Multiple-Dose Up-Titration Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Selexipag, an Orally Available Selective Prostacyclin Receptor Agonist, in Healthy Subjects

Abstract

Objective: The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects. Methods: This was a double-blind, placebo-controlled, randomised, multiple-ascending-dose, up-titration study. Male subjects received increasing oral doses of selexipag (400-1,800 µg; n = 12) or placebo (n = 4) twice daily for 3 days each, using incremental steps of 200 µg between each dose level. Standard safety and tolerability data were collected. Blood samples were taken to assess the pharmacokinetics of selexipag and its active metabolite ACT-333679 and possible effects on platelet aggregation. Results: Dose levels of selexipag up to 1,600 μg were well tolerated and this dose was identified as the maximum tolerated dose. Plasma exposure to ACT-333679 was approximately 4 times higher than that to selexipag. Steady-state conditions for both compounds were reached on day 3 of each dose level, and no accumulation of selexipag or ACT-333679 was observed. Based on the area under the curve and the maximum plasma concentration, the pharmacokinetics of selexipag and ACT-333679 were dose proportional. At the highest dose level, the geometric mean terminal half-life of selexipag and ACT-333679 was 1.4 and 8.7 h, respectively. The observed effects on platelet aggregation were variable without obvious drug- or dose-dependent pattern. Conclusions: Oral administration of increasing doses of selexipag was well tolerated. The present results support the conduct of future clinical trials.

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

“…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]. Based on tolerability observations from the present study and from previous experience [6], gradual upward titrations of selexipag may be warranted. The intent of this note is to provide perspectives on the observed data for both selexipag and ACT-333679, including possible challenges with the up-titration of selexipag.…”

Authors’ Reply to Srinivas: “Pharmacokinetics and Tolerability of the Novel Oral Prostacyclin IP Receptor Agonist Selexipag”

“…Food had no significant effect on exposure to selexipag and ACT-333679, but it decreased the rate of absorption, as shown by a decrease in C max and a delay in the median time to reach maximum plasma/blood concentration (t max ) of 1-1.5 h. The observed increase in exposure of 10 % for selexipag and decrease of 27 % for ACT-333679 is within the pharmacokinetic variability of the compound, which should also be viewed in the light of the low dose administered, in the microgram range [5,6,8]. Also relevant in this context is that in clinical practice, selexipag is used at an individualized dose of 200-1600 lg bid, reached after weekly up-titration [9].…”

“…However, the single-dose data for both selexipag and ACT-333679 showed a dose-proportional increase in both exposure variables across the dose range tested, from 100 to 800 lg [2]. Gradual up-titration to an individual patient's highest tolerated dose is the generally accepted regimen for IP receptor agonists [3], which has now been extensively studied in healthy subjects up to 1800 lg twice daily (bid) as well as in patients up to 1600 lg bid [4][5][6][7]. The pharmacokinetics of selexipag were dose proportional across the entire dose range following multiple doses, as evidenced by the point estimate of the population mean slope for area under the plasma concentration-time curve during a dose interval (AUC s ) and maximum plasma concentration (C max ) [5].…”

Selexipag in the treatment of pulmonary arterial hypertension: design, development, and therapy

“…Selexipag has a half-life of 0.8–2.5 hours and is hydrolyzed to its pharmacologically active metabolite ACT-333679 with a half-life of 6.2–13.5 hours (Figure 3). 24,32 It is rapidly absorbed after oral administration and may be taken with or without food. Single doses above 400 μg led to an increased incidence of headache, nausea, dizziness, and vomiting in normal volunteers.…”

“…Single doses above 400 μg led to an increased incidence of headache, nausea, dizziness, and vomiting in normal volunteers. Gradual up-titration improves tolerability, and the maximum tolerated strength with repeated dosing in normal volunteers was 1,600 μg 32. In the presence of food, the absorption of selexipag was prolonged resulting in a delayed time to peak concentration (T max ) and approximately 30% lower peak plasma concentration (C max ).…”