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Lookup NU author(s): Dr Shelby BarnettORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Barnett S, Ogungbenro K, Ménochet K, Shen H, Lai Y, Humphreys WG, Galetin A
Publication type: Article
Publication status: Published
Journal: Clinical Pharmacology & Therapeutics
Year: 2018
Volume: 104
Issue: 3
Pages: 564-574
Print publication date: 27/08/2018
Online publication date: 15/12/2017
Acceptance date: 05/12/2017
Date deposited: 11/03/2021
ISSN (print): 0009-9236
ISSN (electronic): 1532-6535
Publisher: John Wiley & Sons, Inc.
URL: https://doi.org/10.1002/cpt.983
DOI: 10.1002/cpt.983
PubMed id: 29243231
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