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Zhang WZ, Han JQ, Chin KY, Zakaria R, Hassan NH. Determinants of Health-Related Quality of Life After Transarterial Chemoembolization in Hepatocellular Carcinoma Patients: A Systematic Review. J Clin Med 2025; 14:3941. [PMID: 40507701 PMCID: PMC12155868 DOI: 10.3390/jcm14113941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2025] [Revised: 05/24/2025] [Accepted: 05/29/2025] [Indexed: 06/16/2025] Open
Abstract
Background/Objectives: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide, with transarterial chemoembolization (TACE) commonly used as a palliative approach for patients who are not candidates for surgical resection. Understanding the factors that influence health-related quality of life (HRQoL) after TACE is essential for improving patient-centered care. This systematic review seeks to consolidate current evidence on the variables that impact HRQoL in HCC patients post-TACE. Methods: In adherence to PRISMA guidelines, a comprehensive search was conducted across five English and Chinese databases-PubMed, Scopus, Web of Science, CNKI, and Wanfang-covering studies from database inception to May 2025. Eligible studies were observational and examined factors affecting HRQoL in post-TACE HCC patients. Two independent reviewers performed screening, data extraction, and quality assessment using the Joanna Briggs Institute (JBI) Critical Appraisal Tools. Results: Nine studies met the inclusion criteria, including six cohort studies and three cross-sectional studies. The quality assessment rated seven studies as high quality and two as moderate. A range of validated HRQoL assessment tools was used, with the EORTC QLQ-C30 and FACT-G being the most commonly employed. The factors influencing HRQoL were grouped into five categories: (1) demographic factors (e.g., age, gender, education level); (2) clinical indicators (e.g., liver function, tumor burden); (3) psychological factors (e.g., depression, anxiety, spiritual well-being); (4) social support (e.g., financial status, coping mechanisms); and (5) physical symptoms (e.g., fatigue, pain, appetite loss). Across studies, both symptom severity and psychological distress were consistently associated with lower HRQoL. Conclusions: The HRQoL of HCC patients following TACE is influenced by a complex interplay of demographic, clinical, psychological, social, and symptomatic factors. Tailored, multidimensional interventions addressing these diverse aspects are crucial to optimizing recovery and improving overall well-being.
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Affiliation(s)
- Wei-Zheng Zhang
- Department of Nursing, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (W.-Z.Z.); (R.Z.)
| | - Jin-Qian Han
- Department of Nursing Science, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;
| | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia;
| | - Roshaya Zakaria
- Department of Nursing, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (W.-Z.Z.); (R.Z.)
| | - Nor Haty Hassan
- Department of Nursing, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (W.-Z.Z.); (R.Z.)
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Sah AK, Afzal M, Elshaikh RH, Abbas AM, Shalabi MG, Prabhakar PK, Babker AMA, Khalimova FT, Sabrievna VA, Choudhary RK. Innovative Strategies in the Diagnosis and Treatment of Liver Cirrhosis and Associated Syndromes. Life (Basel) 2025; 15:779. [PMID: 40430206 PMCID: PMC12112768 DOI: 10.3390/life15050779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/27/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Liver cirrhosis continues to be a major global health issue, contributing to high morbidity and mortality due to its progressive nature and associated complications. This review explores recent advancements in the diagnosis and treatment of liver cirrhosis and its related syndromes. Non-invasive diagnostic tools, such as elastography and serum biomarkers, have significantly improved early detection, reducing the need for liver biopsies. Advanced imaging techniques, including MRI and CT, further enhance diagnostic accuracy. In parallel, molecular and genomic research is providing new insights into the pathogenesis of the disease, paving the way for precision medicine. On the treatment front, pharmacological innovations, such as antifibrotic agents and targeted therapies, show promise in slowing disease progression. Endoscopic interventions like variceal banding are improving the management of complications, while advancements in liver transplantation and artificial liver support systems offer life-saving alternatives. Regenerative medicine, particularly stem cell therapy and tissue engineering, is emerging as a promising strategy for liver repair. Managing cirrhosis-related syndromes, including portal hypertension, ascites, hepatic encephalopathy, and hepatorenal syndrome, now involves evolving therapeutic approaches such as transjugular intrahepatic portosystemic shunt (TIPS) and novel pharmacotherapies. Prognostic scoring systems like the MELD and Child-Pugh are being refined with new biomarkers for better risk stratification. The future of cirrhosis care will likely involve the integration of artificial intelligence and machine learning for early diagnosis and personalized treatments, alongside emerging therapies currently under investigation. Despite these advancements, challenges such as costs, accessibility, and healthcare disparities remain barriers to widespread adoption. This review highlights the importance of incorporating innovative diagnostic and therapeutic strategies into clinical practice to improve the outcomes for patients with liver cirrhosis and its complications.
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Affiliation(s)
- Ashok Kumar Sah
- Department of Medical Laboratory Sciences, College of Applied and Health Sciences, A’ Sharqiyah University, Ibra 400, Oman;
| | - Mohd Afzal
- Department of Medical Laboratory Technology, Arogyam Institute of Paramedical & Allied Sciences (Affiliated to H.N.B. Uttarakhand Medical Education University), Roorkee 247661, India;
| | - Rabab H. Elshaikh
- Department of Medical Laboratory Sciences, College of Applied and Health Sciences, A’ Sharqiyah University, Ibra 400, Oman;
| | - Anass M. Abbas
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia; (A.M.A.); (M.G.S.)
| | - Manar G. Shalabi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia; (A.M.A.); (M.G.S.)
| | - Pranav Kumar Prabhakar
- Department of Biotechnology, School of Engineering and Technology, Nagaland University, Meriema, Kohima 797004, India;
| | - Asaad M. A. Babker
- Department of Medical Laboratory Sciences, College of Health Sciences, Gulf Medical University, Ajman 4184, United Arab Emirates;
| | | | - Velilyaeva Aliya Sabrievna
- Department of Psychiatry, Medical Psychology, and Narcology, Samarkand State Medical University, Samarkand 140158, Uzbekistan
| | - Ranjay Kumar Choudhary
- Department of Medical Laboratory Technology, University Institute of Allied Health Sciences, Chandigarh University, Chandigarh 140413, India
- School of Paramedics and Allied Health Sciences, Centurion University of Technology and Management, Sitapur 761211, India
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Xie L, Huang L, Fang X, Zha J, Su Y. Assessing Liver Function in Rat Models of Acute Liver Failure Using Single-Photon Emission Computed Tomography and Cytokine Levels. PLoS One 2025; 20:e0323531. [PMID: 40333907 PMCID: PMC12057927 DOI: 10.1371/journal.pone.0323531] [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: 12/05/2024] [Accepted: 04/10/2025] [Indexed: 05/09/2025] Open
Abstract
OBJECTIVE To evaluate liver function using dynamic hepatobiliary single-photon emission computed tomography (SPECT) in different rat models of acute liver failure. METHODS Twenty-four 6-8-week-old male Sprague-Dawley rats (weight 190-200 g) were evenly divided into four groups. Acute liver failure was induced by intraperitoneal injection of D-galactosamine (D-GalN, 600 mg/kg) and lipopolysaccharide (LPS, 10 µg/kg), common bile duct ligation surgery, and removing 70% of the liver mass. The fourth group served as the control without intervention. The time-activity curves for the liver and heart were generated from dynamic SPECT scans with 99mTc-ethylene hepatobiliary iminodiacetic acid (EHIDA). Image-derived functional parameters (5-minute heart/liver index [HLI5] and 15-minute receptor index [LHL15]) were calculated. Furthermore, correlations of image-derived parameters with serum interleukin-6 (IL-6) levels, liver aspartate aminotransferase (AST) and alanine transaminase (ALT) levels, and liver mRNA expression levels of tumor necrosis factor-α (TNF-α) and chemokine ligand-10 (CXCL-10) were analyzed. RESULTS All animals in the experimental groups exhibited varying degrees of liver damage. The SPECT images and indexes (HLI5 and LHL15) of the experimental groups significantly differed from those of the control group (P < 0.05). In the experimental groups, serum IL-6 levels and liver mRNA levels of TNF-α and CXCL-10 were significantly higher, while liver AST and ALT levels were significantly lower than those in the control group (P < 0.05). CONCLUSION Using SPECT with 99mTc-EHIDA, along with the calculated indexes and levels of various cytokines, presents a dependable method for assessing liver function.
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Affiliation(s)
- Long Xie
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Liqun Huang
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Xueting Fang
- Department of Pathology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Jinshun Zha
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Yingrui Su
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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Chvatal-Medina M, Li Y, Trillos-Almanza MC, Post A, Connelly MA, Moshage H, Bakker SJL, de Meijer VE, Blokzijl H, Dullaart RPF. Plasma Beta-Hydroxybutyrate and All-Cause Mortality in Patients with Liver Cirrhosis. Biomedicines 2025; 13:1120. [PMID: 40426948 PMCID: PMC12109306 DOI: 10.3390/biomedicines13051120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Liver cirrhosis is often accompanied by metabolic dysfunction. Circulating β-hydroxybutyrate (BHB), the most abundant ketone body, is an emerging metabolic biomarker of mitochondrial dysfunction. Methods: In this prospective observational study, we evaluated plasma BHB concentrations in patients with cirrhosis compared to the general population and investigated their association with all-cause mortality in cirrhosis. Plasma BHB, measured by nuclear magnetic resonance spectroscopy, was compared between 125 patients with cirrhosis on the waiting list for liver transplantation (TransplantLines cohort study; NCT03272841) with 125 propensity-score-matched participants from the population-dwelling PREVEND cohort. Associations of BHB with all-cause mortality were established by tertile-based log-rank tests and Cox regression analyses. A generalized additive model was fitted to assess a potential non-linear association between BHB and mortality. Results: Patients with cirrhosis had lower plasma BHB concentrations than matched PREVEND participants (111.5 µmol/L vs. 138.4 µmol/L, p = 0.02). During 133 (interquartile range 42-375) days of follow up, 27 patients died. All-cause mortality was lowest in the middle BHB tertile and highest in the upper BHB tertile (p < 0.001 by log-rank test). A non-linear, J-shaped association between BHB levels and mortality risk was found with a higher risk of death with the highest and lowest BHB levels. In Cox regression analyses, adjusted for age, sex, MELD score, diabetes, and HDL cholesterol, mortality was highest in the highest BHB tertile (T3 vs. T2 HR: 7.6, 95% CI: 2.3-25.6, p < 0.001). Mortality also tended to be higher in the lowest vs. the middle (T1 vs. T2 HR: 3.5, 95% CI: 0.9-11.7, p = 0.06). Sensitivity analyses, excluding diabetic patients and those with metabolic dysfunction-associated steatotic liver disease, confirmed the robustness of these findings. Conclusion: BHB levels exhibit a J-shaped association with the risk of death in patients with liver cirrhosis. The highest circulating BHB levels are independently associated with increased mortality risk, potentially reflecting underlying metabolic dysregulation. Future studies are necessary to validate the utility of BHB as a prognostic target in cirrhosis.
