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Investigation of potential pharmacodynamic and pharmacokinetic interactions between selexipag and warfarin in healthy male subjects

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Conference: 2014 International PHA Conference and Scientific Sessions

Release Date: 06.22.2014

Presentation Type: Abstracts

File Download: 2014 Conference Abstract - Shirin Bruderer

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Patients with pulmonary arterial hypertension (PAH) have a deficiency in prostacyclin and prostacyclin synthase. Therefore, targeting the prostacyclin pathway is an effective treatment option for PAH. Selexipag is a novel, orally available, selective prostacyclin receptor (IP) agonist that is under development for the treatment of PAH.

Background: Patients with pulmonary arterial hypertension (PAH) have a deficiency in prostacyclin and prostacyclin synthase. Therefore, targeting the prostacyclin pathway is an effective treatment option for PAH. Selexipag is a novel, orally available, selective prostacyclin receptor (IP) agonist that is under development for the treatment of PAH. ACT-333679, the active metabolite of selexipag, is also a selective and potent agonist at the IP receptor. 

Methods: In this two-period, cross-over Phase I study, the potential pharmacodynamic and pharmacokinetic interactions between selexipag and warfarin were investigated in 18 healthy male subjects aged 21–42 years. In Period 1, subjects received a single dose of selexipag or placebo on Day 1 followed by twice daily dosing on Days 2 to 12. In Period 2 subjects received the alternative treatment (placebo or selexipag) to that received in Period 1. Subjects received a single oral dose of 20 mg warfarin on the morning of Day 8 of both Periods 1 and 2. 

Results: Repeated administration of 400 μg selexipag had no influence on the rate and extent of absorption (AUC and Cmax) of R- and S-warfarin. Selexipag AUC0-τ, ACT-333679 AUC0-τ, and ACT-333679 Cmax at steady state were not affected by warfarin. Selexipag Cmax was decreased by approximately 6% (not clinically significant). Steady-state levels of selexipag and ACT-333679 at a dose regimen of 400 μg selexipag b.i.d. had no influence on the pharmacodynamic variables as demonstrated by international normalized ratios (INR) calculated for INR AUC(0–144h), INRmax, or INRtmax. Multiple doses of selexipag 400 μg were well tolerated by subjects. There were no consistent differences in the number of treatment-emergent adverse events between subjects treated with selexipag and warfarin, and those treated with placebo and warfarin. There was no evidence of a drug effect on laboratory safety parameters, echocardiography, telemetry, or orthostatic hypotension.

Conclusions: There was no significant interaction between selexipag (400 μg multiple doses), ACT-333679, and warfarin (20 mg single dose).

Type: Clinical Science 

This study was sponsored by Actelion Pharmaceuticals Ltd.