S. Barnett, K. Ogungbenro, Karelle Ménochet
Jan 17, 2018
Citations
3
Influential Citations
56
Citations
Journal
Clinical Pharmacology and Therapeutics
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.