Inhalation as an Efficient Delivery Route of Alprazolam for the Treatment of Acute Seizures: Randomized Study of Staccato® Alprazolam Compared to Oral Alprazolam
Ronald Goldwater1, Tony Daniels2, Andrea Ford3, Aliceson King2, Cedric Laloyaux2, Hugues Chanteux2
1PAREXEL Baltimore Early Phase Clinical Unit, Harbor Hospital Center, 2UCB, 3Veramed
Objective:
To compare the bioavailability of alprazolam administered as Staccato® alprazolam relative to oral alprazolam.
Background:
Staccato® alprazolam is a hand-held device that can provide rapid systemic delivery of alprazolam via inhalation.
Design/Methods:
UP0104/NCT05626439 was a phase 1, open-label, randomized, single-dose, 2-way crossover trial in healthy adults (18-55 years). Pharmacokinetic endpoints were time to maximum plasma concentration (tmax), maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUCinf), and AUC from time 0 to time of the last quantifiable concentration (AUC0-t). Safety endpoints were incidence of treatment-emergent adverse events (TEAEs)/serious TEAEs.
Results:
Twenty-one participants were randomized (mean age 38.9 years, 52.4% male). One (4.8%) participant discontinued. Median tmax of Staccato® alprazolam 2mg and oral alprazolam 2mg was 2.0min and 45.0min, respectively. Geometric mean (GeoMean) Cmax of Staccato® alprazolam 2mg was higher than oral alprazolam 2mg (44.57 vs 31.78 ng/mL; N=21/N=20). GeoMean AUCinf and AUC0-t were lower for Staccato® alprazolam 2mg (370.1 and 358.7 h*ng/mL, N=21) compared to oral alprazolam 2mg (433.9 and 420.9 h*ng/mL, N=20). As the Staccato® device delivers 90% (1.8mg) of the dose, dose-normalized geometric least-squares mean Staccato®/oral alprazolam ratios were 1.5876 for Cmax, 0.9500 for AUCinf, and 0.9488 for AUC0-t. Seven (33.3%) participants reported TEAEs while on Staccato® alprazolam 2mg of whom 5 (23.8%) reported drug-related TEAEs; 4 (19.0%) were noted to have TEAEs of decreased oxygen saturation while somnolent. None of these events were severe/serious. Additionally, 1 [4.8%] participant discontinued due to a TEAE of hypotension.
Conclusions:
Alprazolam absorption following inhalation with the Staccato® device was fast and supports its use for rapid and early seizure termination. Dose-normalized Cmax was approximately 59% higher after Staccato® alprazolam 2mg vs oral alprazolam 2mg. No clinically relevant difference was observed on dose-normalized AUC. A single dose of Staccato® alprazolam 2mg was generally well-tolerated in healthy participants.
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