Effect of gemfibrozil or rifampicin on the pharmacokinetics of selexipag and its active metabolite in healthy subjects

SUMMARY

Aims

Based on in vitro data CYP2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipag with gemfibrozil, a strong CYP2C8 inhibitor and rifampicin, an inducer of CYP2C8.

Methods

The study consisted of two independent parts, each conducted according to an open-label, randomized crossover design. The pharmacokinetics and safety of selexipag and ACT-333679 were studied following single-dose administration either alone or in the presence of multiple-dose gemfibrozil (Part I) or rifampicin (Part II) in healthy male subjects.

Results

Gemfibrozil had comparatively small effects on selexipag (less than 2-fold on any pharmacokinetic variable) but, with respect to ACT-333679, increased maximum plasma concentration (C_max) 3.6 fold (90% CI; 3.1, 4.3), and area under the plasma concentration-time curve from zero to infinity (AUC_(0-∞)) 11.1 fold (90% CI; 9.2, 13.4). The marked increased exposure to ACT-333679, which mediates the majority of pharmacological activity of selexipag, was accompanied by significantly more adverse events such as headache, nausea, and vomiting. Co-administration of rifampicin increased C_max of selexipag 1.8 fold (90% CI; 1.4, 2.2) and its AUC_(0-∞) 1.3 fold (90% CI; 1.1, 1.4). A small increase in C_max (1.3 fold, 90% CI; 1.1, 1.6) and a 63% shortening of t_1/2 reduced AUC_(0-∞) of ACT-333679 by half (90% CI; 0.45, 0.59).

Conclusion

Concomitant administration of selexipag and strong inhibitors of CYP2C8 must be avoided whereas when co-administered with inducers of CYP2C8 dose adjustments of selexipag should be envisaged.

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