Gaining mechanistic insight into coproporphyrin I as endogenous biomarker for OATP1B-mediated drug-drug interactions using population pharmacokinetic modelling and simultion

Research output: Research - peer-reviewArticle

  • External authors:
  • Shelby Barnett
  • Karelle Menochet
  • Hong Shen
  • W. Griffith Humphreys

Abstract

This study evaluates coproporphyrin I (CPI) as a selective endogenous biomarker of OATP1B-mediated drug-drug interactions (DDIs) relative to clinical probe rosuvastatin using nonlinear mixed-effect modelling. Plasma and urine CPI data in the presence/absence of rifampicin were modelled to describe CPI synthesis, elimination clearances and obtain rifampicin in vivo OATP Ki. The biomarker showed stable inter-occasion baseline concentrations and low inter-individual variability (<25%) in subjects with wild type SLCO1B1. Biliary excretion was the dominant CPI elimination route (maximal >85%). Estimated rifampicin in vivo unbound OATP Ki (0.13µM) 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 adequately powered clinical study. Current analysis provides the most detailed evaluation of CPI as endogenous OATP1B biomarker to support optimal DDI study design; further pharmacogenomic and DDI data with a panel of inhibitors are required. This study evaluates coproporphyrin I (CPI) as a selective endogenous biomarker of OATP1B-mediated drug-drug interactions (DDIs) relative to clinical probe rosuvastatin using nonlinear mixed-effect modelling. Plasma and urine CPI data in the presence/absence of rifampicin were modelled to describe CPI synthesis, elimination clearances and obtain rifampicin in vivo OATP Ki. The biomarker showed stable inter-occasion baseline concentrations and low inter-individual variability (<25%) in subjects with wild type SLCO1B1. Biliary excretion was the dominant CPI elimination route (maximal >85%). Estimated rifampicin in vivo unbound OATP Ki (0.13µM) 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 adequately powered clinical study. Current analysis provides the most detailed evaluation of CPI as endogenous OATP1B biomarker to support optimal DDI study design; further pharmacogenomic and DDI data with a panel of inhibitors are required.

Bibliographical metadata

Original languageEnglish
Pages (from-to)1-26
JournalClinical Pharmacology & Therapeutics
Early online date15 Dec 2017
DOIs
StatePublished - 2018