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

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. FUNDING ACKNOWLEDGEMENTS: This study was funded by Alkermes, Inc.