Abstracts

Rationale: The Staccato® inhaler aerosolizes a drug and delivers it deep into the lung for rapid systemic exposure. Staccato alprazolam has been shown to have a rapid onset of effect in an intermittent photic stimulation epilepsy study. In this study, we explored the pharmacokinetics (PK) of Staccato alprazolam in healthy adult smoker and non-smoker participants (ppts). Methods: In this open-label, PK study, healthy adult ppts (≥21 and ≤51 y, smokers [>15 cigarettes/d for ≥2 y and serum cotinine ≥100 ng/mL] and non-smokers [never >5 cigarettes/d, serum cotinine ≤8 ng/mL, and not smoking for ≥2 y]) were eligible. Staccato alprazolam 1 mg was administered as a single dose in the morning following an overnight fast. Blood samples for determination of plasma alprazolam concentrations were collected pre-dose (≤30 min before dosing) and at 2-, 5-, 10-, and 30-min, and 1-, 2-, 4-, 6-, 12-, 24-, and 36-h post-dose. The primary endpoints were maximum concentration (Cmax) and exposure (area under the curve to the last measurable concentration [AUClast]) for alprazolam. Secondary PK endpoints were time to Cmax (Tmax), half-life (t½), and clearance (CL/F). Safety assessments included adverse events (AEs), physical examination findings, electrocardiogram (ECG), vital signs and clinical laboratory test results. PK data were summarized using descriptive statistical summary tables. Point estimates of geometric means ratios and the respective 90% confidence intervals (CIs) were derived, using the non-smoker group as reference. No effect of smoker status was concluded if the 90% CI lies entirely within the range of 80.00% to 125.00%. The secondary PK variable Tmax was analyzed using the Wilcoxon rank sum test. Results: Thirty-six ppts (18 non-smokers and 18 smokers) were enrolled and received a single dose of Staccato alprazolam 1 mg; all ppts completed the study. Half were male. Mean (SD) age was 38.1 (7.92) y and mean (SD) BMI was 25.8 (3.06) kg/m2. Twenty-five (69.4%) were Black, 9 (25.0%) were White, 1 (2.8%) was Asian, and 1 (2.8%) was Other race. Staccato alprazolam AUClast and Tmax were similar between smoker and non-smoker ppts; however, Cmax was significantly greater in smoker ppts (table). Thirty-three ppts (91.7%) reported at least one AE during the study. The most common AEs (incidence ≥10%) were somnolence (72.2% for smokers, 50.0% for non-smokers), dizziness (11.1% and 50.0%), fatigue (22.2% and 5.6%), euphoric mood (16.7% and 5.6%), headache (11.1% and 5.6%), and nausea (11.1% and 0%). All AEs were mild or moderate in intensity; none were serious. Other safety assessments did not reveal any concerns. Conclusions: A single dose of Staccato alprazolam 1 mg administered via hand-held inhaler was rapidly absorbed to a similar extent in healthy smoker and non-smoker ppts based on AUC values. Staccato alprazolam was well tolerated in smoker and non-smoker ppts. These results give further support to developing Staccato alprazolam as a rescue treatment for acute epileptic seizures. Funding: Engage Therapeutics, Inc.