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

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.

Automated summary

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.