Assessment of pharmacokinetic drug‐drug interaction between pradigastat and atazanavir or probenecid

Pradigastat, a novel diacylglycerol acyltransferase-I 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, UGT IA1,-IA3, and-2B7. The in vitro studies using atazanavir as a selective inhibitor of UGT 1 AI and-IA3 indicated that these enzymes contribute similar to 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 UGT IA I,-IA3 inhibitor). The study included 2 parallel cohorts, each with 3 sequential treatment periods and 22 healthy subjects per cohort. The 90%Cl of the geometric mean ratios for C-max,C-ss and AUC(tau,ss) of pradigastat were within 0.80-1.25 when administered in combination with probenecid. However, the C-max,C-ss and AUC(tau,ss) of pradigastat decreased by 31% (90%Cl: 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.