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

Abstract

SUMMARYObjective: 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 (C max ), with all doses demonstrating rapid median time to C max (T max ; 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.

Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful?

“…In total, 38 and 44 publications that included reported CL values were identified for gentamicin and midazolam, respectively. These papers reported a total of 66 and 57 CL values for gentamicin and midazolam, respectively.…”

Chirally Pure Prodrugs and Their Converting Enzymes Lead to High Supersaturation and Rapid Transcellular Permeation of Benzodiazepines

“…[17][18][19][20] Drug absorption was reduced and variable due to leakage or precipitation, and subjects complained of discomfort. More recent DZP and MDZ formulations, designed specifically for nasal administration, require only 100-200 mL to deliver a therapeutic dose, 21,22 which is readily accommodated by the nasal cavity. 23 Rate, extent, and consistency of absorption of these formulations compare favorably against rectal DZP, and display equal or earlier onsets of action.…”

“…23 Rate, extent, and consistency of absorption of these formulations compare favorably against rectal DZP, and display equal or earlier onsets of action. 21,22 Drug delivery is accomplished using spray devices that provide widespread distribution of droplets throughout the nasal cavity, resulting in longer residence times and less leakage, and hence greater bioavailability.…”

Rescue therapies for seizure emergencies: New modes of administration

“…In a phase I study, 53 the T max averaged 10-12 minutes at doses from 2.5-7.5 mg (Figure 2A), whereas the absolute bioavailability ranged from 62-73%. In a phase I study, 53 the T max averaged 10-12 minutes at doses from 2.5-7.5 mg (Figure 2A), whereas the absolute bioavailability ranged from 62-73%.…”

“…Proximagen, Ltd. (formerly Upsher Smith Laboratories) is developing IN MDZ. In a phase I study, 53 the T max averaged 10-12 minutes at doses from 2.5-7.5 mg (Figure 2A), whereas the absolute bioavailability ranged from 62-73%. At doses up to 7.5 mg, the onset of CNS side effects such as psychomotor impairment and sedation occurred within 15 minutes, but these measures returned to baseline values by 4 hours ( Figure 2B).…”