PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3

The aim of the present study was to establish a physiologically based pharmacokinetic (PBPK) model for coproporphyrin I (CP‐I), a biomarker supporting the prediction of drug‐drug interactions (DDIs) involving hepatic organic anion transporting polypeptide 1B (OATP1B), using clinical DDI data with an...

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Bibliographic Details
Published in:CPT: pharmacometrics and systems pharmacology 2018-11, Vol.7 (11), p.739-747
Main Authors: Yoshikado, Takashi, Toshimoto, Kota, Maeda, Kazuya, Kusuhara, Hiroyuki, Kimoto, Emi, Rodrigues, A. David, Chiba, Koji, Sugiyama, Yuichi
Format: Article
Language:English
Subjects:
Biomarkers
Biosynthesis
Drug dosages
Liver
Risk assessment
Simulation
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Summary:The aim of the present study was to establish a physiologically based pharmacokinetic (PBPK) model for coproporphyrin I (CP‐I), a biomarker supporting the prediction of drug‐drug interactions (DDIs) involving hepatic organic anion transporting polypeptide 1B (OATP1B), using clinical DDI data with an OATP1B inhibitor rifampicin (300 and 600 mg, orally). The in vivo inhibition constants of rifampicin used as initial input parameters for OATP1Bs (Ki,u,OATP1Bs) and multidrug resistance‐associated protein two‐mediated biliary excretion were estimated as 0.23 and 0.87 μM, respectively, from previous reports. Sensitivity analysis demonstrated that the Ki,u,OATP1Bs and biosynthesis rate of CP‐I affected the magnitude of the interaction. Ki,u,OATP1Bs values optimized by nonlinear least‐squares fitting were ~0.5‐fold of the initial value. It was determined that the blood concentration‐time profiles of four statins were well‐predicted using corrected individual Ki,u,OATP1B values (ratio of in vitro Ki,u(statin)/in vitro Ki,u(CP‐I)). In conclusion, PBPK modeling of CP‐I supports dynamic prediction of OATP1B‐mediated DDIs.
ISSN:2163-8306
2163-8306
DOI:10.1002/psp4.12348