Pharmacokinetics and Tolerability of Single-dose Staccato® Alprazolam in Adolescents with Epilepsy and Population PK Analysis to Support Dose Selection in Adolescents
Pavel Klein1, Gewalin Aungaroon2, Victor Biton3, Kore Kai Liow4, Steven Phillips5, Thomas Wychowski6, Ahmed Sadek7, Jan-Peer Elshoff8, Robert Roebling8, Aliceson King8, Andrea Ford9, Chiara C Rospo8, Rik Schoemaker10, Hugues Chanteux8
1Mid-Atlantic Epilepsy and Sleep Center, 2Comprehensive Epilepsy Center, Cincinnati Children's Hospital Medical Center, 3Arkansas Epilepsy Program, 4Comprehensive Epilepsy Center, Hawaii Pacific Neuroscience, 5MultiCare Institute for Research and Innovation, 6University of Rochester Medical Center, 7Research Institute of Orlando, 8UCB Pharma, 9Veramed, 10Occams Cooperatie U.A.
Objective:
Evaluate pharmacokinetics (PK)/tolerability of single-dose Staccato® alprazolam 2mg in adolescents with epilepsy. 
Background:

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

Design/Methods:

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: Cmax, AUC, AUC0-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.

Results:

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 tmax 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 Cmax, 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 Cmax at lower bodyweight.

Conclusions:

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.

10.1212/WNL.0000000000204979