Epilepsia. 2025 Oct 24. doi: 10.1111/epi.18643. Online ahead of print.
ABSTRACT
OBJECTIVE: Staccato® alprazolam is a hand-held inhalation device that provides rapid systemic delivery of alprazolam through the intrapulmonary route. This trial explored the pharmacokinetics and tolerability of single-dose Staccato alprazolam 2 mg in adolescents with epilepsy. Pharmacokinetic data were included in a population pharmacokinetic analysis to support adolescent dose selection in the Phase 3 trials.
METHODS: Multicenter, Phase 1, open-label trial in adolescents (12-17 years) with focal, generalized, or focal and generalized epilepsy (UP0100/NCT04857307). A single dose of Staccato alprazolam 2 mg was administered in the morning following overnight fast. Pharmacokinetic data were used to update an existing population pharmacokinetic model in adults, which was used to investigate dosing in adolescents with epilepsy.
RESULTS: Fourteen patients (6 weighing <50 kg, 8 weighing ≥50 kg) were enrolled and administered Staccato alprazolam 2 mg. Individual plasma alprazolam concentration-time profiles indicated generally rapid absorption (median time to maximum plasma concentration [Cmax]: 10.5 [range: 2-120] min) with linear elimination. Geometric mean Cmax, area under the plasma concentration-time curve (AUC) from time 0 to last quantifiable concentration (AUC0-t), AUC from time 0 to infinity (AUCinf), and apparent total body clearance (CL/F) were similar across body weight groups (<50 kg, ≥50 kg). Three patients in the ≥50 kg group reported treatment-emergent adverse events (TEAEs), including dysgeusia, somnolence, dizziness, cough, and hiccups. No severe or serious TEAEs were reported. Simulations of exposure estimates using the updated population pharmacokinetic model indicated similar exposure (AUCinf) for adolescents administered Staccato alprazolam 2 mg compared with the adult reference range, with a slight increase in Cmax at lower body weight.
SIGNIFICANCE: Alprazolam was rapidly absorbed in most adolescent patients with epilepsy following administration with the Staccato device. No clinically relevant differences between body weight groups were observed on primary pharmacokinetic or safety outcomes. Staccato alprazolam 2 mg was well tolerated. Overall, the present data support the use of Staccato alprazolam 2 mg in adolescents with epilepsy (12-17 years of age).
PMID:41133403 | DOI:10.1111/epi.18643