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Affiliation(s)
- Mateo Chvatal-Medina
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
| | - Yakun Li
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
| | - María Camila Trillos-Almanza
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
| | - Adrian Post
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
| | | | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
| | - Stephan J. L. Bakker
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
| | - Vincent E. de Meijer
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
| | - Hans Blokzijl
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
| | - Robin P. F. Dullaart
- Department of Internal Medicine, Division of Endocrinology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
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Nguyen KB, Jacobs S, Tasnim N, Knorr JP. Evaluation of a clinical decision support alert to identify hepatic dysfunction and need for medication therapy adjustment in hospitalized patients. Am J Health Syst Pharm 2025; 82:S2885-S2893. [PMID: 39530199 DOI: 10.1093/ajhp/zxae327] [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: 11/06/2023] [Indexed: 11/16/2024] Open
Abstract
PURPOSE To optimize the hepatic dysfunction alert tool at our institution to identify appropriate patients and minimize irrelevant alerts. METHODS This single-center, retrospective review included adults hospitalized over a 1-month period for whom a hepatic dysfunction alert fired for a medication order placed in the electronic health record. The existing alert determines hepatic dysfunction based on laboratory tests. The primary objective was to determine the proportion of patients with an alert that was deemed to be clinically relevant. Alerts were considered relevant if the patient had a Child-Pugh score in class B or C and were ordered a medication with a hepatic warning from FDA or LiverTox. The performance of 14 alternative models was evaluated. RESULTS A total of 1,541 alerts fired for 309 patients. Of these patients, 155 were randomly selected for the analysis, and the alert was deemed relevant in 86 patients (55%). Patients with relevant alerts were more likely to have documented liver disease and worsening measures on liver function tests. Of the alternative models evaluated, a model that excluded INR and albumin resulted in a 27% decrease in the number of alerts fired, of which 73% were relevant; however, it failed to identify 30% of patients with relevant hepatic dysfunction. None of the other models performed better. CONCLUSION The existing hepatic dysfunction clinical decision support tool correctly identifies patients with relevant hepatic dysfunction only 55% of the time. Alternative models were able to improve the rate of relevant results, but not without missing patients with relevant hepatic dysfunction.
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Affiliation(s)
- Kevin B Nguyen
- St. Christopher's Hospital for Children, Philadelphia, PA, USA
| | - Scott Jacobs
- Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Nissa Tasnim
- Department of Pharmacy, Jefferson Einstein Hospital, Philadelphia, PA, USA
| | - John P Knorr
- Department of Pharmacy, Jefferson Einstein Hospital, Philadelphia, PA, USA
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Jia Y, Liu L, Zhou Y, Yao Y, Cheng Y, Cheng Y, Shen C, Yang R, Zeng R, Wan Z, Zhao Q, Li D, Yuan B, Liao X. Prognostic Implications of Cardiac Geometry in Cirrhosis: Findings From a Large Cohort. Liver Int 2025; 45:e16230. [PMID: 39752186 DOI: 10.1111/liv.16230] [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: 09/13/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND AND AIMS Cirrhosis is characterised by hyperdynamic circulation, which contributes to cirrhotic cardiomyopathy (CCM). However, the expert consensus on CCM did not initially include cardiac structure because of scant evidence. Therefore, this study investigated the associations of cardiac chamber geometry with mortality and CCM. METHODS We retrospectively included 2514 cirrhotic patients from 2011 to 2023. In accordance with the guidelines for echocardiography, left ventricular (LV) hypertrophy (LVH) and LV, left atrial (LA), right ventricular (RV), and right atrial (RA) enlargement were evaluated. Cox and logistic regression analyses were performed to examine the relationships among cardiac chamber, all-cause mortality, and CCM. RESULTS The prevalence rates of LV hypertrophy and LV, LA, RV, and RA enlargement were 21.9%, 21.3%, 30.4%, 5.9%, and 10.9%, respectively. Concentric LVH (HR: 1.305, 95% confidence interval (CI): 1.153-1.466), eccentric LVH (HR: 1.272, 95% CI: 1.139-1.426), LV enlargement (HR: 1.305, 95% CI: 1.153-1.466), and LA enlargement (HR: 1.254, 95% CI: 1.130-1.379) were significantly associated with mortality during the median follow-up of 2.1 years. In a subcohort of 1898 individuals, CCM, with a prevalence of 29.0%, was independently associated with concentric LVH (OR: 1.834, 95% CI: 1.214-2.707), eccentric LVH (OR: 3.063, 95% CI: 2.379-3.903), LV enlargement (OR: 2.519, 95% CI: 2.150-2.977), LA enlargement (OR: 3.559, 95% CI: 2.770-4.321), and RA enlargement (OR: 1.416, 95% CI: 1.025-1.915). LV abnormalities showed 90% specificity and 35% sensitivity for CCM diagnosis. CONCLUSIONS Geometric pattern changes in the LV and LA are prevalent and independently associated with all-cause mortality and CCM. These indicators have potential for hazard stratification and CCM redefinition.
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Affiliation(s)
- Yu Jia
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Lidi Liu
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yiheng Zhou
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Yao
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Cheng
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yonglang Cheng
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Can Shen
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Rong Yang
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Zeng
- Department of Cardiology, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Zhi Wan
- Department of Emergency Medicine, Disaster Medical Center, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Qian Zhao
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
- Teaching & Research Section of General Practice, the General Practice Medical Center, West China Hospital of Sichuan University, Chengdu, China
| | - Dongze Li
- Department of Emergency Medicine, Disaster Medical Center, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Bo Yuan
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
- Teaching & Research Section of General Practice, the General Practice Medical Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaoyang Liao
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
- Teaching & Research Section of General Practice, the General Practice Medical Center, West China Hospital of Sichuan University, Chengdu, China
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Rascón-Martínez DM, Ullah S, Memon MA, Bangash A, Ali A, Ikram Ul Haq M, Mohyuddin A, Khan MK, Ovais F, Mustafa I. Role of Opioid-Sparing Techniques in Pain Management for General Surgery Patients With Hepatic Dysfunction: An Observational Cohort Study. Cureus 2025; 17:e77117. [PMID: 39925486 PMCID: PMC11803128 DOI: 10.7759/cureus.77117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2025] [Indexed: 02/11/2025] Open
Abstract
Introduction Patients with hepatic dysfunction undergoing general surgery face significant perioperative risks due to the liver's critical role in drug metabolism and systemic homeostasis. Opioid-sparing techniques may mitigate these risks by reducing opioid consumption and minimizing hepatic complications. Objective The objective of the study was to evaluate the effectiveness of opioid-sparing techniques in pain management for general surgery patients with hepatic dysfunction and their impact on postoperative outcomes. Methodology This observational cohort study was conducted at Lady Reading Hospital, Peshawar, Pakistan, from November 2023 to October 2024. A total of 100 patients with hepatic dysfunction undergoing elective general surgeries were included, with 50 managed using opioid-sparing techniques and 50 receiving opioid-based analgesia. Pain was assessed using the Numeric Rating Scale (NRS) at six, 12, 24, and 48 hours post-surgery. Opioid consumption was quantified as morphine-equivalent doses over 48 hours. Hepatic function parameters (aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin) and postoperative outcomes, including complications and hospital stay, were analyzed. Results Postoperative pain scores were significantly lower in the opioid-sparing group across all time points (e.g., NRS at six hours: 2.9 ± 0.8 vs. 4.5 ± 1.1, p < 0.001). Opioid consumption was reduced by 67% in the opioid-sparing group (4.1 ± 1.5 mg vs. 12.6 ± 3.8 mg,p < 0.001). Hepatic function parameters remained stable in both groups. The opioid-sparing group had shorter hospital stays (3.8 ± 0.9 days vs. 5.1 ± 1.2 days, p < 0.001) and fewer complications, including nausea (12% vs. 30%, p = 0.02) and respiratory depression (0% vs. 10%, p = 0.04). Conclusion Opioid-sparing techniques improve pain management, reduce opioid consumption, and minimize postoperative complications in patients with hepatic dysfunction undergoing general surgery. These findings support incorporating opioid-sparing protocols into perioperative care for this high-risk population.
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Affiliation(s)
| | - Samid Ullah
- Gastroenterology and Hepatology, Khalifa Gul Nawaz Teaching Hospital, Medical Teaching Institution Bannu, Bannu, PAK
| | - Muhammad Anwar Memon
- General Surgery, Liaquat University of Medical and Health Sciences, Jamshoro, PAK
| | - Adil Bangash
- General Surgery, Lady Reading Hospital, Peshawar, PAK
| | - Ayub Ali
- College of Medicine, King Faisal University, Hofuf, SAU
| | | | | | | | - Fatima Ovais
- Anesthesia, Dr. Faisal Masood Teaching Hospital, Sargodha, PAK
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Kim KP, Kim KM, Ryoo BY, Choi WM, Cha WC, Kang M, Sinn DH, Goh MJ, Kim DY, Lee MJ, Lim S, Kim D, Baek K, Kim J, Choi EJ, Lee D, Kim JA, Kim KH. Prognostic Efficacy of the Albumin-Bilirubin Score and Treatment Outcomes in Hepatocellular Carcinoma: A Large-Scale, Multi-Center Real-World Database Study. Liver Cancer 2024; 13:610-628. [PMID: 39687041 PMCID: PMC11649259 DOI: 10.1159/000539724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 06/01/2024] [Indexed: 12/18/2024] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with treatment outcomes closely tied to liver function. This study evaluates the prognostic utility of the albumin-bilirubin (ALBI) score compared to the traditional Child-Pugh (CP) grading, leveraging real-world evidence from a large-scale, multi-center database. Methods The Liver Cancer IN Korea (LINK) research network, a multi-center initiative, retrospectively collected electronic health records from three academic hospitals in South Korea, encompassing HCC patients diagnosed between 2015 and 2020. Inclusion criteria mandated at least one HCC treatment and excluded patients with other primary cancer diagnoses. The study followed patients until death, the last visit, or June 2021, employing standardized data processing and rule-based algorithms for data consistency. The prognostic efficacy of ALBI scores and CP scores was compared through time-dependent receiver operating characteristic (ROC) curves and the inverse probability censoring weighting method. Results From 25,248 newly diagnosed patients, 10,297 were included, with 65.82% having hepatitis B etiology and a mean follow-up of 27.49 months. Patients' classification by modified ALBI (mALBI) grade at diagnosis revealed: grade 1 (48.87%), 2a (20.50%), 2b (24.54%), and 3 (5.17%), with a minimal percentage missing (0.92%). Transarterial therapy (54.07%) and tyrosine kinase inhibitors (84.14% as the first-line systemic therapy) were predominant treatments. The ALBI score demonstrated greater prognostic efficacy than the CP score in long-term outcomes, with time-dependent area under the ROC curve analysis showing a score of 0.71 for ALBI versus 0.67 for CP at 60 months. Furthermore, higher mALBI grades were significantly associated with poorer survival outcomes, as indicated by both univariate and multivariate Cox proportional regression model analyses (p < 0.001). Conclusions The study confirmed the ALBI score's superior prognostic ability over the CP score, especially evident in long-term outcomes, suggesting a shift toward more nuanced liver function assessment tools in real-world clinical practice.
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Affiliation(s)
- Kyu-Pyo Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Won Chul Cha
- Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Mira Kang
- Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Myung Ji Goh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Min Ji Lee
- Real-World Evidence Team, ALYND, Yonsei University Health System, Seoul, Republic of Korea
| | - Subin Lim
- Real-World Evidence Team, ALYND, Yonsei University Health System, Seoul, Republic of Korea
| | - DongKyu Kim
- Real-World Evidence Team, ALYND, Yonsei University Health System, Seoul, Republic of Korea
| | - Kyoungdae Baek
- Real-World Evidence Team, ALYND, Yonsei University Health System, Seoul, Republic of Korea
| | - Joohyun Kim
- Real World Solutions, IQVIA Solutions Korea Ltd., Seoul, Republic of Korea
| | - Eui Jun Choi
- Real World Solutions, IQVIA Solutions Korea Ltd., Seoul, Republic of Korea
| | - Doik Lee
- Real World Solutions, IQVIA Solutions Korea Ltd., Seoul, Republic of Korea
| | - Jung-Ae Kim
- Real World Solutions, IQVIA Solutions Korea Ltd., Seoul, Republic of Korea
| | - Ki-Hun Kim
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Hao K, Paik AJ, Han LH, Makary MS. Yttrium-90 radioembolization treatment strategies for management of hepatocellular carcinoma. World J Radiol 2024; 16:512-527. [PMID: 39494134 PMCID: PMC11525828 DOI: 10.4329/wjr.v16.i10.512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 10/14/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024] Open
Abstract
As the third leading cause of cancer-related deaths worldwide, hepatocellular carcinoma (HCC) represents a significant global health challenge. This paper provides an introduction and comprehensive review of transarterial radioembolization (TARE) with Yttrium-90 (Y90), a widely performed transcatheter procedure for HCC patients who are not suitable candidates for surgery. TARE involves the targeted delivery of radioactive microspheres to liver tumors, offering a promising treatment option for managing HCC across various stages of the disease. By evaluating Y90 TARE outcomes across early, intermediate, and advanced stages of HCC, the review aims to present a thorough understanding of its efficacy and safety. Additionally, this paper highlights future research directions focusing on the potential of combination therapies with systemic and immunotherapies, as well as personalized treatments. The exploration of these innovative approaches aims to improve treatment outcomes, reduce adverse events, and provide new therapeutic opportunities for HCC patients. The review underscores the importance of ongoing research and clinical trials to optimize TARE further and integrate it into comprehensive HCC treatment paradigms.
