A Phase I Open-Label Study to Evaluate the Effects of Rifampin on the Pharmacokinetics of Olanzapine and Samidorphan Administered in Combination in Healthy Human Subjects.

Background: A 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.

Objective: The aim of this study was to evaluate the effects of CYP3A4 induction on the single-dose pharmacokinetics of OLZ/SAM in healthy subjects.

Methods: In 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.

Results: Compared 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.

Conclusions: Coadministration with rifampin decreased total systemic exposure (based on AUC∞) of olanzapine and samidorphan by 48% and 73%, respectively.