Open AccessExpanded Physiologically‐Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction
Author(s) -
Asaumi Ryuta,
Menzel Karsten,
Lee Wooin,
Nunoya Kenichi,
Imawaka Haruo,
Kusuhara Hiroyuki,
Sugiyama Yuichi
Publication year - 2019
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12457
Subject(s) - endogeny , biomarker , organic anion transporting polypeptide , pharmacokinetics , chemistry , rifampicin , pharmacology , biology , biochemistry , antibiotics , transporter , gene
As rifampicin can cause the induction and inhibition of multiple metabolizing enzymes and transporters, it has been challenging to accurately predict the complex drug–drug interactions ( DDI s). We previously constructed a physiologically‐based pharmacokinetic ( PBPK ) model of rifampicin accounting for the components for the induction of cytochrome P450 ( CYP ) 3A/ CYP 2C9 and the inhibition of organic anion transporting polypeptide 1B ( OATP 1B). This study aimed to expand and verify the PBPK model for rifampicin by incorporating additional components for the induction of OATP 1B and CYP 2C8 and the inhibition of multidrug resistance protein 2. The established PBPK model was capable of accurately predicting complex rifampicin‐induced alterations in the profiles of glibenclamide, repaglinide, and coproporphyrin I (an endogenous biomarker of OATP 1B activities) with various dosing regimens. Our comprehensive rifampicin PBPK model may enable quantitative prediction of DDI s across diverse potential victim drugs and endogenous biomarkers handled by multiple metabolizing enzymes and transporters.