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Simultaneously Predicting the Pharmacokinetics of CES1-Metabolized Drugs and Their Metabolites Using Physiologically Based Pharmacokinetic Model in Cirrhosis Subjects
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. Pharmaceutics2024, 16, 234.
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.
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. Pharmaceutics2024, 16, 234.
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.
Abstract
Hepatic carboxylesterase 1(CES1) metabolizes many prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aim to develop a semi-physiologically based pharmacokinetic model(Semi-PBPK model) to simultaneously predict 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. The parameters including organ blood flows, plasma binding protein concentrations, functional liver volume, hepatic enzymatic activity, glomerular filtration rate(GFR) and gastrointestinal transit rate were introduced into the simulation. Pharmacokinetic profiles of these drugs and their active metabolites were simulated in 100 virtual subjects. The developed semi-PBPK model, following validation in healthy subjects, was extrapolated to LC patients. Most of the observations are within the 5% and 95% quantile of simulations from 100 virtual patients. The estimated AUC and Cmax are within 0.5-2-fold of observation. The sensitivity analysis showed that the decreased plasma exposure of active metabolite due to the decreased CES1 was partly attenuated by the decreased GFR. Conclusion: The developed PBPK model has successfully predicted pharmacokinetics of CES1 substrates and their metabolites in healthy subjects and LC patients, which assists in tailoring dosages of CES1 substrates in LC patients.
Keywords
carboxylesterase 1; liver cirrhosis; physiologically based pharmacokinetic model; prodrugs; pharmacokinetics.
Subject
Medicine and Pharmacology, Medicine and Pharmacology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
