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

Aims Based on in vitro data, there is evidence to suggest that cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipagand its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipagwith gemfibrozil, a strong CYP2C8inhibitor, 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 selexipagand 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 Gemfibrozilhad comparatively small effects on selexipag(less than 2-fold difference in any pharmacokinetic variable) but, with respect to ACT-333679, increased the maximum plasma concentration ( Cmax) 3.6-fold [90% confidence interval (CI) 3.1, 4.3] and the area under the plasma concentration–time curve from zero to infinity (AUC0–∞) 11.1-fold (90% CI 9.2, 13.4). The marked increased exposure to ACT-333679, which mediates the majority of the pharmacological activity of selexipag, was accompanied by significantly more adverse events such as headache, nausea and vomiting. Coadministration of rifampicinincreased the Cmaxof selexipag1.8-fold (90% CI 1.4, 2.2) and its AUC0–∞ 1.3-fold (90% CI 1.1, 1.4); its effects on ACT-333679 were to increase its Cmax1.3-fold (90% CI 1.1, 1.6), shorten its half-life by 63% and reduce its AUC0–∞ by half (90% CI 0.45, 0.59). Conclusion Concomitant administration of selexipagand strong inhibitors of CYP2C8must be avoided, whereas when coadministered with inducers of CYP2C8, dose adjustments of selexipagshould be envisaged.