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A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers

Objective: This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710). Methods: Subjects receiv...

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Detalles Bibliográficos
Autores principales: Cassella, James V., Spyker, Daniel A., Yeung, Paul P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dustri-Verlag Dr. Karl Feistle 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611162/
https://www.ncbi.nlm.nih.gov/pubmed/26501204
http://dx.doi.org/10.5414/CP202457
Descripción
Sumario:Objective: This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710). Methods: Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart + oral placebo, two doses of inhaled placebo + oral placebo, or two doses of inhaled placebo + oral moxifloxacin (400 mg; positive control), with ≥ 3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (ΔΔQTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔQTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazett-corrected QT duration and QTcI outliers. Pharmacokinetics and adverse events (AEs) were also assessed. Results: Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔQTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔQTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean C(max), 177 ng/mL; median t(max) 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE. Conclusions: Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study.