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: Anisha Mendonza, Imad Hanna, Dan Meyers, Phillip Koo, Srikanth Neelakantham, Bing Zhu, Tapan Majumdar, Sam Rebello, Gangadhar Sunkara, Jin Chen
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 56 Issue 3 Pg. 355-64 (Mar 2016) ISSN: 1552-4604 [Electronic] England
• PMID: 26189431 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015, The American College of Clinical Pharmacology.

Chemical References

• Acetates
• Aminopyridines
• pradigastat
• Mefenamic Acid
• Atazanavir Sulfate
• UDP-glucuronosyltransferase, UGT1A3
• UGT1A1 enzyme
• UGT2B7 protein, human
• Glucuronosyltransferase
• Probenecid

Topics

• Acetates (blood, pharmacokinetics)
• Adolescent
• Adult
• Aminopyridines (blood, pharmacokinetics)
• Atazanavir Sulfate (pharmacology)
• Dose-Response Relationship, Drug
• Drug Interactions
• Female
• Glucuronosyltransferase (antagonists & inhibitors)
• Healthy Volunteers
• Humans
• Male
• Mefenamic Acid (pharmacology)
• Middle Aged
• Probenecid (pharmacology)
• Young Adult