PT - JOURNAL ARTICLE AU - Michel R. Corboz AU - Zhili Li AU - Vladimir Malinin AU - Adam J. Plaunt AU - Donna M. Konicek AU - Franziska G. Leifer AU - Kuan-Ju Chen AU - Charles E. Laurent AU - Han Yin AU - Marzena C. Biernat AU - Dany Salvail AU - Jianguo Zhuang AU - Fadi Xu AU - Aidan Curran AU - Walter R. Perkins AU - Richard W. Chapman TI - Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug AID - 10.1124/jpet.117.242099 DP - 2017 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 348--357 VI - 363 IP - 3 4099 - http://jpet.aspetjournals.org/content/363/3/348.short 4100 - http://jpet.aspetjournals.org/content/363/3/348.full SO - J Pharmacol Exp Ther2017 Dec 01; 363 AB - 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 µM) in receptor binding and enzyme inhibition assays, including binding to prostaglandin E2 receptor 2, prostaglandin D2 receptor 1, prostaglandin I2 receptor, and prostaglandin E2 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 µg/kg), sustained pulmonary vasodilation over 3 hours; inhaled TRE (6 µg/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 µg/ml) consistently produced cough, but C16TR-LNP (30 µg/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.