Organic Anion Transporting Polypeptide‐Mediated Transport of, and Inhibition by, Asunaprevir, an Inhibitor of Hepatitis C Virus NS3 Protease

Asunaprevir (ASV), an investigational, highly protein-bound inhibitor of hepatitis C virus NS3 protease, shows considerable hepatic compartmentalization in animal models. Preclinical data showed ASV inhibition of human OATP1B1 (IC50 = 0.3 μM), OATP2B1 (0.27 μM), and, to a lesser extent OATP1B3 (3.0 μM), confirmed by modest (<2-fold) clinical elevations in rosuvastatin exposure with concomitant ASV. Although no significant OATP transport of ASV was observed in vitro at standard micromolar assay concentrations, clinical coadministration of ASV with a single dose of the OATP inhibitor rifampin gave large, variable increases in ASV plasma Cmax (21-fold mean) and AUCinf (15-fold mean), consistent with reduced hepatic uptake. In vitro reevaluation at therapeutically relevant low-nanomolar concentrations of unbound ASV showed active, saturable human hepatocyte uptake (Km = 0.685 μM) and rifampin-reversible transport by OATP1B1 and OATP2B1, but not OATP1B3. At therapeutically relevant concentrations, ASV is therefore a sensitive substrate for, and weak inhibitor of, human OATP1B1, 1B3 and 2B1.