A physiologically based pharmacokinetic drug-disease model to predict carvedilol exposure in adult and paediatric heart failure patients by incorporating pathophysiological changes in hepatic and renal blood flows

Clinical Pharmacokinetics
Muhammad Fawad RasoolStephanie Läer

Abstract

Chronic diseases are associated with pathophysiological changes that could have profound impacts on drug pharmacokinetic behaviour, with a potential need to modify the administered drug therapy. It is important to acknowledge that most patients with chronic illnesses do not have a single, predominant condition but suffer from multiple comorbidities. The rapid advancement in physiologically based pharmacokinetic (PBPK) modelling, as well as the increasing quantitative knowledge of disease-related pathophysiological changes, facilitate building of drug-disease models. However, there are only a few published examples of PBPK models incorporating the pathophysiological changes that occur with chronic diseases. The objective of this study was to develop PBPK models that incorporate the haemodynamic changes in hepatic and renal blood flows occurring in chronic heart failure (CHF) and to evaluate these changes in adults and children, using carvedilol as a model drug. After a comprehensive literature search to select the model input parameters, two PBPK models were developed. Model 1 was based on human liver and intestinal microsome clearances, and model 2 was based on clearance by specific cytochrome P450 enzymes. After evaluation of ...Continue Reading

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Citations

Jun 18, 2016·European Journal of Drug Metabolism and Pharmacokinetics·Muhammad Fawad RasoolStephanie Läer
Jul 5, 2018·The Journal of Pharmacy and Pharmacology·Mariana GuimarãesNikoletta Fotaki
Sep 9, 2018·British Journal of Clinical Pharmacology·Arduino A Mangoni, Elzbieta A Jarmuzewska
Dec 18, 2018·Expert Opinion on Drug Metabolism & Toxicology·Anne SmitsKarel Allegaert
Feb 7, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Marike VisserDawn A Merritt
Sep 8, 2016·Micromachines·Ahmad Rezaei KolahchiAmir Sanati-Nezhad
Feb 29, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Cordula StillhartAnette Müllertz
Oct 13, 2021·Journal of Pharmacokinetics and Pharmacodynamics·Limei ChengGuo-Wei Wei

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Software Mentioned

Simcyp ® Simulator
ADAM
OriginPro
Phoenix WinNonLin
Simcyp ®
Simcyp

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