143 A Combination of Olanzapine and Samidorphan Has No Clinically Relevant Effect on QT Prolongation up to Supratherapeutic Doses

Abstract

ALKS 3831, a combination of olanzapine and samidorphan (OLZ/SAM) in development for schizophrenia, is intended to mitigate olanzapine-associated weight gain. This thorough QT (tQT) study evaluated OLZ/SAM effects on electrocardiogram parameters. In this randomized, double-blind, parallel-group study, 100 patients with stable schizophrenia were randomized 3:2 to either receive OLZ/SAM 10/10 mg (therapeutic dose) on days 2-4, 20/20 mg on days 5-8, and 30/30 mg (supratherapeutic dose) on days 9-13 with moxifloxacin-matching placebo on days 1 and 14, or a single dose of moxifloxacin 400 mg and matching placebo on days 1 and 14 (nested crossover design). Drug concentration relation to change from baseline in Fridericia-corrected QTc (ΔQTcF) was evaluated using a linear mixed-effect concentration-QTc (C-QTc) model. Adverse events were assessed. The slope (90% CI) of the C-QTc was not significant for olanzapine or samidorphan (0.03 [-0.01, 0.08] and 0.01 [-0.01, 0.04] msec per ng/mL, respectively). Predicted placebo-corrected ΔQTcF (90% CI) was 2.33 (-2.72, 7.38) and 1.38 (-3.37, 6.12) msec at the observed geometric mean maximal concentration of olanzapine (62.6 ng/mL) and samidorphan (75.1 ng/mL), respectively, on day 13. A clinically relevant QT effect (ie, placebo-corrected ΔQTcF ≥10 msec) can be excluded for olanzapine and samidorphan concentrations up to ≈110 and ≈160 ng/mL, respectively. Assay sensitivity was confirmed by the C-QTc relationship of moxifloxacin. OLZ/SAM was well tolerated. OLZ/SAM, in doses and plasma concentrations up to supratherapeutic levels, was well tolerated and had no clinically relevant effects on electrocardiogram parameters, including QT interval, in patients with schizophrenia. This study was funded by Alkermes, Inc.