Pharmacokinetics of Midazolam Nasal Spray in Pediatric Subjects with Epilepsy (S55.005)

Objective: Characterize pharmacokinetics (PK) of midazolam (MDZ) nasal spray (USL261) in pediatric subjects with epilepsy. Background: USL261 is in development as rescue treatment for individuals with intermittent bouts of increased seizure activity. Design/Methods: This open-label, phase 1 study evaluated single-dose PK of USL261. Subjects (2–13 years) with focal or generalized epilepsy received 5.0, 2.5, or 1.25 mg USL261 based on body weight (≥40–≤60, ≥20– 0–6 ), maximum observed plasma concentration (C max ), and time to C max (T max ). PK parameters were summarized by cohort and prior/concomitant use of cytochrome P450 3A4/5 (CYP3A4/5) inducing antiepileptic drugs (AEDs). Results: All 36 enrolled individuals (n=12/cohort) completed the study and were included in PK analyses. MDZ exposure was similar between the lower-dose cohorts (AUC 0–6 geometric mean [GM]: 37.2 and 38.4 ng·h/mL in 1.25 and 2.5 mg cohorts, respectively) and higher in the 5.0 mg cohort (75.2 ng·h/mL). C max was similar across cohorts (GM: 33.7–37.3 ng/mL) and median T max was 0.25 hours for all cohorts. PK results were similar regardless of CYP3A4/5-inducing AED status. 1-OH-MDZ PK were similar across all cohorts (GM AUC 0–6 : 12.5–15.3 ng·h/mL; C max : 3.6–5.6 ng/mL). Median T max was slightly longer in the 5.0 mg cohort versus lower-dose cohorts (1.5 versus 0.5 hours). 1-OH-MDZ AUC 0–6 and C max values were generally higher in subjects taking CYP3A4/5-inducing AEDs. Conclusions: MDZ was rapidly absorbed with no observed dose-dependent C max differences; AUC values for MDZ were highest following 5.0 mg USL261. MDZ PK parameters were similar regardless of CYP3A4/5-inducing AED status. 1-OH-MDZ AUC and C max were similar across cohorts and higher in subjects taking CYP3A4/5-inducing AEDs. T max for 1-OH-MDZ was slightly longer than for MDZ. These PK results support the continued development of USL261 in pediatric patients with epilepsy. Study Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Berg has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Bancke has received person compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Kapelan has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Meng has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Moe has receievd personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Van Ess has received personal compensation for activities with Upsher-Smith Laboratories Inc. as an employee.