Grundy John S, King Christopher D, Adams John W, Cabell Christopher H
Nonclinical Development & Clinical Pharmacology Department, Arena Pharmaceuticals, Inc., San Diego, CA, USA.
Research Department, Arena Pharmaceuticals, Inc., San Diego, CA, USA.
Pulm Circ. 2020 May 14;10(2):2045894020922814. doi: 10.1177/2045894020922814. eCollection 2020 Apr-Jun.
Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single-center, randomized, double-blind, placebo-controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate-release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty-two healthy subjects (single ascending dose ( = 32) and multiple ascending dose ( = 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 µg (single dose), but not 200 µg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0-1.5 h post-dose and mean terminal elimination half-life values from 20.5-26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady-state plasma exposure measures were observed where evaluable, with mean steady-state peak-to-trough ratios ranging from 3.34-4.49 (QD dosing) and 1.95-2.36 (BID dosing). Mean effective half-life values ranged from 17.5-18.4 h, reflecting ∼1.7-fold (QD dosing) and ∼2.6-fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediate-release ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady-state peak-to-trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended-release formulation to facilitate QD dosing.
利纳帕格（APD811）是一种口服、强效且选择性的前列环素受体（IP）激动剂，正被开发用于治疗肺动脉高压。两项单中心、随机、双盲、安慰剂对照的1期研究（单次递增剂量和多次递增剂量）在健康受试者中评估了利纳帕格的口服速释胶囊制剂。采集血样评估血浆药代动力学，监测安全性和耐受性数据，包括不良事件、生命体征、实验室检查结果、体格检查和心电图。82名健康受试者（单次递增剂量组（n = 32）和多次递增剂量组（n = 50））完成了研究。除了1例强度为中度的严重不良事件（心房颤动）外，未观察到具有临床意义的安全问题。在单次递增剂量研究中，利纳帕格在高达100μg（单次剂量）时耐受性良好，但在200μg时因恶心和呕吐而不耐受。观察到剂量成比例的利纳帕格血浆暴露量测量值。给药后1.0 - 1.5小时内达到最大血浆浓度，平均终末消除半衰期值为20.5 - 26.4小时。在多次递增剂量研究中，利纳帕格的耐受性随每日一次（QD）或每日两次（BID）剂量增加而降低。在可评估的情况下观察到剂量成比例的稳态血浆暴露量测量值，平均稳态峰谷比范围为3.34 - 4.49（QD给药）和1.95 - 2.36（BID给药）。平均有效半衰期值范围为17.5 - 18.4小时，反映出血浆暴露量有1.7倍（QD给药）和2.6倍（BID给药）的蓄积。口服速释利纳帕格的安全性和耐受性总体上与该药物类别预期一致，但似乎有必要进行更个体化的剂量递增。利纳帕格表现出良好的药代动力学特性，BID给药产生所需的最小稳态峰谷波动。总体而言，结果支持对利纳帕格进行进一步的临床研究，并指导开发缓释制剂以促进QD给药。
