Authors :
Presenting Author: Robert Roebling, MD – UCB Pharma, Monheim am Rhein, Germany
Yoshinobu Hayakawa, MPharma – UCB Pharma, Tokyo, Japan; Chiara Rospo, MChem – UCB Pharma, Braine l'Alleud, Belgium; Ana Paula Bartmann, 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. This study assessed the safety, tolerability, and pharmacokinetics (PK) of Staccato
® alprazolam compared with placebo in healthy Japanese, Chinese, and Caucasian participants.
Methods:
UP0101 (NCT04782388) was a Phase 1, double-blind, placebo-controlled study in healthy Japanese, Chinese, and Caucasian participants aged 18–55 years randomized 4:1 by interactive response technology to a single inhaled dose of Staccato
® alprazolam 2 mg or Staccato
® placebo. Blood samples for determining plasma alprazolam were collected at 0 (pre-dose), 1, 2, 5, 10 and 30 min, and 1, 2, 4, 6, 12, 24, 36, and 48 hours post-dose. Primary (Japanese and Chinese participants) and secondary (Caucasian participants) PK endpoints were Cmax, AUCinf and AUC0-t. Primary safety endpoints were treatment-emergent adverse events (TEAEs) and serious TEAEs in Japanese and Chinese participants.
Results:A total of 10 participants each of Japanese, Chinese, and Caucasian ethnicities were randomized 4:1 to Staccato® alprazolam 2 mg or Staccato® placebo. All participants completed the study. Following Staccato® administration, alprazolam was rapidly absorbed and distributed with a median Tmax of 1.5 to 2 min followed by typical biphasic elimination. The distribution phase was very short (5-10 min), leading to a very sharp peak, then plasma concentrations steadily declined until 48 hours post-dose (Figure). The GeoMean Cmax of alprazolam was numerically higher for Japanese (93.0 ng/mL) and Chinese (56.6 ng/mL) vs Caucasian (37.4 ng/mL) participants (Japanese/Caucasian ratio estimate [90% confidence interval (CI)]: 2.488 [1.515, 4.087]; Chinese/Caucasian ratio estimate [90% CI]: 1.515 [0.922, 2.489]). GeoMean alprazolam AUC0-inf values were similar for Japanese (529.0 h*ng/mL) and Chinese (460.8 h*ng/mL) vs Caucasian (526.7h*ng/mL) participants (Japanese/Caucasian ratio estimate [90% CI]: 1.004 [0.776, 1.299]; Chinese/Caucasian ratio estimate [90% CI]: 0.875 [0.676, 1.132]); showed a similar trend to AUC0-inf.The tolerability profile of Staccato® alprazolam was similar in Japanese, Chinese, and Caucasian participants. Somnolence and sedation were the most common TEAEs (Table). There were no deaths, serious, severe, or respiratory TEAEs, or discontinuations due to TEAEs.Conclusions:
Alprazolam was very rapidly absorbed when administered with the Staccato® device, as demonstrated by a very short Tmax achieved within 2 min post-dose in most participants. High Cmax was observed in Japanese and Chinese participants. However, across the three ethnic groups alprazolam concentrations were similar by 5-10 minutes post-dose, and there were no differences between the total exposure of alprazolam (as shown by AUCinf and AUC0-t) suggesting no need for dose adjustments. Staccato® alprazolam was generally well tolerated across the three ethnic groups and displayed a safety profile consistent with that known from oral alprazolam. No new safety signals were identified.Funding:
UCB Pharma-sponsored