March 14, 2016
A team of investigators at the AES conference gave two presentations of their research on the midazolam (MDZ) nasal spray (USL261), which is being developed for rescue treatment of seizures in patients who need treatment for intermittent bouts of increased seizure activity, also known as seizure clusters or acute repetitive seizures. It is intended to be delivered intranasally, without active inhalation by the patient. USL261 has been granted orphan drug designation for this use by the Food and Drug Administration (FDA).
In one presentation, the team studied the use of USL261 as an alternative to rectal diazemap, 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 older adults, the objective of this study was to evaluate pharmacodynamics (PD) and tolerability of USL261 in non-geriatric and geriatric adults.
Single-doses of USL261 (2.5 mg and 5 mg) were evaluated in a phase I, 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 and safety assessments included incidence of treatment emergent adverse events (TEAEs), respiratory rate, and oxygen saturation percentage (SO2).
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.
The team’s other presentation compared USL261 pharmacokinetics (PK) in non-geriatric and geriatric adults, in order to inform its potential use in older patients. Again, single-doses of USL261 (2.5 mg and 5 mg) were evaluated in a phase I, randomized, double-blind, 2-way crossover study in generally healthy geriatric (≥65 years; n=18) and non-geriatric (18-40 years; n=12) participants. But, for this second evaluation, blood sampling was performed prior to and through 24 hours 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).
Following a single 2.5 or 5 mg dose of USL261, overall (AUC0-∞) and maximum (Cmax) plasma MDZ exposure were higher in geriatric participants than in 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 to guide dosing recommendations in geriatric patients.