Staccato^® alprazolam is a hand-held device providing rapid systemic delivery of alprazolam via inhalation.

Phase 1, open-label study in adolescents (12?17 years) with epilepsy (focal/generalized/focal and generalized) (UP0100; NCT04857307). Eligibility criteria: bodyweight ≥29kg, body mass index 14?32kg/m², normal spirometry, non-smokers, ≥1 concomitant anti-seizure medication. Staccato^® alprazolam 2mg was administered in the morning. Blood samples were collected pre-dose, 2, 10 and 30 minutes, and 1, 2, 6, 24, and 36 hours post-dose. Primary PK endpoints: C_max, AUC, AUC_0-t, CL/F. Primary safety endpoints: treatment-emergent adverse events (TEAEs); serious TEAEs. PK data were used to update an existing population PK model in adults and perform a covariate analysis; that model was used to perform simulations to investigate dosing in adolescents.

14 patients (12 female; mean age: 15.1 [range 12?17] years; mean bodyweight: 54.5 [range 33.5?81.2] kg) were enrolled. Following Staccato^® alprazolam 2mg administration, individual plasma alprazolam concentration-time profiles indicated generally rapid absorption (median t_max 10.5 [range 2?120] minutes) with first-order (linear) elimination (geometric mean [GeoMean] elimination half-life 7.6 hours). Relatively high inter-subject variability was noted in absorption phase. GeoMean C_max, AUC, and CL/F were similar across bodyweight subgroups (<50kg/≥50kg). TEAEs (dysgeusia, somnolence [both n=3], dizziness, cough and hiccups [all n=2]) were confined to patients ≥50kg, all of mild/moderate intensity. No serious TEAEs were reported. Exposure estimates from simulations indicated similar exposure (AUC) for adolescents administered adult doses of alprazolam 2mg, with slight increase in C_max at lower bodyweight.

Alprazolam PK following Staccato^® administration in adolescents with epilepsy was as expected (rapid absorption and high variability). Staccato^® alprazolam 2mg was well tolerated. Bodyweight had no clinically relevant effect on PK/safety variables. Modelling data suggest an adult alprazolam dose of 2mg can be applied to adolescents without adaptation.