Inhaled loxapine and intramuscular lorazepam in healthy volunteers: a randomized placebo-controlled drug-drug interaction study

Daniel A Spyker, James V Cassella, Randall R Stoltz, Paul P Yeung, Daniel A Spyker, James V Cassella, Randall R Stoltz, Paul P Yeung

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.

Keywords: Bipolar I disorder; drug–drug interactions; inhaled loxapine; lorazepam; pharmacodynamics; schizophrenia.

Figures

Figure 1
Figure 1
The Staccato delivery system (A) and schematic representation of the mechanism of drug delivery (B).
Figure 2
Figure 2
Patient disposition. IM, intramuscular.
Figure 3
Figure 3
Mean respiration rate over time. AUC, area under the curve; CI, confidence interval; IM, intramuscular; LS, least squares.
Figure 4
Figure 4
Mean pulse oximetry over time. AUC, area under the curve; CI, confidence interval; IM; intramuscular; LS, least squares.
Figure 5
Figure 5
Secondary outcome measures. Heart rate (A); systolic blood pressure (B); diastolic blood pressure (C); sedation visual analog scale (D). AUC, area under the curve; CI, confidence interval; IM, intramuscular; LS, least squares.

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Source: PubMed

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