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

DOI Web Site Web Site 被引用文献11件
  • Shelby Barnett
    Centre for Applied Pharmacokinetic Research University of Manchester UK
  • Kayode Ogungbenro
    Centre for Applied Pharmacokinetic Research University of Manchester UK
  • Karelle Ménochet
    Investigative ADME, UCB Slough UK
  • Hong Shen
    Pharmaceutical Candidate Optimization, Bristol‐Myers Squibb Princeton New Jersey USA
  • Yurong Lai
    Pharmaceutical Candidate Optimization, Bristol‐Myers Squibb Princeton New Jersey USA
  • W. Griffith Humphreys
    Pharmaceutical Candidate Optimization, Bristol‐Myers Squibb Princeton New Jersey USA
  • Aleksandra Galetin
    Centre for Applied Pharmacokinetic Research University of Manchester UK

説明

<jats:p>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 <jats:italic>in vivo</jats:italic> OATP Ki. The biomarker showed stable interoccasion baseline concentrations and low interindividual variability (<25%) in subjects with wildtype <jats:italic>SLCO1B1</jats:italic>. Biliary excretion was the dominant CPI elimination route (maximal >85%). Estimated rifampicin <jats:italic>in vivo</jats:italic> 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.</jats:p>

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