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Affiliation(s)
- Kelly Hao
- College of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Andrew J Paik
- College of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Lauren H Han
- College of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Mina S Makary
- Department of Radiology, The Ohio State University Medical Center, Columbus, OH 43210, United States
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10
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Prasad B, Al-Majdoub ZM, Wegler C, Rostami-Hodjegan A, Achour B. Quantitative Proteomics for Translational Pharmacology and Precision Medicine: State of The Art and Future Outlook. Drug Metab Dispos 2024; 52:1208-1216. [PMID: 38821856 DOI: 10.1124/dmd.124.001600] [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: 02/28/2024] [Revised: 05/02/2024] [Accepted: 05/22/2024] [Indexed: 06/02/2024] Open
Abstract
Over the past 20 years, quantitative proteomics has contributed a wealth of protein expression data, which are currently used for a variety of systems pharmacology applications, as a complement or a surrogate for activity of the corresponding proteins. A symposium at the 25th North American International Society for the Study of Xenobiotics meeting, in Boston, in September 2023, was held to explore current and emerging applications of quantitative proteomics in translational pharmacology and strategies for improved integration into model-informed drug development based on practical experience of each of the presenters. A summary of the talks and discussions is presented in this perspective alongside future outlook that was outlined for future meetings. SIGNIFICANCE STATEMENT: This perspective explores current and emerging applications of quantitative proteomics in translational pharmacology and precision medicine and outlines the outlook for improved integration into model-informed drug development.
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Affiliation(s)
- Bhagwat Prasad
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.); Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (Z.M.A.-M., A.R.-H.); Department of Plant Physiology, Umeå University, Umeå, Sweden (C.W.); Certara UK, Sheffield, United Kingdom (A.R.-H.); and Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, the University of Rhode Island, Kingston, Rhode Island (B.A.)
| | - Zubida M Al-Majdoub
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.); Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (Z.M.A.-M., A.R.-H.); Department of Plant Physiology, Umeå University, Umeå, Sweden (C.W.); Certara UK, Sheffield, United Kingdom (A.R.-H.); and Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, the University of Rhode Island, Kingston, Rhode Island (B.A.)
| | - Christine Wegler
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.); Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (Z.M.A.-M., A.R.-H.); Department of Plant Physiology, Umeå University, Umeå, Sweden (C.W.); Certara UK, Sheffield, United Kingdom (A.R.-H.); and Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, the University of Rhode Island, Kingston, Rhode Island (B.A.)
| | - Amin Rostami-Hodjegan
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.); Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (Z.M.A.-M., A.R.-H.); Department of Plant Physiology, Umeå University, Umeå, Sweden (C.W.); Certara UK, Sheffield, United Kingdom (A.R.-H.); and Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, the University of Rhode Island, Kingston, Rhode Island (B.A.)
| | - Brahim Achour
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.); Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (Z.M.A.-M., A.R.-H.); Department of Plant Physiology, Umeå University, Umeå, Sweden (C.W.); Certara UK, Sheffield, United Kingdom (A.R.-H.); and Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, the University of Rhode Island, Kingston, Rhode Island (B.A.)
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11
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Shenavandeh S, Taghavi SA, Nekooeian A, Moini M. Pharmacological considerations in pharmacotherapy of rheumatology patients with liver disease: a brief narrative review. Reumatologia 2024; 62:282-293. [PMID: 39381733 PMCID: PMC11457314 DOI: 10.5114/reum/191791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 07/30/2024] [Indexed: 10/10/2024] Open
Abstract
The presence of chronic liver diseases such as metabolic dysfunction-associated steatosis liver disease, viral hepatitis, and cirrhosis may affect the treatment plan in patients with rheumatologic disorders, with concern about the adverse effects of the rheumatic medications on the course of liver disease. Advanced liver disease can change the elimination and activation of many drugs. In addition, there are concerns about the risk of viral reactivation after using biologics and immunosuppressants in patients with chronic viral hepatitis. This narrative review will assess the considerations that should be made before starting the most frequently used drugs in all common rheumatic diseases and patients with chronic liver diseases including chronic viral hepatitis.
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Affiliation(s)
- Saeedeh Shenavandeh
- Division of Rheumatology, Department of Internal Medicine, Shiraz University of Medical Science, Iran
| | | | | | - Maryam Moini
- Division of Gastroenterology, University of Ottawa, Canada
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12
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Rostami-Hodjegan A, Al-Majdoub ZM, von Grabowiecki Y, Yee KL, Sahoo S, Breitwieser W, Galetin A, Gibson C, Achour B. Dealing With Variable Drug Exposure Due to Variable Hepatic Metabolism: A Proof-of-Concept Application of Liquid Biopsy in Renal Impairment. Clin Pharmacol Ther 2024; 116:814-823. [PMID: 38738484 DOI: 10.1002/cpt.3291] [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: 12/06/2023] [Accepted: 04/20/2024] [Indexed: 05/14/2024]
Abstract
Precision dosing strategies require accounting for between-patient variability in pharmacokinetics (PK), affecting drug exposure, and in pharmacodynamics (PD), affecting response achieved at the same drug concentration at the site of action. Although liquid biopsy for assessing different levels of molecular drug targets has yet to be established, individual characterization of drug elimination pathways using liquid biopsy has recently been demonstrated. The feasibility of applying this approach in conjunction with modeling tools to guide individual dosing remains unexplored. In this study, we aimed to individualize physiologically-based pharmacokinetic (PBPK) models based on liquid biopsy measurements in plasma from 25 donors with different grades of renal function who were previously administered oral midazolam as part of a microdose cocktail. Virtual twin models were constructed based on demographics, renal function, and hepatic expression of relevant pharmacokinetic pathways projected from liquid biopsy output. Simulated exposure (AUC) to midazolam was in agreement with observed data (AFE = 1.38, AAFE = 1.78). Simulated AUC variability with three dosing approaches indicated higher variability with uniform dosing (14-fold) and stratified dosing (13-fold) compared with individualized dosing informed by liquid biopsy (fivefold). Further, exosome screening revealed mRNA expression of 532 targets relevant to drug metabolism and disposition (169 enzymes and 361 transporters). Data related to these targets can be used to further individualize PBPK models for pathways relevant to PK of other drugs. This study provides additional verification of liquid biopsy-informed PBPK modeling approaches, necessary to advance strategies that seek to achieve precise dosing from the start of treatment.
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Affiliation(s)
- Amin Rostami-Hodjegan
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK
- Certara, Princeton, New Jersey, USA
| | - Zubida M Al-Majdoub
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK
| | | | - Ka Lai Yee
- Merck & Co., Inc., Rahway, New Jersey, USA
| | - Sudhakar Sahoo
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - Wolfgang Breitwieser
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - Aleksandra Galetin
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK
| | | | - Brahim Achour
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, Rhode Island, USA
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13
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Ramaswamy A, Shukla A, Engineer R, Sundaram S, Srinivas S, Kulkarni S, Patkar S, Baijal S, Kale A, Kapoor A, Mukund A, Choudhari A, Rauthan A, Mathew AS, Panchal R, Bhattacharya K, Patil P, Shetty N, Gala K, Kumar L, Thiruchunapalli D, Kalra N, Sahoo TP, Krishna MV, Lavingia V, Mohanka R, Talwar V, Ostwal V, Bhargava P, Poddar J, Singal A, Goel M. Evaluation and Management of Unresectable Hepatocellular Carcinoma: Multidisciplinary Indian Consensus Statements from a Delphi Panel. South Asian J Cancer 2024. [DOI: 10.1055/s-0044-1788569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2025] Open
Abstract
Background India, like many parts of Asia, likely faces a high burden of hepatocellular carcinoma (HCC), though large-scale data on etiology, presentation, and outcomes are lacking. There appears to be a predominance of unresectable, advanced-stage HCC at presentation in India with variable level of expertise in India to manage these scenarios. This publication summarizes the latest evidence with cognizance of the unique challenges faced in India by treating clinicians.
Methods A multidisciplinary panel of medical oncologists, gastroenterologists, hepatologists, interventional radiologists, and hepatobiliary surgical oncologists held a meeting in June 2022 and reviewed the evidence available for management of HCC. The meeting concentrated on the recognition and management of HCC not amenable to surgical approaches in the Indian context. A literature review of these aspects of management was conducted and consensus statements with level of evidence and grades of recommendation were prepared by individual specialists in each field. Statements were evaluated by the modified Delphi method.
Key Content and Findings The panel comprising 22 experts formulated 40 consensus statements with regard to defining unresectable HCC, optimization of underlying conditions prior to management, rationale use of various liver-directed therapies (LDTs) in unresectable HCC, and systemic therapeutic options in this group of patients.
Conclusion Our consensus statements offer practical, yet evidence-based management guidelines for treating unresectable HCC in the Indian context. There is an emphasis on the crucial need for combining available approaches for LDT, even if less well studied though possibly effective, with standard systemic therapy.
