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Pharmacokinetics and Pharmacodynamics of the Selective Prostacyclin Receptor Agonist Selexipag


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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 - Nicholas L.

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Background: Targeting the prostacyclin pathway is an effective treatment option for pulmonary arterial hypertension (PAH). Patients with PAH have a deficiency of prostacyclin and prostacyclin synthase. Selexipag is a first in class, orally available, selective prostacyclin (IP) receptor agonist. Selexipag is hydrolyzed to its active metabolite ACT-333679, which is also a selective and potent agonist at the IP receptor.

Methods: In a previous study, up-titration of selexipag was well tolerated up to 600 µg. To explore tolerability over a wider dose range, we performed a randomized, placebo-controlled, double-blind, multiple-period, multiple-ascending dose study in 16 healthy male subjects. Subjects were administered 400 μg selexipag b.i.d. for 3 days. The dose was up-titrated every third day with steps of 200 μg b.i.d., up to a maximum dose of 1800 µg b.i.d. Tolerability, pharmacokinetics, and effects on platelet aggregation, blood coagulation, and bone turnover markers were assessed throughout the study.

Results: Multiple oral doses of selexipag, up to 1600 µg b.i.d. were well tolerated. At 1800 µg b.i.d. there was an increase in moderate adverse events (AEs) that required concomitant medication. The maximum tolerated dose of selexipag was defined as 1600 µg b.i.d. AEs reported in the study included headache, myalgia, nausea, jaw pain, and arthralgia. No effects of treatment with selexipag on safety laboratory parameters, vital signs, echocardiography parameters, or physical examination were detected. Pharmacokinetic properties of selexipag and ACT-333679 were comparable to previous studies and neither accumulated during the 3 days of administration. AUCτ and Cmax of both selexipag and ACT-333679 increased approximately dose-proportionally. Selexipag had no relevant effects on platelet aggregation, blood coagulation, or bone turnover markers.

Conclusions: Doses of selexipag up to 1600 µg b.i.d. are well tolerated when using an up-titration scheme and can be applied in future studies.

Type: Clinical Science