Pharmacokinetics and Tolerability of the Novel Oral Prostacyclin IP Receptor Agonist Selexipag

Abstract

PurposeTargeting 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 an orally available and selective prostacyclin receptor (IP receptor) agonist. Selexipag is hydrolyzed to its active metabolite ACT-333679, also a selective and potent agonist at the IP receptor.MethodsIn this phase I study the pharmacokinetics (PK) and tolerability of single and multiple ascending doses of selexipag were investigated in a double-blind, placebo-controlled manner in 64 healthy male subjects. An additional group of 12 subjects received an open-label dose of selexipag 400 μg in the fasted condition and after a meal.ResultsMaximum plasma concentrations of selexipag and ACT-333679 were reached within 2.5 and 4 h, respectively, with mean half-lives of 0.7–2.3 and 9.4–14.22 h. In the presence of food, exposure to ACT-333679 was decreased by 27 %. The most frequent adverse event was headache. Selexipag was well tolerated up to a single dose of 400 μg and multiple doses of 600 μg following an up-titration step. No relevant treatment-related effects on vital signs, clinical laboratory, and electrocardiogram (ECG) parameters were detected.ConclusionSelexipag exhibits a good tolerability profile and PK properties that warrant further investigation.

Comment on: “Pharmacokinetics and Tolerability of the Novel Oral Prostacyclin IP Receptor Agonist Selexipag”

“…In sharp contrast, no such limitation appeared to have been observed with selexipag. Similar comparisons for the metabolite exposure data between the 600 and 800 lg selexipag doses suggested a 1.2-fold increment when the selexipag dose increment was about 1.33-fold [5]. Therefore, the comparative selexipag and ACT-333679 data indicate that perhaps the formation of ACT-333679 via the hydrolysis mechanism may be predominantly pre-systemic in nature and, therefore, the absorption limitation of selexipag at the higher dose of 800 lg appears to be inconsequential to its exposure.…”

“…Examination of the exposure data, either peak plasma drug concentration (C max ) or area under the plasma concentration-time curve (AUC inf ), between the 600 and 800 lg doses suggests minimal improvement in the exposure of selexipag in spite of a 1.33-fold dose increment [5]. In sharp contrast, no such limitation appeared to have been observed with selexipag.…”

“…In a recent issue of the journal, Kaufmann et al [5] published a comprehensive report describing the safety, tolerability, and pharmacokinetics of both selexipag and its metabolite, ACT-333679, in human subjects. The singleand multiple-dose studies were conducted in a rigorous manner to ensure complete characterization of the clinical pharmacology of selexipag and ACT-333679 [5].…”

“…The singleand multiple-dose studies were conducted in a rigorous manner to ensure complete characterization of the clinical pharmacology of selexipag and ACT-333679 [5]. While summarizing the study findings, the authors stated that further studies are warranted specifically to examine higher dose levels with up-titration of the drug [5].…”

“…The single-dose pharmacokinetic data for selexipag are suggestive of absorption limitations of the drug at a threshold single dose of 800 lg in human subjects [5]. Examination of the exposure data, either peak plasma drug concentration (C max ) or area under the plasma concentration-time curve (AUC inf ), between the 600 and 800 lg doses suggests minimal improvement in the exposure of selexipag in spite of a 1.33-fold dose increment [5].…”