai Changzheng Hospital), Shanghai 200003, China
| | - Yunlei Yun
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University(Shanghai Changzheng Hospital), Shanghai 200003, China
| | - Lili Cui
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University(Shanghai Changzheng Hospital), Shanghai 200003, China
| | - Zhipeng Wang
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University(Shanghai Changzheng Hospital), Shanghai 200003, China
| | - Juanjuan Hou
- College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming City, Yunnan Province 650500, China; Department of Pharmacy, Second Affiliated Hospital of Naval Medical University(Shanghai Changzheng Hospital), Shanghai 200003, China
| | - Mao Tang
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University(Shanghai Changzheng Hospital), Shanghai 200003, China
| | - Chen Bu
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University(Shanghai Changzheng Hospital), Shanghai 200003, China
| | - Shouhong Gao
- College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming City, Yunnan Province 650500, China; Department of Pharmacy, Second Affiliated Hospital of Naval Medical University(Shanghai Changzheng Hospital), Shanghai 200003, China.
| | - Rongzi Shao
- The 960th Hospital of PLA Joint Logistics Support Force, Jinan 250014, China.
| | - Xia Tao
- College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming City, Yunnan Province 650500, China; Department of Pharmacy, Second Affiliated Hospital of Naval Medical University(Shanghai Changzheng Hospital), Shanghai 200003, China.
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Yamada T, Belabbas T, Suetsugu K, Hirota T, Mori Y, Kato K, Akashi K, Egashira N, Ieiri I. Factors Influencing Serum Posaconazole Concentrations in Patients With Hematologic Malignancies Receiving Delayed-Release Tablets. Ther Drug Monit 2024; 46:603-610. [PMID: 38648660 DOI: 10.1097/ftd.0000000000001196] [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: 12/12/2023] [Accepted: 01/30/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Posaconazole (PCZ) plays a crucial role in the prophylaxis and treatment of invasive fungal infections in hematologic malignancies. PCZ concentrations reportedly vary among patients receiving delayed-release tablets (DRT). However, the factors influencing these concentrations remain insufficiently elucidated. Therefore, this study aimed to evaluate the factors influencing PCZ concentrations and their effect on the probability of target attainment (PTA) using a population pharmacokinetic (PPK) approach. We also explored the relationship between PCZ exposure and hepatotoxicity. METHODS This retrospective study included adult patients with hematologic malignancies who received PCZ DRT. A PPK model was developed based on observational data for 130 concentrations in 28 patients. Simulation analyses were performed to assess the PTA at standard doses of 0.7 and 1.0 mg/L for prophylaxis and treatment, respectively. Estimated concentrations were used to evaluate the correlation between PCZ exposure and hepatotoxicity. RESULTS Significant factors influencing PCZ concentrations included body weight, serum total protein levels, and diarrhea. Diarrhea correlated with decreased PCZ concentrations resulting in up to 26% lower PTA compared with that without diarrhea. Moreover, PTA declined markedly as the total protein levels decreased from 6.6 g/dL to 4.4 g/dL. The incidence of hepatotoxicity was 17.4% (4/23); no significant relationship could be established between the PCZ concentrations and hepatotoxicity ( P = 0.188). CONCLUSIONS We identified the factors affecting PCZ exposure, which could not be detected by PPK analysis using data from clinical trials. Our results suggest that the generally recommended dose of PCZ causes underexposure in patients with hematologic malignancies characterized by high body weight, hypoproteinemia, or concurrent diarrhea. Therapeutic drug monitoring for DRT may be recommended, especially in patients with these risk factors.
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Affiliation(s)
- Takaaki Yamada
- Department of Pharmacy, Kyushu University Hospital, Higashi-ku, Fukuoka, Japan
- Department of Clinical Pharmacology and Therapeutics, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama-shi, Wakayama, Japan
| | - Tassadit Belabbas
- Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan ; and
| | - Kimitaka Suetsugu
- Department of Pharmacy, Kyushu University Hospital, Higashi-ku, Fukuoka, Japan
| | - Takeshi Hirota
- Department of Pharmacy, Kyushu University Hospital, Higashi-ku, Fukuoka, Japan
- Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan ; and
| | - Yasuo Mori
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Koji Kato
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Nobuaki Egashira
- Department of Pharmacy, Kyushu University Hospital, Higashi-ku, Fukuoka, Japan
- Department of Clinical Pharmacology and Therapeutics, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama-shi, Wakayama, Japan
- Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan ; and
| | - Ichiro Ieiri
- Department of Pharmacy, Kyushu University Hospital, Higashi-ku, Fukuoka, Japan
- Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan ; and
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Castro-Balado A, Varela-Rey I, Mejuto B, Mondelo-García C, Zarra-Ferro I, Rodríguez-Jato T, Fernández-Ferreiro A. Updated antimicrobial dosing recommendations for obese patients. Antimicrob Agents Chemother 2024; 68:e0171923. [PMID: 38526051 PMCID: PMC11064535 DOI: 10.1128/aac.01719-23] [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] [Indexed: 03/26/2024] Open
Abstract
The prevalence of obesity has increased considerably in the last few decades. Pathophysiological changes in obese patients lead to pharmacokinetic (PK) and pharmacodynamic (PD) alterations that can condition the correct exposure to antimicrobials if standard dosages are used. Inadequate dosing in obese patients can lead to toxicity or therapeutic failure. In recent years, additional antimicrobial PK/PD data, extended infusion strategies, and studies in critically ill patients have made it possible to obtain data to provide a better dosage in obese patients. Despite this, it is usually difficult to find information on drug dosing in this population, which is sometimes contradictory. This is a comprehensive review of the dosing of different types of antimicrobials (antibiotics, antifungals, antivirals, and antituberculosis drugs) in obese patients, where the literature on PK and possible dosing strategies in obese adults was critically assessed.
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Affiliation(s)
- Ana Castro-Balado
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Iria Varela-Rey
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Beatriz Mejuto
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
| | - Cristina Mondelo-García
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Irene Zarra-Ferro
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Teresa Rodríguez-Jato
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Anxo Fernández-Ferreiro
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
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Boyer J, Hoenigl M, Kriegl L. Therapeutic drug monitoring of antifungal therapies: do we really need it and what are the best practices? Expert Rev Clin Pharmacol 2024; 17:309-321. [PMID: 38379525 DOI: 10.1080/17512433.2024.2317293] [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: 10/26/2023] [Accepted: 02/07/2024] [Indexed: 02/22/2024]
Abstract
INTRODUCTION Despite advancements, invasive fungal infections (IFI) still carry high mortality rates, often exceeding 30%. The challenges in diagnosis, coupled with limited effective antifungal options, make managing IFIs complex. Antifungal drugs are essential for IFI management, but their efficacy can be diminished by drug-drug interactions and pharmacokinetic variability. Therapeutic Drug Monitoring (TDM), especially in the context of triazole use, has emerged as a valuable strategy to optimize antifungal therapy. AREAS COVERED This review provides current evidence regarding the potential benefits of TDM in IFI management. It discusses how TDM can enhance treatment response, safety, and address altered pharmacokinetics in specific patient populations. EXPERT OPINION TDM plays a crucial role in achieving optimal therapeutic outcomes in IFI management, particularly for certain antifungal agents. Preclinical studies consistently show a link between therapeutic drug levels and antifungal efficacy. However, clinical research in mycology faces challenges due to patient heterogeneity and the diversity of fungal infections. TDM's potential advantages in guiding Echinocandin therapy for critically ill patients warrant further investigation. Additionally, for drugs like Posaconazole, assessing whether serum levels or alternative markers like saliva offer the best measure of efficacy is an intriguing question.
