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首页> 外文期刊>Pulmonary Circulation >Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate-release oral formulation in healthy volunteers
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Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate-release oral formulation in healthy volunteers

机译：选择性前列环素受体激动剂RALINEPAG的安全性，耐受性和药代动力学在健康志愿者中立即释放口腔制剂的单一和多剂量的研究

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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 ( n ?=?32) and multiple ascending dose ( n ?=?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.
机译：RALINEPAG（APD811），口服，有效和选择性前列环素受体（IP）激动剂正在开发用于治疗肺动脉高血压。两个，单中心，随机，双盲，安慰剂控制，第1期研究（单一升序剂量和多个上升剂量）评估了健康受试者的口腔立即释放胶囊制剂。血样评估了血浆药代动力学和安全性和耐受性数据监测不良事件，生命体征，实验室发现，体检和心电图。八十二个健康受试者（单个上升剂量（n？= 32）和多个上升剂量（n？=Δ50））完成了研究。没有观察到临床上显着的安全问题，除了一个严重的心房颤动的严重不良事件被认为是中度的强度。在单一的上升剂量研究中，RalinePAG可容许高达100Ωμg（单剂量），但由于恶心和呕吐，不是200≤μg。观察剂量比例平均ralinepag等离子体暴露措施。在剂量后的1.0-1.5μm+中达到最大血浆浓度，平均末端消除半衰期从20.5-26.4℃。在多个上升剂量研究中，RALINEPAG可耐受性随着QD或BID剂量的增加而降低。观察到剂量比例稳态等离子体暴露措施，其中评估，平均稳态峰 - 槽比率范围为3.34-4.49（QD计量剂）和1.95-2.36（出价给药）。平均有效的半衰期值范围从17.5-18.4？H，反映血浆暴露中的〜1.7倍（QD剂量）和〜2.6倍（竞选给药）积累。口腔立即释放的ralinepag的安全性和耐受性通常与对该药物类别的预期一致，但似乎有必要的个性化剂量升级。 RalinePag表现出良好的药代动力学性质，具有出价给药，产生所需的最小稳态峰 - 波动波动。总体而言，结果支持进一步临床调查RalinePAG并引导延长释放配方的发展，以促进QD计量。

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