Pharmacokinetics of USL261, a Novel Intranasal Formulation of Midazolam, in Subjects with Epilepsy (P3.285)

OBJECTIVE: To assess the pharmacokinetics of a single dose of USL261, a formulation of midazolam optimized for intranasal administration, in subjects with epilepsy on a stable antiepileptic drug regimen. BACKGROUND: USL261 is in development for the outpatient rescue treatment of seizures in patients with intermittent bouts of increased seizure activity (eg, seizure clusters, or acute repetitive seizures). In subjects without epilepsy, USL261 demonstrated rapid absorption and increased bioavailability compared with intranasal administration of midazolam formulated for injection/intravenous delivery. DESIGN/METHODS: This randomized, open-label, inpatient study enrolled 90 subjects (12-65 years old). Venous blood samples of subjects treated with USL261 single dose (2.5, 5.0, and 7.5 mg) were collected pre-dose and up to 12 hours post dose. Plasma concentrations and standard pharmacokinetic parameters for midazolam and its major metabolite, 1-hydroxymidazolam (1-OH MZ), were measured. RESULTS: Median T ma x of midazolam was 10-15 minutes, with mean C max of 45.2, 64.0, and 66.5 ng/mL and mean AUC 0-inf of 56.6, 119, and 131 ng•hr/mL in the 2.5, 5.0, and 7.5 mg dosing groups, respectively. Both mean midazolam AUC 0-inf and C max increased with ascending USL261 doses. Mean terminal midazolam T 1/2 ranged from 2.8 to 4.2 hours. Median T max of 1-OH MZ was 45-60 minutes, with mean C max of 6.4, 8.9, and 13.8 ng/mL, and mean AUC 0-inf of 37.2, 43.4, and 64.3 ng•hr/mL in the 2.5, 5.0, and 7.5 mg dosing groups, respectively. The PK parameters of 1-OH MZ paralleled those of the parent compound. CONCLUSION: The unique formulation of USL261 demonstrated rapid absorption and elimination in subjects with epilepsy. Following single-dose administration of USL261, a dose-dependent increase in C max and AUC 0-inf was observed for midazolam and its major metabolite. These results support the continued development of USL261 for outpatient rescue treatment of seizures in patients who require control of intermittent bouts of increased seizure activity. STUDY SUPPORTED BY: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Bancke has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Dworak has received personal compensation for activities with Upsher-Smith Laboratories, Inc. Dr. Halvorsen has received personal compensation for activities with Upsher-Smith Laboratories, Inc. Dr. Halvorsen holds stock in Medtronic Inc., Stryker, Elan Corp., Teva Neuroscience, Gilead, Pfizer Inc., and Amgen Inc.