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Affiliation(s)
- Johannes Boyer
- Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Martin Hoenigl
- Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- BioTechMed, Graz, Austria
- Translational Mycology Working Group, ECMM Excellence Center for Clinical Mycology, Medical University of Graz, Graz, Austria
| | - Lisa Kriegl
- Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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6
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Bui J, Gellatly R, Othman J, Lindsay J. Subtherapeutic concentrations of posaconazole tablet: determining risk factors and effectiveness of a standardized dose adjustment in hematology inpatients. Leuk Lymphoma 2022; 63:3418-3425. [PMID: 36175159 DOI: 10.1080/10428194.2022.2126282] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Posaconazole is indicated for antifungal prophylaxis in hematology patients at high-risk of invasive fungal infections (IFI). Consensus guidelines recommend maintaining steady-state trough concentrations above 0.7 mg/L; however, upto one-third of patients return subtherapeutic concentrations which is associated with breakthrough IFI. This retrospective observational study of 496 concentrations from 90 hematology inpatients prescribed posaconazole tablet (PCZ-tab) between May 2017 and May 2019 identified 24% (n = 121) of posaconazole concentrations were subtherapeutic after the dosage of 300 mg daily. On multivariable analyses, diarrhea (p = 0.002), male gender (p = 0.018), and concurrent regular metoclopramide (p = 0.002) were significantly associated with subtherapeutic posaconazole concentrations. Eighty-nine percent of patients (n = 16) who underwent dose adjustment to 200 mg twice daily successfully achieved target posaconazole concentrations at first steady-state measurement. This study confirms that therapeutic drug monitoring of posaconazole remains necessary as subtherapeutic posaconazole concentrations are relatively common, and that dose adjustment of 200 mg twice daily, safely enabled achievement of therapeutic concentrations.
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Affiliation(s)
- Jessica Bui
- Clinical Pharmacy Department, Royal North Shore Hospital, Sydney, Australia.,Department of Infectious Diseases, Royal North Shore Hospital, Sydney, Australia
| | - Rochelle Gellatly
- Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia.,Pharmacy Department, Surrey Memorial Hospital, Surrey, Canada
| | - Jad Othman
- Haematology Department, Royal North Shore Hospital, Sydney, Australia
| | - Julian Lindsay
- Haematology Department, Royal North Shore Hospital, Sydney, Australia.,National Centre for Infection in Cancer, Peter MacCallum Cancer Centre, Melbourne, Australia.,Vaccine and Infectious Disease and Clinical Research Division, Fred Hutchinson Cancer Research Center, SE, USA
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7
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Huang S, Ding Q, Yang N, Sun Z, Cheng Q, Liu W, Li Y, Chen X, Wu C, Pei Q. External evaluation of published population pharmacokinetic models of posaconazole. Front Pharmacol 2022; 13:1005348. [PMID: 36249756 PMCID: PMC9561726 DOI: 10.3389/fphar.2022.1005348] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 09/13/2022] [Indexed: 11/13/2022] Open
Abstract
Population pharmacokinetic (PopPK) models of posaconazole have been established to promote the precision dosing. However, the performance of these models extrapolated to other centers has not been evaluated. This study aimed to conduct an external evaluation of published posaconazole PopPK models to evaluate their predictive performance. Posaconazole PopPK models screened from the PubMed and MEDLINE databases were evaluated using an external dataset of 213 trough concentration samples collected from 97 patients. Their predictive performance was evaluated by prediction-based diagnosis (prediction error), simulation-based diagnosis (visual predictive check), and Bayesian forecasting. In addition, external cohorts with and without proton pump inhibitor were used to evaluate the models respectively. Ten models suitable for the external dataset were finally included into the study. In prediction-based diagnostics, none of the models met pre-determined criteria for predictive indexes. Only M4, M6, and M10 demonstrated favorable simulations in visual predictive check. The prediction performance of M5, M7, M8, and M9 evaluated using the cohort without proton pump inhibitor showed a significant improvement compared to that evaluated using the whole cohort. Consistent with our expectations, Bayesian forecasting significantly improved the predictive per-formance of the models with two or three prior observations. In general, the applicability of these published posaconazole PopPK models extrapolated to our center was unsatisfactory. Prospective studies combined with therapeutic drug monitoring are needed to establish a PopPK model for posaconazole in the Chinese population to promote individualized dosing.
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Affiliation(s)
- Shuqi Huang
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Qin Ding
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Nan Yang
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Zexu Sun
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Qian Cheng
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Wei Liu
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yejun Li
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xin Chen
- Department of Pharmacy, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Cuifang Wu
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Cuifang Wu, ; Qi Pei,
| | - Qi Pei
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Cuifang Wu, ; Qi Pei,
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Challenges in the Treatment of Invasive Aspergillosis in Immunocompromised Children. Antimicrob Agents Chemother 2022; 66:e0215621. [PMID: 35766509 PMCID: PMC9295552 DOI: 10.1128/aac.02156-21] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Invasive aspergillosis (IA) is associated with significant morbidity and mortality. Voriconazole remains the drug of choice for the treatment of IA in children; however, the complex kinetics of voriconazole in children make dosing challenging and therapeutic drug monitoring (TDM) essential for treatment success. The overarching goal of this review is to discuss the role of voriconazole, posaconazole, isavuconazole, liposomal amphotericin B, echinocandins, and combination antifungal therapy for the treatment of IA in children. We also provide a detailed discussion of antifungal TDM in children.
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Ashok A, Mangalore RP, Morrissey CO. Azole Therapeutic Drug Monitoring and its Use in the Management of Invasive Fungal Disease. CURRENT FUNGAL INFECTION REPORTS 2022. [DOI: 10.1007/s12281-022-00430-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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10
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Teh BW, Yeoh DK, Haeusler GM, Yannakou CK, Fleming S, Lindsay J, Slavin MA. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2021. Intern Med J 2021; 51 Suppl 7:67-88. [PMID: 34937140 DOI: 10.1111/imj.15588] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Antifungal prophylaxis can reduce morbidity and mortality from invasive fungal disease (IFD). However, its use needs to be optimised and appropriately targeted to patients at highest risk to derive the most benefit. In addition to established risks for IFD, considerable recent progress in the treatment of malignancies has resulted in the development of new 'at-risk' groups. The changing epidemiology of IFD and emergence of drug resistance continue to impact choice of prophylaxis, highlighting the importance of active surveillance and knowledge of local epidemiology. These guidelines aim to highlight emerging risk groups and review the evidence and limitations around new formulations of established agents and new antifungal drugs. It provides recommendations around use and choice of antifungal prophylaxis, discusses the potential impact of the changing epidemiology of IFD and emergence of drug resistance, and future directions for risk stratification to assist optimal management of highly vulnerable patients.
