Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug
Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug
复制标题
DOI：
10.1124/jpet.117.242099
复制
发表时间：
2017-12-01
影响因子：
3.5
通讯作者：
Chapman, Richard W.
中科院分区：
文献类型：
--
作者：
Corboz, Michel R.;Li, Zhili;Chapman, Richard W.
本文描述了十六烷基曲前列环素 (C16TR) 的临床前药理学和药代动力学 (PK)，它是曲前列环素 (TRE) 的前药，配制在脂质纳米颗粒 (LNP) 中，作为肺血管扩张剂吸入。 C16TR 在受体结合和酶抑制测定中没有显示活性（> 10 μM），包括与前列腺素 E-2 受体 2、前列腺素 D-2 受体 1、前列腺素 I-2 受体和前列腺素 E-2 受体 4 的结合； TRE 与这些前列腺素受体均有效结合。 C16TR 对大鼠血液中 ADP 诱导的血小板聚集没有影响（高达 200 nM）。在缺氧的大鼠中，吸入 C16TR-LNP 产生剂量依赖性（0.06-6 mg/kg）、持续肺血管舒张超过 3 小时；吸入 TRE (6 mg/kg) 在早期具有活性，但在 3 小时后失去作用。大鼠吸入 C16TR-LNP 的单剂量和多剂量 PK 研究显示，血浆和肺的 TRE Cmax 和曲线下面积 (AUC) 呈比例剂量依赖性增加；在单剂量 PK 研究中，狗的血浆水平也观察到了类似的结果。在这两个物种中，与吸入 TRE 相比，吸入 C16TR-LNP 可以延长血浆 TRE 水平，并降低血浆 TRE Cmax。吸入的 C16TR-LNP 在大鼠和狗中具有良好的耐受性； TRE 相关副作用包括咳嗽、呼吸道刺激和呕吐，只有在狗吸入高剂量的 C16TR-LNP 后才会出现。在豚鼠中，吸入TRE（30μg/ml）持续产生咳嗽，但C16TR-LNP（30μg/ml）没有引起任何效果。这些结果表明，C16TR-LNP 具有长效肺血管舒张作用，在动物研究中具有良好的耐受性，并且可能需要比吸入 TRE 更低的给药频率，并且副作用可能更少。
This article describes the preclinical pharmacology and pharmacokinetics (PK) of hexadecyl-treprostinil (C16TR), a prodrug of treprostinil (TRE), formulated in a lipid nanoparticle (LNP) for inhalation as a pulmonary vasodilator. C16TR showed no activity (> 10 mu M) in receptor binding and enzyme inhibition assays, including binding to prostaglandin E-2 receptor 2, prostaglandin D-2 receptor 1, prostaglandin I-2 receptor, and prostaglandin E-2 receptor 4; TRE potently bound to each of these prostanoid receptors. C16TR had no effect (up to 200 nM) on platelet aggregation induced by ADP in rat blood. In hypoxia-challenged rats, inhaled C16TR-LNP produced dose-dependent (0.06-6 mg/kg), sustained pulmonary vasodilation over 3 hours; inhaled TRE (6 mg/kg) was active at earlier times but lost its effect by 3 hours. Single-and multiple-dose PK studies of inhaled C16TR-LNP in rats showed proportionate dose-dependent increases in TRE Cmax and area under the curve (AUC) for both plasma and lung; similar results were observed for dog plasma levels in single-dose PK studies. In both species, inhaled C16TR-LNP yielded prolonged plasma TRE levels and a lower plasma TRE Cmax compared with inhaled TRE. Inhaled C16TR-LNP was well tolerated in rats and dogs; TRE-related side effects included cough, respiratory tract irritation, and emesis and were seen only after high inhaled doses of C16TR-LNP in dogs. In guinea pigs, inhaled TRE ( 30 mu g/ml) consistently produced cough, but C16TR-LNP ( 30 mu g/ml) elicited no effect. These results demonstrate that C16TR-LNP provides long-acting pulmonary vasodilation, is well tolerated in animal studies, and may necessitate less frequent dosing than inhaled TRE with possibly fewer side effects.