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 3e4 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.

Physiologically‐Based Pharmacokinetic Modeling for Predicting Drug Interactions of a Combination of Olanzapine and Samidorphan

“…Simulated exposures were within 1.25‐fold of observed data for both olanzapine and samidorphan. PBPK modeling predicted no interaction between olanzapine and samidorphan when administered in combination, which is consistent with the distinct metabolic pathways of olanzapine and samidorphan and observed data from clinical studies …”

“…Simulated plasma concentrations and pharmacokinetic parameters were also in good agreement with observed data ( Figure ; Table ). Simulated plasma C‐T profiles of olanzapine and samidorphan following a single oral dose of OLZ/SAM in healthy subjects were consistent with observed data ( Figure ), as were simulated C‐T profiles of olanzapine and samidorphan following multiple once‐daily oral doses of OLZ/SAM 10/10 in patients with schizophrenia ( Figure ).…”

“…The two models were combined to represent administration of olanzapine and samidorphan in combination as OLZ/SAM in virtual trial simulations to ensure the same virtual individual with the exact same system/physiological parameters was administered olanzapine and samidorphan together at the same time in the same biosystem as in clinical studies with OLZ/SAM . Model‐simulated C‐T profiles well described the observed data in multiple clinical studies for model validation.…”

“…The PBPK models for olanzapine and samidorphan were first developed and verified using observed data from clinical studies in which olanzapine or samidorphan was administered alone . The models were then combined to represent administration of olanzapine and samidorphan in combination as OLZ/SAM in virtual trial simulations to ensure the same virtual individual was administered olanzapine and samidorphan together as in clinical studies with OLZ/SAM . Specifically, the PBPK models were verified by comparing simulated C‐T profiles and pharmacokinetic parameters, including C max and AUC, for olanzapine and/or samidorphan with observed data obtained from clinical studies .…”

“…Pharmacokinetic data from clinical studies indicated a lack of DDI between olanzapine and samidorphan when the two drugs are administered in combination, consistent with their distinct metabolic pathways. The effects of CYP1A2 and CYP3A4 inhibition and induction on the pharmacokinetics of olanzapine and samidorphan have been evaluated in clinical studies ( Table ).…”