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Affiliation(s)
- Benjamin W Teh
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Daniel K Yeoh
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Department of Infectious Diseases, Perth Children's Hospital, Perth, Western Australia, Australia
| | - Gabrielle M Haeusler
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Department of Infectious Diseases, Royal Children's Hospital, Melbourne, Victoria, Australia.,Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Costas K Yannakou
- Department of Molecular Oncology and Cancer Immunology, Epworth Freemasons Hospital, Epworth HealthCare, Melbourne, Victoria, Australia
| | - Shaun Fleming
- Malignant Haematology and Stem Cell Transplantation Service, Alfred Health, Melbourne, Victoria, Australia
| | - Julian Lindsay
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Department of Haematology, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Monica A Slavin
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Immunocompromised Host Infection Service, Royal Melbourne Hospital, Melbourne, Victoria, Australia
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11
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Clinical and Pharmacological Considerations for Concomitant Administration of Posaconazole and Isavuconazole with Letermovir. Antimicrob Agents Chemother 2021; 65:AAC.00274-21. [PMID: 33782007 DOI: 10.1128/aac.00274-21] [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: 02/11/2021] [Accepted: 03/22/2021] [Indexed: 12/22/2022] Open
Abstract
We sought in this case-control retrospective study to compare posaconazole and isavuconazole (PCZ and IVC, respectively) plasma trough concentration (C trough) levels in high-risk allogeneic hematopoietic cell transplant (HCT) recipients who received letermovir (LET) or not. PCZ/IVC C trough levels were not found to be significantly different between cases and controls, as they were 1.31 mg/liter (median) (interquartile range [IQR], 0.90) versus 1.36 mg/liter (IQR, 1.16) (P = 0.31) and 3.20 mg/liter (IQR, 2.40) versus 2.35 mg/liter (IQR, 1.50) (P = 0.17), respectively. In conclusion, we observed PCZ/IVC C trough levels within the expected range and no significant effect of LET coadministration.
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12
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Bhatnagar S, Mukherjee D, Salem AH, Miles D, Menon RM, Gibbs JP. Dose adjustment of venetoclax when co-administered with posaconazole: clinical drug-drug interaction predictions using a PBPK approach. Cancer Chemother Pharmacol 2021; 87:465-474. [PMID: 33398386 DOI: 10.1007/s00280-020-04179-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 10/12/2020] [Indexed: 12/17/2022]
Abstract
PURPOSE Venetoclax, a targeted anticancer agent approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, is a substrate of cytochrome P450 (CYP) 3A enzyme (CYP3A4). Posaconazole, commonly used to prevent invasive fungal infections in neutropenic patients with hematological malignancies, potently inhibits CYP3A4. The purpose of this evaluation was to predict venetoclax exposures following co-administration of posaconazole at doses not previously studied clinically. METHODS Two physiologically based pharmacokinetic (PBPK) models were developed for posaconazole based on published parameters, one for an oral suspension and another for delayed released tablets. Parameter optimization, guided by sensitivity analyses, was conducted such that the models could replicate clinical exposures of posaconazole and drug-drug interactions with sensitive CYP3A substrates including venetoclax. The clinically verified posaconazole PBPK models were then utilized to predict DDI with a previously published venetoclax PBPK model at clinically relevant dosing scenarios. RESULTS The posaconazole PBPK models predicted posaconazole exposure and DDI related fold changes with acceptable prediction errors for both posaconazole formulations. The model predicted exposures of venetoclax, when co-administered with a 300 mg QD dose of delayed release tablets of posaconazole, were in concordance with observed data. Increasing the posaconazole dose to 500 mg QD increased venetoclax exposures by about 12% relative to 300 mg QD, which were still within the venetoclax safe exposure range. CONCLUSIONS The posaconazole PBPK models were developed and clinically verified. Predictions using the robust PBPK model confirmed the venetoclax label recommendation of 70 mg in the presence of posaconazole at doses up to 500 mg QD.
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Affiliation(s)
- Sumit Bhatnagar
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, Dept. R4PK, Bldg. AP31-3, North Chicago, IL, 60064, USA.
| | - Dwaipayan Mukherjee
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, Dept. R4PK, Bldg. AP31-3, North Chicago, IL, 60064, USA
| | - Ahmed Hamed Salem
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, Dept. R4PK, Bldg. AP31-3, North Chicago, IL, 60064, USA.,Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Dale Miles
- Clinical Pharmacology, Genentech Inc, South San Francisco, CA, USA
| | - Rajeev M Menon
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, Dept. R4PK, Bldg. AP31-3, North Chicago, IL, 60064, USA
| | - John P Gibbs
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, Dept. R4PK, Bldg. AP31-3, North Chicago, IL, 60064, USA
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13
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Kraljevic M, Khanna N, Medinger M, Passweg J, Masouridi-Levrat S, Chalandon Y, Mueller NJ, Schanz U, Vernaz N, Van Delden C, Neofytos D. Clinical considerations on posaconazole administration and therapeutic drug monitoring in allogeneic hematopoietic cell transplant recipients. Med Mycol 2020; 59:701-711. [PMID: 33381803 DOI: 10.1093/mmy/myaa106] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/14/2020] [Accepted: 12/03/2020] [Indexed: 12/26/2022] Open
Abstract
There is a paucity of data on posaconazole (PCZ) dosing and therapeutic-drug-monitoring (TDM) in allogeneic hematopoietic cell transplant recipients (allogeneic-HCTr). This was a 3-year retrospective multicenter study (January 1, 2016 to December 31, 2018) in adult allogeneic-HCTr who received PCZ (intravenously, IV and/or as delayed-release tablet, DRT) as prophylaxis or treatment for ≥7 consecutive days (D) with at least 1-PCZ-level available using data of the Swiss Transplant Cohort Study. The primary objective was to describe the distribution of PCZ-level and identify predictors of therapeutic PCZ-level and associations between PCZ-dosing and PCZ-level. A total of 288 patients were included: 194 (67.4%) and 94 (32.6%) received PCZ as prophylaxis and treatment, respectively, for a median of 90 days (interquartile range, IQR: 42-188.5). There were 1944 PCZ-level measurements performed, with a median PCZ level of 1.3 mg/L (IQR: 0.8-1.96). PCZ-level was <0.7 mg/L in 383/1944 (19.7%) and <1.0 mg/L in 656/1944 (33.7%) samples. PCZ-level was <0.7 mg/L in 260/1317 (19.7%) and <1.0 mg/L in 197/627 (31.4%) in patients who received PCZ-prophylaxis versus treatment, respectively. There were no significant differences in liver function tests between baseline and end-of-treatment. There were nine (3.1%) breakthrough invasive fungal infections (bIFI), with no difference in PCZ levels between patients with or without bIFI. Despite a very intensive PCZ-TDM, PCZ-levels remain below target levels in up to one-third of allogeneic-HCTr. Considering the low incidence of bIFI observed among patients with PCZ levels in the targeted range, our data challenge the clinical utility of routine universal PCZ-TDM.
