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Clinical Pharmacokinetics of Pradigastat, a Novel Diacylglycerol Acyltransferase 1 Inhibitor

Chen, Jin, Meyers, Charles, Keefe, Debbi, Yu, Jing and Sunkara, Gangadhar (2017) Clinical Pharmacokinetics of Pradigastat, a Novel Diacylglycerol Acyltransferase 1 Inhibitor. Journal of Drug Design and Research.


Background: Familial chylomicronemia syndrome (FCS) is a rare lipid disease resulting in severe hypertriglyceridemia caused by complete lipoprotein lipase (LPL) deficiency. Pradigastat, a highly potent and specific diacylglycerol acyltransferase 1 (DGAT1) inhibitor that blocks chylomicron triglyceride (TG) synthesis, is an attractive therapy for patients with FCS.

Objective: To summarize the data from in vitro and clinical pharmacokinetic studies of pradigastat.

Results: Following oral administration, pradigastat was slowly absorbed and slowly eliminated. Food intake does not impact pradigastat exposure to any clinically relevant extent. Pradigastat is primarily metabolized by hepatic glucuronosyltransferase (UGT) enzymes UGT1A1 and UGT1A3, and is eliminated in feces through the biliary pathway. The exposure of pradigastat doubled in patients with severe hepatic impairment but did not change in patients with mild to moderate hepatic impairment and in patients with renal impairment. Pradigastat has low drug-drug interaction potential and had no interaction with atazanavir, probenecid, rosuvastatin, digoxin, warfarin, and oral contraceptives. Pradigastat substantially reduces plasma fasting TG levels (70% at 40 mg), post-prandial TG, and apo48 in FCS patients. Pradigastat has no effect on the QTc interval in humans, hence there is no dysrhythmia risk associated with prolonged QTc and it does not induce photosensitivity in humans at the highest clinical dose of 40 mg.

Conclusion: Pradigastat can be taken without food. No dose adjustment is needed in consideration of drug-drug interaction, and no dose adjustment is needed for patients with mild to moderate hepatic impairment or with renal impairment.

Item Type: Article
Keywords: Pradigastat, LCQ908, pharmacokinetics, pharmacodynamics, familial chylomicronemia, FCS, ADME
Date Deposited: 12 Apr 2017 00:45
Last Modified: 12 Apr 2017 00:45


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