Safety and pharmacokinetics of ralinepag, a novel oral prostacyclin receptor agonist

Background: Ralinepag is an oral, potent, highly selective prostacyclin receptor agonist and is in development for pulmonary arterial hypertension. Ralinepag was formulated as an immediate-release (IR) capsule, later modified to an extended-release (XR) tablet to optimize administration for once-daily dosing. Methods: This phase I study evaluated the pharmacokinetic (PK) profile and relative bioavailability of ralinepag XR. There were two cohorts of healthy participants (n = 12 each). One received a single dose of ralinepag IR (30 µg) followed by single ascending doses of XR (60, 120, and 180 µg), and the other received single ascending doses of selexipag (200, 400, and 600 µg). Participants titrated to the highest tolerated dose. There was a 7-day washout period between each dose. Results: The ralinepag XR formulation showed a reduced maximum observed concentration (C_max), delayed time of maximum observed concentration (T_max), and similar area under the curve compared with the IR formulation. Ralinepag XR demonstrated a gradual increase in plasma concentration over 8 to 12 hours, followed by a slow decline, with a half-life of 19-23 hours. In contrast, the active metabolite of selexipag (MRE-269) exhibited a sharp peak with a half-life of 9-10 hours. Ralinepag XR was well-tolerated by healthy volunteers, with 9 of 12 participants reaching the highest dose. Adverse events were qualitatively similar to oral prostacyclin class therapies. Conclusion: Ralinepag XR has a half-life suitable for once-daily dosing. The reduced C_max and delayed T_max contributes to lower peak-to-trough fluctuations and may provide favorable effects for sustained efficacy and improved tolerability.