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Affiliation(s)
- Mateja Kraljevic
- Division of Infectious Diseases, University Hospital of Basel, Basel, Switzerland
| | - Nina Khanna
- Division of Infectious Diseases, University Hospital of Basel, Basel, Switzerland
| | - Michael Medinger
- Department of Hematology, Bone Marrow Transplant Unit, University Hospital of Basel, Basel, Switzerland
| | - Jakob Passweg
- Department of Hematology, Bone Marrow Transplant Unit, University Hospital of Basel, Basel, Switzerland
| | - Stavroula Masouridi-Levrat
- Hematology Division, Oncology Department, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Yves Chalandon
- Hematology Division, Oncology Department, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Nicolas J Mueller
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Switzerland
| | - Urs Schanz
- Department of Hematology, Bone Marrow Transplant Unit, University Hospital of Zurich, Zurich, Switzerland
| | - Nathalie Vernaz
- Medical Directorate, Finance Directorate Geneva University Hospitals, University of Geneva, Geneva, Switzerland
| | - Christian Van Delden
- Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland
| | - Dionysios Neofytos
- Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland
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14
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Jia MM, Zhang QW, Qin ZF, Lu RQ, Tian XK, Yang J, Zhang XJ. Deciphering the Relationship Between the Trough Concentration of Posaconazole and Its Efficacy and Safety in Chinese Patients With Hematological Disorders. Front Pharmacol 2020; 11:575463. [PMID: 33154724 PMCID: PMC7586309 DOI: 10.3389/fphar.2020.575463] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/15/2020] [Indexed: 01/24/2023] Open
Abstract
Posaconazole (PCZ) is effective in preventing and salvage treatment invasive fungal infections in patients with hematologic disorders. However, PCZ displays highly variable individual pharmacokinetics affecting its efficacy and safety. To investigate the correlation between PCZ concentration and efficacy and safety, the following key influencing factors were explored. A total of 285 trough plasma concentrations (Cmin) of 81 Chinese patients receiving PCZ oral suspension for prophylaxis or treatment of invasive fungal infections were collected in this study. The relationships between Cmin values and clinical response and hepatotoxicity were investigated as well as the incidence of clinical response under different Cmin values of PCZ with a logistic regression model. The concentration of PCZ showed remarkable differences among patients with haematologic disorders. PCZ Cmin values of 0.76 and 1.0 µg/mL were both associated with an over 80% probability of successful response to prophylaxis and treatment of fungal infections, respectively. No association between Cmin values and hepatotoxicity was noted (P > 0.05). Gender, albumin, and co-administration of proton pump inhibitor (PPI) were identified as independent factors influencing PCZ Cmin by multiple linear regression analysis. Furthermore, patients’ C-reactive protein (CRP), albumin, and co-administration of PPI exhibited significant effects on the therapeutic window of patients receiving PCZ for prophylaxis. The plasma concentration is closely associated with therapeutic efficacy of PCZ. It is necessary to adjust the dosing regimens based on PCZ Cmin to obtain an optimal therapeutic response.
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Affiliation(s)
- Meng-Meng Jia
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Qi-Wen Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Zi-Fei Qin
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Run-Qing Lu
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xue-Ke Tian
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Jing Yang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Xiao-Jian Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
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15
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Corallo CE, Ivulich SP, Kotecha DS, Morrissey O. Dementia-Like Symptoms Associated With Posaconazole. J Pharm Pract 2020; 35:135-139. [PMID: 33084474 DOI: 10.1177/0897190020958235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Posaconazole is widely used in lung transplant recipients as pre-emptive therapy or universal fungal prophylaxis. In this patient group, posaconazole is increasingly used instead of voriconazole due to the concerns of an increased risk of squamous cell carcinoma (SCC) with voriconazole, particularly with its long-term use. Dose dependent toxicity has not been identified for posaconazole in the registration trials of intravenous (IV) and modified-release tablet formulations. This is supported by post-marketing experience. We describe a lung transplant recipient who experienced dementia-like symptoms almost 3 years after commencing posaconazole for treatment of Aspergillus fumigatus complex and Lomentospora prolificans (formerly Scedosporium prolificans) fungal infections. Symptoms resolved upon discontinuation of posaconazole, but recurred when re-challenged at a lower dose more than a year later. To the best of our knowledge, this is the first case reporting a dementia-like state with posaconazole.
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Affiliation(s)
| | | | - Dr Sakhee Kotecha
- Department of Allergy, Immunology & Respiratory Medicine, The Alfred, Melbourne, Victoria, Australia
| | - Orla Morrissey
- Department of Infectious Diseases, Alfred Health, Melbourne, Victoria, Australia
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16
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Kosmidis C, Rodriguez-Goncer I, Rautemaa-Richardson R, Richardson MD, Moore CB, Denning DW. Therapeutic drug monitoring and adverse events of delayed-release posaconazole tablets in patients with chronic pulmonary aspergillosis. J Antimicrob Chemother 2020; 74:1056-1061. [PMID: 30590533 DOI: 10.1093/jac/dky539] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/12/2018] [Accepted: 11/24/2018] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Posaconazole delayed-release tablets offer better bioavailability than the liquid suspension, but no post-marketing data are available in immunocompetent hosts such as those with chronic pulmonary aspergillosis (CPA). OBJECTIVES To explore the pharmacokinetics and adverse event (AE) profile of posaconazole tablets in patients with CPA. METHODS Patients started on posaconazole tablets at the National Aspergillosis Centre (NAC), Manchester, UK between February 2014 and October 2015 were identified from the NAC database and analysed retrospectively. The medical records were reviewed for factors that could affect posaconazole serum levels and the development of AEs. RESULTS Seventy-two patients were included; 50 (69%) were male and the mean age was 48.5 ± 12 years. Therapeutic levels (≥1 mg/L) were achieved in 90% of cases on 200 mg versus 90% of cases on 300 mg daily (P = not significant). Based on multivariate analysis, female sex (P = 0.041), a 100 mg daily dose (P < 0.001), asthma (P = 0.01) and bronchiectasis (P = 0.001) were associated with subtherapeutic levels. Forty-nine (68%) patients developed AEs, mainly fatigue (37%), dyspnoea (18%) and nausea (12%). AEs were present on 115/196 (59%) occasions on 300 mg/day and on 45/115 (39%) occasions on 200 mg/day (P < 0.01). The mean level was 1.81 ± 0.96 mg/L for patients reporting no AEs and 1.90 ± 1.11 mg/L for those reporting AEs (P = not significant). Factors associated with AEs of grade ≥2 were a daily dose of 300 versus 200 mg (P = 0.001) and asthma (P = 0.008). CONCLUSIONS A lower-than-recommended posaconazole tablet dose achieved therapeutic levels in most patients and was better tolerated. Males were more likely to achieve a therapeutic level. Underlying conditions affected the degree and frequency of AEs.
