Abstracts

Rationale: USL261 is a proprietary intranasal (IN) formulation of midazolam (MZ) being developed for the orphan indication of rescue treatment of seizures in patients who require control of intermittent bouts of increased seizure activity, often referred to as seizure clusters or acute repetitive seizures. The only product approved in the US for this indication is rectal diazepam gel which has a route of delivery that may be undesirable. MZ for injection (MZ-inj) given IN has been reported to be an effective alternative treatment but is not optimized for the IN route of administration. USL261 has been formulated for easy and rapid administration of MZ by healthcare providers and in an outpatient setting. This study was designed to assess the pharmacokinetics (PK) of USL261 in healthy volunteers and compare these results with MZ-inj given IN (MZ-inj IN) and by IV infusion. Methods: This single-dose, open-label, 5-way crossover study randomly assigned healthy adult subjects (N=25) to 1 of 5 sequences of MZ with 5 subjects per dosing sequence. The dosing regimens included 2.5, 5.0, and 7.5 mg USL261 delivered in a single actuation 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 IN (0.5 mL in each nostril given by needleless syringe). The interval between dose regimens was ≥3 days. Venous blood samples were collected before and periodically after dosing for a period of 12 hr to determine plasma concentrations of MZ. Standard PK parameters were calculated, including maximum plasma concentration (C_max), time to peak plasma concentration (T_max), area under the plasma concentration-time curve (AUC), and half-life (t_1/2). Results: The three increasing doses of USL261 provided increasing mean C_max values of 58.8 (2.5 mg), 73.5 (5 mg), and 92.7 ng/mL (7.5 mg) and increasing mean AUC_0-∞ values of 93.4 (2.5 mg), 170 (5 mg) and 238 ng●hr/mL (7.5 mg). Maximum plasma MZ concentrations were rapidly achieved in all USL261 dose groups (mean T_max=11.5-16.0 min). Despite identical IN doses, the 5.0 mg dose of USL261 resulted in a higher mean C_max (73.5 vs 55.2 ng/mL), higher mean AUC_0-∞ (170.1 vs 128.1 ng●hr/mL) and an earlier T_max (13.4 vs 18.4 min) than the 5.0 mg dose of MZ-inj IN. The mean relative bioavailability of 5 mg USL261 was 134% compared with an equal dose of MZ-inj IN. The mean absolute bioavailability of USL261 2.5 mg (vs 2.5 mg MZ-inj administered IV) was 73%. The mean terminal t_1/2 was similar for each dosing regimen, ranging from 3.61 to 3.98 hr. Conclusions: C_max and AUC_0-∞ increased linearly with increasing doses of USL261. USL261 provided rapid delivery of MZ with a greater C_max and AUC and an earlier T_max compared to an equal dose of MZ-inj IN, thus demonstrating improved bioavailability of this new IN formulation compared with MZ-inj IN. Based on its PK profile, USL261 demonstrated the characteristics of an optimal formulation for the outpatient delivery of MZ intranasally and supports the further development of USL261 for the rescue treatment of patients with intermittent bouts of increased seizure activity.