Effect of Pradigastat, a Diacylglycerol Acyltransferase 1 Inhibitor, on the QTcF Interval in Humans.
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.
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Charles D
CD
Meyers
Novartis Pharma AG, Basel, Switzerland.
Adele
A
Noe
Novartis Healthcare Private Limited, Hyderabad, Telangana, India.
Atish
A
Salunke
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Aishwarya
A
Movva
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Kenneth
K
Kulmatycki
Novartis Healthcare Private Limited, Hyderabad, Telangana, India.
Srikanth
S
Neelakantham
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Anne
A
Crissey
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Tapan
T
Majumdar
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Jin
J
Chen
D000085:Acetates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000293:Adolescent; D000328:Adult; D000631:Aminopyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D015992:Body Mass Index; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D024841:Fluoroquinolones / Q000009:adverse effects; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000188:drug therapy; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D000077266:Moxifloxacin; D055815:Young Adult
D000085:Acetates; D000631:Aminopyridines; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; C000594809:pradigastat; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase; D000077266:Moxifloxacin
QTc interval; moxifloxacin; pradigastat