Abstract:
:The objective of this study was to establish effects of inhaled loxapine on the QTc interval in this randomized, placebo-controlled, double-blind crossover study. Forty-eight healthy volunteers received a single inhaled placebo or 10 mg loxapine. Plasma concentrations of loxapine increased with a median Tmax of 1 minute and a mean Cmax of 312 ng/mL. After an initial rapid distribution phase, plasma concentrations of loxapine declined with a terminal half-life of 8 hours. Exposure to the active metabolite 7-OH-loxapine was 15% of the parent compound based on mean AUCinf and its terminal half-life was 12 hours. Inhaled loxapine did not increase QT intervals, as demonstrated by the upper bound of the 1-sided 95% CIs placed on the point estimate of the placebo-subtracted change of QTcI (ΔΔQTcI) being less than 10 milliseconds at all 11 post-dose times. The maximum ΔΔQTcI occurred at 1 hour post-dose (LSmean 5.42 milliseconds, upper confidence bound 7.75 milliseconds). The study outcome was validated by the demonstrated assay sensitivity using the positive control moxifloxacin maximum ΔΔQTcI occurred at 3 hour post-dose (LSmean 8.36 milliseconds, lower confidence bound 5.82 milliseconds). The analyses of QTc outliers, and the lack of emergent diagnostic findings for QTcI, QTcB, and QTcF; and simple mean placebo-subtracted changes of QTcI and QTcF supported the primary QT analysis conclusion that this is a negative finding and there is no apparent QT prolongation associated with the therapeutic dose of inhaled loxapine.
journal_name
J Clin Pharmacoljournal_title
Journal of clinical pharmacologyauthors
Spyker DA,Voloshko P,Heyman ER,Cassella JVdoi
10.1002/jcph.257subject
Has Abstractpub_date
2014-06-01 00:00:00pages
665-74issue
6eissn
0091-2700issn
1552-4604journal_volume
54pub_type
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