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Affiliation(s)
- Anant Ramaswamy
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Akash Shukla
- Department of Gastroenterology, Seth Gordhandas Sunderdas Medical College (GSMC) & King Edward Memorial (KEM) Hospital, Mumbai, Maharashtra, India
- Department of Hepatology, Sir H.N. Reliance Foundation Hospital, Mumbai, Maharashtra, India
| | - Reena Engineer
- Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Sridhar Sundaram
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Sujay Srinivas
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Suyash Kulkarni
- Department of Radiodiagnosis, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Shraddha Patkar
- Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Sanjay Baijal
- Department of Diagnostic and Interventional Radiology, Medanta Hospital, Gurugram, Haryana, India
| | - Aditya Kale
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Akhil Kapoor
- Department of Medical Oncology, Tata Memorial Hospital (TMH), Homi Bhabha Cancer Hospital (HBCH) and Mahamana Pt Madan Mohan Malaviya Cancer Centre (MPMMCC), Varanasi, Uttar Pradesh, India
| | - Amar Mukund
- Department of Interventional Radiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Amit Choudhari
- Department of Radio-diagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Amit Rauthan
- Department of Medical Oncology, Manipal Hospital, Bangalore, Karnataka, India
| | - Ashwathy Susan Mathew
- Department of Radiation Oncology, Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India
| | - Rushi Panchal
- Department of Radiation Oncology, MS Patel Cancer Centre, Shree Krishna Hospital, Bhaikaka University, Karamsad-Anand, Gujarat, India
| | - Kausik Bhattacharya
- Department of Radiation Oncology, AIG Hospitals. Hyderabad, Telangana, India
| | - Prachi Patil
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Nitin Shetty
- Department of Radiodiagnosis, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Mumbai, Maharashtra, India
| | - Kunal Gala
- Department of Radio-diagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Lijesh Kumar
- Department of Endovascular and Interventional Radiology, Lisie Hospital, Kochi, Kerala, India
| | - Deepashree Thiruchunapalli
- Department of Interventional Radiology, Dr. Rela Institute and Medical Centre, Chennai, Tamil Nadu, India
| | - Naveen Kalra
- Department of Radio-diagnosis, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Tarini Prasad Sahoo
- Department of Medical Oncology, Silverline Hospital, Bhopal, Madhya Pradesh, India
| | - M Vamshi Krishna
- Department of Medical Oncology and Hematology, Institute of Oncology, AIG Hospital, Hyderabad, Telangana, India
| | - Viraj Lavingia
- Department of Medical Oncology, HCG Cancer Centre, Ahmedabad, Gujarat, India
| | - Ravi Mohanka
- Department of Liver Transplant and HPB Surgery, Sir H.N. Reliance Hospital, Mumbai, Maharashtra, India
| | - Vineet Talwar
- Department of Medical Oncology Rajiv Gandhi Cancer Institute, Delhi, India
| | - Vikas Ostwal
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Prabhat Bhargava
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Jyoti Poddar
- Radiation Oncologist, Therapy Area Medical Expert (Hepatocellular Carcinoma) Roche (India) Pvt Limited
| | - Amit Singal
- Department of Medicine, UT Southwestern Medical Center, Dallas, Texas, United States
| | - Mahesh Goel
- Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
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14
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Kanodia J, Giovinazzo H, Yates W, Bourdet DL, McRae MP, Helmke SM, Everson GT. Hepatic Dysfunction Quantified by HepQuant DuO Outperforms Child-Pugh Classification in Predicting the Pharmacokinetics of Ampreloxetine. Clin Pharmacol Ther 2024; 116:186-193. [PMID: 38654484 DOI: 10.1002/cpt.3265] [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: 12/18/2023] [Accepted: 03/22/2024] [Indexed: 04/26/2024]
Abstract
HepQuant tests quantify liver function from clearance of deuterium- and 13C-labeled cholates administered either intravenously and orally (SHUNT) or orally (DuO). Hepatic impairment studies have relied on clinical or laboratory criteria like Child-Pugh classification to categorize the degree of hepatic dysfunction. We compared HepQuant tests with Child-Pugh classification in predicting the pharmacokinetics of ampreloxetine. Twenty-one subjects with hepatic impairment (8 Child-Pugh A, 7 Child-Pugh B, and 6 Child-Pugh C), and 10 age- and sex-matched controls were studied. The pharmacokinetics of ampreloxetine were measured after oral administration of a single dose of 10 mg. Disease severity index (DSI), portal-systemic shunting (SHUNT%), hepatic reserve, and hepatic filtration rates (HFRs) were measured from serum samples obtained after intravenous administration of [24-13C]-cholate and oral administration of [2,2,4,4-2H]cholate. Ampreloxetine plasma exposure (AUC0-inf) was similar to controls in Child-Pugh A, increased 1.7-fold in subjects with Child-Pugh B, and 2.5-fold in subjects with Child-Pugh C and correlated with both Child-Pugh score and HepQuant parameters. The variability observed in ampreloxetine exposure (AUC0-inf) in subjects with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) was explained by HepQuant parameters. Multivariable regression models demonstrated that DSI, SHUNT%, and Hepatic Reserve from SHUNT and DuO were superior predictors of ampreloxetine exposure (AUC0-inf) compared to Child-Pugh score. HepQuant DSI, SHUNT%, and hepatic reserve were more useful predictors of drug exposure than Child-Pugh class for ampreloxetine and thus may better optimize dose recommendations in patients with liver disease. The simple-to-administer, oral-only DuO version of the HepQuant test could enhance clinical utility.
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Affiliation(s)
- Jitendra Kanodia
- Theravance Biopharma US, Inc., South San Francisco, California, USA
| | - Hugh Giovinazzo
- Theravance Biopharma US, Inc., South San Francisco, California, USA
| | - Wayne Yates
- Theravance Biopharma US, Inc., South San Francisco, California, USA
| | - David L Bourdet
- Theravance Biopharma US, Inc., South San Francisco, California, USA
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15
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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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16
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Bahrami F, Rossi RM, De Nys K, Joerger M, Radenkovic MC, Defraeye T. Implementing physics-based digital patient twins to tailor the switch of oral morphine to transdermal fentanyl patches based on patient physiology. Eur J Pharm Sci 2024; 195:106727. [PMID: 38360153 DOI: 10.1016/j.ejps.2024.106727] [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: 07/12/2023] [Revised: 12/20/2023] [Accepted: 02/12/2024] [Indexed: 02/17/2024]
Abstract
Fentanyl transdermal patches are widely implemented for cancer-induced pain treatment due to the high potency of fentanyl and gradual drug release. However, transdermal fentanyl up-titration for opioid-naïve patients is difficult, which is why opioid treatment is often started with oral/iv morphine. Based on the daily dose of morphine, the initial dose of the fentanyl patch is decided upon. After reaching a stable level of pain, the switch is made from oral/iv morphine to transdermal fentanyl. There are standard calculation tools for transferring from oral/iv morphine to transdermal fentanyl, which is the same for all patients. By considering the variations in the physiology of the patients, a unique switching strategy cannot meet the needs of different patients. This study explores the outcome in terms of pain relief and minute ventilation during opioid therapy. For this, we used physics-based simulations on a virtually-generated population of patients, and we applied the same therapy to all patients. We could show that patients' physiology, such as gender, age, and weight, greatly impact the outcome of the therapy; as such, the correlation coefficient between pain intensity and age is 0.89, and the correlation coefficient between patient's weight and maximum plasma concentration of morphine and fentanyl is -0.98 and -0.97. Additionally, a different combination of the duration of overlap between morphine and fentanyl therapy with different doses of fentanyl was considered for the virtual patients to find the best opioid-switching strategy for each patient. We explored the impact of combining physiological features to determine the best-suited strategy for virtual patients. Our findings suggest that tailoring morphine and fentanyl therapy only based on a limited number of features is insufficient, and increasing the number of impactful physiological features positively influences the outcome of the therapy.
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Affiliation(s)
- Flora Bahrami
- Laboratory for Biomimetic Membranes and Textiles, Empa, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, St. Gallen CH-9014, Switzerland; ARTORG Center for Biomedical Engineering Research, University of Bern, Mittelstrasse 43, Bern CH-3012, Switzerland
| | - René Michel Rossi
- Laboratory for Biomimetic Membranes and Textiles, Empa, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, St. Gallen CH-9014, Switzerland
| | - Katelijne De Nys
- Kantonsspital St. Gallen, Palliativzentrum, Rorschacherstrasse 95, St. Gallen CH-9000, Switzerland; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, ON2 Herestraat 49 - box 424, Leuven BE-3000, Belgium
| | - Markus Joerger
- Kantonsspital St. Gallen, Medizinische Onkologie und Hämatologie, Rorschacherstrasse 95, St. Gallen CH-9000, Switzerland
| | - Milena Cukic Radenkovic
- Laboratory for Biomimetic Membranes and Textiles, Empa, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, St. Gallen CH-9014, Switzerland
| | - Thijs Defraeye
- Laboratory for Biomimetic Membranes and Textiles, Empa, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, St. Gallen CH-9014, Switzerland.
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17
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Lv YF, Zhu B, Meng MM, Wu YF, Dong CB, Zhang Y, Liu BW, You SL, Lv S, Yang YP, Liu FQ. Development of a new Cox model for predicting long-term survival in hepatitis cirrhosis patients underwent transjugular intrahepatic portosystemic shunts. World J Gastrointest Surg 2024; 16:491-502. [PMID: 38463355 PMCID: PMC10921221 DOI: 10.4240/wjgs.v16.i2.491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/23/2023] [Accepted: 01/12/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND Transjugular intrahepatic portosystemic shunt (TIPS) placement is a procedure that can effectively treat complications of portal hypertension, such as variceal bleeding and refractory ascites. However, there have been no specific studies on predicting long-term survival after TIPS placement. AIM To establish a model to predict long-term survival in patients with hepatitis cirrhosis after TIPS. METHODS A retrospective analysis was conducted on a cohort of 224 patients who underwent TIPS implantation. Through univariate and multivariate Cox regression analyses, various factors were examined for their ability to predict survival at 6 years after TIPS. Consequently, a composite score was formulated, encompassing the indication, shunt reasonability, portal venous pressure gradient (PPG) after TIPS, percentage decrease in portal venous pressure (PVP), indocyanine green retention rate at 15 min (ICGR15) and total bilirubin (Tbil) level. Furthermore, the performance of the newly developed Cox (NDC) model was evaluated in an internal validation cohort and compared with that of a series of existing models. RESULTS The indication (variceal bleeding or ascites), shunt reasonability (reasonable or unreasonable), ICGR15, postoperative PPG, percentage of PVP decrease and Tbil were found to be independent factors affecting long-term survival after TIPS placement. The NDC model incorporated these parameters and successfully identified patients at high risk, exhibiting a notably elevated mortality rate following the TIPS procedure, as observed in both the training and validation cohorts. Additionally, in terms of predicting the long-term survival rate, the performance of the NDC model was significantly better than that of the other four models [Child-Pugh, model for end-stage liver disease (MELD), MELD-sodium and the Freiburg index of post-TIPS survival]. CONCLUSION The NDC model can accurately predict long-term survival after the TIPS procedure in patients with hepatitis cirrhosis, help identify high-risk patients and guide follow-up management after TIPS implantation.
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Affiliation(s)
- Yi-Fan Lv
- Liver Disease Minimally Invasive Diagnosis and Treatment Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Bing Zhu
- Liver Vascular Disease Diagnosis and Treatment Center, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100039, China
| | - Ming-Ming Meng
- Liver Disease Minimally Invasive Diagnosis and Treatment Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Yi-Fan Wu
- Liver Disease Minimally Invasive Diagnosis and Treatment Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Cheng-Bin Dong
- Liver Disease Minimally Invasive Diagnosis and Treatment Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Yu Zhang
- Liver Disease Minimally Invasive Diagnosis and Treatment Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Bo-Wen Liu
- Liver Disease Minimally Invasive Diagnosis and Treatment Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Shao-Li You
- Liver Vascular Disease Diagnosis and Treatment Center, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100039, China
| | - Sa Lv
- Liver Vascular Disease Diagnosis and Treatment Center, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100039, China
| | - Yong-Ping Yang
- Liver Vascular Disease Diagnosis and Treatment Center, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100039, China
| | - Fu-Quan Liu
- Liver Disease Minimally Invasive Diagnosis and Treatment Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
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18
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Luo X, Zhang Z, Mu R, Hu G, Liu L, Liu X. Simultaneously Predicting the Pharmacokinetics of CES1-Metabolized Drugs and Their Metabolites Using Physiologically Based Pharmacokinetic Model in Cirrhosis Subjects. Pharmaceutics 2024; 16:234. [PMID: 38399287 PMCID: PMC10893190 DOI: 10.3390/pharmaceutics16020234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/29/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Hepatic carboxylesterase 1 (CES1) metabolizes numerous prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aimed to develop a semi-physiologically based pharmacokinetic (semi-PBPK) model to simultaneously predict the pharmacokinetics of CES1 substrates and their active metabolites in liver cirrhosis (LC) patients. Six prodrugs (enalapril, benazepril, cilazapril, temocapril, perindopril and oseltamivir) and three direct-acting drugs (flumazenil, pethidine and remimazolam) were selected. Parameters such as organ blood flows, plasma-binding protein concentrations, functional liver volume, hepatic enzymatic activity, glomerular filtration rate (GFR) and gastrointestinal transit rate were integrated into the simulation. The pharmacokinetic profiles of these drugs and their active metabolites were simulated for 1000 virtual individuals. The developed semi-PBPK model, after validation in healthy individuals, was extrapolated to LC patients. Most of the observations fell within the 5th and 95th percentiles of simulations from 1000 virtual patients. The estimated AUC and Cmax were within 0.5-2-fold of the observed values. The sensitivity analysis showed that the decreased plasma exposure of active metabolites due to the decreased CES1 was partly attenuated by the decreased GFR. Conclusion: The developed PBPK model successfully predicted the pharmacokinetics of CES1 substrates and their metabolites in healthy individuals and LC patients, facilitating tailored dosing of CES1 substrates in LC patients.
