Pharmacokinetics, pharmacodynamics, and safety of USL261, a midazolam formulation optimized for intranasal delivery, in a randomized study with healthy volunteers.

OBJECTIVE: To compare the pharmacokinetics, pharmacodynamics, and tolerability of USL261, a midazolam formulation optimized for intranasal delivery, versus midazolam intravenous (IV) solution administered intranasally (MDZ-inj IN) or intravenously (MDZ-inj IV) in healthy adults. METHODS: In this phase 1, five-way crossover, open-label study, 25 healthy adults (aged 18-42 years) were randomly assigned to receive 2.5, 5.0, and 7.5 mg USL261; 2.5 mg MDZ-inj IV; and 5.0 mg MDZ-inj IN. Blood samples were collected for 12 h post dose to determine pharmacokinetic profiles. Pharmacodynamic assessments of sedation and psychomotor impairment also were conducted. Adverse events, oxygen saturation, and vital signs were recorded. RESULTS: Increasing USL261 dose corresponded with increases in midazolam area under the concentration time curve (AUC) and maximum observed plasma concentration (Cmax ), with all doses demonstrating rapid median time to Cmax (Tmax ; 10-12 min). USL261 also demonstrated increased absorption, with a 134% relative bioavailability, compared with the same MDZ-inj IN dose. USL261 was associated with dose-dependent increases in sedation and psychomotor impairment (p < 0.05); however, these effects lasted <4 h and generally did not differ from MDZ-inj IN or MDZ-inj IV at comparable doses. No serious adverse events (SAEs) or deaths were reported, and no treatment-emergent adverse events (TEAEs) led to study discontinuation. SIGNIFICANCE: Compared with intranasal delivery of a midazolam formulation intended for IV delivery, USL261, optimized for intranasal administration demonstrated improved bioavailability with similar pharmacodynamic effects. Therefore, USL261 may be a preferable alternative to the currently approved rectal diazepam treatment for intermittent bouts of increased seizure activity.