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Affiliation(s)
- Chris Kosmidis
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.,National Aspergillosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Southmoor Road, Manchester, UK
| | - Isabel Rodriguez-Goncer
- National Aspergillosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Southmoor Road, Manchester, UK
| | - Riina Rautemaa-Richardson
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.,National Aspergillosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Southmoor Road, Manchester, UK.,Mycology Reference Centre Manchester, ECMM Centre of Excellence, Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, UK
| | - Malcolm D Richardson
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.,Mycology Reference Centre Manchester, ECMM Centre of Excellence, Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, UK
| | - Caroline B Moore
- Mycology Reference Centre Manchester, ECMM Centre of Excellence, Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, UK
| | - David W Denning
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.,National Aspergillosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Southmoor Road, Manchester, UK
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17
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Van Daele R, Spriet I, Maertens J. Posaconazole in prophylaxis and treatment of invasive fungal infections: a pharmacokinetic, pharmacodynamic and clinical evaluation. Expert Opin Drug Metab Toxicol 2020; 16:539-550. [DOI: 10.1080/17425255.2020.1764939] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Ruth Van Daele
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
- Pharmacy Department, University Hospitals Leuven, Leuven, Belgium
| | - Isabel Spriet
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
- Pharmacy Department, University Hospitals Leuven, Leuven, Belgium
| | - Johan Maertens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium
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18
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Abdul-Aziz MH, Alffenaar JWC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, Neely MN, Paiva JA, Pea F, Sjovall F, Timsit JF, Udy AA, Wicha SG, Zeitlinger M, De Waele JJ, Roberts JA. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper .. Intensive Care Med 2020; 46:1127-1153. [PMID: 32383061 PMCID: PMC7223855 DOI: 10.1007/s00134-020-06050-1] [Citation(s) in RCA: 591] [Impact Index Per Article: 118.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/10/2020] [Indexed: 12/12/2022]
Abstract
Purpose This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients.
Methods Literature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes. Results TDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients. Conclusion Although TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide. Electronic supplementary material The online version of this article (10.1007/s00134-020-06050-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mohd H Abdul-Aziz
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4029, Australia
| | - Jan-Willem C Alffenaar
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.,Westmead Hospital, Westmead, NSW, Australia.,Marie Bashir Institute of Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia
| | - Matteo Bassetti
- Infectious Diseases Clinic, Department of Health Sciences, University of Genoa, Genoa and Hospital Policlinico San Martino - IRCCS, Genoa, Italy
| | - Hendrik Bracht
- Department of Anaesthesiology, University Ulm, Ulm, Germany
| | - George Dimopoulos
- Department of Critical Care, University Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece
| | - Deborah Marriott
- Department of Microbiology and Infectious Diseases, St. Vincent's Hospital, Sydney, NSW, Australia
| | - Michael N Neely
- Department of Paediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.,Division of Infectious Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Jose-Artur Paiva
- Department of Medicine, Faculty of Medicine of Porto, Porto, Portugal.,Department of Emergency and Intensive Care Medicine, Centro Hospitalar Universitario de São João, Porto, Portugal
| | - Federico Pea
- Institute of Clinical Pharmacology, SM Misericordia University Hospital, ASUFC, Udine, Italy
| | - Fredrik Sjovall
- Department of Perioperative Medicine, Skåne University Hospital, Malmö, Sweden
| | - Jean F Timsit
- Department of Intensive Care Medicine and Infectious Diseases, Bichat-Claude Bernard University Hospital, AP-HP, Paris, France.,Infection, Antimicrobials, Modelling, Evolution (IAME), Paris Diderot University, Paris, France
| | - Andrew A Udy
- Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.,Department of Intensive Care and Hyperbaric Medicine, The Alfred, Melbourne, VIC, Australia
| | - Sebastian G Wicha
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany
| | - Markus Zeitlinger
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Jan J De Waele
- Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium
| | - Jason A Roberts
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4029, Australia. .,Department of Intensive Care Medicine and Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. .,Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia. .,Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.
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19
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Liu K, Wu D, Li J, Chen H, Ning H, Zhao T, Dai H, Chen L, Mangin E, Winchell GA, Waskin H, Jiang J, Qiu Y, Zhao XM. Pharmacokinetics and Safety of Posaconazole Tablet Formulation in Chinese Participants at High Risk for Invasive Fungal Infection. Adv Ther 2020; 37:2493-2506. [PMID: 32319040 DOI: 10.1007/s12325-020-01341-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Indexed: 01/07/2023]
Abstract
INTRODUCTION This study characterized the multidose pharmacokinetic (PK) characteristics of posaconazole tablets used as prophylactic antifungal therapy in Chinese patients with acute myelogenous leukemia (AML) at risk for invasive fungal infection (IFI). METHODS Participants in this open-label, single-arm, phase 1b study received posaconazole 300 mg twice daily on day 1 and then once daily for up to 28 days. In the intensive PK sampling subgroup, posaconazole was administered under fasting conditions on days 1 and 8, and blood samples were regularly collected over 24 h. Trough PK sampling was conducted in all participants on days 1, 2, 3, 8, 14, 21, and 28 without regard for food intake. Population PK characteristics were predicted using PK modeling. Primary endpoints were steady-state average concentration (Cavg) and percentage of participants with steady-state Cavg (predicted and observed) > 500 ng/ml. Treatment safety and efficacy were secondary endpoints. RESULTS Sixty-five adult Chinese participants were enrolled. On day 8, steady-state arithmetic mean Cavg was 1610 ng/ml (% coefficient of variation [%CV] 42.8%) in the intensive PK subgroup (n = 20). All participants achieved a steady-state Cavg > 500 ng/ml. Predicted Cavg (pCavg) was 1770 ng/ml (%CV 33.7%) in the total population (n = 64); 92.2% of participants had pCavg values ≥ 500 ng/ml (n = 59). The posaconazole tablet safety profile was consistent with that of the oral formulation, and the IFI rate was 3%. CONCLUSION In Chinese AML patients, the posaconazole 300-mg tablet provided PK data comparable with those of previous studies and was generally well tolerated and efficacious. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT02387983.
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20
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Using State Transition Models to Explore How the Prevalence of Subtherapeutic Posaconazole Exposures Impacts the Clinical Utility of Therapeutic Drug Monitoring for Posaconazole Tablets and Oral Suspension. Antimicrob Agents Chemother 2019:AAC.01435-19. [PMID: 31527039 DOI: 10.1128/aac.01435-19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Therapeutic drug monitoring (TDM) has been recommended in guidelines for patients receiving posaconazole oral suspension, but its utility in patients receiving posaconazole tablet, which has an improved bioavailability, remains unclear. We used state transition models with first-order Monte Carlo microsimulation to re-examine the posaconazole exposure-response relationships reported in two Phase III clinical trials (prophylaxis with posaconazole oral suspension - Models 1 & 2) and a third multicenter observational TDM study (Model 3). We simulated the impact of TDM-guided interventions to improve initial average posaconazole concentrations (Cavg) to reduce clinical failure (in Models 1 & 2) and breakthrough invasive fungal disease (bIFD) in Model 3. Simulations were then repeated using posaconazole tablet Cavg distributions in place of the oral suspension formulation. In all three models with posaconazole oral suspension, TDM interventions associated with maximal improvement in posaconazole Cavg reduced absolute rates of subtherapeutic exposures (Cavg < 700 ng/mL) by 25-49%. Predicted reductions in absolute clinical failure rates were 11% in Model 1 and 6.5% in Model 2, and a 12.6% reduction in bIFD in Model 3. With the tablet formulation, maximally-effective TDM interventions reduced subtherapeutic exposures by approximately 5% in all three models and absolute clinical failure rates by 3.9% in Model 1, and 1.6% in Model 2; and a 1.6% reduction in bIFD in Model 3. Our modeling suggests that routine TDM during prophylaxis with posaconazole tablets may have limited clinical utility unless populations with higher prevalence (>10%) of subtherapeutic exposures can be identified based on clinical risk factors.
