Pharmacokinetics of Diazepam Buccal Soluble Film in Adult Patients with Epilepsy: Comparison of Bioavailability with Periictal and Interictal Administration
Abstract number :
2.453
Submission category :
7. Antiepileptic Drugs / 7B. Clinical Trials
Year :
2018
Submission ID :
551841
Source :
www.aesnet.org
Presentation date :
12/2/2018 4:04:48 PM
Published date :
Nov 5, 2018, 18:00 PM
Authors :
Michael A. Rogawski, University of California - Davis; Hui Gong, Rancho Los Amigos National Rehabilitation Center; Kore Liow, University of Hawaii John Burns School of Medicine; Sami Aboumatar, Austin Epilepsy Care Center; Pavel Klein, Mid-Atlantic Epilep
Rationale: Diazepam buccal soluble film (DBSF) is a novel dosage form of diazepam under development for the management of selected patients with refractory epilepsy who require intermittent use of diazepam to control episodes of increased seizure activity. In this study, we sought to assess pharmacokinetic (PK) performance during or immediately after a seizure. Subjects were investigated while undergoing a clinical epilepsy monitoring unit (EMU) evaluation and on another PK-only visit, with the visits separated by approximately 3 weeks. We investigated the diazepam maximal plasma concentration (Cmax), time to maximal concentration (Tmax), and partial area under the curve (partial AUC) at 2 or 4 hours following a single 12.5 mg dose administered during both visits. Methods: Adult men and women ages 17-65 years with poorly controlled tonic clonic seizures or focal seizures with impaired awareness (N=35) were enrolled in a single-dose crossover study to receive DBSF 12.5 mg under both interictal (Treatment A) and ictal/peri-ictal (Treatment B) conditions in a clinical EMU setting. Plasma samples for analysis of diazepam were obtained pre-dose and at intervals until 2 hours or 4 hours after dosing. Administration was classified as interictal if there was no observed seizure activity in the preceding 4 hours and as ictal/periictal if DBSF was given during clinically observed seizure activity or within 5 minutes of cessation of seizure activity. Subjects were monitored for adverse events (AE) throughout the study. Results: Pharmacokinetic (PK) profiles valid for analysis for both treatment conditions were available for 21 subjects. Most of these subjects had samples collected up to 4 hours but 3 subjects were sampled only up to 2 hours. Subjects were excluded from analysis if both treatments were not completed (N=4), if critical PK time points were missed as adjudicated by an expert blinded to the concentration data (N=3), if pre-dose diazepam concentrations were greater than 5% of Cmax (N=2), or if DBSF was administered in a manner contrary to instructions (N=5). The table shows values for Cmax, AUC(0-2h), and AUC(0-4h) (geometric means) and the ratio of the geometric means (Treatment B/Treatment A) with 90% CI. Values for Cmax, AUC(0-2h), and AUC(0-4h) were similar in the interictal and ictal/periictal state, and median values for Tmax were not significantly different. DBSF 12.5 mg was safe and well tolerated. The most common adverse event possibly related to drug was somnolence reported in two (5.7 %) of 35 subjects. There were no serious adverse events related to study drug, and no subject withdrew because of an adverse event. Conclusions: These results demonstrate that a single dose of DBSF 12.5 mg administered to adults with epilepsy provides exposure to diazepam under ictal/peri-ictal conditions that is comparable to that obtained under inter-ictal conditions. Funding: Funded by Aquestive Therapeutics Inc
