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

Abstract

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 (AUC_0-∞) and a 2.17-fold increase in maximum plasma concentration (C_max) of olanzapine, and a 1.52-fold increase in AUC_0-∞ and a 1.63-fold increase in C_max 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 AUC_0-∞, and a 1.32- and 1.37-fold increase in C_max 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

Acknowledgments

This study was sponsored by Alkermes, Inc. The authors would also like to thank Mark S. Todtenkopf, PhD, who assisted in the preparation and proofreading of the manuscript. Medical writing and editorial support was provided by Peloton Advantage, LLC (Parsippany, NJ), and funded by Alkermes, Inc. Alkermes, Inc. is a pharmaceutical company developing OLZ/SAM, a combination product of olanzapine and samidorphan for the treatment of schizophrenia, and has funded this study.

Author contributions

All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

Lei Sun, Sergey Yagoda, Yangchun Du, and Lisa von Moltke are employees and shareholders of Alkermes, Inc. The authors report no other conflicts of interest in this work.

Supplementary materials

Table S1 Mean plasma levels of olanzapine and samidorphan in subjects with moderate hepatic impairment and healthy control subjects after a single oral dose of OLZ/SAM (5 mg olanzapine/10 mg samidorphan)

Table S2 Mean plasma and urine levels of olanzapine and samidorphan in subjects with severe renal impairment and healthy control subjects after a single oral dose of OLZ/SAM (5 mg olanzapine/10 mg samidorphan)