In vivo Characterization of the Opioid Receptor–Binding Profiles of Samidorphan and Naltrexone in Rats: Comparisons at Clinically Relevant Concentrations

Abstract

Introduction

The atypical antipsychotic olanzapine is approved for the treatment of schizophrenia and bipolar I disorder; however, weight gain and metabolic dysregulation associated with olanzapine therapy have limited its clinical utility. In clinical studies, treatment with the combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain while providing antipsychotic efficacy similar to that of olanzapine. Although samidorphan is structurally similar to the opioid receptor antagonist naltrexone, the two differ in their pharmacokinetics and in vitro binding affinities to mu, delta, and kappa opioid receptors (MOR, DOR, and KOR, respectively). The objective of this series of nonclinical studies was to compare the in vivo binding profiles of samidorphan and naltrexone and their receptor occupancies at MOR, DOR, and KOR in rat brains.

Methods

Male rats were injected with samidorphan or naltrexone to obtain total and unbound plasma and brain concentrations representing levels observed in humans at clinically relevant oral doses. Subsequently, samidorphan and naltrexone brain receptor occupancy at MOR, DOR, and KOR was measured using ultra-performance liquid chromatography and high-resolution accurate-mass mass spectrometry.

Results

A dose-dependent increase in samidorphan occupancy was observed at MOR, DOR, and KOR (EC₅₀: 5.1, 54.7, and 42.9 nM, respectively). Occupancy of naltrexone at MOR (EC₅₀: 15.5 nM) and KOR was dose dependent; minimal DOR occupancy was detected. At the clinically relevant unbound brain concentration of 23.1 nM, samidorphan bound to MOR, DOR, and KOR with 93.2%, 36.1%, and 41.9% occupancy, respectively. At 33.5 nM, naltrexone bound to MOR and KOR with 79.4% and 9.4% occupancy, respectively, with no binding at DOR.

Discussion

At clinically relevant concentrations, samidorphan occupied MOR, DOR, and KOR, whereas naltrexone occupied only MOR and KOR. The binding profile of samidorphan differs from that of naltrexone, with potential clinical implications.

Keywords:

• ALKS 3831
• bipolar I disorder
• Lybalvi
• olanzapine
• opioid receptor
• schizophrenia

Abbreviations

C_max, maximum plasma concentration; DOR, delta opioid receptor; EC₅₀, half-maximal effective concentration; HRAM, high-resolution accurate-mass; IC₅₀, half-maximal inhibitory concentration; KOR, kappa opioid receptor; LC-MS, liquid chromatography/mass spectrometry; LC-MS/MS, tandem mass spectrometry; MOR, mu opioid receptor; OLZ/SAM, a combination of olanzapine and samidorphan; UPLC, ultra-performance liquid chromatography.

Acknowledgments

The authors thank Mark S. Todtenkopf, PhD, of Alkermes, Inc., for assistance in the preparation and critical review of this manuscript. They also thank Michaela Cullum-Doyle, Adjovi Rodriguez, Abigail Hanks, Issam Ayoub, and Praveen Srivistava of Alkermes, Inc., for their technical assistance. Editorial support was provided by Peloton Advantage, LLC, an OPEN Health company, and funded by Alkermes, Inc.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

This study was sponsored by Alkermes, Inc. L.A. Tan, N. Gajipara, M. Bacolod, and Y. Zhou are employees of Alkermes, Inc., and may own stock/options in the company. M. Namchuk, L. Sun, and J.I. Cunningham were employees of Alkermes, Inc., at the time of this study, and may own stock/options in the company. M. Namchuk reports personal fees from Arrakis Therapeutics and Sionna Therapeutics, personal fees from Axonis, and grants from AbbVie outside the submitted work. The authors report no other conflicts of interest in this work.