title: Pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor in overweight or obese, but otherwise healthy human subjects.
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 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.
authors: Novartis Institutes for BioMedical Research (NIBR), Cambridge, MA, USA.
authors: Charles D
authors: CD
authors: Meyers
authors: NIBR, East Hanover, NJ, USA.
authors: Ahmed
authors: A
authors: Amer
authors: Alcon Laboratories, Inc., Fort Worth, TX, USA.
authors: Tapan
authors: T
authors: Majumdar
authors: NIBR, East Hanover, NJ, USA.
authors: Jin
authors: J
authors: Chen
mesh_terms: D000085:Acetates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D050177:Overweight; D055815:Young Adult
chemical_list: D000085:Acetates; D000631:Aminopyridines; C000594809:pradigastat; D051048:Diacylglycerol O-Acyltransferase
keywords: DGAT1 inhibitor; pharmacodynamics; pharmacokinetics; pradigastat; triglyceride