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Dynamically simulating the interaction of midazolam and the CYP3A4 inhibitor itraconazole using individual coupled whole-body physiologically-based pharmacokinetic (WB-PBPK) models by Michaela Vossen; Michael Sevestre; Christoph Niederalt; In-Jin Jang; Stefan Willmann; Andrea N Edginton is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

What is Dynamically simulating the interaction of midazolam and the CYP3A4 inhibitor itraconazole using individual coupled whole-body physiologically-based pharmacokinetic (WB-PBPK) models about?

## Background Drug-drug interactions resulting from the inhibition of an enzymatic process can have serious implications for clinical drug therapy. Quantification of the drugs internal exposure increase upon administration with an inhibitor requires understanding to avoid the drug reaching toxic thresholds. In this study, we aim to predict the effect of the CYP3A4 inhibitors, itraconazole (ITZ) and its primary metabolite, hydroxyitraconazole (OH-ITZ) on the pharmacokinetics of the anesthetic, midazolam (MDZ) and its metabolites, 1' hydroxymidazolam (1OH-MDZ) and 1' hydroxymidazolam glucuronide (1OH-MDZ-Glu) using mechanistic whole body physiologically-based pharmacokinetic simulation models. The model is build on MDZ, 1OH-MDZ and 1OH-MDZ-Glu plasma concentration time data experimentally determined in 19 CYP3A5 genotyped adult male individuals, who received MDZ intravenously in a basal state. The model is then used to predict MDZ, 1OH-MDZ and 1OH-MDZ-Glu concentrations in an CYP3A-inhibited state following ITZ administration. ## Results For the basal state model, three linked WB-PBPK models (MDZ, 1OH-MDZ, 1OH-MDZ-Glu) for each individual were elimination optimized that resulted in M

Who reads Dynamically simulating the interaction of midazolam and the CYP3A4 inhibitor itraconazole using individual coupled whole-body physiologically-based pharmacokinetic (WB-PBPK) models?

Author

Michaela Vossen; Michael Sevestre; Christoph Niederalt; In-Jin Jang; Stefan Willmann; Andrea N Edginton

Publisher

BioMed Central; Springer (Biomed Central Ltd.); [London]: BioMed Central, 2004-; Springer Science and Business Media LLC (ISSN 1742-4682)

Published

2007

Language

EN

ISBN

9781742468235

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)