Effect of Pradigastat, a Diacylglycerol Acyltransferase 1 Inhibitor, on the QTcF Interval in Humans
| Autor: | Srikanth Neelakantham, Tapan K. Majumdar, Aishwarya Movva, Atish Salunke, Charles D. Meyers, Kenneth Kulmatycki, Anne Crissey, Jin Chen, Adele Noe |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male Adolescent Moxifloxacin Aminopyridines Pharmaceutical Science Positive control Acetates Pharmacology Placebo 030226 pharmacology & pharmacy QT interval Body Mass Index Electrocardiography Young Adult 03 medical and health sciences 0302 clinical medicine Pradigastat Double-Blind Method Pharmacokinetics Heart Rate Humans Medicine Pharmacology (medical) Diacylglycerol O-Acyltransferase Enzyme Inhibitors Dose-Response Relationship Drug business.industry Healthy Volunteers Long QT Syndrome Tolerability 030220 oncology & carcinogenesis Anesthesia Hyperlipoproteinemia Type I Diacylglycerol Acyltransferase business Fluoroquinolones medicine.drug |
| Zdroj: | Clinical Pharmacology in Drug Development. 5:450-459 |
| ISSN: | 2160-763X |
| DOI: | 10.1002/cpdd.278 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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