Pharmacokinetics and Short-term Safety of ALKS 3831, a Fixed-dose Combination of Olanzapine and Samidorphan, in Adult Subjects with Schizophrenia

Abstract

Purpose: ALKS 3831 is composed of a flexible dose of olanzapine and a fixed dose of 10-mg samidorphan (a novel opioid system modulator), designed to provide the established antipsychotic efficacy of olanzapine and to mitigate olanzapine-induced weight gain. To support clinical development of ALKS 3831, we conducted a multicenter, randomized, open-label, Phase I study to obtain steady-state exposure for olanzapine and samidorphan and short-term safety at the intended therapeutic dose range of ALKS 3831 10/10 (10-mg olanzapine/10-mg samidorphan) to ALKS 3831 20/10 (20-mg olanzapine/10-mg samidorphan) in subjects with schizophrenia. Methods: After a 1-week olanzapine lead-in period, 42 subjects (14 women) with schizophrenia were randomly assigned (1:1) to receive ALKS 3831 10/10 or ALKS 3831 20/10 bilayer oral tablets once daily for 14 days. Plasma concentrations of olanzapine and samidorphan were quantified by using an LC-MS/MS method. Pharmacokinetic parameters were calculated according to noncompartmental analysis. Safety was monitored throughout the study. Findings: After a 1-week olanzapine lead-in phase with titration of olanzapine dose up to 15 mg/d, the steady-state concentration of olanzapine was reached in 3–4 days and that of samidorphan was reached in 5 days after initiation of once-daily oral administration of ALKS 3831 10/10 or ALKS 3831 20/10. At steady state, exposure to olanzapine increased dose proportionally from 10 mg (ALKS 3831 10/10) to 20 mg (ALKS 3831 20/10), and exposure to samidorphan was similar between the 2 ALKS 3831 dose groups, indicating that different dose levels of olanzapine in ALKS 3831 had no impact on the pharmacokinetic profile of samidorphan. ALKS 3831 was well tolerated, and no safety concerns unique to ALKS 3831 compared with olanzapine monotherapy were identified. Implications: In the present study, samidorphan exposure was not affected by different dose levels of olanzapine in ALKS 3831. In addition, olanzapine exposure as a component of ALKS 3831 was comparable with previously published data for olanzapine monotherapy. The present data indicate that combining olanzapine with samidorphan does not affect the pharmacokinetic profile of either drug and support continued clinical evaluation of ALKS 3831. ClinicalTrials.gov identifier: NCT02804568.