Key result
Concomitant administration of clopidogrel with selexipag increased the AUC of the active metabolite ACT-333679 by 1.90-fold (90% CI 1.69-2.14) in healthy Japanese volunteers.
Why the study?
The effects of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 had not been fully elucidated in the Japanese population.
Does concomitant administration of clopidogrel alter the pharmacokinetics of selexipag and its active metabolite ACT-333679 in healthy Japanese volunteers?
Does concomitant administration of clopidogrel alter the pharmacokinetics of selexipag and its active metabolite ACT-333679 in healthy Japanese volunteers?
Effect estimate: 1.90-fold increase (95% CI 1.69-2.14)
Clopidogrel significantly increases the exposure to the active metabolite of selexipag in Japanese volunteers, suggesting a need for dose adjustment when co-administered.
May indicate interaction warranting caution with co-administration; leaves open dose adjustment needs in patients.
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.
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Katayama et al. (2020) studied Healthy volunteers (n=14). Clopidogrel vs. Selexipag alone was evaluated on AUC 0-∞ of ACT-333679 (active metabolite of selexipag) (1.90-fold increase, 95% CI 1.69-2.14). Concomitant administration of clopidogrel with selexipag increased the AUC of the active metabolite ACT-333679 by 1.90-fold (90% CI 1.69-2.14) in healthy Japanese volunteers.
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