Authors :
Presenting Author: Pavel Klein, MD – Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, USA
Gewalin Aungaroon, MD – Comprehensive Epilepsy Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; Victor Biton, MD – Arkansas Epilepsy Program, Little Rock, AR, USA; Kore Kai Liow, MD – Hawaii Pacific Neuroscience, Comprehensive Epilepsy Center, Honolulu, HI, USA; Steven Phillips, MD – MultiCare Institute for Research and Innovation, Tacoma, WA, USA; Thomas Wychowski, MD – University of Rochester Medical Center, Rochester, NY, USA; Ahmed Sadek, MD – Research Institute of Orlando, Orlando, FL, USA; Jan-Peer Elshoff, PhD – UCB Pharma, Monheim am Rhein, Germany; Robert Roebling, MD – UCB Pharma, Monheim am Rhein, Germany; Aliceson King, MD – UCB Pharma, Smyrna, GA, USA; Andrea Ford – Veramed, Twickenham, UK; Chiara Rospo, MChem – UCB Pharma, Braine-l'Alleud, Belgium; Rik Schoemaker, PhD – Occams Coöperatie U.A., Amstelveen, The Netherlands; Hugues Chanteux, Pharm, PhD – UCB Pharma, Brussels, Belgium
Rationale:
Staccato
® alprazolam, a hand-held device providing rapid systemic delivery of alprazolam via inhalation, is under investigation for rapid termination of an ongoing seizure.
Age-related differences in lung function may affect pulmonary drug delivery. Bodyweight (BW; affecting clearance/drug exposure) varies greatly during adolescence. This study explores PK/tolerability of single-dose Staccato® alprazolam 2mg in adolescents with epilepsy. PK data were included in a population PK analysis to support adolescent dose selection in Phase 3.Methods:
Multicenter, Phase 1, open-label study in adolescents (12‒17 yrs) with focal, generalized, or focal and generalized epilepsy (UP0100; NCT04857307). Eligible patients had BW ≥29 kg, body mass index 14‒32 kg/m², normal spirometry, were non-smokers (≥6 months prior to screening) and taking ≥1 concomitant anti-seizure medication. A single dose of Staccato
® alprazolam 2mg was administered in the morning following overnight fast. Serial blood samples were collected pre-dose, 2, 10 and 30 mins, and 1, 2, 6, 24, and 36 hrs post-dose for alprazolam plasma PK evaluation by noncompartmental analysis. Primary PK endpoints: Cmax; area under plasma concentration-time curve from time 0 to infinity (AUC); area under plasma concentration-time curve from time 0 to time of last quantifiable concentration (AUC0-t); apparent total body clearance (CL/F). Primary safety endpoints: treatment-emergent adverse events (TEAEs); serious TEAEs. PK data were used to update an existing population PK model in adult patients and perform a covariate analysis; that model was used to perform simulations to investigate dosing in adolescent patients with epilepsy.
Results:
A total of 14 patients (12 female; mean age: 15.1 [range 12‒17] yrs; mean BW: 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] mins) with first-order (linear) elimination (geometric mean [GeoMean] elimination half-life 7.6 hrs). Relatively high inter-subject variability was noted in absorption phase (Figure A). GeoMean Cmax, plasma exposure (AUC), and CL/F were similar across subgroups (Table). TEAEs (dysgeusia, somnolence [both n=3], dizziness, cough and hiccups [all n=2]) were confined to patients ≥50 kg, all of mild/moderate intensity. No serious TEAEs or clinically relevant changes in lab parameters, vital signs, or ECG 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 BW (Figure B).
Conclusions:
Alprazolam PK following Staccato
® administration in adolescents with epilepsy was as expected, with rapid absorption and high variability. Staccato
® alprazolam 2mg was well tolerated. BW had no clinically relevant effect on PK/safety variables. Modeling data suggest an adult alprazolam dose of 2mg can be applied to adolescents without adaptation.
Funding:
UCB Pharma-sponsored