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Affiliation(s)
| | | | | | | | - Li Liu
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; (X.L.); (Z.Z.); (R.M.); (G.H.)
| | - Xiaodong Liu
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; (X.L.); (Z.Z.); (R.M.); (G.H.)
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19
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Zhao Z, Bo Z, Ye N, Dong Y, Xu Y, Wang B, Yang F, Liu L, Liu Z. Impact of sarcopenia on postoperative outcomes after hepatectomy in older patients with intrahepatic cholangiocarcinoma: A multicentre cohort study. Liver Int 2024; 44:155-168. [PMID: 37804070 DOI: 10.1111/liv.15757] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 08/24/2023] [Accepted: 09/22/2023] [Indexed: 10/08/2023]
Abstract
BACKGROUND AND AIMS Sarcopenia is associated with poor prognosis, but its role in older patients with intrahepatic cholangiocarcinoma (ICC) is unclear. We aimed to evaluate the impact of sarcopenia on the prognosis of older patients with ICC undergoing hepatectomy. METHODS A total of 363 patients with ICC following hepatectomy from 2015 to 2021 were retrospectively reviewed at five institutions. Sarcopenia was evaluated using skeletal muscle index by computed tomography images. Patients were divided into four subgroups according to sarcopenia and age. Postoperative outcomes including complication, overall survival (OS) and recurrence-free survival (RFS) were evaluated. Risk factors were identified through univariate and multivariate Cox regression analyses. RESULTS 302 patients were included in the analysis. The median age was 63 years and there were 128 patients (42.4%) aged over 65 years. 192 patients (63.6%) were diagnosed with sarcopenia, while 180 patients (59.6%) experienced myosteatosis. Older patients experienced a higher incidence of sarcopenia and myosteatosis, and worse postoperative outcomes than younger patients. In the subgroup of patients with sarcopenia, older patients experienced a significant shorter OS than younger patients, which was not observed in patients without sarcopenia. According to the multivariate Cox regression analysis, lymphatic metastasis (p < .001), blood transfusion (p = .004), low serum albumin (p = .051), sarcopenia (p = .024), and myosteatosis (p = .004) were identified as independent risk factors of OS in older patients, meanwhile tumour size (p = .013) and lymphatic metastasis (p < .001) were independent risk factors of RFS. CONCLUSIONS Sarcopenia and myosteatosis have a significant adverse impact on postoperative outcomes in older patients with ICC undergoing hepatectomy.
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Affiliation(s)
- Zhengxiao Zhao
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhiyuan Bo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ni Ye
- Department of General Practice, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yulong Dong
- Department of Oncology, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yingfei Xu
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Binbin Wang
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Facai Yang
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Sichuan, China
| | - Liwei Liu
- Department of Pediatric, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhendong Liu
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
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20
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Petiunin O, Shevchenko R, Brek O, Kolomenskyi O. Clinical classification of liver cirrhosis - a way to plan individual definitive treatment. WIADOMOSCI LEKARSKIE (WARSAW, POLAND : 1960) 2024; 77:160-165. [PMID: 38431821 DOI: 10.36740/wlek202401120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2024]
Abstract
OBJECTIVE Aim: To develop clinical classification of liver cirrhosis, which can aid individualization and planning definitive treatment for this group of patients. PATIENTS AND METHODS Materials and Methods: Computerized search of the literature was performed via PubMed using the following medical subject headings or keywords: "liver", "cirrhosis" and "classification"; or "liver", "cirrhosis" and "complications"; or "liver", "cirrhosis" and "treatment"; or "portal" ", "hypertension" and "complications". Articles were independently evaluated by each author, the etiological, morphological and current clinical classifications of LC were analyzed, their advantages and disadvantages identified, and after discussion classification of LC was developed by consensus. CONCLUSION Conclusions: The developed clinical classification of liver cirrhosis will facilitate the planning of therapeutic tactics for each patient, allow to personalize the treatment of patients with this pathology.
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Affiliation(s)
| | | | - Ostap Brek
- KHARKIV NATIONAL MEDICAL UNIVERSITY, KHARKIV, UKRAINE
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21
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Armani S, Geier A, Forst T, Merle U, Alpers DH, Lunnon MW. Effect of changes in metabolic enzymes and transporters on drug metabolism in the context of liver disease: Impact on pharmacokinetics and drug-drug interactions. Br J Clin Pharmacol 2023. [PMID: 38148609 DOI: 10.1111/bcp.15990] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/07/2023] [Accepted: 12/13/2023] [Indexed: 12/28/2023] Open
Abstract
Changes in the pharmacokinetic and resulting pharmacodynamic properties of drugs are common in many chronic liver diseases, leading to adverse effects, drug interactions and increased risk of over- or underdosing of medications. Structural and functional hepatic impairment can have major effects on drug metabolism and transport. This review summarizes research on the functional changes in phase I and II metabolic enzymes and in transport proteins in patients with metabolic diseases such as type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis and cirrhosis, providing a clinical perspective on how these changes affect drug uptake and metabolism. Generally, a decrease in expression and/or activity of many enzymes of the cytochrome P450 family (e.g. CYP2E1 and CYP3A4), and of influx and efflux transporters (e.g. organic anion-transporting polypeptide [OATP]1B1, OATP2B1, OAT2 and bile salt export pump), has been recently documented in patients with liver disease. Decreased enzyme levels often correlate with increased severity of chronic liver disease. In subjects with hepatic impairment, there is potential for strong alterations of drug pharmacokinetics due to reduced absorption, increased volume of distribution, metabolism and extraction. Due to the altered pharmacokinetics, specific drug-drug interactions are also a potential issue to consider in patients with liver disease. Given the huge burden of liver disease in western societies, there is a need to improve awareness among all healthcare professionals and patients with liver disease to ensure appropriate drug prescriptions.
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Affiliation(s)
- Sara Armani
- CRS Clinical Research Services, Mannheim, Germany
| | - Andreas Geier
- Department of Internal Medicine and Hepatology, University Hospital, Würzburg, Germany
| | - Thomas Forst
- CRS Clinical Research Services, Mannheim, Germany
| | - Uta Merle
- Department of Internal Medicine IV, University Hospital, Heidelberg, Germany
| | - David H Alpers
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
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22
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Small BG, Hatley O, Jamei M, Gardner I, Johnson TN. Incorporation and Performance Verification of Hepatic Portal Blood Flow Shunting in Minimal and Full PBPK Models of Liver Cirrhosis. Clin Pharmacol Ther 2023; 114:1264-1273. [PMID: 37620290 DOI: 10.1002/cpt.3032] [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: 06/01/2023] [Accepted: 08/16/2023] [Indexed: 08/26/2023]
Abstract
Patho-physiological changes in liver cirrhosis create portacaval shunts that allow blood flow to bypass the hepatic portal vein into the systemic circulation affecting drug pharmacokinetics (PKs). The objectives of this work were to implement a physiologically-based pharmacokinetic (PBPK) framework describing shunted blood flows in virtual patients with differing degrees of liver cirrhosis; and to assess the minimal and full PBPK model's performance using drugs with intermediate to high hepatic extraction. Single dose concentration-time profiles and PK parameters for oral ibrutinib, midazolam, propranolol, and buspirone were simulated in healthy volunteers (HVs) and subjects with cirrhosis (Child-Pugh severity score (CP-A, CP-B, or CP-C)). Model performance was verified by comparing predicted to observed fold-changes in PK parameters between HVs and cirrhotic subjects. The verified model was used to simulate the PK changes for simvastatin in patients with cirrhosis. The predicted area under the curve ratios (AUCCirr :AUCHV ) for ibrutinib were 3.38, 6.87, and 11.46 using the minimal PBPK model with shunt and 1.61, 2.58, and 4.33 without the shunt, these compared with observed values of 4.33, 8.14, and 9.04, respectively. For ibrutinib, propranolol, and buspirone, including a shunt in the PBPK model improved the prediction of the AUCCirr :AUCHV and maximum plasma concentration ratios (CmaxCirr :CmaxHV ). For midazolam, an intermediate extraction drug, the differences were less clear. Simulated simvastatin dose adjustments in cirrhosis suggested that 20 mg in CP-A and 10 mg in CP-B could be used clinically. A mechanistic model-informed understanding of the anatomic and pathophysiology of cirrhosis will facilitate improved dose prediction and adjustment in this vulnerable population.
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Affiliation(s)
- Ben G Small
- Certara UK Limited (Simcyp Division), Sheffield, UK
| | | | - Masoud Jamei
- Certara UK Limited (Simcyp Division), Sheffield, UK
| | - Iain Gardner
- Certara UK Limited (Simcyp Division), Sheffield, UK
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23
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Chothe PP, Mitra P, Nakakariya M, Ramsden D, Rotter CJ, Sandoval P, Tohyama K. Drug transporters in drug disposition - the year 2022 in review. Drug Metab Rev 2023; 55:343-370. [PMID: 37644867 DOI: 10.1080/03602532.2023.2252618] [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: 05/15/2023] [Accepted: 08/11/2023] [Indexed: 08/31/2023]
Abstract
On behalf of all the authors, I am pleased to share our third annual review on drug transporter science with an emphasis on articles published and deemed influential in signifying drug transporters' role in drug disposition in the year 2022. As the drug transporter field is rapidly evolving several key findings were noted including promising endogenous biomarkers, rhythmic activity, IVIVE approaches in transporter-mediated clearance, new modality interaction, and transporter effect on gut microbiome. As identified previously (Chothe et Cal. 2021, 2022) the goal of this review is to highlight key findings without a comprehensive overview of each article and to this end, each coauthor independently selected 1-3 peer-reviewed articles published or available online in the year 2022 (Table 1). Each article is summarized in synopsis and commentary with unbiased viewpoints by each coauthor. We strongly encourage readers to consult original articles for specifics of the study. Finally, I would like to thank all coauthors for their continued support in writing this annual review on drug transporters and invite anyone interested in contributing to future versions of this review.
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Affiliation(s)
- Paresh P Chothe
- Department of Drug Metabolism and Pharmacokinetics, Oncology Research and Development, AstraZeneca, Waltham, MA, USA
| | - Pallabi Mitra
- Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA
| | - Masanori Nakakariya
- Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Japan
| | - Diane Ramsden
- Department of Drug Metabolism and Pharmacokinetics, Oncology Research and Development, AstraZeneca, Waltham, MA, USA
| | - Charles J Rotter
- Global Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc. (TDCA), San Diego, CA, USA
| | - Philip Sandoval
- Global Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc. (TDCA), Lexington, MA, USA
| | - Kimio Tohyama
- Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Japan
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24
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Cai L, Ke M, Wang H, Wu W, Lin R, Huang P, Lin C. Physiologically based pharmacokinetic model combined with reverse dose method to study the nephrotoxic tolerance dose of tacrolimus. Arch Toxicol 2023; 97:2659-2673. [PMID: 37572130 DOI: 10.1007/s00204-023-03576-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/02/2023] [Indexed: 08/14/2023]
Abstract
Nephrotoxicity is the most common side effect that severely limits the clinical application of tacrolimus (TAC), an immunosuppressive agent used in kidney transplant patients. This study aimed to explore the tolerated dose of nephrotoxicity of TAC in individuals with different CYP3A5 genotypes and liver conditions. We established a human whole-body physiological pharmacokinetic (WB-PBPK) model and validated it using data from previous clinical studies. Following the injection of 1 mg/kg TAC into the tail veins of male rats, we developed a rat PBPK model utilizing the drug concentration-time curve obtained by LC-MS/MS. Next, we converted the established rat PBPK model into the human kidney PBPK model. To establish renal concentrations, the BMCL5 of the in vitro CCK-8 toxicity response curve (drug concentration range: 2-80 mol/L) was extrapolated. To further investigate the acceptable levels of nephrotoxicity for several distinct CYP3A5 genotypes and varied hepatic function populations, oral dosing regimens were extrapolated utilizing in vitro-in vivo extrapolation (IVIVE). The PBPK model indicated the tolerated doses of nephrotoxicity were 0.14-0.185 mg/kg (CYP3A5 expressors) and 0.13-0.155 mg/kg (CYP3A5 non-expressors) in normal healthy subjects and 0.07-0.09 mg/kg (CYP3A5 expressors) and 0.06-0.08 mg/kg (CYP3A5 non-expressors) in patients with mild hepatic insufficiency. Further, patients with moderate hepatic insufficiency tolerated doses of 0.045-0.06 mg/kg (CYP3A5 expressors) and 0.04-0.05 mg/kg (CYP3A5 non-expressors), while in patients with moderate hepatic insufficiency, doses of 0.028-0.04 mg/kg (CYP3A5 expressors) and 0.022-0.03 mg/kg (CYP3A5 non-expressors) were tolerated. Overall, our study highlights the combined usage of the PBPK model and the IVIVE approach as a valuable tool for predicting toxicity tolerated doses of a drug in a specific group.
