The DGAT1 inhibitor pradigastat does not induce photosensitivity in healthy human subjects: a randomized controlled trial using three defined sunlight exposure conditions.

The DGAT1 inhibitor, pradigastat, demonstrated a mild phototoxicity signal in preclinical studies. Therefore, this clinical trial was conducted to assess the risk of photosensitivity in humans. 47 healthy adults were randomized to part A (double-blind, placebo-controlled; 3 : 1 pradigastat : placebo) or part B (open-label positive control ciprofloxacin, investigator blind). Three irradiation conditions (1. full range UVB/UVA, 2. UVA only, 3. 1/2 MED from UVB/UVA + 16 J cm(-2) UVA) were applied to simulate different sunlight exposure conditions. Photosensitizing potential was assessed by determining the minimum erythemal dose (MED) and calculating the photosensitivity index (PI) at 1 and 24 h. Local skin reactions were recorded as a secondary endpoint. Following full UVB/UVA irradiation, there were no significant differences in MED or PI between groups. With UVA-only, no changes in MED or PI were observed for the pradigastat or placebo groups. For ciprofloxacin, there was a significant reduction in MED at 24 h (-32%, vs. 24 h baseline), which correlated to a PI of 1.61. The difference in mean PI between ciprofloxacin-pradigastat, and ciprofloxacin-placebo, was significant at 24 h (p < 0.001). Local skin erythema scores were comparable between pradigastat and placebo, but higher with ciprofloxacin. Pradigastat was not shown to induce photosensitivity reactions, while significant responses were seen with the positive control. These results strongly suggest that pradigastat will not induce photosensitivity reactions in individuals administered doses up to 40 mg per day, which is the highest intended clinical dose. Furthermore, the design of this clinical trial may serve as a prototype for future regulatory clinical photosensitivity studies.

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

PURPOSE: The purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acyltransferase-1 inhibitor, on the pharmacokinetics of acetaminophen, a gastric emptying marker. METHODS: Twenty-five healthy subjects were enrolled and received 1000 mg acetaminophen with meal in period 1, pradigastat (100 mg × 3 days followed by 40 mg × 7 days, 1 h before meal) in period 2, and 1000 mg acetaminophen at -2, -1, 0, +1, and +3 h with respect to meal timing in presence of steady-state pradigastat (40-mg maintenance dose) during periods 3-7. RESULTS: The geometric mean ratio and 90% confidence interval of Cmax and AUC of acetaminophen were within 80-125% suggesting that the rate ad extent of acetaminophen were not affected when given at various time points with respect to pradigastat/meal timing. The acetaminophen Tmax was also not impacted under all treatment conditions but increased from 0.75 to 2.00 h when administered 1 h after food. CONCLUSION: In the presence of steady-state pradigastat, the pharmacokinetics of acetaminophen is unchanged, when given before, with, or 3 h after a meal. However, when given 1 h after a meal, the Tmax of acetaminophen was delayed by ∼1.25 h without affecting Cmax or AUC.

Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor.

OBJECTIVE: An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. METHODS: The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. RESULTS: Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC(50) value of 5 µM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17ß glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC(50) values of 1.66 ± 0.95 µM, 3.34 ± 0.64 µM, and 0.973 ± 0.11 µM, respectively. In the presence of steady state pradigastat concentrations, AUC(τ, ss) of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC(τ, ss) and C(max, ss) were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. CONCLUSION: These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin.

Assessment of pharmacokinetic drug-drug interaction between pradigastat and atazanavir or probenecid.

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.

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

BACKGROUND AND OBJECTIVE: Pradigastat, a diacylglycerol acyltransferase1 inhibitor, is being developed for the treatment of familial chylomicronemia syndrome. The primary objective of this clinical study was to evaluate the effect of renal impairment on the pharmacokinetics of pradigastat. METHODS: In an open-label, parallel-group study, the single-dose (40 mg) pharmacokinetics of pradigastat were evaluated in patients with mild (n = 9), moderate (n = 10) and severe renal impairment (n = 9) compared with matched healthy subjects (n = 28). The protein binding and urinary excretion of pradigastat were also assessed in this study. RESULTS: In patients with mild and moderate renal impairment the geometric means of the maximum plasma concentration (C max) and the area under the plasma concentration-time curve from time zero to infinity (AUC inf) of pradigastat were similar as compared with healthy subjects. In patients with severe renal impairment, the geometric means of the C max and AUC inf increased by 40 % [geometric mean ratio 1.41; 90 % confidence interval (CI) 0.92-2.14] and 18 % (geometric mean ratio 1.18; 90 % CI 0.68-2.05), respectively. There was no significant correlation between renal function (measured by creatinine clearance) and C max or AUC inf. Protein binding values were >99 % and the urinary excretion of pradigastat was minimal in all subjects. There were no severe adverse events in the study and mild transient diarrhoea was the most common adverse event. The safety profile was similar between patients with renal impairment and healthy subjects. CONCLUSION: There was no change in the pharmacokinetics of pradigastat in patients with mild and moderate renal impairment. In patients with severe renal impairment, the mean exposure C max and AUC inf of pradigastat were increased by 40 and 18 %, respectively.

Effect of Hepatic Impairment on the Pharmacokinetics of Pradigastat, a Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor.

BACKGROUND AND OBJECTIVE: Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, is under development to treat familial chylomicronemia syndrome. The potential impact of hepatic impairment on the pharmacokinetics of pradigastat was evaluated in this study. METHODS: In this study, a single oral dose of 20 mg pradigastat was administered first to patients with mild and moderate hepatic impairment (n = 10/group) and subsequently to patients with severe hepatic impairment (n = 6). The pharmacokinetics of pradigastat were compared between each patient group and the respective matched healthy subjects. RESULTS: As compared with the respective matched healthy groups, the geometric mean ratios of the area under the plasma concentration-time curve from time zero to infinity (AUC inf) (h · ng/mL) were 1.49, 1.06 and 1.99 in mild, moderate and severe hepatic impairment patients, respectively; the observed maximum plasma concentration (C max) (ng/mL) values were 0.97, 1.28 and 2.74, respectively; and the total body clearance of the drug from plasma (CL/F) (L/h) values were 0.67, 0.95 and 0.50, respectively. The elimination half-life and plasma protein binding of pradigastat were comparable among all the patients. There were no apparent relationships between AUC inf or C max and albumin or bilirubin levels (R (2) < 0.3; p > 0.05). Overall, 19 adverse events (AEs) were reported in 13 patients. The incidence of AEs appeared to increase with increasing severity of hepatic impairment. CONCLUSION: No clinically significant differences in the pharmacokinetics of pradigastat were observed in mild and moderate hepatic impairment patients compared with healthy subjects. However, the systemic exposure of pradigastat doubled while the clearance decreased by half in patients with severe hepatic impairment compared with healthy subjects. All treatments were well tolerated in the study.

Pharmacokinetic and pharmacodynamic drug-drug interaction assessment between pradigastat and digoxin or warfarin.

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.