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

Lindy Bancke,1Heather Dworak,2Mark Halvorsen1
1Maple Grove, MN, USA, 2Morristown, NJ, USA


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 Tmax of midazolam was 10-15 minutes, with mean Cmax of 45.2, 64.0, and 66.5 ng/mL and mean AUC0-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 AUC0-inf and Cmax increased with ascending USL261 doses. Mean terminal midazolam T1/2 ranged from 2.8 to 4.2 hours. Median Tmax of 1-OH MZ was 45-60 minutes, with mean Cmax of 6.4, 8.9, and 13.8 ng/mL, and mean AUC0-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 Cmax and AUC0-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.
Category - Epilepsy and Clinical Neurophysiology (EEG): Other

Tuesday, April 29, 2014 3:00 PM

P3: Poster Session III: Epilepsy and Clinical Neurophysiology: AED (3:00 PM-6:30 PM)

 

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