@article {Corboz348, author = {Michel R. Corboz and Zhili Li and Vladimir Malinin and Adam J. Plaunt and Donna M. Konicek and Franziska G. Leifer and Kuan-Ju Chen and Charles E. Laurent and Han Yin and Marzena C. Biernat and Dany Salvail and Jianguo Zhuang and Fadi Xu and Aidan Curran and Walter R. Perkins and Richard W. Chapman}, title = {Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug}, volume = {363}, number = {3}, pages = {348--357}, year = {2017}, doi = {10.1124/jpet.117.242099}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 {\textmu}M) 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{\textendash}6 {\textmu}g/kg), sustained pulmonary vasodilation over 3 hours; inhaled TRE (6 {\textmu}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 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 {\textmu}g/ml) consistently produced cough, but C16TR-LNP (30 {\textmu}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.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/363/3/348}, eprint = {https://jpet.aspetjournals.org/content/363/3/348.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }