Pharmacokinetic and pharmacodynamic drug–drug interaction assessment between pradigastat and digoxin or warfarin

Abstract

Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, was evaluated for both pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions when co-administered with digoxin or warfarin in healthy subjects. This open-label study included two parallel subject cohorts each with three sequential treatment periods. Forty subjects were enrolled in the study with 20 subjects allocated to each cohort. PK and PD (PT/INR for warfarin only) samples were collected in each period. The statistical analysis results showed that the 90% CIs of the geometric mean ratios of digoxin, R-warfarin, and S-warfarin PK parameters (AUC and Cmax) were all within 0.80-1.25 interval. The 90% CIs of the geometric mean ratios of pradigastat PK parameters (AUC and Cmax) were within 0.80-1.25 interval when co-administered with warfarin; while co-administration with digoxin slightly reduced pradigastat exposure (∼15%). The results also showed that 90% CIs of the geometric mean ratios of warfarin PD parameters (AUC(PT), PTmax, AUC(INR), and INRmax) were within 0.80-1.25 interval. Pradigastat and digoxin or warfarin had no relevant clinical PK or PD drug-drug interactions. Administration of pradigastat and warfarin or pradigastat and digoxin as a mono or combined treatment appears to be safe and tolerated.

Assessment of pharmacokinetic drug-drug interaction between pradigastat and acetaminophen in healthy subjects

“…Indeed, pradigastat achieved steady-state levels with a loading dose of 100 mg for 3 days followed by 40 mg for 7 days and maintained throughout periods 3-7. This is consistent with earlier reports on pradigastat supporting the use of this regimen [4,12].…”

“…Pradigastat pharmacokinetic profile indicates a slow absorption with a median T max of ∼10 h and a long terminal half-life of ∼150 h [4]. It is metabolized by UDPglucuronosyltransferase (UGT) enzymes and excreted as unchanged drug or glucuronide conjugates in feces via the bile [5].…”

Effect of Renal Impairment on the Pharmacokinetics of Pradigastat, a Novel Diacylglycerol Acyltransferase1 (DGAT1) Inhibitor

“…The higher mean AUC inf observed in the moderate renal impairment group was attributable to a patient with an exceptionally high AUC inf value (Fig. 3, subject with AUC inf = 225,000 hÁng/mL), resulting in large interpatient variability (117 %), which was higher than the range of the previously reported inter-subject variability of pradigastat (50-60 %) [5]. This subject also had abnormal large double peaks at 72 and 192 h. When this patient's data was excluded, the mean AUC inf value (35,200 hÁng/ mL) was lower than that of severe patients and comparable to the mean AUC inf value of matched healthy control subjects (34,500 hÁng/mL).…”

“…As the inter-subject CV of the pharmacokinetics of pradigastat was found to be about 60 % [5], the sample size of 10 had 80 % power to detect a difference in pradigastat systemic exposure of 2-fold (by a two-sided t test at a significance level of 0.1).…”

“…After oral administration, pradigastat is slowly absorbed, with a median time to reach the maximum plasma concentration (t max ) of *10 h, and is eliminated with a half-life of *150 h [5]. Pradigastat exhibits linear and time-independent pharmacokinetics (data on file).…”