Abstracts

Rationale: Diazepam buccal soluble film (DBF) is a novel dosage form of diazepam under development for the treatment of acute repetitive seizures (ARS). In a study reported earlier (Rogawski et al., AES Abst. 2.453, 2018), we demonstrated that pharmacokinetic (PK) performance of DBF following a single 12.5 mg dose was similar under periictal and interictal conditions. The legacy product diazepam rectal gel (Diastat) is dosed acording to a weight-based dosing scheme. This study was undertaken to compare diazepam exposures obtained with DBF when dosing according to a weight-based regimen and as a fixed dose. 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. 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. PK profiles were simulated based on body weight and robust evidence of dose-proportionality of the DBF product from healthy volunteer studies and population PK modeling.  Results: The table shows predicted 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% confidence intervals. On average, predicted PK parameters were 17-18% higher compared with the 12.5-mg fixed-dose regimen, with median Cmax values 263 ng/mL (interquartile range (IQR) 197-301 ng/mL), and 247 ng/mL (IQR 152-329 ng/mL) for the interictal and ictal/periictal conditions, respectively. Weight-based dosing provided a modest reduction in inter-subject variability. As expected, predicted values for Cmax, AUC(0-2h), and AUC(0-4h) were similar in interictal and ictal/periictal state. The figure shows the mean of the simulated plasma concentrations over time.  Conclusions: The simulated weight-based dosing regimen for administration of DBF to adults with epilepsy was associated with a higher predicted exposure than that observed with a fixed dose of 12.5 mg. These results suggest that the weight-based dosing regimen applied here (average dose 14.9 mg) is associated with therapeutic diazepam plasma concentrations under both interictal and ictal/periictal conditions.  Funding: This study was funded by Aquestive Therapeutics Inc