• Lei Sun, David McDonnell, Miao Yu, Vipul Kumar, and Lisa von Moltke.
• Clinical Pharmacology and Translational Medicine, Alkermes, Inc., 852 Winter Street, Waltham, MA, 02451, USA. Lei.sun@alkermes.com.
• Clin Drug Investig. 2019 May 1; 39 (5): 477-484.

BackgroundA combination of the atypical antipsychotic olanzapine and opioid receptor antagonist samidorphan (OLZ/SAM) is in development for the treatment of schizophrenia. The goal of OLZ/SAM is to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain and many associated long-term metabolic consequences. The primary metabolic pathways for olanzapine are direct glucuronidation via uridine 5'-diphospho-glucuronosyltransferase (UGT)1A4 and cytochrome P450 (CYP)-mediated oxidation, mainly by CYP1A2. In contrast, the samidorphan metabolic pathway is mediated predominantly by CYP3A4.ObjectiveThe aim of this study was to evaluate the effects of CYP3A4 induction on the single-dose pharmacokinetics of OLZ/SAM in healthy subjects.MethodsIn this phase I, single-center, open-label, two-period study, 24 healthy volunteers received a single oral dose of OLZ/SAM 10/10 (10 mg olanzapine/10 mg samidorphan) on day 1. After a 14-day washout, 600 mg of rifampin (rifampicin), a strong CYP3A4 inducer, as well as an inducer of UGT enzymes and a weak inducer of CYP1A2, was administered once daily on days 15‒21. A single oral dose of OLZ/SAM 10/10 was coadministered with rifampin 600 mg on day 22. Olanzapine and samidorphan pharmacokinetic parameters were determined after OLZ/SAM dosing on days 1 and 22. The geometric mean ratio of maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from zero to infinity (AUC∞) for olanzapine and samidorphan in the presence and absence of rifampin, along with its two-sided 90% confidence interval, were derived from a linear mixed-effects model. Safety was monitored throughout the study.ResultsCompared with OLZ/SAM alone, coadministration of OLZ/SAM with rifampin decreased the Cmax and AUC∞ of olanzapine by 11% and 48%, and that of samidorphan by 44% and 73%, respectively. OLZ/SAM 10/10 was generally well tolerated in this study.ConclusionCoadministration with rifampin decreased total systemic exposure (based on AUC∞) of olanzapine and samidorphan by 48% and 73%, respectively.

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