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Pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor in overweight or obese, but otherwise healthy human subjects
Author(s) -
Meyers Charles D.,
Amer Ahmed,
Majumdar Tapan,
Chen Jin
Publication year - 2015
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.509
Subject(s) - postprandial , tolerability , pharmacokinetics , medicine , pharmacodynamics , placebo , triglyceride , pharmacology , endocrinology , dosing , insulin , adverse effect , cholesterol , alternative medicine , pathology
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 overweight or obese 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 t max of ∼10 hours and eliminated slowly with a long half‐life. With multiple oral doses, a 10‐ to17‐fold higher systemic exposure was observed. Pradigastat treatment (single and multiple doses) led to 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.