A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers
| Autor: | Paul P. Yeung, Daniel A. Spyker, James V. Cassella |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Cmax Loxapine Action Potentials Placebo QT interval Risk Assessment Drug Administration Schedule Young Adult Double-Blind Method Moxifloxacin Heart Conduction System Administration Inhalation pharmacodynamics Medicine thorough QT/QTc Humans Pharmacology (medical) Dosing Least-Squares Analysis Biotransformation Pharmacology inhalation Cross-Over Studies business.industry Middle Aged Crossover study Confidence interval Healthy Volunteers Treatment Outcome Anesthesia repeat dose Female business medicine.drug Research Article Antipsychotic Agents |
| Zdroj: | International Journal of Clinical Pharmacology and Therapeutics |
| ISSN: | 0946-1965 |
| Popis: | 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 Bazettcorrected 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 Cmax, 177 ng/mL; median tmax 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. |
| Databáze: | OpenAIRE |
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