Pharmacokinetics of Staccato® alprazolam in healthy adult participants in two phase 1 studies: An open‐label smoker study and a randomized, placebo‐controlled ethnobridging study

Abstract Objective Staccato ® alprazolam is a single‐use, drug–device combination delivering alprazolam to the deep lung that is being evaluated as treatment for rapid and early seizure termination. This article reports pharmacokinetic (PK) data from two phase 1 studies of Staccato alprazolam in healthy adult participants. Methods The smoker study (EPK‐002/NCT03516305) was an open‐label, nonrandomized, single‐dose, PK study in smokers and nonsmokers aged 21–50 years, administered a single inhaled dose of 1 mg Staccato alprazolam. The ethnobridging study (UP0101/NCT04782388) was a double‐blind, placebo‐controlled study in Japanese, Chinese, and Caucasian participants aged 18–55 years randomized 4:1 to a single inhaled dose of Staccato alprazolam 2 mg or Staccato placebo. Results In the smoker study, 36 participants (18 smokers, 18 nonsmokers) were enrolled and received Staccato alprazolam. Following Staccato administration, alprazolam was rapidly absorbed, with a median time to peak drug plasma concentration ( T max ) of 2 min in both smokers (range = 2–30 min) and nonsmokers (range = 2–60 min). Staccato alprazolam was rapidly absorbed to a similar extent in both smokers and nonsmokers. The most commonly reported treatment‐emergent adverse events (TEAEs) were somnolence and dizziness. In the ethnobridging study, 10 participants each of Japanese, Chinese, and Caucasian ethnicities were randomized 4:1 to Staccato alprazolam or Staccato placebo. Following Staccato administration, alprazolam was rapidly absorbed and distributed, with a median T max of 1.5–2 min in Japanese (range = 1–2 min), Chinese (range = 1–34 min), and Caucasian (range = 1–120 min) participants. Somnolence and sedation were the most commonly reported TEAEs. In both studies, there were no deaths, and no participants reported serious or severe TEAEs, or discontinued due to TEAEs. Significance Alprazolam was rapidly absorbed, and therapeutic drug levels were achieved within 2 min postdose when administered to the lung with the Staccato device. Staccato alprazolam was generally well tolerated and displayed a safety profile consistent with that known from other alprazolam applications. No new safety signals were identified.