Effectiveness of Diazepam Nasal Spray Does Not Vary Across Times of Day Associated With Meals and Fasting in Patients With Seizure Clusters: Post Hoc Results From a Long-Term, Open-Label Safety Study
Abstract number :
3.421
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2022
Submission ID :
2232952
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:28 AM
Authors :
David Cook, PhD – Neurelis, Inc., San Diego, CA; Richard Gustin, PhD – Neurelis, Inc., San Diego, CA; Sunita Misra, MD, PhD – Neurelis, Inc., San Diego, CA; James Wheless, MD – Le Bonheur Children’s Hospital, University of Tennessee Health Science Center, Memphis, TN; Kore Liow, MD – Hawaii Pacific Neuroscience, Honolulu, HI and John A. Burns School of Medicine, University of Hawaii, Honolulu, HI; Adrian Rabinowicz, MD – Neurelis, Inc., San Diego, CA; Enrique Carrazana, MD – Neurelis, Inc., San Diego, CA and John A. Burns School of Medicine, University of Hawaii, Honolulu, HI
This is a Late Breaking abstract
Rationale: Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. In a long-term safety study of diazepam nasal spray, the use of a second dose was used as a proxy measure of effectiveness. Nasal administration is designed to bypass the gastrointestinal (GI) tract, thus mitigating potential issues with variable drug absorption and delayed absorption due to the fed/fasted state. Although some nasal formulations have shown dual peaks in plasma concentration associated with intranasal and enteral absorption, diazepam nasal spray (with an alkylsaccharide excipient to enhance absorption across the nasal mucosa) has demonstrated a single peak concentration in short-term studies. To further test this expectation, a post hoc analysis of second doses was performed to evaluate the independence of fed/fasted state and treatment effectiveness in a long-term study of seizure clusters in the community setting.
Methods: This was a long-term, open-label, repeat-dose safety study of diazepam nasal spray in patients aged 6–65 years with frequent seizure clusters and epilepsy. Age- and weight-based doses of diazepam nasal spray were administered. Patients and care partners were instructed to administer second doses 4–12 hours after the initial dose if needed. Dosing and timing of second doses could be adjusted by the investigator for efficacy or safety reasons. To assess impact of time of day on the proxy measure for effectiveness, the number of treated episodes requiring a second dose was grouped based on timing of the first dose and analyzed across 12- and 4-hour periods of the day, approximating periods of fed or fasting states.
Results: A total of 175 patients were enrolled in the study; 163 patients received ≥1 dose of diazepam nasal spray. Of a total of 3853 treated seizure clusters, 485 (12.6%) were treated with a second dose, including 152 (3.9%) treated within 4 hours of first dosing. When evaluated by 12-hour periods, the proportion of second doses given in the daytime (likely a fed state) was generally similar to second doses given at night (likely a fasting state) (Figure 1). Similarly, the analysis using 4-hour periods shows no apparent trends by time of day (Figure 2).
Conclusions: In this long-term study, there was no clinically meaningful trend of seizure clusters using a second dose when analyzed by time of day. Further, if bioavailability were delayed owing to gastric absorption, use of second doses within 4 hours would be expected to be elevated during the fed state; however, data show that use of second doses within 4 hours was lower during daytime hours. These findings suggest that in the clinical setting, factors regularly related to time of day (eg, meals) do not influence the effectiveness of diazepam nasal spray. This aligns with the expected result that a nasally delivered medication would not be influenced by fed/fasted state because it bypasses the GI tract.
Funding: Neurelis, Inc.
Anti-seizure Medications