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21
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Meza-Menchaca T, Ramos-Ligonio A, López-Monteon A, Vidal Limón A, Kaluzhskiy LA, V Shkel T, V Strushkevich N, Jiménez-García LF, Agredano Moreno LT, Gallegos-García V, Suárez-Medellín J, Trigos Á. Insights into Ergosterol Peroxide's Trypanocidal Activity. Biomolecules 2019; 9:E484. [PMID: 31547423 PMCID: PMC6770379 DOI: 10.3390/biom9090484] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 08/15/2019] [Accepted: 08/19/2019] [Indexed: 12/20/2022] Open
Abstract
Trypanosoma cruzi, which causes Chagas disease, is a significant health threat in many countries and affects millions of people. Given the magnitude of this disease, a broader understanding of trypanocidal mechanisms is needed to prevent and treat infection. Natural endoperoxides, such as ergosterol peroxide, have been shown to be toxic to parasites without causing harm to human cells or tissues. Although prior studies have demonstrated the trypanocidal activity of ergosterol peroxide, the cellular and molecular mechanisms remain unknown. The results of this study indicate that a free-radical reaction occurs in T. cruzi following ergosterol peroxide exposure, leading to cell death. Using a combination of biochemical, microscopic and in silico experimental approaches, we have identified, for the first time, the cellular and molecular cytotoxic mechanism of an ergosterol peroxide obtained from Pleurotus ostreatus (Jacq) P. Kumm. f. sp. Florida.
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Affiliation(s)
- Thuluz Meza-Menchaca
- Laboratorio de Genómica Humana, Facultad de Medicina, Universidad Veracruzana, Médicos y Odontólogos S/N, Col. Unidad del Bosque, Xalapa C.P. 91010, Veracruz, Mexico.
| | - Angel Ramos-Ligonio
- LADISER, Inmunología y Biología Molecular, Facultad de Ciencias Químicas, Universidad Veracruzana, Orizaba 94340, Veracruz, Mexico.
| | - Aracely López-Monteon
- LADISER, Inmunología y Biología Molecular, Facultad de Ciencias Químicas, Universidad Veracruzana, Orizaba 94340, Veracruz, Mexico.
| | - Abraham Vidal Limón
- Centro de Nanociencias y Nanotecnología, Universidad Nacional Autónoma de México, Carr. Tijuana-Ensenada, Col. Pedregal Playitas, Ensenada C.P. 22860, Baja California, Mexico.
| | - Leonid A Kaluzhskiy
- Institute of Biomedical Chemistry, 10 building 8, Pogodinskaya Street, 119121 Moscow, Russia.
| | - Tatjana V Shkel
- Institute of Bioorganic Chemistry NASB, Kuprevich Street, 220141 Minsk, Belarus.
| | | | - Luis Felipe Jiménez-García
- Laboratorio de Microscopía Electrónica, Facultad de Ciencias, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior, Ciudad Universitaria, México D.F. 04510, Mexico.
| | - Lourdes Teresa Agredano Moreno
- Laboratorio de Nano-Biología Celular, Departamento de Biología Celular, Facultad de Ciencias, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior, Ciudad Universitaria, México D.F. 04510, Mexico.
| | - Verónica Gallegos-García
- Facultad de Enfermería y Nutrición, UASLP, Av. Niño Artillero 130, Zona Universitaria Poniente, San Luis Potosí C.P. 78240, Mexico.
| | - Jorge Suárez-Medellín
- Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa 91190, Mexico.
| | - Ángel Trigos
- Centro de Investigación de Micología Aplicada, Universidad Veracruzana, Xalapa 91010, Veracruz, Mexico.
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22
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Willeman T, Tonini J, Garnaud C, Bailly S, Gandia P, Stanke-Labesque F, Maubon D, Gautier-Veyret E. Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach. Fundam Clin Pharmacol 2019; 34:279-287. [PMID: 31505058 DOI: 10.1111/fcp.12507] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 07/22/2019] [Accepted: 09/03/2019] [Indexed: 01/31/2023]
Abstract
Therapeutic drug monitoring (TDM) of antifungal triazole was recommended, except for isavuconazole (ISA) whose target trough concentrations (Cmin ) need to be specified. Concerning posaconazole (POS), tablet formulation results in higher exposure but no upper Cmin threshold has been yet proposed. We aimed to investigate the pharmacokinetic-pharmacodynamic relationship of POS and ISA, using a bioassay approach as surrogate marker of antifungal activity, in order to refine the therapeutic Cmin of both antifungals. A bioassay using a cellulose disk diffusion method was performed to determine the growth inhibition zone (GIZ) of POS and ISA on Aspergillus fumigatus and Candida parapsilosis (ISA only). GIZs of plasma from patients undergoing TDM for POS (n = 136) or ISA (n = 40) were determined. GIZs of plasma patients and antifungal Cmin were highly correlated for ISA (A. fumigatus: ρ = 0.942, P < 0.0001; C. parapsilosis: ρ = 0.949, P < 0.0001) and POS (ρ = 0.922, P < 0.0001), and these relationships were represented with a Michaelis-Menten model. Based on this modeling, the recommended thresholds of 0.7, 1, and 1.25 mg/L for the POS Cmin corresponded to 50.1, 55.2, and 59.1% of the maximal GIZ, respectively. We propose an upper threshold of 4.8 mg/L for the POS Cmin and a lower threshold of 2.0 mg/L for the Cmin of ISA, as they respectively corresponded to concentrations leading to 90% and 50% of the maximal GIZ on A. fumigatus. The determination of antifungal activity using this bioassay allowed refining target Cmin of POS and ISA, especially the upper threshold of POS (4.8 mg/L) and the lower threshold of ISA (2.0 mg/L).
