pradigastat and Hyperlipoproteinemia-Type-I

Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supratherapeutic concentrations of pradigastat on the QTc interval, 2 studies were conducted. The first study assessed the safety, tolerability, and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100, and 115 mg over 60 minutes) in healthy adults. Single intravenous doses were safe, well tolerated, and at the higher doses resulted in supratherapeutic pradigastat exposure. The second was a parallel, 3-arm thorough QTc study in which healthy male subjects were randomized to pradigastat (115 mg intravenously), moxifloxacin (400 mg oral, positive control), or placebo. Following intravenous administration, pradigastat exposure peaked at 4 times the therapeutic concentration and did not prolong the baseline-adjusted and placebo-corrected QTc intervals. During the 60-minute pradigastat infusion, a number of infusion reactions and a small mean decrease in QTc were observed. Both effects disappeared when the infusion was stopped, suggesting that an infusate excipient may have been responsible. As expected, moxifloxacin significantly increased the QTc interval at multiple points, confirming the study's sensitivity to detect a true positive effect. Pradigastat is therefore unlikely to increase the risk of dysrhythmias associated with QTc prolongation in humans.

Topics: Acetates; Adolescent; Adult; Aminopyridines; Body Mass Index; Diacylglycerol O-Acyltransferase; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Enzyme Inhibitors; Fluoroquinolones; Healthy Volunteers; Heart Rate; Humans; Hyperlipoproteinemia Type I; Long QT Syndrome; Male; Moxifloxacin; Young Adult

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.. 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.. 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.. 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.

Topics: Acetates; Aged; Aminopyridines; Body Mass Index; Case-Control Studies; Diacylglycerol O-Acyltransferase; Enzyme Inhibitors; Female; Humans; Hyperlipoproteinemia Type I; Male; Middle Aged; Protein Binding; Renal Insufficiency

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.. 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.. 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.. 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.

Topics: Acetates; Aminopyridines; Body Mass Index; Diacylglycerol O-Acyltransferase; Enzyme Inhibitors; Female; Glucuronides; Hepatic Insufficiency; Humans; Hyperlipoproteinemia Type I; Male; Middle Aged; Protein Binding

Familial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS.. Six FCS patients were enrolled in an open-label clinical study. Following a 1-week very low fat diet run-in period patients underwent baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 & 10 mg, respectively). Treatment periods were separated by washout periods of ≥4 weeks. Fasting TG levels were assessed weekly through the treatment periods. Postprandial TGs, ApoB48 and lipoprotein lipid content were also monitored.. Following once daily oral dosing, steady-state exposure was reached by Day 14. There was an approximately dose proportional increase in pradigastat exposure at studied doses. Pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting triglyceride over 21 days of treatment. The reduction in fasting TG was almost entirely accounted for by a reduction in chylomicron TG. Pradigastat treatment also led to substantial reductions in postprandial TG as well as apo48 (both fasting and postprandial). Pradigastat was safe and well tolerated, with only mild, transient gastrointestinal adverse events.. The novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease.. ClinicalTrials.gov identifier NCT01146522 .

Topics: Acetates; Adult; Aged; Aminopyridines; Apolipoprotein B-48; Diacylglycerol O-Acyltransferase; Female; Humans; Hyperlipoproteinemia Type I; Male; Middle Aged; Triglycerides