Gaining Mechanistic Insight Into Coproporphyrin I as Endogenous Biomarker for OATP1B-Mediated Drug-Drug Interactions Using Population Pharmacokinetic Modeling and Simulation.
Clin Pharmacol Ther
; 104(3): 564-574, 2018 09.
Article
en En
| MEDLINE
| ID: mdl-29243231
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
3_ND
Problema de salud:
3_tuberculosis
Asunto principal:
Rifampin
/
Simulación por Computador
/
Coproporfirinas
/
Transportador 1 de Anión Orgánico Específico del Hígado
/
Biomarcadores Farmacológicos
/
Antibióticos Antituberculosos
/
Modelos Biológicos
Tipo de estudio:
Etiology_studies
/
Risk_factors_studies
Límite:
Humans
/
Male
Idioma:
En
Revista:
Clin Pharmacol Ther
Año:
2018
Tipo del documento:
Article
País de afiliación:
Reino Unido