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Affiliation(s)
- Théo Willeman
- Laboratoire de Pharmacologie, Pharmacogénétique et Toxicologie, CHU Grenoble Alpes, Grenoble, France
| | - Julia Tonini
- Laboratoire de Pharmacologie, Pharmacogénétique et Toxicologie, CHU Grenoble Alpes, Grenoble, France
| | - Cécile Garnaud
- CNRS, CHU Grenoble Alpes, Grenoble INP*, TIMC-IMAG, Institute of Engineering Univ. Grenoble Alpes, Univ. Grenoble Alpes, 38000, Grenoble, France
| | - Sébastien Bailly
- Inserm, CHU Grenoble Alpes, Univ. Grenoble Alpes, HP2, 38000, Grenoble, France
| | - Peggy Gandia
- UMR1436-INTHERES, 31076, Toulouse, France.,Laboratoire de Pharmacocinétique et Toxicologie, CHU Toulouse, Toulouse, France
| | | | - Danièle Maubon
- CNRS, CHU Grenoble Alpes, Grenoble INP*, TIMC-IMAG, Institute of Engineering Univ. Grenoble Alpes, Univ. Grenoble Alpes, 38000, Grenoble, France
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23
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Märtson AG, Veringa A, van den Heuvel ER, Bakker M, Touw DJ, van der Werf TS, Span LFR, Alffenaar JWC. Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations. Mycoses 2019; 62:698-705. [PMID: 31145490 PMCID: PMC6852019 DOI: 10.1111/myc.12948] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 05/16/2019] [Accepted: 05/22/2019] [Indexed: 01/25/2023]
Abstract
Posaconazole is indicated for prophylaxis and treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) of posaconazole is used to optimise drug exposure. The aim of this study was to analyse and describe the TDM practices and exposure of posaconazole tablets. Patients who received posaconazole for treatment or prophylaxis of fungal infections were included in the study. The following therapeutic window was defined: if concentration was low (<0.7 mg/L for prophylaxis or < 1.5 mg/L for treatment) or high (>3.75 mg/L), the hospital pharmacist provided the physician with dosage advice, which implementation to patient care was analysed. A longitudinal analysis was performed to analyse if different confounding variables had an effect on posaconazole concentrations. Forty-seven patients were enrolled resulting in 217 posaconazole trough concentrations. A median of 3 (IQR 1-7) samples was measured per patient. The median concentration was 1.7 mg/L (IQR 0.8-2.7) for prophylaxis and 1.76 mg/L (IQR 1.3-2.3) for treatment. Overall, 78 posaconazole concentrations were out of the therapeutic window. For 45 (54%) of these concentrations, a dosage change was recommended. In the longitudinal analysis, the laboratory markers and patient baseline variables did not have an effect on posaconazole concentrations. Adequate posaconazole exposure was shown in 64% (affected 28 patients) of the measured concentrations. TDM practice of posaconazole can be improved by increasing the implementation rate of dose recommendation by a multidisciplinary antifungal stewardship team.
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Affiliation(s)
- Anne-Grete Märtson
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Anette Veringa
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Edwin R van den Heuvel
- Department of Mathematics and Computer Science, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Martijn Bakker
- Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Daan J Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Tjip S van der Werf
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Lambert F R Span
- Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jan-Willem C Alffenaar
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia
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24
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Amsden JR, Slain D. Dosing Antifungals in Obesity: a Literature Review. CURRENT FUNGAL INFECTION REPORTS 2019. [DOI: 10.1007/s12281-019-0335-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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25
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Otu A, Bongomin F, Kosmidis C, Denning DW. Acute kidney injury: an unusual complication of posaconazole use. J Chemother 2019; 30:380-383. [PMID: 30663547 DOI: 10.1080/1120009x.2018.1522472] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Triazole antifungals are useful in the treatment of Aspergillus disease and these drugs have side effects which clinicians should be aware of. Posaconazole is an orally administered second-generation triazole antifungal agent which inhibits lanosterol 14-alpha-demethylase, an enzyme that converts lanosterol to ergosterol, a vital component of the fungal cell membrane. Posaconazole has a favorable side effect profile, is safe and well tolerated when compared to the earlier generation of triazole antifungals. Common side effects of posaconazole include gastrointestinal, hepatobiliary, neurological, and skin and subcutaneous disorders. Renal disorders are classed as an uncommon side effect of posaconazole, occurring in ∼0.1-1% of patients. We describe 2 episodes of acute kidney injury (AKI) in a Caucasian whose Aspergillus lung disease was being treated with posaconazole. Regular monitoring of renal function may be necessary for patients on posaconazole to facilitate early identification of acute kidney injury which is reversible.
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Affiliation(s)
- Akaninyene Otu
- a University of Calabar , Calabar , Cross River State , Nigeria.,b The National Aspergillosis Centre, 2nd Floor Education and Research Centre , Manchester University NHS Foundation Trust , Manchester , UK
| | - Felix Bongomin
- b The National Aspergillosis Centre, 2nd Floor Education and Research Centre , Manchester University NHS Foundation Trust , Manchester , UK.,c Faculty of Biology, Medicine and Health , The University of Manchester , Manchester , UK
| | - Chris Kosmidis
- b The National Aspergillosis Centre, 2nd Floor Education and Research Centre , Manchester University NHS Foundation Trust , Manchester , UK.,d Manchester Academic Health Science Centre, 2nd Floor Education and Research Centre , Manchester University NHS Foundation Trust , Manchester , UK
| | - David W Denning
- b The National Aspergillosis Centre, 2nd Floor Education and Research Centre , Manchester University NHS Foundation Trust , Manchester , UK.,c Faculty of Biology, Medicine and Health , The University of Manchester , Manchester , UK.,d Manchester Academic Health Science Centre, 2nd Floor Education and Research Centre , Manchester University NHS Foundation Trust , Manchester , UK
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26
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Song ZW, Pan YC, Huang ZC, Liu WX, Zhao RS, Jing HM, Dong F. Posaconazole-associated severe hyperbilirubinemia in acute myeloid leukemia following chemotherapy: A case report. World J Clin Cases 2018; 6:1206-1209. [PMID: 30613684 PMCID: PMC6306636 DOI: 10.12998/wjcc.v6.i16.1206] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 11/20/2018] [Accepted: 11/24/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Posaconazole is a widely used azole antifungal agent, and posaconazole-associated severe hyperbilirubinemia is usually rare in clinical practice. We herein report a 58-year-old male with acute myeloid leukemia, who developed fungal infection following chemotherapy.
CASE SUMMARY After administration of posaconazole oral suspension, the patient developed severe hyperbilirubinemia and jaundice (Common Terminology Criteria for Adverse Events, CTCAE -Grade 3) with a serum total bilirubin (T-BIL) peak level of 170 μmol/L, alkaline phosphatase level of 739 U/L, alanine aminotransferase level of 99 U/L, and gamma-glutamyl transpeptidase level of 638 U/L. After posaconazole withdrawal and symptomatic treatment with liver-protective agents, the level of T-BIL and other laboratory data decreased gradually, and related symptoms disappeared. After medication analysis and literature review, we consider that the patient had a cholestatic type of posaconazole-induced liver injury, which was related to intracellular mitochondrial DNA damage. The case demonstrates that when patients with hematological malignancy develop severe infection following chemotherapy, combination of anti-infective drugs may contribute to a higher risk of severe drug-induced liver injury.
CONCLUSION This is the first thoroughly documented case report of posaconazole-associated severe hyperbilirubinemia. Therefore, in order to avoid severe adverse events, liver and renal function should be monitored closely before and during the administration of posaconazole.
