RT Journal Article
SR Electronic
T1 Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.117.242099
DO 10.1124/jpet.117.242099
A1 Michel R Corboz
A1 Zhili Li
A1 Vladimir Malinin
A1 Adam J Plaunt
A1 Donna M Konicek
A1 Franziska G Leifer
A1 Kuan-Ju Chen
A1 Charles E Laurent
A1 Han Yin
A1 Marzena C Biernat
A1 Dany Salvail
A1 Jianguo Zhuang
A1 Fadi Xu
A1 Aidan Curran
A1 Walter R Perkins
A1 Richard W Chapman
YR 2017
UL http://jpet.aspetjournals.org/content/early/2017/09/13/jpet.117.242099.abstract
AB This report 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 EP2, DP1, IP and EP4; TRE potently bound to each of these prostanoid receptors. C16TR had no effect (up to 200 nM) on platelet aggregation induced by adenosine diphosphate (ADP) in rat blood. In hypoxia-challenged rats, inhaled C16TR-LNP produced dose-dependent (0.06 - 6 µg/kg) and sustained pulmonary vasodilation over 3 h; inhaled TRE (6 µg/kg) was active at earlier times but lost its effect by 3 h. Single and multiple dose PK studies of inhaled C16TR-LNP in rats showed proportionate dose-dependent increases in Cmax and AUC for both plasma and lung; similar results were observed for dog plasma levels in single dose PK studies. Inhaled C16TR-LNP yielded significantly prolonged TRE plasma levels with a Cmax that was significantly lower than that for inhaled TRE. Inhaled C16TR-LNP was well tolerated in rats and dogs with TRE-related side effects such as cough, respiratory tract irritation and emesis only seen 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.