Abstract
OBJECTIVE: To assess the pharmacokinetics (PK) of USL261, a formulation of midazolam (MZ) optimized for easy and rapid intranasal (IN) administration, and compare these results with the PK of MZ for injection (MZ-inj) administered IN and by IV infusion in healthy volunteers.
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: 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: Increasing doses of USL261 provided linearly increasing mean Cmax values of 58.8, 73.5, and 92.7 ng/mL and mean AUC0-∞ values of 93.4, 170, and 238 ng•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-∞ (170 vs 128 ng•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: 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.
Supported by: Upsher-Smith Laboratories, Inc.
Disclosure: Dr. Bancke has received personal compensation for activities with Upsher-Smith Laboratories, Inc. Dr. Dworak has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Halvorsen has received personal compensation for activities with Upsher-Smith Laboratories, Inc as an employee. Dr. Halvorsen holds stock in Medtronic, Stryker, Elan, Teva, Gilead, and Pfizer.
Tuesday, March 19 2013, 7:30 am-12:00 pm
- Copyright © 2013 by AAN Enterprises, Inc.
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