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Affiliation(s)
- Zai-Wei Song
- Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
| | - Yu-Chen Pan
- Department of Hematology, Peking University Third Hospital, Beijing 100191, China
| | - Zhen-Cheng Huang
- Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
| | - Wen-Xi Liu
- Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
| | - Rong-Sheng Zhao
- Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
| | - Hong-Mei Jing
- Department of Hematology, Peking University Third Hospital, Beijing 100191, China
| | - Fei Dong
- Department of Hematology, Peking University Third Hospital, Beijing 100191, China
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27
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Pre-Existing Liver Disease and Toxicity of Antifungals. J Fungi (Basel) 2018; 4:jof4040133. [PMID: 30544724 PMCID: PMC6309049 DOI: 10.3390/jof4040133] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 12/05/2018] [Accepted: 12/07/2018] [Indexed: 12/17/2022] Open
Abstract
Pre-existing liver disease in patients with invasive fungal infections further complicates their management. Altered pharmacokinetics and tolerance issues of antifungal drugs are important concerns. Adjustment of the dosage of antifungal agents in these cases can be challenging given that current evidence to guide decision-making is limited. This comprehensive review aims to evaluate the existing evidence related to antifungal treatment in individuals with liver dysfunction. This article also provides suggestions for dosage adjustment of antifungal drugs in patients with varying degrees of hepatic impairment, after accounting for established or emerging pharmacokinetic–pharmacodynamic relationships with regard to antifungal drug efficacy in vivo.
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28
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Cojutti PG, Candoni A, Lazzarotto D, Rabassi N, Fanin R, Hope W, Pea F. Co-administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed-released tablets in adult patients with haematological malignancies. Br J Clin Pharmacol 2018; 84:2544-2550. [PMID: 29975796 DOI: 10.1111/bcp.13707] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 06/27/2018] [Accepted: 06/29/2018] [Indexed: 01/07/2023] Open
Abstract
AIMS The aim of this study was to determine clinical variables associated with posaconazole exposure among adult patients with haematological malignancies who received posaconazole tablets for prophylaxis of invasive fungal infections (IFIs). METHODS The study population included adult patients with haematological malignancies who received posaconazole delayed-release tablets for prophylaxis of IFIs after induction chemotherapy for acute leukaemia or graft-versus-host-disease (GVHD) complicating hematopoietic stem cell transplantation (HSCT) in the period January 2016-December 2017. RESULTS Sixty-six consecutive patients with 176 posaconazole Cmin were included for evaluation in the study. Subtherapeutic posaconazole concentrations (< 0.7 mg l-1 ) were observed at least once in 33.3% of patients (22/66), and overall in 17.0% of therapeutic drug monitoring (TDM) episodes (30/176). At multilevel linear regression, use of PPIs (P = 0.008), use of intermediate or high dose steroids (>0.7 mg kg-1 daily) (P = 0.022) and male gender (P = 0.025) were significantly associated with decreased Cmin , whereas time from starting therapy (P = 0.032) was associated with increased Cmin in our patient population. CONCLUSION Posaconazole exposure during treatment with delayed-released tablet formulation may be affected by the use of PPIs and/or of intermediate or high dose steroids.
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Affiliation(s)
- Pier Giorgio Cojutti
- Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.,Department of Medicine, University of Udine, Udine, Italy
| | - Anna Candoni
- Division of Haematology, Santa Maria della Misericordia University Hospital, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
| | - Davide Lazzarotto
- Division of Haematology, Santa Maria della Misericordia University Hospital, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
| | - Nicholas Rabassi
- Division of Haematology, Santa Maria della Misericordia University Hospital, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
| | - Renato Fanin
- Department of Medicine, University of Udine, Udine, Italy.,Division of Haematology, Santa Maria della Misericordia University Hospital, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
| | - William Hope
- Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Federico Pea
- Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.,Department of Medicine, University of Udine, Udine, Italy
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29
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Invasive fungal infections in high-risk patients: report from TIMM-8 2017. Future Sci OA 2018; 4:FSO307. [PMID: 30057784 PMCID: PMC6060393 DOI: 10.4155/fsoa-2018-0019] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 03/08/2018] [Indexed: 02/08/2023] Open
Abstract
Trends in Medical Mycology (TIMM) is the biennial meeting of the Infectious Disease Group of the European Organisation for Research and Treatment of Cancer (EORTC) and the European Confederation of Medical Mycology (ECMM). It brings together clinicians and researchers from across the world to share the latest R&Ds in medical mycology. Despite advances in treatment, invasive fungal infections remain a major cause of morbidity and mortality in certain high-risk groups of patients, particularly in immunocompromised patients, including those undergoing solid organ transplantation and those with acute leukemia. The challenges for clinicians are now compounded by the rapid development of multidrug resistance. The latest data and approaches to identifying patients at high risk for invasive fungal infections, ensuring early diagnosis and achieving effective treatment, including when and how to use therapeutic drug monitoring with azoles, were shared with >1000 clinicians and researchers from around the world attending the eighth TIMM, held in Belgrade, Serbia, in October 2017 (TIMM-8 2017).
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30
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Antifungal Prophylaxis with Posaconazole Delayed-Release Tablet and Oral Suspension in a Real-Life Setting: Plasma Levels, Efficacy, and Tolerability. Antimicrob Agents Chemother 2018; 62:AAC.02655-17. [PMID: 29581116 DOI: 10.1128/aac.02655-17] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Accepted: 03/18/2018] [Indexed: 02/07/2023] Open
Abstract
We continuously determined posaconazole plasma concentrations (PPCs) in 61 patients with hematological malignancies receiving posaconazole (PCZ) delayed-release tablets (DRT; 48 patients; median duration of intake, 92 days) and PCZ oral solution (OS; 13 patients; median duration of intake, 124 days). PCZ DRT and OS antifungal prophylaxis was efficient and well tolerated. Thirty-four of 48 patients (71%) receiving DRT always had PPCs of >0.7 mg/liter, while 14 of 48 patients (29%) had at least one PPC of ≤0.7 mg/liter. In patients receiving OS, 4 of 13 patients (31%) always had PPCs of >0.7 mg/liter, 6 of 13 patients (46%) had at least one PPC of ≤0.7 mg/liter, and 3 (23%) patients never reached a PPC of 0.7 mg/liter. In patients with at least one determined PPC, the mean proportion of all PPCs of >0.7 mg/liter was 91% for PCZ DRT, whereas it was 52% for PCZ OS (P = 0.001). In the per sample analysis, PPCs were significantly more likely to be >0.7 mg/liter in patients receiving DRT than in patients receiving OS (PPCs were >0.7 mg/liter in 91.4% [297/325] of patients receiving DRT versus 70.3% [85/121] of patients receiving OS; P < 0.001). Patients receiving PCZ DRT had higher proportions of PPCs of >0.7 mg/liter than patients receiving OS both in the per patient and in the per sample analyses. Two patients (3%) had side effects during PCZ prophylaxis, and one (2%) had fungal breakthrough infection. Therapeutic drug monitoring enables detection of extended periods of PPCs of ≤0.7 mg/liter (e.g., due to nonadherence or graft-versus-host disease), which may also be associated with the loss of protective intracellular PCZ concentrations, regardless of the PCZ formulation.
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