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Affiliation(s)
- Limin Cai
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou, 350005, People's Republic of China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Meng Ke
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou, 350005, People's Republic of China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Han Wang
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou, 350005, People's Republic of China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Wanhong Wu
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou, 350005, People's Republic of China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Rongfang Lin
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou, 350005, People's Republic of China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Pinfang Huang
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou, 350005, People's Republic of China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Cuihong Lin
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou, 350005, People's Republic of China.
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China.
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25
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Gradel KO. Interpretations of the Role of Plasma Albumin in Prognostic Indices: A Literature Review. J Clin Med 2023; 12:6132. [PMID: 37834777 PMCID: PMC10573484 DOI: 10.3390/jcm12196132] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
This review assesses how publications interpret factors that influence the serum or plasma albumin (PA) level in prognostic indices, focusing on inflammation and nutrition. On PubMed, a search for "albumin AND prognosis" yielded 23,919 results. From these records, prognostic indices were retrieved, and their names were used as search strings on PubMed. Indices found in 10 or more original research articles were included. The same search strings, restricted to "Review" or "Systematic review", retrieved yielded on the indices. The data comprised the 10 latest original research articles and up to 10 of the latest reviews. Thirty indices had 294 original research articles (6 covering two indices) and 131 reviews, most of which were from recent years. A total of 106 articles related the PA level to inflammation, and 136 related the PA level to nutrition. For the reviews, the equivalent numbers were 54 and 65. In conclusion, more publications mention the PA level as a marker of nutrition rather than inflammation. This is in contrast to several general reviews on albumin and nutritional guidelines, which state that the PA level is a marker of inflammation but not nutrition. Hypoalbuminemia should prompt clinicians to focus on the inflammatory aspects in their patients.
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Affiliation(s)
- Kim Oren Gradel
- Center for Clinical Epidemiology, Odense University Hospital, 5000 Odense, Denmark; ; Tel.: +45-21-15-80-85
- Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark
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26
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Liu B, Gao S, Guo J, Kou F, Liu S, Zhang X, Wang X, Cao G, Chen H, Liu P, Xu H, Gao Q, Yang R, Zhu X. A Novel Nomogram for Predicting the Overall Survival in Patients with Unresectable HCC after TACE plus Hepatic Arterial Infusion Chemotherapy. Transl Oncol 2023; 34:101705. [PMID: 37257332 PMCID: PMC10245107 DOI: 10.1016/j.tranon.2023.101705] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/14/2023] [Accepted: 05/23/2023] [Indexed: 06/02/2023] Open
Abstract
BACKGROUND AND AIM Transarterial chemoembolization combined with hepatic arterial infusion chemotherapy (TACE-HAIC) has shown encouraging efficacy in the treatment of unresectable hepatocellular carcinoma (HCC). We aimed to develop a novel nomogram to predict overall survival (OS) of patients with unresectable HCC treated with TACE-HAIC. METHODS A total of 591 patients with unresectable HCC treated with TACE-HAIC between May 2009 and September 2020 were enrolled. These patients were randomly divided into training and validation cohorts. The independent prognostic factors were identified with Cox proportional hazards model. The model's discriminative ability and accuracy were validated using concordance index (C-index), calibration plots, the area under the time-dependent receiver operating characteristic curve (AUC) and decision curve analyses (DCAs). RESULTS The median OS was 15.6 months. A nomogram was established based on these factors, including tumor size, vein invasion, extrahepatic metastasis, tumor number, alpha fetoprotein (AFP), and albumin-bilirubin (ALBI), to predict OS for patients with unresectable HCC treated with TACE-HAIC. The C-index of the nomogram were 0.717 in the training cohort and 0.724 in validation cohort. The calibration plots demonstrated good agreement between the predicted outcomes and the actual observations. The AUC values were better than those of three conventional staging systems. The results of DCA indicated that the nomogram may have clinical usefulness. The patients in the low-risk group had a longer OS than those in intermediate-risk and high-risk groups (P<0.001). CONCLUSION A prognostic nomogram was developed and validated to assist clinicians in accurately predicting the OS of patients with unresectable HCC after TACE-HAIC.
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Affiliation(s)
- Baojiang Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Song Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jianhai Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Fuxin Kou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Shaoxing Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xin Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaodong Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Guang Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hui Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Peng Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Haifeng Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Qinzong Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Renjie Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xu Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China.
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27
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Zhang H, Zeng SL, Wu YZ, Zhang RX, Liu LJ, Xue Q, Chen JQ, Wong KKY, Xu JF, Ren YG, Fang CH, Liu CB. Handheld photoacoustic imaging of indocyanine green clearance for real-time quantitative evaluation of liver reserve function. BIOMEDICAL OPTICS EXPRESS 2023; 14:3610-3621. [PMID: 37497492 PMCID: PMC10368033 DOI: 10.1364/boe.493538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/25/2023] [Accepted: 06/09/2023] [Indexed: 07/28/2023]
Abstract
Preoperative assessment of liver function reserve (LFR) is essential for determining the extent of liver resection and predicting the prognosis of patients with liver disease. In this paper, we present a real-time, handheld photoacoustic imaging (PAI) system-based noninvasive approach for rapid LFR assessment. A linear-array ultrasound transducer was sealed in a housing filled with water; its front end was covered with a plastic wrap. This PAI system was first implemented on phantoms to confirm that the photoacoustic (PA) intensity of indocyanine green (ICG) in blood reflects the concentration of ICG in blood. In vivo studies on normal rabbits and rabbits with liver fibrosis were carried out by recording the dynamic PA signal of ICG in their jugular veins. By analyzing the PA intensity-time curve, a clear difference was identified in the pharmacokinetic behavior of ICG between the two groups. In normal rabbits, the mean ICG clearance rate obtained by PAI at 15 min after administration (PAI-R15) was below 21.6%, whereas in rabbits with liver fibrosis, PAI-R15 exceeded 62.0% because of poor liver metabolism. The effectiveness of the proposed method was further validated by the conventional ICG clearance test and pathological examination. Our findings suggest that PAI is a rapid, noninvasive, and convenient method for LFR assessment and has immense potential for assisting clinicians in diagnosing and managing patients with liver disease.
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Affiliation(s)
- Hai Zhang
- Department of Ultrasound, Shenzhen People's Hospital, The Second Clinical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China
| | - Si-Lue Zeng
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
- Research Laboratory for Biomedical Optics and Molecular Imaging, CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Yun-Zhu Wu
- Department of Ultrasound, Shenzhen People's Hospital, The Second Clinical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China
- Research Laboratory for Biomedical Optics and Molecular Imaging, CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- Department of Ultrasound, West China Second University Hospital, Sichuan University, SiChuan 610044, China
| | - Ruo-Xin Zhang
- Shen Zhen Bay Laboratory, Guang Ming, ShenZhen,518000, China
| | - Liang-Jian Liu
- Research Laboratory for Biomedical Optics and Molecular Imaging, CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Qiang Xue
- Department of Ultrasound, Shenzhen People's Hospital, The Second Clinical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China
- Research Laboratory for Biomedical Optics and Molecular Imaging, CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Jing-Qin Chen
- Research Laboratory for Biomedical Optics and Molecular Imaging, CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Kenneth K Y Wong
- The University of Hong Kong, Department of Electrical and Electronic Engineering, Hong Kong, China
| | - Jin-Feng Xu
- Department of Ultrasound, Shenzhen People's Hospital, The Second Clinical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China
| | - Ya-Guang Ren
- Research Laboratory for Biomedical Optics and Molecular Imaging, CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Chi-Hua Fang
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Cheng-Bo Liu
- Research Laboratory for Biomedical Optics and Molecular Imaging, CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
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28
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Kollipara S, Ahmed T, Praveen S. Physiologically based pharmacokinetic modeling (PBPK) to predict drug-drug interactions for encorafenib. Part II. Prospective predictions in hepatic and renal impaired populations with clinical inhibitors and inducers. Xenobiotica 2023; 53:339-356. [PMID: 37584612 DOI: 10.1080/00498254.2023.2246153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/06/2023] [Accepted: 08/06/2023] [Indexed: 08/17/2023]
Abstract
Encorafenib, a potent BRAF kinase inhibitor gets significantly metabolised by CYP3A4 (83%) and CYP2C19 (16%) and is a substrate for P-glycoprotein (P-gp). Due to significant metabolism by CYP3A4, encorafenib exposure can increase in hepatic and renal impairment and may lead to altered magnitude of drug-drug interactions (DDI). Hence, it is necessary to assess the exposures & DDI's in impaired population.Physiologically based pharmacokinetic modelling (PBPK) was utilised to determine the exposures of encorafenib in hepatic and renal impairment along with altered DDI's. Prospective DDI's were predicted with USFDA recommended clinical CYP3A4, CYP2C19, P-gp inhibitors and CYP3A4 inducers.PBPK models for encorafenib, perpetrators simulated PK parameters within 2-folds error. Encorafenib exposures significantly increased in hepatic as compared to renal impairment because of reduced CYP3A4 levels.Hepatic impairment caused changes in inhibition and induction DDI's, when compared to healthy population. Renal impairment did not cause significant changes in DDIs except for itraconazole. P-gp, CYP2C19 inhibitors did not result in altered DDI's. The DDI's were found to have insignificant correlation with relative exposure increase of perpetrators in case of impairment. Overall, this work signifies use of PBPK modelling for DDI's evaluations in hepatic and renal impairment populations.
