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

Abstract

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.

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

“…Furthermore, OATP1B1/2B1-mediated uptake into the hepatocyte may also be a saturable process if concentrations of asunaprevir within the portal circulation are sufficient. Saturation of OATP1B1/2B1-mediated asunaprevir transport into the hepatocyte may improve dose proportionality at higher doses, as observed in the clinical data, potentially because of greater reliance on passive uptake, consistent with in vitro data [16].…”

“…(&15-fold) values of a single 200 mg tablet of asunaprevir, with very broad ranges of interindividual variability from 5-fold to [200-fold for C max and from 5-fold to 67-fold for AUC ? [16]. Notably, while steady-state rifampin would have been expected to significantly reduce plasma exposure to asunaprevir via induction of metabolism, coadministration of asunaprevir 200 mg twice daily and rifampin 600 mg once daily for 6-7 days in the second part of the study showed an asunaprevir plasma concentration-time curve similar to that of asunaprevir alone, but there was a shift to a shorter T max (Fig.…”

“…Active transport of [ 3 H]-asunaprevir (10 nM) by organic anion-transporting polypeptide (OATP) 1B1 and OATP2B1, although not by OATP1B3, was confirmed in human embryonic kidney (HEK293) cells overexpressing these transporters because of the ability of rifampin to inhibit that uptake [16]. Therefore, preferential asunaprevir localization to the liver at clinically relevant exposures is attributable in large part to active uptake by OATP transporters [16].…”

“…However, a study in healthy volunteers (study AI447-015) showed steady-state asunaprevir (200 mg twice-daily tablet) to be only a weak inhibitor of rosuvastatin hepatic uptake in vivo, resulting in increases in the single-dose rosuvastatin plasma AUC ? of only 40 % [16]. The much weaker in vivo effect of asunaprevir on exposure of a representative OATP1B1 substrate compared with cyclosporine is likely a function of the very high protein binding of asunaprevir and its correspondingly low free drug concentrations at therapeutic dosing.…”

“…The much weaker in vivo effect of asunaprevir on exposure of a representative OATP1B1 substrate compared with cyclosporine is likely a function of the very high protein binding of asunaprevir and its correspondingly low free drug concentrations at therapeutic dosing. It is unlikely that asunaprevir administration will require a priori dose adjustments for concomitant OATP substrates [16]. A graphical summary of the effect of asunaprevir on the pharmacokinetics of other drugs is presented in Fig.…”