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

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 ( AE s) 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% CI s 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 AE s, premature discontinuations due to AE s, or treatment‐related AE s.