Pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor in overweight or obese, but otherwise healthy human subjects

• Published in: Journal of clinical pharmacology Vol. 55; no. 9; p. 1031
• Main Authors: Meyers, Charles D, Amer, Ahmed, Majumdar, Tapan, Chen, Jin
• Format: Journal Article
• Language: English
• Published: England 01.09.2015
• Subjects: Acetates - administration & dosage; Acetates - adverse effects; Acetates - pharmacokinetics; Adolescent; Adult; Aminopyridines - administration & dosage; Aminopyridines - adverse effects; Aminopyridines - pharmacokinetics; Area Under Curve; Diacylglycerol O-Acyltransferase - antagonists & inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Female; Half-Life; Humans; Male; Middle Aged; Overweight; Young Adult; triglyceride; pharmacokinetics; DGAT1 inhibitor; pharmacodynamics; pradigastat
• DOI: 10.1002/jcph.509

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 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 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.