Gaining Mechanistic Insight Into Coproporphyrin I as Endogenous Biomarker for OATP1B-Mediated Drug-Drug Interactions Using Population Pharmacokinetic Modeling and Simulation.

Shelby Barnett,Hong Shen,Yurong Lai,W Griffith Humphreys,Karelle Ménochet,Aleksandra Galetin,Kayode Ogungbenro

doi:10.1002/cpt.983

Abstract

This study evaluated coproporphyrin I (CPI) as a selective endogenous biomarker of OATP1B‐mediated drug–drug interactions (DDIs) relative to clinical probe rosuvastatin using nonlinear mixed‐effect modeling. Plasma and urine CPI data in the presence/absence of rifampicin were modeled to describe CPI synthesis, elimination clearances, and obtain rifampicin in vivo OATP Ki. The biomarker showed stable interoccasion baseline concentrations and low interindividual variability (<25%) in subjects with wildtype SLCO1B1. Biliary excretion was the dominant CPI elimination route (maximal >85%). Estimated rifampicin in vivo unbound OATP Ki (0.13 μM) using CPI data was 2‐fold lower relative to rosuvastatin. Model‐based simulations and power calculations confirmed sensitivity of CPI to identify moderate and weak OATP1B inhibitors in an adequately powered clinical study. Current analysis provides the most detailed evaluation of CPI as an endogenous OATP1B biomarker to support optimal DDI study design; further pharmacogenomic and DDI data with a panel of inhibitors are required.

Highlights

This study evaluated coproporphyrin I (CPI) as a selective endogenous biomarker of OATP1B-mediated drug–drug interactions (DDIs) relative to clinical probe rosuvastatin using nonlinear mixed-effect modeling
Study Highlights þ WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? CPI is proposed as a promising endogenous biomarker for assessing OATP1B-mediated DDIs, based on increased plasma exposure following administration of a strong Organic anion transporting polypeptides (OATP) inhibitor, rifampicin. þ WHAT QUESTION DID THIS STUDY ADDRESS? A semimechanistic model was developed to evaluate CPI as an endogenous OATP1B biomarker and its synthesis, elimination routes, and selectivity
The model developed was applied to assess sensitivity of CPI to identify moderate and weak OATP1B inhibitors and perform power calculations to guide optimal clinical DDI study design. þ HOW THIS MIGHT CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE Modeling and simulation presented the utility of CPI as a selective endogenous biomarker for investigating weak to potent OATP1Bmediated DDIs in adequately powered clinical DDI study

Summary

Introduction

This study evaluated coproporphyrin I (CPI) as a selective endogenous biomarker of OATP1B-mediated drug–drug interactions (DDIs) relative to clinical probe rosuvastatin using nonlinear mixed-effect modeling. Organic anion transporting polypeptides (OATP) 1B1 and 1B3 play a crucial role in the hepatic uptake of a variety of drugs and are associated with numerous drug–drug interactions (DDIs).[1,2,3,4,5] In recent years there is an increasing interest in identifying suitable endogenous biomarkers for investigation of transporter function and transporter-mediated DDI risk in early drug development.[4,6,7] Such biomarker data, in conjunction with modeling and simulation, would lead to improved prioritization and informed design of subsequent DDI studies with clinical probes and allow simultaneous investigation of multiple transporters. Use of endogenous biomarkers has many potential advantages (e.g., assessment of complex DDIs, evaluation of the interaction risk in patient populations), this approach is associated with a number of challenges, as summarized recently.[4,7]

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