Expanded 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

Abstract

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 (DDIs). We previously constructed a physiologically‐based pharmacokinetic (PBPK) model of rifampicin accounting for the components for the induction of cytochrome P450 (CYP) 3A/CYP2C9 and the inhibition of organic anion transporting polypeptide 1B (OATP1B). This study aimed to expand and verify the PBPK model for rifampicin by incorporating additional components for the induction of OATP1B and CYP2C8 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 OATP1B activities) with various dosing regimens. Our comprehensive rifampicin PBPK model may enable quantitative prediction of DDIs across diverse potential victim drugs and endogenous biomarkers handled by multiple metabolizing enzymes and transporters.

Substantially Increased Plasma Coproporphyrin‐I Concentrations Associated With OATP1B1*15 Allele in Japanese General Population

“…22 In fact, CP-I was used for OATP1B activity phenotyping in clinical drug-drug interaction studies 24,[37][38][39] and in model-based analysis of drug-drug interactions. 23,[40][41][42] Three previous studies reported the relationship between plasma CP-I concentrations and OATP1B1 polymorphism, but the numbers of participants in all studies were insufficient to detect significant differences among the genotypes. 25,27,28 In the present study of a large sample from the Japanese Hepatic failure decreased mRNA levels of OATPs in liver biopsy specimens in a previous study.…”

“…Currently, CP‐I is assumed to be the most sensitive and specific biomarker for phenotyping of OATP1B activity compared with the other endogenous biomarkers and probe drugs, such as HMG‐CoA reductase inhibitors 22 . In fact, CP‐I was used for OATP1B activity phenotyping in clinical drug‐drug interaction studies 24,37–39 and in model‐based analysis of drug‐drug interactions 23,40–42 . Three previous studies reported the relationship between plasma CP‐I concentrations and OATP1B1 polymorphism, but the numbers of participants in all studies were insufficient to detect significant differences among the genotypes 25,27,28 .…”

Intestinal P‐gp and Putative Hepatic OATP1B Induction: International Transporter Consortium Perspective on Drug Development Implications

“…Incorporation of OATP1B induction into PBPK models for the OATP1B substrates glibenclamide, repaglinide, and coproporphyrin I more accurately described the clinically observed interactions following multiple-dose rifampin administration than models incorporating only CYP induction and OATP1B inhibition. 21 Nonetheless, improved PBPK model fit can only support a hypothesis, but does not provide unequivocal mechanistic proof of a DDI mechanism.…”

Evaluation of Pharmacokinetic Drug–Drug Interactions: A Review of the Mechanisms, In Vitro and In Silico Approaches

“…For the perpetrator PBPK model, it is crucial to correctly predict the unbound concentrations at the site of the drug interaction (e.g., intestine, liver, or kidneys) and provide accurate estimates of the interaction parameters (e.g., K i , E max ). The above aspects are of key importance to simultaneously evaluate multiple inhibitions and induction mechanisms and to accurately predict the potential of DDIs [ 81 , 82 ].…”

“…For enzyme-based metabolism, Equation (18) shows the CL μ,int of the victim drug in the absence of the perpetrator, and Equation (19) indicates the dynamic changes of the CL μ,int of the victim drug in the presence of the perpetrator. Regarding the transporter-mediated elimination, the impact of the perpetrator on the PS uptake and/or PS efflux of the victim drug can be determined in a similar way as CL μ,int [ 82 ]. If intestine clearance can be ignored and CL μ,int,h in the liver is known, CL μ,int , PS uptake , and PS efflux can be obtained from Equation (11) (“extended clearance concept”) via back-calculation.…”