Authors :
Presenting Author: Tony Daniels, BSc – UCB Pharma, Morrisville, NC, USA
Ronald Goldwater, MD – PAREXEL Baltimore Early Phase Clinical Unit, Harbor Hospital Center, Baltimore, MD, USA
Andrea Ford, MSc – Veramed, Twickenham, UK
Hester Kramer, PhD – UCB Pharma, Braine l'Alleud, Belgium
Aliceson King, MD – UCB Pharma, Smyrna, GA, USA
Hugues Chanteux, Pharm, PhD – UCB Pharma, Braine l'Alleud, Belgium
Rationale: Staccato
® alprazolam is a hand-held device that can provide rapid systemic delivery of alprazolam via inhalation, with the potential to provide rapid and early seizure termination. Here, we compare the plasma concentration of alprazolam following administration via inhalation with the Staccato
® device relative to oral alprazolam administration using data from a phase I clinical trial.
Methods: UP0104/NCT05626439 was a phase I, single-center, open-label, randomized, single-dose, 2-way crossover trial evaluating
Staccato
® alprazolam 2 mg relative to oral alprazolam 2 mg tablets in healthy adult participants (aged 18-55 years). Pharmacokinetic (PK) parameters assessed: plasma concentrations of alprazolam; maximum plasma concentration (C
max); area under the plasma concentration-time curve from time 0 to infinity (AUC
inf); apparent volume of distribution (V
z/F); apparent total body clearance (CL/F).
Results: Overall, 21 participants were randomized (mean age 38.9 years, 52.4% male). One participant discontinued. The Staccato
® device enables a rapid systemic delivery of alprazolam as demonstrated by plasma concentrations achieved at 2 min post-dose (median t
max of
‡2 min for Staccato
® alprazolam vs
‡45 min for oral alprazolam). At this timepoint, alprazolam levels were in a clinically relevant range relative to C
max reached with oral alprazolam 2 mg (
Figure 1). The geometric mean (GeoMean) C
max of Staccato
® alprazolam 2 mg was higher relative to oral alprazolam 2 mg (
‡44.57 vs
‡31.78 ng/mL). GeoMean
AUC
inf was lower with Staccato
® alprazolam 2 mg relative to oral alprazolam 2 mg (
‡370.1 vs
‡433.9 h*ng/mL). Accounting for the actual dose delivered via the Staccato
® device (90% of 2 mg Staccato
® alprazolam dose is emitted and inhaled by participants), dose-normalized C
max and AUC
inf geometric least-squares mean Staccato
®/oral alprazolam ratios were 1.5876 and 0.9500. V
z/F and CL/F corrected for actual dose of Staccato
® alprazolam were similar between both treatments (
Table 1). Metabolite-to-parent ratios (4-hydroxyalprazolam and α-hydroxyalprazolam) based on AUC
inf were lower for Staccato
® alprazolam 2 mg (GeoMean: 0.09777 and 0.02773 h*ng/mL, respectively) compared to oral alprazolam 2 mg (GeoMean: 0.1233 and 0.02879 h*ng/mL, respectively). Urinary excretion of unchanged alprazolam was very low and accounted for 0.54% (dose-adjusted) and 1.2% of the dose for Staccato
® alprazolam 2 mg and oral alprazolam 2 mg, respectively.
Conclusions: The distribution and elimination of alprazolam following administration by inhalation were comparable to those observed after oral administration. Absorption following inhalation with Staccato
® device was very fast and showed that clinically relevant plasma alprazolam concentrations, comparable to the C
max of oral alprazolam, can be achieved within 2 minutes post-dose. Thus, alprazolam administration via the Staccato
® device is an efficient delivery route for the treatment of acute seizures.
Funding: UCB Pharma-sponsored.
‡Data values presented at EILAT XVII 2024 included here to aid understanding.