4.5 Article

Clopidogrel, a CYP2C8 inhibitor, causes a clinically relevant increase in the systemic exposure to the active metabolite of selexipag in healthy subjects

期刊

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
卷 87, 期 1, 页码 119-128

出版社

WILEY
DOI: 10.1111/bcp.14365

关键词

clopidogrel; drug interactions; pharmacokinetics; selexipag

资金

  1. Actelion Pharmaceuticals

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This study evaluated the interaction of selexipag and clopidogrel in healthy male subjects, showing that clopidogrel had a moderate effect on the active metabolite ACT-333679 but a minimal effect on selexipag itself. Regardless of CYP2C8 genotype, the exposure of selexipag and ACT-333679 was comparable with clopidogrel. PK modeling and simulations supported the recommendation of adjusting selexipag dosing frequency or dose when coadministered with clopidogrel to maintain therapeutic levels of ACT-333679.
Aims Selexipag is a prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension. Cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. This study evaluated the interaction of selexipag and clopidogrel, a CYP2C8 inhibitor. Methods The study had a 2-treatment, 1-sequence, crossover design. Pharmacokinetics (PK) and CYP2C8 genotype were assessed in healthy male subjects administered selexipag (200 mu g twice daily [b.i.d.]) alone or with clopidogrel (300 mg single dose or 75 mg once daily [o.d.]). PK modelling and simulation were conducted to support dosing recommendations. Results Clopidogrel had a comparatively small effect on selexipag (<1.5-fold difference in any PK variable). For ACT-333679, the major contributor to the drug effect, the area under the plasma concentration-time curve during a dose interval and the maximum plasma concentration increased 2.25-fold (90% confidence interval [CI] 2.06, 2.46) and 1.69-fold (90% CI 1.55, 1.84), respectively with clopidogrel 300 mg and 2.70-fold (90% CI 2.45, 2.96) and 1.90-fold (90% CI 1.72, 2.11), respectively with clopidogrel 75 mg. The effect of clopidogrel on selexipag and ACT-333679 exposure was comparable for all identified CYP2C8 genotypes. PK simulations predicted comparable exposure to ACT-333679 following selexipag 400 mu g b.i.d., 400 mu g o.d. in combination with clopidogrel 75 mg o.d and 200 mu g b.i.d. with clopidogrel 75 mg o.d. Conclusion Results suggest that ACT-333679 exposure can be maintained within the therapeutic range by reducing selexipag dosing frequency to o.d. or dose to half, when selexipag is coadministered with clopidogrel.

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