Diazepam Buccal Soluble Film Formulation Shows Comparable Exposure Across Seizure Periods

Keith J. Kendall, the chief executive officer of Aquestive Therapeutics

Keith J. Kendall

A single dose of diazepam buccal soluble film (BSF), tentatively named Libervant (Aquestive Therapeutics), at a dose of 12.5 mg has been shown to provide comparable exposure to the therapy during interictal conditions when administered under ictal and periictal conditions.¹

According to the results of a poster presentation at the American Epilepsy Society’s annual meeting in New Orleans, Louisiana, this novel dosage form of diazepam had comparable times to maximal concentration (T_max) in both 2-hour (P = .8620) and 4-hour periods (P = .5708). In seeking to assess the pharmacokinetic performance during or immediately after a seizure, all patients were assessed while undergoing a clinical epilepsy monitoring unit evaluation and on another pharmacokinetic-only visit, separated by roughly 3 weeks.

"Often it can be very difficult to administer treatment during periods of increased seizure activity. Currently, the only non-injected formulation of diazepam approved for the acute treatment of seizures is a rectally-applied gel," Keith J. Kendall, the chief executive officer of Aquestive Therapeutics, said when the positive results were announced in October.² "These pharmacokinetic findings, taken together with other [diazepam buccal soluble film] studies, will help advance the development of Libervant as an alternative to currently approved therapies. We are very excited to have achieved this critical milestone in the program."

The study measured diazepam BSF in patients with poorly controlled tonic-clonic seizures or focal seizures with impaired awareness (n = 35) in a crossover fashion. All patients received 12.5-mg diazepam BSF in both interictal (Treatment A), defined as no observed seizure activity in the preceding 4 hours, and ictal/peri-ictal (Treatment B), defined as administration of clinically observed seizure activity or within 5 minutes of cessation of seizure activity.

In total, data was collected for 21 patients at the 2-hour mark, and 18 patients at the 4-hour mark. At 2 hours, the T_max was 0.680 hours for the interictal period and 0.983 hours for the ictal/periictal period. At 4 hours, T_max was 0.767 hours for the interictal period and 0.533 hours for the ictal/periictal period.

The diazepam maximal plasma concentration (C_max) was 198.76 ng/mL for the interictal period and 184.40 ng/mL for the ictal/periictal period at 2 hours, for a B/A ratio of geometric means of 92.77% (90% CI, 74.5 to 112.53). Likewise, at 4-hours, the C_max was 190.34 ng/mL and 184.40 ng/mL for the interictal and ictal/periictal periods, respectively, for a B/A ratio of geometric means of 95.54 (90% CI, 73. 34 to 121.89).

Statistical analysis revealed the area under the curve (AUC) was 264.57 ng.h/mL for the interictal period and 248.06 ng.h/mL for the ictal/periictal period (B/A ratio, 93.76; 90% CI, 73.86 to 119.02). The AUCs for the 4-hour period were 483.79 and 433.32 for the interictal and ictal/periictal periods, respectively (B/A ratio, 89.57; 90% CI, 69.21 to 115.91).

Dizapem BSF was found, overall, to be safe and well tolerated at the 12.5-mg dose. The most common adverse event (AE) that was considered to be possibly related to the drug was somnolence, which was reported in 2 (5.7 %) of 35 patients. There were no serious adverse events related to study drug, and no subject withdrew because of an AE.

This form of the therapy is undergoing development for the management of selected patients with refractory epilepsy who require intermittent use of diazepam to control episodes of increased seizure activity. Due to the fact that during a seizure, changes might occur in the oral environment that could impact absorption, leading to this assessment to whether such changes—if any—are associated with alterations in the absorption of BSF delivered diazepam.

Currently, diazepam is available in several forms, with its main epileptic use as a rectal gel used as a rescue therapy for clustered and repeating seizures. Although it is sometimes administered by emergency health care personnel in injection form to halt seizures, an at-home alternative, Diastat, was approved by the FDA in 1997.³

It exists in an oral tablet form, with many generic varieties, though it is generally thought to be too slowly absorbed to halt seizures and is overall only moderately effective in treating epilepsy. Additionally, consistent daily use of the therapy renders it essentially ineffective, as tolerance, as well as dependence, can develop.

REFERENCE:

1. Rogawski MA, Gong H, Liow K, et al. Pharmacokinetics of diazepam buccal film in adult patients with epilepsy: Comparison of bioavailability with periictal and interictal administration. Presented at: American Epilepsy Society Annual Meeting; New Orleans, Louisiana; November 30 to December 4, 2018. aesnet.org/meetings_events/annual_meeting_abstracts/view/551841

2. Aquestive Therapeutics Inc. (AQST) Reports Positive Topline Results for Complete Diazepam Buccal Film Adult Epilepsy Monitoring Unit Clinical Study [press release]. Warren, NJ: Aquestive Therapeutics, Inc; Published October 25, 2018. prnewswire.com/news-releases/aquestive-therapeutics-announces-completion-of-diazepam-buccal-film-adult-epilepsy-monitoring-unit-emu-clinical-study-with-positive-topline-results-300737597.html. Accessed December 1, 2018.

3. Diazepam. Epilepsy Foundation website. epilepsy.com/medications/diazepam/advanced. Accessed December 1, 2018.