Clinical evaluation of drug–drug interactions between the cytochrome P450 substrates selexipag and clopidogrel in Japanese volunteers

Aims: The strong cytochrome P450 (CYP) 2C8 inhibitor gemfibrozil has been demonstrated to increase the area under the plasma concentration–time curve from 0 to infinity (AUC_0–∞) of ACT-333679, an active metabolite of selexipag, by 11-fold. Similarly to gemfibrozil, the CYP2C8 inhibitor clopidogrel increased ACT-333679 concentration by 1.9-fold after a single loading dose (300 mg once daily) and 2.7-fold after repeated treatment with the maintenance dose (75 mg once daily) in Europeans. However, the effects of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 have not been fully elucidated in the Japanese population. Methods: We investigated the effect of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 in 14 healthy Japanese volunteers. Results: The concomitant administration of clopidogrel with selexipag did not influence the maximum concentration and AUC_0-∞ of selexipag, whereas it significantly increased AUC_0-∞ of ACT-333679 by approximately 1.90-fold (90% confidence interval 1.69–2.14) without changing the maximum concentration. When selexipag was administered 1 day after clopidogrel was discontinued, the increase in AUC_0-∞ of ACT-333679 was 1.37-fold (90% confidence interval 0.93–2.02), suggesting that, although the inhibitory effect of clopidogrel on CYP2C8 was reduced, it persisted for at least 1 day after withdrawal. Conclusion: Our results demonstrated the impact of clopidogrel on the pharmacokinetics of selexipag and its active metabolite and suggested that selexipag should be carefully prescribed with clopidogrel with dose adjustment or reducing the dosing frequency in Japanese clinical settings.