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Affiliation(s)
- Sivacharan Kollipara
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh, India
| | - Tausif Ahmed
- Biopharmaceutics Group, Global Clinical Management, Dr. Reddy's Laboratories Ltd., Integrated Product Development Organization (IPDO), Hyderabad, Telangana, India
| | - Sivadasu Praveen
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh, India
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29
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Murphy WA, Adiwidjaja J, Sjöstedt N, Yang K, Beaudoin JJ, Spires J, Siler SQ, Neuhoff S, Brouwer KLR. Considerations for Physiologically Based Modeling in Liver Disease: From Nonalcoholic Fatty Liver (NAFL) to Nonalcoholic Steatohepatitis (NASH). Clin Pharmacol Ther 2023; 113:275-297. [PMID: 35429164 PMCID: PMC10083989 DOI: 10.1002/cpt.2614] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 04/05/2022] [Indexed: 01/27/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), representing a clinical spectrum ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), is rapidly evolving into a global pandemic. Patients with NAFLD are burdened with high rates of metabolic syndrome-related comorbidities resulting in polypharmacy. Therefore, it is crucial to gain a better understanding of NAFLD-mediated changes in drug disposition and efficacy/toxicity. Despite extensive clinical pharmacokinetic data in cirrhosis, current knowledge concerning pharmacokinetic alterations in NAFLD, particularly at different stages of disease progression, is relatively limited. In vitro-to-in vivo extrapolation coupled with physiologically based pharmacokinetic and pharmacodynamic (IVIVE-PBPK/PD) modeling offers a promising approach for optimizing pharmacologic predictions while refining and reducing clinical studies in this population. Use of IVIVE-PBPK to predict intra-organ drug concentrations at pharmacologically relevant sites of action is particularly advantageous when it can be linked to pharmacodynamic effects. Quantitative systems pharmacology/toxicology (QSP/QST) modeling can be used to translate pharmacokinetic and pharmacodynamic data from PBPK/PD models into clinically relevant predictions of drug response and toxicity. In this review, a detailed summary of NAFLD-mediated alterations in human physiology relevant to drug absorption, distribution, metabolism, and excretion (ADME) is provided. The application of literature-derived physiologic parameters and ADME-associated protein abundance data to inform virtual NAFLD population development and facilitate PBPK/PD, QSP, and QST predictions is discussed along with current limitations of these methodologies and knowledge gaps. The proposed methodologic framework offers great potential for meaningful prediction of pharmacological outcomes in patients with NAFLD and can inform both drug development and clinical practice for this population.
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Affiliation(s)
- William A Murphy
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jeffry Adiwidjaja
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Simulations Plus, Inc., Lancaster, California, USA
| | - Noora Sjöstedt
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Kyunghee Yang
- DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
| | - James J Beaudoin
- DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
| | | | - Scott Q Siler
- DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, North Carolina, 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, North Carolina, USA
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30
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Ladumor MK, Storelli F, Liang X, Lai Y, Enogieru OJ, Chothe PP, Evers R, Unadkat J. Predicting changes in the pharmacokinetics of CYP3A-metabolized drugs in hepatic impairment and insights into factors driving these changes. CPT Pharmacometrics Syst Pharmacol 2022; 12:261-273. [PMID: 36540952 PMCID: PMC9931433 DOI: 10.1002/psp4.12901] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/07/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022] Open
Abstract
Physiologically based pharmacokinetic models, populated with drug-metabolizing enzyme and transporter (DMET) abundance, can be used to predict the impact of hepatic impairment (HI) on the pharmacokinetics (PK) of drugs. To increase confidence in the predictive power of such models, they must be validated by comparing the predicted and observed PK of drugs in HI obtained by phenotyping (or probe drug) studies. Therefore, we first predicted the effect of all stages of HI (mild to severe) on the PK of drugs primarily metabolized by cytochrome P450 (CYP) 3A enzymes using the default HI module of Simcyp Version 21, populated with hepatic and intestinal CYP3A abundance data. Then, we validated the predictions using CYP3A probe drug phenotyping studies conducted in HI. Seven CYP3A substrates, metabolized primarily via CYP3A (fraction metabolized, 0.7-0.95), with low to high hepatic availability, were studied. For all stages of HI, the predicted PK parameters of drugs were within twofold of the observed data. This successful validation increases confidence in using the DMET abundance data in HI to predict the changes in the PK of drugs cleared by DMET for which phenotyping studies in HI are not available or cannot be conducted. In addition, using CYP3A drugs as an example, through simulations, we identified the salient PK factors that drive the major changes in exposure (area under the plasma concentration-time profile curve) to drugs in HI. This theoretical framework can be applied to any drug and DMET to quickly determine the likely magnitude of change in drug PK due to HI.
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Affiliation(s)
- Mayur K. Ladumor
- Department of PharmaceuticsUniversity of Washington School of PharmacySeattleWashingtonUSA
| | - Flavia Storelli
- Department of PharmaceuticsUniversity of Washington School of PharmacySeattleWashingtonUSA
| | - Xiaomin Liang
- Drug MetabolismGilead Sciences Inc.Foster CityCaliforniaUSA
| | - Yurong Lai
- Drug MetabolismGilead Sciences Inc.Foster CityCaliforniaUSA
| | | | - Paresh P. Chothe
- Global Drug Metabolism and PharmacokineticsTakeda Development Center USA, Inc.LexingtonMassachusettsUSA
| | - Raymond Evers
- Preclinical Sciences and Translational SafetyJanssen Research & Development, LLCSpring HousePennsylvaniaUSA
| | - Jashvant D. Unadkat
- Department of PharmaceuticsUniversity of Washington School of PharmacySeattleWashingtonUSA
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Lin J, Kimoto E, Yamazaki S, Vourvahis M, Bergman A, Rodrigues AD, Costales C, Li R, Varma MVS. Effect of Hepatic Impairment on OATP1B Activity: Quantitative Pharmacokinetic Analysis of Endogenous Biomarker and Substrate Drugs. Clin Pharmacol Ther 2022; 113:1058-1069. [PMID: 36524426 DOI: 10.1002/cpt.2829] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022]
Abstract
Hepatic impairment (HI) is known to modulate drug disposition and may lead to elevated plasma exposure. The aim of this study was to quantitate the in vivo OATP1B-mediated hepatic uptake activity in populations with varying degrees of HI. First, we measured baseline levels of plasma coproporphyrin-I, an endogenous OATP1B biomarker, in an open-label, parallel cohort study in adult subjects with normal liver function and mild, moderate, and severe HI (n = 24, 6/cohort). The geometric mean plasma concentrations of coproporphyrin-I were 1.66-fold, 2.81-fold (P < 0.05), and 7.78-fold (P < 0.0001) higher in mild, moderate, and severe impairment than those healthy controls. Second, we developed a dataset of 21 OATP1B substrate drugs with HI data extracted from literature. Median disease-to-healthy plasma area under the curve (AUC) ratios for substrate drugs were ~ 1.4, 3.0, and 6.4 for mild, moderate, and severe HI, respectively. Additionally, significant linear relationship was noted between AUC ratios of substrate drugs without and with co-administration of rifampin, a prototypic OATP1B inhibitor, and AUC ratios in moderate (P < 0.01) and severe (P < 0.001) HI. Third, a physiologically-based pharmacokinetic model analysis was conducted with 10 substrate drugs following estimation of relative OATP1B functional activity in virtual disease population models using coproporphyrin-I data and verification of substrate models with rifampin drug-drug interaction data. This approach adequately predicted plasma AUC change particularly in moderate (9 of 10 within 2-fold) and severe (5 of 5 within 2-fold) HI. Collective findings indicate progressive reduction, by as much as 90-92%, in OATP1B activity in the HI population.
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Affiliation(s)
- Jian Lin
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, Connecticut, USA
| | - Emi Kimoto
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, Connecticut, USA
| | - Shinji Yamazaki
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc., San Diego, California, USA
| | - Manoli Vourvahis
- Clinical Pharmacology, Global Product Development, Pfizer Inc., New York, New York, USA
| | - Arthur Bergman
- Clinical Pharmacology, Early Clinical Development, Pfizer Inc., Cambridge, Massachusetts, USA
| | - A David Rodrigues
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, Connecticut, USA
| | - Chester Costales
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, Connecticut, USA
| | - Rui Li
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc., Cambridge, Massachusetts, USA
| | - Manthena V S Varma
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, Connecticut, USA
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Vijaywargi G, Kollipara S, Ahmed T, Chachad S. Predicting transporter mediated drug-drug interactions via static and dynamic physiologically based pharmacokinetic modeling: A comprehensive insight on where we are now and the way forward. Biopharm Drug Dispos 2022. [PMID: 36413625 DOI: 10.1002/bdd.2339] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 10/07/2022] [Accepted: 11/04/2022] [Indexed: 11/23/2022]
Abstract
The greater utilization and acceptance of physiologically-based pharmacokinetic (PBPK) modeling to evaluate the potential metabolic drug-drug interactions is evident by the plethora of literature, guidance's, and regulatory dossiers available in the literature. In contrast, it is not widely used to predict transporter-mediated DDI (tDDI). This is attributed to the unavailability of accurate transporter tissue expression levels, the absence of accurate in vitro to in vivo extrapolations (IVIVE), enzyme-transporter interplay, and a lack of specific probe substrates. Additionally, poor understanding of the inhibition/induction mechanisms coupled with the inability to determine unbound concentrations at the interaction site made tDDI assessment challenging. Despite these challenges, continuous improvements in IVIVE approaches enabled accurate tDDI predictions. Furthermore, the necessity of extrapolating tDDI's to special (pediatrics, pregnant, geriatrics) and diseased (renal, hepatic impaired) populations is gaining impetus and is encouraged by regulatory authorities. This review aims to visit the current state-of-the-art and summarizes contemporary knowledge on tDDI predictions. The current understanding and ability of static and dynamic PBPK models to predict tDDI are portrayed in detail. Peer-reviewed transporter abundance data in special and diseased populations from recent publications were compiled, enabling direct input into modeling tools for accurate tDDI predictions. A compilation of regulatory guidance's for tDDI's assessment and success stories from regulatory submissions are presented. Future perspectives and challenges of predicting tDDI in terms of in vitro system considerations, endogenous biomarkers, the use of empirical scaling factors, enzyme-transporter interplay, and acceptance criteria for model validation to meet the regulatory expectations were discussed.
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Affiliation(s)
- Gautam Vijaywargi
- Biopharmaceutics Group, Global Clinical Management, Dr. Reddy's Laboratories Ltd., Integrated Product Development Organization (IPDO), Hyderabad, Telangana, India
| | - Sivacharan Kollipara
- Biopharmaceutics Group, Global Clinical Management, Dr. Reddy's Laboratories Ltd., Integrated Product Development Organization (IPDO), Hyderabad, Telangana, India
| | - Tausif Ahmed
- Biopharmaceutics Group, Global Clinical Management, Dr. Reddy's Laboratories Ltd., Integrated Product Development Organization (IPDO), Hyderabad, Telangana, India
| | - Siddharth Chachad
- Biopharmaceutics Group, Global Clinical Management, Dr. Reddy's Laboratories Ltd., Integrated Product Development Organization (IPDO), Hyderabad, Telangana, India
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A Physiologically Based Pharmacokinetic Model to Predict the Impact of Metabolic Changes Associated with Metabolic Associated Fatty Liver Disease on Drug Exposure. Int J Mol Sci 2022; 23:ijms231911751. [PMID: 36233052 PMCID: PMC9570165 DOI: 10.3390/ijms231911751] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/09/2022] [Accepted: 09/26/2022] [Indexed: 11/17/2022] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease, with an estimated prevalence of between 20 and 30% worldwide. Observational data supported by in vitro and pre-clinical animal models of MAFLD suggest meaningful differences in drug disposition in MAFLD patients. This study aimed to build a physiologically based pharmacokinetic (PBPK) model reflecting observed changes in physiological and molecular parameters relevant to drug disposition that are associated with MAFLD. A comprehensive literature review and meta-analysis was conducted to identify all studies describing in vivo physiological changes along with in vitro and pre-clinical model changes in CYP 1A2, 2C9, 2C19, 2D6 and 3A4 protein abundance associated with MAFLD. A MAFLD population profile was constructed in Simcyp (version 19.1) by adapting demographic and physiological covariates from the Sim-Healthy population profile based on a meta-analysis of observed data from the published literature. Simulations demonstrated that single dose and steady state area under the plasma concentration time curve (AUC) for caffeine, clozapine, omeprazole, metoprolol, dextromethorphan and midazolam, but not s-warfarin or rosiglitazone, were increased by >20% in the MAFLD population compared to the healthy control population. These findings indicate that MAFLD patients are likely to be experience meaningfully higher exposure to drugs that are primarily metabolized by CYP 1A2, 2C19, 2D6 and 3A4, but not CYP2C9. Closer monitoring of MAFLD patients using drugs primarily cleared by CYP 1A2, 2C19 and 3A4 is warranted as reduced metabolic activity and increased drug exposure are likely to result in an increased incidence of toxicity in this population.
