Abstract
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 (AUCinf) (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 AUCinf 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.
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Acknowledgments
The authors would like to thank Anjana Mallela and Vennila Dharman for their medical writing assistance with this manuscript.
This study was supported by Novartis Pharma AG, Basel, Switzerland.
Conflict of interest/disclosure
All authors are employees of Novartis, except for T. Majumdar who was employed by Novartis Pharma during the study conduct and manuscript development, and is currently employed by Alcon Laboratories, Inc.
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Registered at ClinicalTrials.gov as NCT01594957.
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Hirano, M., Meyers, D., Golla, G. et al. Effect of Hepatic Impairment on the Pharmacokinetics of Pradigastat, a Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor. Clin Pharmacokinet 54, 761–770 (2015). https://doi.org/10.1007/s40262-015-0235-9
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DOI: https://doi.org/10.1007/s40262-015-0235-9