Abstracts

Rationale: Midazolam (MDZ) nasal spray (USL261) is in development as rescue treatment for patients with intermittent bouts of increased seizure activity. USL261 pharmacokinetics (PK) have been evaluated in adolescents, adults, and geriatric individuals. An objective of this study was to characterize the PK of USL261 in pediatric subjects with epilepsy to inform its potential use in this population. Methods: This open-label, phase 1 study evaluated single-dose PK of USL261 in pediatric subjects (aged 2?"13) with focal or generalized epilepsy. Subjects were assigned to 5.0, 2.5, or 1.25 mg USL261 by body weight (?-40 to =60 kg, ?-20 to < 40 kg, and ?-10 to < 20 kg, respectively). Blood sampling was performed predose and at cohort-specific timepoints up to 10 hours postdose. Non-compartmental PK parameters were calculated for MDZ and its major active metabolite 1-hydroxymidazolam (1-OH-MDZ), including: area under the plasma concentration-time curve from time zero until 6 hours postdose (AUC0-6), maximum observed plasma concentration (Cmax), and time to Cmax (Tmax). PK values were summarized by dose cohort and by cytochrome P450 (CYP3A4/5) status (inducer vs. non-inducer), based on concomitant and recent antiepileptic drug (AED) use. Results: Thirty-six individuals were enrolled (n=12/cohort); all subjects completed the study and were included in PK analyses. Aside from expected age, weight, and BMI differences, demographic and baseline characteristics were similar across cohorts. MDZ exposure was similar between the two lower-dose cohorts (AUC0-6 geometric mean: 37.2 and 38.4 ngh/mL in 1.25 and 2.5 mg cohorts, respectively) and higher in the 5.0 mg cohort (75.2 ngh/mL). Cmax geometric mean for MDZ was similar across all cohorts (37.3, 35.1, and 33.7 ng/mL in the 5.0, 2.5, and 1.25 mg cohorts, respectively); median Tmax values were the same for all cohorts (0.25 h). Similar PK results were observed in subjects with or without CYP3A4/5-inducing AEDs, though the number of subjects in each category was small following stratification. 1-OH-MDZ exposure was similar across all cohorts; geometric mean for AUC0-6 ranged from 12.5 to 15.3 ngh/mL and Cmax ranged from 3.6 to 5.6 ng/mL. Median Tmax was slightly longer in the 5.0 mg cohort compared with the lower dosing cohorts (1.5 vs 0.5 h). 1-OH-MDZ AUC0-6 and Cmax values were generally higher in subjects taking CYP3A4/5-inducing AEDs. Conclusions: MDZ was rapidly absorbed following single doses of USL261 (1.25 ?" 5.0 mg) in pediatric subjects, and no dose-dependent differences in Cmax were observed; AUC values for MDZ were highest following 5.0 mg USL261. Similar PK results for MDZ were observed regardless of CYP3A4/5-inducer status. AUC and Cmax for 1-OH-MDZ were similar across dosing cohorts, and higher in subjects taking CYP3A4/5-inducing AEDs. Tmax for the active metabolite was slightly longer than for MDZ. These PK results support the continued development of USL261 in pediatric patients with epilepsy. Funding: Support: Upsher-Smith Laboratories, Inc.