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Sun LY, Jia HD, Liang L, Huang DS, Yang T. Letter: sex disparities in presentation and prognosis of 1110 patients with hepatocellular carcinoma. Aliment Pharmacol Ther 2022; 56:552-553. [PMID: 35804470 DOI: 10.1111/apt.16973] [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: 04/17/2022] [Accepted: 05/03/2022] [Indexed: 12/09/2022]
Abstract
LINKED CONTENTThis article is linked to El‐Khateeb et al papers. To view these articles, visit https://doi.org/10.1111/apt.16489This letter is linked to Nicole E. Rich et al's article. To view this article, visit https://doi.org/10.1111/apt.15917.
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Affiliation(s)
- Li-Yang Sun
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
- Graduate Department, Bengbu Medical College, Bengbu, China
| | - Hang-Dong Jia
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Lei Liang
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Dong-Sheng Huang
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
- Graduate Department, Bengbu Medical College, Bengbu, China
- Hangzhou Medical College, Hangzhou, China
| | - Tian Yang
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
- Hangzhou Medical College, Hangzhou, China
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35
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Gao XN, Nie XY, Gao JL, Heng TF, Zhang YQ, Hua L, Sun YQ, Feng ZY, Wang MX, Jia L. Pharmacokinetic Study of Nalbuphine in Surgical Patients Undergoing General Anesthesia with Varying Degrees of Liver Dysfunction. Drug Des Devel Ther 2022; 16:2383-2393. [PMID: 35923933 PMCID: PMC9341258 DOI: 10.2147/dddt.s371596] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/09/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose This study aimed to characterize the pharmacokinetics of nalbuphine in patients undergoing general anesthesia with varying degrees of liver dysfunction. Patients and Methods Twenty-four patients were enrolled and divided into three cohorts based on liver function: normal liver function (n = 13), mild liver dysfunction (n = 5), and moderate/severe liver dysfunction (n = 6). During the induction of anesthesia, they received 15 mg of nalbuphine intravenously. Venous blood samples were collected from each patient. The plasma concentration of nalbuphine was determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of nalbuphine were calculated by non-compartmental analysis (NCA) using Phoenix WinNonlin software. Results Compared with the normal liver function group, the plasma elimination half-life (T1/2) of nalbuphine was increased by approximately 33% in the moderate/severe liver dysfunction group (2.66 h vs 3.54 h, P<0.05), and the volume of distribution (Vd) increased by approximately 85% (100.08 L vs 184.95 L, P<0.05). Multivariate analysis revealed that weight and platelet were associated with clearance (CL); total bilirubin as an independent factor was associated with T1/2, and weight associated with area under the curve (AUC(0→∞)) independently. Conclusion The T1/2, mean residence time, and Vd of nalbuphine in patients with moderate/severe liver dysfunction were prolonged or increased significantly compared with those in the normal liver function group. These data suggest that it may need to be used with caution when nalbuphine is administered to patients with moderate or severe liver dysfunction.
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Affiliation(s)
- Xiao-nan Gao
- Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Xu-yang Nie
- Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Jing-lin Gao
- Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Tian-fang Heng
- Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Yu-qi Zhang
- Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Li Hua
- Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Ya-qi Sun
- Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Zhang-ying Feng
- Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Ming-xia Wang
- Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
- Correspondence: Ming-xia Wang, Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, People’s Republic of China, Tel +86 311-66696233, Email
| | - Li Jia
- Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
- Li Jia, Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, People’s Republic of China, Email
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Applications, Challenges, and Outlook for PBPK Modeling and Simulation: A Regulatory, Industrial and Academic Perspective. Pharm Res 2022; 39:1701-1731. [PMID: 35552967 DOI: 10.1007/s11095-022-03274-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/25/2022] [Indexed: 12/20/2022]
Abstract
Several regulatory guidances on the use of physiologically based pharmacokinetic (PBPK) analyses and physiologically based biopharmaceutics model(s) (PBBM(s)) have been issued. Workshops are routinely held, demonstrating substantial interest in applying these modeling approaches to address scientific questions in drug development. PBPK models and PBBMs have remarkably contributed to model-informed drug development (MIDD) such as anticipating clinical PK outcomes affected by extrinsic and intrinsic factors in general and specific populations. In this review, we proposed practical considerations for a "base" PBPK model construction and development, summarized current status, challenges including model validation and gaps in system models, and future perspectives in PBPK evaluation to assess a) drug metabolizing enzyme(s)- or drug transporter(s)- mediated drug-drug interactions b) dosing regimen prediction, sampling timepoint selection and dose validation in pediatric patients from newborns to adolescents, c) drug exposure in patients with renal and/or and hepatic organ impairment, d) maternal-fetal drug disposition during pregnancy, and e) pH-mediated drug-drug interactions in patients treated with proton pump inhibitors/acid-reducing agents (PPIs/ARAs) intended for gastric protection. Since PBPK can simulate outcomes in clinical studies with enrollment challenges or ethical issues, the impact of PBPK models on waivers and how to strengthen study waiver is discussed.
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37
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Vasilogianni AM, El-Khateeb E, Al-Majdoub ZM, Alrubia S, Rostami-Hodjegan A, Barber J, Achour B. Proteomic quantification of perturbation to pharmacokinetic target proteins in liver disease. J Proteomics 2022; 263:104601. [DOI: 10.1016/j.jprot.2022.104601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 04/06/2022] [Accepted: 04/25/2022] [Indexed: 10/18/2022]
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El-Khateeb E, Achour B, Al-Majdoub ZM, Barber J, Rostami-Hodjegan A. Non-uniformity of Changes in Drug-Metabolizing Enzymes and Transporters in Liver Cirrhosis: Implications for Drug Dosage Adjustment. Mol Pharm 2021; 18:3563-3577. [PMID: 34428046 PMCID: PMC8424631 DOI: 10.1021/acs.molpharmaceut.1c00462] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
![]()
Liver cirrhosis is
a chronic disease that affects the liver structure,
protein expression, and overall metabolic function. Abundance data
for drug-metabolizing enzymes and transporters (DMET) across all stages
of disease severity are scarce. Levels of these proteins are crucial
for the accurate prediction of drug clearance in hepatically impaired
patients using physiologically based pharmacokinetic (PBPK) models,
which can be used to guide the selection of more precise dosing. This
study aimed to experimentally quantify these proteins in human liver
samples and assess how they can impact the predictive performance
of the PBPK models. We determined the absolute abundance of 51 DMET
proteins in human liver microsomes across the three degrees of cirrhosis
severity (n = 32; 6 mild, 13 moderate, and 13 severe),
compared to histologically normal controls (n = 14),
using QconCAT-based targeted proteomics. The results revealed a significant
but non-uniform reduction in the abundance of enzymes and transporters,
from control, by 30–50% in mild, 40–70% in moderate,
and 50–90% in severe cirrhosis groups. Cancer and/or non-alcoholic
fatty liver disease-related cirrhosis showed larger deterioration
in levels of CYP3A4, 2C8, 2E1, 1A6, UGT2B4/7, CES1, FMO3/5, EPHX1,
MGST1/3, BSEP, and OATP2B1 than the cholestasis set. Drug-specific
pathways together with non-uniform changes of abundance across the
enzymes and transporters under various degrees of cirrhosis necessitate
the use of PBPK models. As case examples, such models for repaglinide,
dabigatran, and zidovudine were successful in recovering disease-related
alterations in drug exposure. In conclusion, the current study provides
the biological rationale behind the absence of a single dose adjustment
formula for all drugs in cirrhosis and demonstrates the utility of
proteomics-informed PBPK modeling for drug-specific dose adjustment
in liver cirrhosis.
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Affiliation(s)
- Eman El-Khateeb
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester M13 9PT, U.K.,Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Brahim Achour
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester M13 9PT, U.K
| | - Zubida M Al-Majdoub
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester M13 9PT, U.K
| | - Jill Barber
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester M13 9PT, U.K
| | - Amin Rostami-Hodjegan
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester M13 9PT, U.K.,Certara UK Ltd. (Simcyp Division), Sheffield S1 2BJ, U.K
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39
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El-Khateeb E, Al-Majdoub ZM, Rostami-Hodjegan A, Barber J, Achour B. Proteomic Quantification of Changes in Abundance of Drug-Metabolizing Enzymes and Drug Transporters in Human Liver Cirrhosis: Different Methods, Similar Outcomes. Drug Metab Dispos 2021; 49:610-618. [PMID: 34045218 DOI: 10.1124/dmd.121.000484] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
Model-based assessment of the effects of liver disease on drug pharmacokinetics requires quantification of changes in enzymes and transporters responsible for drug metabolism and disposition. Different proteomic methods are currently used for protein quantification in tissues and in vitro systems, each with specific procedures and requirements. The outcome of quantitative proteomic assays using four different methods (one targeted and three label-free) applied to the same sample set was compared in this study. Three pooled cirrhotic liver microsomal samples corresponding to cirrhosis with nonalcoholic fatty liver disease, biliary disease, or cancer and a control microsomal pool were analyzed using quantification concatemer-based targeted proteomics, the total protein approach (TPA), high three ion intensity (Hi3) approach, and intensity-based absolute quantification (iBAQ) to determine the absolute and relative abundance in disease compared with control. The relative abundance data provided a "disease perturbation factor" (DPF) for each target protein. Absolute and relative abundances generated by standard-based label-free methods (iBAQ and Hi3) showed good agreement with targeted proteomics (limited bias and scatter), but TPA (standard-free method) overestimated absolute abundances by approximately 2-fold. The DPF was consistent between different proteomic methods but varied between enzymes and transporters, indicating discordance of effects of cirrhosis on various metabolism-related proteins. The DPF ranged from no change (e.g., for glucuronosyltransferase-1A6 in nonalcoholic fatty liver disease group) to less than 0.3 (e.g., carboxylesterases-1 in cirrhosis of biliary origin). SIGNIFICANCE STATEMENT: This study demonstrated that relative changes in enzymes and transporters (DPF) are independent of the quantitative proteomic methods used. Standard-based label-free methods, such as high three ion intensity (Hi3) and intensity-based absolute quantification (iBAQ) methods, were less biased and more precise than the total protein approach (TPA) when compared with targeted data. The DPF reconciled differences across proteomic methods observed with absolute levels. Using this approach, differences were revealed in the expression of enzymes/transporters in cirrhosis associated with different etiologies.
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Affiliation(s)
- Eman El-Khateeb
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, UK (E.E.-K., Z.M.A.-M., A.R.-H., J.B., B.A.); Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt (E.E.-K.); and Certara UK Ltd. (Simcyp Division), Sheffield, UK (A.R.-H.)
| | - Zubida M Al-Majdoub
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, UK (E.E.-K., Z.M.A.-M., A.R.-H., J.B., B.A.); Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt (E.E.-K.); and Certara UK Ltd. (Simcyp Division), Sheffield, UK (A.R.-H.)
| | - Amin Rostami-Hodjegan
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, UK (E.E.-K., Z.M.A.-M., A.R.-H., J.B., B.A.); Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt (E.E.-K.); and Certara UK Ltd. (Simcyp Division), Sheffield, UK (A.R.-H.)
| | - Jill Barber
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, UK (E.E.-K., Z.M.A.-M., A.R.-H., J.B., B.A.); Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt (E.E.-K.); and Certara UK Ltd. (Simcyp Division), Sheffield, UK (A.R.-H.)
| | - Brahim Achour
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, UK (E.E.-K., Z.M.A.-M., A.R.-H., J.B., B.A.); Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt (E.E.-K.); and Certara UK Ltd. (Simcyp Division), Sheffield, UK (A.R.-H.)
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