Abstract Details

Title Pharmacokinetics of USL261, a Novel Formulation of Intranasal Midazolam

Topic Epilepsy

Presentation(s) P02 - (-)

Poster/Presentation
Number 212

Objective

Background BACKGROUND: USL261 is being developed for outpatient rescue treatment of intermittent bouts of increased seizure activity. MZ-inj has been reported to be used IN for seizure emergencies but is not optimized for IN dosing.

Design/Methods DESIGN/METHODS: Healthy adult subjects (N=25) were randomly assigned to 1 of 5 MZ treatment sequences of a 5-way crossover study. Each subject received 2.5, 5.0, and 7.5 mg USL261 delivered by a unit-dose nasal spray device; 2.5 mg MZ-inj (5 mg/mL) administered via 15-min IV infusion; and 5.0 mg MZ-inj administered IN. Treatments were separated by ?3 days. Standard MZ PK parameters (AUC, Cmax, Tmax) were calculated from blood samples collected before dosing and at set time points up to 12 hr post-dosing.

Results RESULTS: Increasing doses of USL261 provided linearly increasing mean Cmax values of 58.8, 73.5, and 92.7 ng/mL and mean AUC0-[infin] values of 93.4, 170, and 238 ng[bull]hr/mL. Median Tmax ranged from 10 to 12 min. USL261 5.0 mg demonstrated a higher mean Cmax (73.5 vs 55.2 ng/mL) and mean AUC0-[infin] (170 vs 128 ng[bull]hr/mL; relative bioavailability = 134%) and achieved Tmax quicker (10 vs 15 min) than MZ-inj IN 5.0 mg. The mean absolute bioavailability of USL261 2.5 mg was 73% compared with MZ-inj 2.5 mg IV. The mean terminal t1/2 was 3.6-4.0 hr in each group.

Conclusions CONCLUSIONS: All doses of USL261 demonstrated desirable PK, with greater Cmax and AUC and an earlier Tmax compared with MZ-inj IN, thus demonstrating improved bioavailability. The PK profile of USL261 supports its further clinical development for outpatient treatment of seizure clusters.

Authors/Disclosures
PRESENTER	No disclosure on file
Heather A. Dworak (Upsher-smith Laboratoriesclinical Development)	No disclosure on file
Mark Halvorsen, PharmD (Upsher-Smith Laboratories, LLC)	Dr. Halvorsen has received personal compensation for serving as an employee of Upsher-Smith Laboratories, LLC. Dr. Halvorsen has stock in Pfizer. Dr. Halvorsen has stock in Amgen. Dr. Halvorsen has stock in Stryker.
Jeffrey A. Cohen, MD (Cleveland Clinic)	Dr. Cohen has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Convelo. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astoria. Dr. Cohen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Viatris. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PSI. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Shionogi. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celltrion.

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