Abstracts

Rationale: Midazolam (MDZ) nasal spray (USL261) is in development for the treatment of patients with intermittent bouts of increased seizure activity. Given the effect of age on IV MDZ pharmacokinetics (PK) noted in the literature, an objective of this study was to compare USL261 PK in non-geriatric and geriatric adults, to inform its potential use in elderly patients.Methods: Single-doses of USL261 (2.5 mg and 5 mg) were evaluated in a phase 1, randomized, double-blind, 2-way crossover study in generally healthy geriatric (≥65 years; n=18) and non-geriatric (18-40 years; n=12) participants. Blood sampling was performed prior to and through 24 h post-dose, with ≥4 days between doses. PK parameters estimated for MDZ and its major active metabolite (1-OH-MDZ) included area under the plasma concentration-time curve (AUC0-∞), maximum observed plasma concentration (Cmax), time to Cmax (Tmax), and terminal elimination half-life (t1/2). Geometric least-squares (LS) mean ratios and 90% confidence intervals (CI) of AUC0-∞ and Cmax for both age groups were compared.Results: Exposure to MDZ was higher in the geriatric versus non-geriatric group at both dose levels (geometric mean AUC0-∞: 2.5 mg, 70 vs 54 ng*hr/mL; 5 mg, 157 vs 110 ng*hr/mL, respectively). Cmax values were also higher in geriatric participants (geometric mean: 2.5 mg, 27.1 vs 22.5 ng/mL; 5 mg, 55.8 vs 46.1 ng/mL), but no differences were observed in median Tmax, which was similar across both USL261 doses (range: 14.5-17.3 min). Mean t1/2 values were longer in geriatric (8.1 h for both doses) compared with non-geriatric participants (5.7 and 6.1 h for the 2.5 and 5 mg doses, respectively). Following a single 5 mg USL261 dose, MDZ AUC0-∞and Cmax were 45% and 21% higher, respectively, in geriatric versus non-geriatric participants (geometric LS mean geriatric/non-geriatric ratios [90% CI] for MDZ AUC0-∞ and Cmax of 1.45 [1.04-2.02] and 1.21 [0.85-1.72], respectively). For 1-OH-MDZ, similar age-related PK trends were observed, with higher AUC, Cmax, and t1/2 in the geriatric group. Adverse event rates and severity were similar between cohorts.Conclusions: Following a single 2.5 or 5 mg dose of USL261, overall (AUC0-∞ ) and maximum (Cmax) plasma MDZ exposure were higher in geriatric versus non-geriatric participants. This higher exposure was associated with longer t1/2 values. These results are similar to observed data from intravenous MDZ, suggesting USL261 PK differences in the geriatric population reflect a decrease in clearance rather than an increase in fractional absorption. USL261 was rapidly absorbed following both 2.5 and 5 mg doses, independent of age group. Adverse event rates were similar between cohorts, suggesting the magnitude of increased exposures in geriatric participants observed in this study may not negatively affect tolerability. These data support the continued development of USL261 for the rescue treatment of patients with intermittent bouts of increased seizure activity, and help guide dosing recommendations in geriatric patients. Support: Upsher-Smith Laboratories, Inc.