Corboz Michel R, Li Zhili, Malinin Vladimir, Plaunt Adam J, Konicek Donna M, Leifer Franziska G, Chen Kuan-Ju, Laurent Charles E, Yin Han, Biernat Marzena C, Salvail Dany, Zhuang Jianguo, Xu Fadi, Curran Aidan, Perkins Walter R, Chapman Richard W
Insmed Incorporated, Research & Development, Bridgewater, New Jersey (M.R.C., Z.L., V.M., A.J.P., D.M.K., F.G.L., K.-J.C., W.R.P., R.W.C.); IPS Therapeutique Inc., Sherbrooke, Québec, Canada (C.E.L., H.Y., M.C.B., D.S.); Lovelace Respiratory Research Institute, Pathophysiology Program, Albuquerque, New Mexico (J.Z., F.X.); and Envigo CRS Inc., East Millstone, New Jersey (A.C.)
Insmed Incorporated, Research & Development, Bridgewater, New Jersey (M.R.C., Z.L., V.M., A.J.P., D.M.K., F.G.L., K.-J.C., W.R.P., R.W.C.); IPS Therapeutique Inc., Sherbrooke, Québec, Canada (C.E.L., H.Y., M.C.B., D.S.); Lovelace Respiratory Research Institute, Pathophysiology Program, Albuquerque, New Mexico (J.Z., F.X.); and Envigo CRS Inc., East Millstone, New Jersey (A.C.).
J Pharmacol Exp Ther. 2017 Dec;363(3):348-357. doi: 10.1124/jpet.117.242099. Epub 2017 Sep 13.
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 M) in receptor binding and enzyme inhibition assays, including binding to prostaglandin E receptor 2, prostaglandin D receptor 1, prostaglandin I receptor, and prostaglandin E 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 g/kg), sustained pulmonary vasodilation over 3 hours; inhaled TRE (6 g/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 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 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 g/ml) consistently produced cough, but C16TR-LNP (30 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.
本文描述了十六烷基曲前列尼尔（C16TR）的临床前药理学和药代动力学（PK），C16TR是曲前列尼尔（TRE）的前体药物，制成脂质纳米颗粒（LNP）用于吸入，作为一种肺血管扩张剂。C16TR在受体结合和酶抑制试验中无活性（>10 μM），包括与前列腺素E受体2、前列腺素D受体1、前列腺素I受体和前列腺素E受体4的结合；TRE能有效结合这些前列腺素受体中的每一种。C16TR对大鼠血液中ADP诱导的血小板聚集无影响（高达200 nM）。在缺氧应激的大鼠中，吸入C16TR-LNP产生剂量依赖性（0.06-6 μg/kg），在3小时内持续肺血管扩张；吸入TRE（6 μg/kg）在早期有活性，但在3小时时失去作用。大鼠吸入C16TR-LNP的单剂量和多剂量PK研究表明，血浆和肺中的TRE和曲线下面积（AUC）呈剂量依赖性成比例增加；在单剂量PK研究中，犬血浆水平也观察到类似结果。在这两个物种中，与吸入TRE相比，吸入C16TR-LNP产生的血浆TRE水平延长，血浆TRE峰浓度较低。大鼠和犬吸入C16TR-LNP耐受性良好；与TRE相关的副作用包括咳嗽、呼吸道刺激和呕吐，仅在犬吸入高剂量C16TR-LNP后出现。在豚鼠中，吸入TRE（30 μg/ml）持续引起咳嗽，但C16TR-LNP（30 μg/ml）无作用。这些结果表明，C16TR-LNP可提供长效肺血管扩张作用，在动物研究中耐受性良好，与吸入TRE相比，给药频率可能更低，副作用可能更少。
