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

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 inhibi... Full description

Journal Title: The Journal of pharmacology and experimental therapeutics December 2017, Vol.363(3), pp.348-357
Main Author: Corboz, Michel R
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1521-0103 ; PMID: 28904003 Version:1 ; DOI: 10.1124/jpet.117.242099
Link: http://pubmed.gov/28904003
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title: Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug
format: Article
creator:
  • 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
subjects:
  • Drug Delivery Systems
  • Antihypertensive Agents -- Therapeutic Use
  • Epoprostenol -- Analogs & Derivatives
  • Hypertension, Pulmonary -- Drug Therapy
  • Prodrugs -- Administration & Dosage
  • Vasodilator Agents -- Administration & Dosage
ispartof: The Journal of pharmacology and experimental therapeutics, December 2017, Vol.363(3), pp.348-357
description: 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.
language: eng
source:
identifier: E-ISSN: 1521-0103 ; PMID: 28904003 Version:1 ; DOI: 10.1124/jpet.117.242099
fulltext: no_fulltext
issn:
  • 15210103
  • 1521-0103
url: Link


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titlePreclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug
creatorCorboz, 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
ispartofThe Journal of pharmacology and experimental therapeutics, December 2017, Vol.363(3), pp.348-357
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subjectDrug Delivery Systems ; Antihypertensive Agents -- Therapeutic Use ; Epoprostenol -- Analogs & Derivatives ; Hypertension, Pulmonary -- Drug Therapy ; Prodrugs -- Administration & Dosage ; Vasodilator Agents -- Administration & Dosage
descriptionThis 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.
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titlePreclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug
descriptionThis 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.
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authorCorboz, 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
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abstractThis 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.
doi10.1124/jpet.117.242099
pmid28904003
issn00223565
oafree_for_read
date2017-12