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 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.
Copyright © 2017 The Author(s).
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Inhalation
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Animals
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Antihypertensive Agents / administration & dosage
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Antihypertensive Agents / pharmacokinetics
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Antihypertensive Agents / pharmacology
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Antihypertensive Agents / therapeutic use*
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Dogs
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Dose-Response Relationship, Drug
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Drug Compounding
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Drug Delivery Systems* / adverse effects
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Drug Evaluation, Preclinical
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Epoprostenol / administration & dosage
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Epoprostenol / analogs & derivatives*
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Epoprostenol / metabolism
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Epoprostenol / pharmacokinetics
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Epoprostenol / pharmacology
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Epoprostenol / therapeutic use
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Excipients / administration & dosage
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Excipients / adverse effects
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Excipients / chemistry
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Female
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Guinea Pigs
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Humans
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Hypertension, Pulmonary / blood
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Hypertension, Pulmonary / drug therapy*
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Lung / blood supply
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Lung / drug effects
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Lung / metabolism
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Male
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Nanoparticles / administration & dosage
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Nanoparticles / adverse effects
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Nanoparticles / chemistry
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Phosphatidylethanolamines / administration & dosage
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Phosphatidylethanolamines / adverse effects
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Phosphatidylethanolamines / chemistry
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Platelet Aggregation / drug effects
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Polyethylene Glycols / administration & dosage
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Polyethylene Glycols / adverse effects
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Polyethylene Glycols / chemistry
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Prodrugs / administration & dosage*
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Prodrugs / pharmacokinetics
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Prodrugs / pharmacology
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Prodrugs / therapeutic use
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Rats, Sprague-Dawley
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Squalene / administration & dosage
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Squalene / adverse effects
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Squalene / analogs & derivatives
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Squalene / chemistry
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Vasodilation / drug effects
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Vasodilator Agents / administration & dosage*
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Vasodilator Agents / pharmacokinetics
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Vasodilator Agents / pharmacology
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Vasodilator Agents / therapeutic use
Substances
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1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000)
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Antihypertensive Agents
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Excipients
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Phosphatidylethanolamines
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Prodrugs
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Vasodilator Agents
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hexadecyl-treprostinil
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Polyethylene Glycols
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Squalene
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Epoprostenol
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squalane
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treprostinil