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Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Pradigastat, a Novel Diacylglycerol Acyltransferase 1 Inhibitor in Healthy Human Subjects

Meyers, Charles and Amer, Ahmed and Majumdar, Tapan and Chen, Jin (2015) Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Pradigastat, a Novel Diacylglycerol Acyltransferase 1 Inhibitor in Healthy Human Subjects. Journal of Clinical Pharmacology, 55 (9). pp. 1031-1041. ISSN 00912700

Abstract

Pradigastat is a potent and selective inhibitor of diacylglycerol acyltransferase 1, an enzyme highly expressed in the small intestine that plays a key role in postprandial triglyceride synthesis. This first-in-human study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat administered at single and multiple doses in healthy subjects. In single-dose cohorts (n = 72), subjects were randomized sequentially to receive single doses of pradigastat (1, 3, 10, 30, 100, or 300 mg) or placebo under fasted condition and prior to breakfast. In multiple-dose cohorts (n = 106), subjects were randomized to receive pradigastat (1, 5, 10, or 25 mg) or placebo prior to breakfast for 14 days. Following a single oral dosing, pradigastat was absorbed slowly with a median tmax of ~10 hours and eliminated slowly with a long half-life. With multiple oral doses, a 10- to 17-fold higher systemic exposure was observed. Pradigastat treatment (single and multiple doses) led to a dose-dependent suppression of postprandial triglyceride excursions over 9 hours following a high-fat meal test. In addition, pradigastat suppressed postprandial glucose and insulin, and increased plasma glucagon-like peptide-1 levels. Overall, pradigastat was safe and tolerated at single and multiple doses in healthy subjects.

Item Type: Article
Keywords: DGAT1 inhibitor, pradigastat, pharmacokinetics, pharmacodynamics, triglyceride
Date Deposited: 27 Apr 2016 23:45
Last Modified: 27 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/24598

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