title: Assessment of pharmacokinetic drug-drug interaction between pradigastat and atazanavir or probenecid.
abstract: Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, has activity in common metabolic diseases associated with abnormal accumulation of triglycerides. In vitro studies suggest that glucuronidation is the predominant metabolism pathway for elimination of pradigastat in humans and confirmed the role of uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes, UGT1A1, -1A3, and -2B7. The in vitro studies using atazanavir as a selective inhibitor of UGT1A1 and -1A3 indicated that these enzymes contribute ∼55% toward the overall glucuronidation pathway. Therefore, a clinical study was conducted to assess the potential for drug interaction between pradigastat and probenecid (purported general UGT inhibitor) or atazanavir (selective UGT1A1, -1A3 inhibitor). The study included 2 parallel cohorts, each with 3 sequential treatment periods and 22 healthy subjects per cohort. The 90%CI of the geometric mean ratios for Cmax,ss and AUCτ,ss of pradigastat were within 0.80-1.25 when administered in combination with probenecid. However, the Cmax,ss and AUCτ,ss of pradigastat decreased by 31% (90%CI: 0.62-0.78) and 26% (0.67-0.82), respectively, when administered in combination with atazanavir. This magnitude of decrease in pradigastat steady-state exposure is not considered clinically relevant. Pradigastat was well tolerated by all subjects, either alone or in combination with atazanavir or probenecid.
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Anisha
authors.initials: A
authors.lastname: Mendonza
authors.affiliation: Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Imad
authors.initials: I
authors.lastname: Hanna
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Meyers
authors.affiliation: Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Koo
authors.affiliation: Novartis Healthcare Pvt Ltd, Hyderabad, India.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Neelakantham
authors.affiliation: Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Alcon Laboratories, Fort Worth, TX, USA.
authors.forename: Tapan
authors.initials: T
authors.lastname: Majumdar
authors.affiliation: Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Rebello
authors.affiliation: Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Gangadhar
authors.initials: G
authors.lastname: Sunkara
authors.affiliation: Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
mesh_terms: D000085:Acetates / Q000097:blood / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D000631:Aminopyridines / Q000097:blood / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008528:Mefenamic Acid / Q000494:pharmacology; D008875:Middle Aged; D011339:Probenecid / Q000494:pharmacology*; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D000085:Acetates; D000631:Aminopyridines; D000069446:Atazanavir Sulfate; D014453:Glucuronosyltransferase; D008528:Mefenamic Acid; D011339:Probenecid; D000099148:UGT1A1 Enzyme; C000594809:pradigastat; C122075:UDP-glucuronosyltransferase, UGT1A3; C491474:UGT2B7 protein, human
keywords: UGT inhibitors; atazanavir; drug-drug interaction; pharmacokinetics; pradigastat; probenecid