Effect of rifampin-mediated OATP1B1 and OATP1B3 transporter inhibition on the pharmacokinetics of the P2Y12 receptor antagonist selatogrel.

In vitro studies have indicated that the P2Y12 receptor antagonist selatogrel is a substrate of organic-anion-transporting-polypeptide (OATP)1B1 and OATP1B3 that are known to mediate hepatic uptake. Selatogrel is primarily eliminated via the biliary route. Therefore, the study aim was to investigate the effect of rifampin-mediated OATP1B1 and OATP1B3 inhibition on the pharmacokinetics (PK) of selatogrel. This was a randomized, double-blind, placebo-controlled, two-period, cross-over study in 14 healthy subjects. In each period, a single subcutaneous dose of 4 mg selatogrel was administered, either immediately after a single intravenous 30 min infusion of 600 mg rifampin or after placebo. Plasma samples were collected for 36 h and analyzed using a validated LC-MS/MS method. PK parameters of selatogrel were calculated using non-compartmental analysis. The effect of rifampin was explored based on geometric mean Cmax and AUC0-∞ ratios and for tmax by Wilcoxon signed rank test. In addition, the safety and tolerability of the study treatments were evaluated. The geometric mean ratios of Cmax and AUC0-∞ were 1.19 (90% CI: 1.11, 1.28) and 1.43 (90% CI: 1.36, 1.51), respectively, indicating a minor selatogrel exposure increase when administered after an infusion of rifampin compared to placebo. Rifampin administration did not affect t½ or tmax of selatogrel. All study treatments were safe and well tolerated. A single dose of 600 mg rifampin, a potent OATP1B1/1B3 inhibitor, did not impact the PK of selatogrel to a clinically relevant extent suggesting that OATP1B1 and OATP1B3 transporters do not play a major role in the elimination of selatogrel. This article is protected by copyright. All rights reserved.

RCT Entities:   Population Interventions Outcomes