Influence of rifampin‐mediated OATP 1B1/1B3 inhibition on the pharmacokinetics of clazosentan

: Clazosentan is a selective endothelin A receptor antagonist in development for the prevention and treatment of vasospasm postsubarachnoid hemorrhage. It is a substrate of organic anion-transporting polypeptide 1B1/1B3 based on preclinical data. This randomized, double-blind, two-period, cross-over study investigated the pharmacokinetics, safety, and tolerability of an intravenous infusion of clazosentan (15 mg/hour for 3 hours) after the intravenous administration of placebo or rifampin (600 mg/100 mL in 30 minutes). A total of 14 healthy male participants were enrolled resulting in 13 completers. Clazosentan exposure was three to four times higher after organic anion-transporting polypeptide 1B1/1B3 inhibition, as reflected by the geometric mean ratio (90% confidence interval) of area under the plasma concentration-time curve from zero to infinity: 3.88 (3.24-4.65). Clearance and volume of distribution decreased to a similar extent. Elimination half-life was not affected. A similar pattern but a higher incidence and frequency of adverse events were observed when clazosentan was given with rifampin than with placebo.