Ataya Ali, Coons James C, Patzlaff Natalie, Broderick Meredith, Seaman Scott, Sood Namita, Patricia George M, Chakinala Murali M
Division of Pulmonary and Critical Care Medicine, University of Florida, 1549 Gale Lemerand Drive, Gainesville, FL 32610-3008.
University of Pittsburgh School of Pharmacy, 200 Lothrop Street, Pittsburgh, PA, 15213.
JHLT Open. 2025 Apr 23;9:100270. doi: 10.1016/j.jhlto.2025.100270. eCollection 2025 Aug.
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.
This phase I study evaluated the pharmacokinetic (PK) profile and relative bioavailability of ralinepag XR. There were two cohorts of healthy participants ( = 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.
The ralinepag XR formulation showed a reduced maximum observed concentration (C), delayed time of maximum observed concentration (T), 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.
Ralinepag XR has a half-life suitable for once-daily dosing. The reduced C and delayed T contributes to lower peak-to-trough fluctuations and may provide favorable effects for sustained efficacy and improved tolerability.
利奥西呱是一种口服、强效、高度选择性的前列环素受体激动剂，正在用于肺动脉高压的研发。利奥西呱最初制成速释（IR）胶囊，后来改为缓释（XR）片剂，以优化每日一次给药的方式。
这项I期研究评估了利奥西呱XR的药代动力学（PK）特征和相对生物利用度。有两组健康参与者（每组n = 12）。一组先接受单剂量的利奥西呱IR（30 μg），随后接受单剂量递增的XR（60、120和180 μg），另一组接受单剂量递增的司来帕格（200、400和600 μg）。参与者滴定至最高耐受剂量。每剂之间有7天的洗脱期。
与IR制剂相比，利奥西呱XR制剂的最大观察浓度（Cmax）降低，最大观察浓度时间（Tmax）延迟，曲线下面积相似。利奥西呱XR在8至12小时内血浆浓度逐渐升高，随后缓慢下降，半衰期为19 - 23小时。相比之下，司来帕格的活性代谢物（MRE - 269）表现出一个尖锐的峰值，半衰期为9 - 10小时。健康志愿者对利奥西呱XR耐受性良好，12名参与者中有9名达到了最高剂量。不良事件在性质上与口服前列环素类疗法相似。
利奥西呱XR的半衰期适合每日一次给药。Cmax降低和Tmax延迟有助于降低峰谷波动，并可能为持续疗效和改善耐受性提供有利影响。
