Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug.

Autor:	Corboz MR; 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.) michel.corboz@insmed.com., Li Z; 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.)., Malinin V; 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.)., Plaunt AJ; 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.)., Konicek DM; 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.)., Leifer FG; 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.)., Chen KJ; 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.)., Laurent CE; 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.)., Yin H; 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.)., Biernat MC; 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.)., Salvail D; 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.)., Zhuang J; 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.)., Xu F; 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.)., Curran A; 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.)., Perkins WR; 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.)., Chapman RW; 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.).
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2017 Dec; Vol. 363 (3), pp. 348-357. Date of Electronic Publication: 2017 Sep 13.
DOI:	10.1124/jpet.117.242099
Abstrakt:	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 µ 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 µ g/kg), sustained pulmonary vasodilation over 3 hours; inhaled TRE (6 µ 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 C max 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 C max 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 µ g/ml) consistently produced cough, but C16TR-LNP (30 µ 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. (Copyright © 2017 The Author(s).)
Databáze:	MEDLINE
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