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 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 (ΔΔTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔTcI 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 ΔΔTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔTcI 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.
Alexza Pharmaceuticals, Inc., Mountain View, CA and Teva Pharmaceuticals, Frazer, PA, USA.
James V
JV
Cassella
Daniel A
DA
Spyker
Paul P
PP
Yeung
D000200:Action Potentials; D000280:Administration, Inhalation; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D001711:Biotransformation; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D064368:Healthy Volunteers; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016018:Least-Squares Analysis; D008152:Loxapine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment; D016896:Treatment Outcome; D055815:Young Adult
D014150:Antipsychotic Agents; C035233:8-hydroxyloxapine; D008152:Loxapine