Tolerability and Pharmacodynamics of Midazolam Nasal Spray (USL261) in Healthy Geriatric and Non-Geriatric Adults
Abstract number :
2.259
Submission category :
7. Antiepileptic Drugs
Year :
2015
Submission ID :
2326781
Source :
www.aesnet.org
Presentation date :
12/6/2015 12:00:00 AM
Published date :
Nov 13, 2015, 12:43 PM
Authors :
A. K. Berg, M. J. Myrvik, P. J. Van Ess
Rationale: Midazolam (MDZ) nasal spray (USL261) is in development as an alternative to rectal diazepam, the only FDA-approved non-intravenous treatment for patients with intermittent bouts of increased seizure activity. As amnesic and sedative properties with MDZ have been observed, and adverse events may be enhanced in the elderly, an objective of this study was to evaluate pharmacodynamics (PD) and tolerability of USL261 in non-geriatric and geriatric adults.Methods: Single-doses of USL261 (2.5 mg and 5 mg) were evaluated in a phase 1, randomized, double-blind, 2-way crossover study (≥4 day washout period) in generally healthy geriatric (≥65 years; n=18) and non-geriatric (18-40 years; n=12) participants. PD assessments included Stanford Sleepiness Scale (SSS) and Observer's Assessment of Alertness/Sedation Scale (OAA/S) sum score to assess sedation, and Digit-Symbol Substitution Test (DSST) percent correct and trial completion rate to assess psychomotor performance. Analysis of variance was used to determine significance. Maximum observed PD effect (Emax) and time to Emax (Teffect) were evaluated. Tolerability/safety assessments included incidence of treatment emergent adverse events (TEAEs), respiratory rate, and oxygen saturation percentage (SO2).Results: For both age groups, sedation (SSS and OAA/S) was more pronounced with 5 mg USL261 relative to 2.5 mg (P<.05). For both doses, mean Emax values were similar between age groups (NS). Median Teffect for SSS occurred within 1 h in both age groups. Median Teffect for OAA/S occurred earlier in the geriatric (14 min) versus the non-geriatric group (22-28 min). For baseline-adjusted DSST parameters, psychomotor impairment, as indicated by Emax, was more evident following the higher dose (P<.01) and was similar (trial completion rate) to slightly more pronounced (percent correct) in geriatric participants (NS). DSST Teffect generally occurred within 1 h for both age groups and occurred earlier in the geriatric group. Return to baseline for all PD assessments was generally achieved within 4 h. No participants discontinued from the study. All TEAEs were mild/moderate and occurred with similar frequency in both geriatric (89%) and non-geriatric (83%) participants. TEAE severity did not worsen with increased USL261 dose and common TEAEs were consistent with nasal administration. Individual SO2 values remained ≥90% at all measured time points.Conclusions: Following a single 2.5 or 5 mg USL261 dose in geriatric and non-geriatric adults, PD effects were observed shortly after drug administration and return to baseline generally within 4 h. There were no significant differences in sedation and psychomotor impairment between the age groups, and PD effects were significantly more pronounced with 5 mg USL261 versus 2.5 mg. USL261 was well tolerated in both age and dose groups. These data support the continued development of USL261 for the rescue treatment of patients with intermittent bouts of increased seizure activity in adults of all ages. Support: Upsher-Smith Laboratories, Inc.
Antiepileptic Drugs