title: Inhaled loxapine and intramuscular lorazepam in healthy volunteers: a randomized placebo-controlled drug-drug interaction study.
abstract: Pharmacodynamic effects and safety of single-dose inhaled loxapine administered via the Staccato(®) system and intramuscular (IM) lorazepam in combination versus each agent alone were compared in a randomized, double-blind, crossover study in healthy volunteers. Subjects received: inhaled loxapine 10 mg + IM lorazepam 1 mg; inhaled loxapine 10 mg + IM placebo; IM lorazepam 1 mg + Staccato placebo in random order, each separated by a 3-day washout. Primary endpoints were maximum effect (minimum value) and area under the curve (AUC) from baseline to 2 h post treatment for respirations/min and pulse oximetry. Least-squares means (90% confidence interval [CI]) for concomitant treatment versus each agent alone were derived and equivalence (no difference) confirmed if the 90% CI was within 0.8-1.25. Blood pressure (BP), heart rate (HR), sedation (100-mm visual analog scale), and adverse events (AEs) were recorded. All 18 subjects (mean age, 20.4 years; 61% male) completed the study. There was no difference between inhaled loxapine + IM lorazepam and either agent alone on respiration or pulse oximetery during the 12-h postdose period, confirmed by 90% CIs for AUC and C min ratios. BP and HR were no different for inhaled loxapine + IM lorazepam and each agent alone over a 12-h postdose period. Although the central nervous system sedative effects were observed for each treatment in healthy volunteers, the effect was greater following concomitant lorazepam 1 mg IM + inhaled loxapine 10 mg administration. There were no deaths, serious AEs, premature discontinuations due to AEs, or treatment-related AEs.
authors.affiliation: Alexza Pharmaceuticals, Inc. Mountain View California.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Spyker
authors.affiliation: Alexza Pharmaceuticals, Inc. Mountain View California.
authors.forename: James V
authors.initials: JV
authors.lastname: Cassella
authors.affiliation: Covance Clinical Research Unit Evansville Indiana.
authors.forename: Randall R
authors.initials: RR
authors.lastname: Stoltz
authors.affiliation: Teva Pharmaceuticals Frazer Pennsylvania.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Yeung
keywords: Bipolar I disorder; drug–drug interactions; inhaled loxapine; lorazepam; pharmacodynamics; schizophrenia