Pharmacokinetics, pharmacodynamics, and tolerability of USL261, midazolam nasal spray: Randomized study in healthy geriatric and non-geriatric adults

AIM Characterize pharmacokinetics, pharmacodynamics, and safety/tolerability of USL261 in geriatric adults to inform its potential for treating bouts of increased seizure activity. METHODS Phase 1, randomized, double-blind, 2-way crossover study in healthy geriatric (≥65years; n=18) and non-geriatric (18-40years; n=12) adults evaluated single USL261 doses (2.5 and 5.0mg) administered intranasally. Pharmacokinetic parameters were estimated for midazolam and 1-hydroxymidazolam (active metabolite), including area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), time to Cmax (Tmax), and half-life (t1/2). Stanford Sleepiness Scale and Observer's Assessment of Alertness/Sedation assessed sedation; Digit-Symbol Substitution Test assessed psychomotor performance. RESULTS Midazolam exposure and plasma concentrations were higher in geriatric versus non-geriatric adults (geometric mean AUC0-∞ [ng*h/mL] 2.5mg: 70 vs 54, respectively; 5.0mg: 157 vs 110; Cmax [ng/mL] 2.5mg: 27.1 vs 22.5; 5.0mg: 55.8 vs 46.1). USL261 was rapidly absorbed, with no differences in median Tmax (14.5-17.3min); mean t1/2 was longer in geriatric subjects. Similar age-related trends were observed for 1-hydroxymidazolam. Mean maximum observed pharmacodynamic effects were not significantly different between age groups, though were more pronounced following 5.0 versus 2.5mg (P<.05); return to baseline was generally achieved within 4h. USL261 was generally well tolerated, with similar adverse event rates between age groups. CONCLUSIONS Despite increased midazolam exposure in geriatric subjects, there were no differences between age groups in pharmacodynamic effects or adverse event rates. USL261 was rapidly absorbed and pharmacodynamic effects returned to baseline within ~4h, regardless of age. Dose-dependent pharmacokinetic and maximum pharmacodynamic effects were observed. Overall, pharmacokinetic findings for USL261 were similar to studies evaluating intravenous midazolam, whereas pharmacodynamic effects were less pronounced in the elderly than previously reported.