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Effect of hepatic and renal impairment on the pharmacokinetics of olanzapine and samidorphan given in combination as a bilayer tablet

Authors Sun L, Yagoda S, Du Y, von Moltke L

Received 12 February 2019

Accepted for publication 25 July 2019

Published 22 August 2019 Volume 2019:13 Pages 2941—2955


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Jianbo Sun

Lei Sun,1 Sergey Yagoda,2 Yangchun Du,3 Lisa von Moltke2

1Department of Clinical Pharmacology and Translational Medicine, Alkermes, Inc., Waltham, MA, USA; 2Department of Clinical Research, Alkermes, Inc., Waltham, MA, USA; 3Department of Biostatistics, Alkermes, Inc., Waltham, MA, USA

Correspondence: Lei Sun
Clinical Pharmacology and Translational Medicine, Alkermes, Inc., 852 Winter Street, Waltham, MA 02451, USA
Tel +1 781 609 6151
Fax +1 781 609 5851

Background: A combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain.
Methods: Two multicenter, open-label, parallel-cohort studies were performed to evaluate the effect of moderate hepatic impairment (Child-Pugh score 7–9 [class B]; study 1) and severe renal impairment (estimated glomerular filtration rate: 15–29 mL/min/1.73 m2,; study 2) on the pharmacokinetics, safety, and tolerability of a single dose of OLZ/SAM 5/10 mg.
Results: There was a 1.67-fold increase in area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) and a 2.17-fold increase in maximum plasma concentration (Cmax) of olanzapine, and a 1.52-fold increase in AUC0-∞ and a 1.63-fold increase in Cmax of samidorphan, in subjects with moderate hepatic impairment compared with healthy control subjects. Compared with healthy control subjects, subjects with severe renal impairment had a 33% and 56% reduction in clearance, a 1.51- and 2.31-fold increase in AUC0-∞, and a 1.32- and 1.37-fold increase in Cmax of olanzapine and samidorphan, respectively.
Conclusion: OLZ/SAM 5/10 mg was generally well tolerated under the conditions of the studies, with a safety profile consistent with that observed in other clinical studies of OLZ/SAM.

Keywords: olanzapine, samidorphan, renal impairment, hepatic impairment, pharmacokinetics

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