Pharmacokinetic Characteristics of Diazepam Nasal Spray in Children with Epilepsy 2 to 5 Years of Age
Abstract number :
2.365
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
985
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Eric Segal, MD – Hackensack University Medical Center, Hackensack Meridian School of Health, and Northeast Regional Epilepsy Group
James Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES – LeBonheur Children’s Hospital
Muhammad Zafar, MD, FACNS – Duke University Hospital
Leock Ngo, PhD – Neurelis, Inc.
Evelyn Shih, MD, PhD – Neurelis, Inc.
Enrique Carrazana, MD – Neurelis, Inc; John A. Burns School of Medicine, University of Hawaii
Adrian Rabinowicz, MD – Neurelis, Inc.; Center for Molecular Biology and Biotechnology, Charles E. Schmidt College of Science, Florida Atlantic University
Rationale: Benzodiazepines are used for acute treatment of seizure clusters, which have been defined as 2 or more seizures in a 24-hour period. Despite use for more than 2 decades, the pharmacokinetics (PK) of rectal diazepam in children age 2–5 years have not been characterized. Diazepam nasal spray (Valtoco®) is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years, and diazepam rectal gel has a similar indication for patients aged ≥2 years. Here, we present the results from a phase 1/2a study that characterized the PK of the diazepam nasal spray formulation following a single dose in children aged 2–5 years.
Methods: Pediatric patients aged 2–5 years with epilepsy and seizure clusters were included. Study personnel administered diazepam nasal spray in weight-based doses of 5, 10, or 15 mg (0.5 mg/kg, based on diazepam rectal gel label). Blood samples were taken predose and at 15, 45, 60, 75, 90, 120, 150, 180, 195, 210, 240, 300, and 360 minutes after dosing. Three separate sampling sequences were used so that each patient provided 6 blood samples (predose, 360 min, and 4 samples between 0–360 min, spaced 45–120 min apart). PK parameters of area under the curve for the first 6 hours (AUC[0–6h]), maximum concentration (Cmax), and time to Cmax (Tmax) were calculated. PK characteristics were examined using a diazepam population PK model, which was previously developed using data from pediatric and adult subjects (aged 6–59 years).
Results: Of the 35 pediatric patients (60% male), 18 were aged 2–3 years, and 17 were aged 4–5 years; 28 received 10 mg diazepam nasal spray, 4 received 15 mg, and 3 received 5 mg. Diazepam was readily absorbed after intranasal administration, with diazepam levels detected at the first time point of sample collection (including patients with samples at 15 minutes). Mean AUC(0–6h) and Cmax of diazepam following the 10 mg dose was 1038.10 h*ng/mL and 279.91 ng/mL, respectively, for patients aged 4–5 years and 1041.76 h*ng/mL and 269.25 ng/mL, respectively, for patients aged 2–3 years, supporting similar PK profiles across the 2 age groups (Figure). Median Tmax ranged from 3.083 to 5.350 hours, independent of age and dose; however, this reflected the sparse sampling approach (Table). The time to reach a threshold concentration for antiseizure activity was far shorter. The PK data from this cohort adequately fitted within the previously developed population model in subjects aged 6–59 years, with parameter estimates within 1%–2% of the previous analysis. There were no changes in vital signs or respiration and no cases of nasal irritation developed following single-dose administration.
Conclusions: In this PK study conducted in children aged 2–5 years, diazepam nasal spray was readily absorbed and exposure was similar, independent of age or dose. These data are consistent with the known PK for older children (0.3 mg/kg dosing) and adults (0.2 mg/kg dosing) and confirm the adequacy of the 0.5 mg/kg dosing paradigm for diazepam nasal spray for children age 2–5 years.
Funding:
Neurelis, Inc.
Anti-seizure Medications