Premium
Assessment of pharmacokinetic drug‐drug interaction between pradigastat and atazanavir or probenecid
Author(s) -
Mendonza Anisha,
Hanna Imad,
Meyers Dan,
Koo Phillip,
Neelakantham Srikanth,
Zhu Bing,
Majumdar Tapan,
Rebello Sam,
Sunkara Gangadhar,
Chen Jin
Publication year - 2016
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.595
Subject(s) - probenecid , atazanavir , drug , pharmacokinetics , pharmacology , drug drug interaction , medicine , virology , human immunodeficiency virus (hiv) , antiretroviral therapy , viral load
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 C max,ss and AUC τ,ss of pradigastat were within 0.80–1.25 when administered in combination with probenecid. However, the C max,ss and AUC τ,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.