EX-99.2 3 ex99_2.htm EXHIBIT 99.2
Exhibit 99.2

FOR SUBMISSION TO AES

Simulation of the Pharmacokinetics of Diazepam Buccal Film in Adult Patients with Epilepsy with Weight-adjusted Dosing

Allen H Heller, Gary Slatko, Michael A Rogawski

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 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/kg) is associated with therapeutic diazepam plasma concentrations under both interictal and ictal/periictal conditions.

Funding: Supported by Aquestive Therapeutics Inc.

Table: Simulated Pharmacokinetic Parameters Following DBF in the Interictal and Ictal/Periictal State Using a Weight-based Regimen1

 
2-hour Profiles; N=21
      
           
   
A. Interictal
B. Ictal/periictal
Ratio of Geometric
Means B/A (%)2
90% CI (%)3
   
Geometric Mean
Geometric Mean
    
 
Cmax (ng/mL)
234.73
217.77
92.77
74.5–112.53
 
AUC(0-2h) (ng•h/mL)
321.50
301.52
93.76
73.86–119.02

 
4-hour Profiles; N=18
      
           
   
A. Interictal
B. Ictal/periictal
Ratio B/A
90% CI (%)
   
Geometric Mean
Geometric Mean
    
 
Cmax (ng/mL)
224.19
211.96
95.54
73.34–121.89
 
AUC(0-4h) (ng•h/mL)
569.82
510.37
89.57
69.21–115.91
           
 
1 Weight-based regimen: 38-50 kg: 10 mg; 51-62 kg: 12.5 mg; 63-87 kg: 15 mg; 88-111 kg: 17.5 mg.
2 Calculated using least-squares means according to the formula: exp (difference) × 100.
3 90% geometric confidence interval using ln-transformed data.

Figure: Simulated Mean Diazepam Plasma Concentrations Following Administration of DBF in the Interictal or Ictal/Periictal State (N=16-21) Using a Weight-based Regimen


Predicted plasma concentrations based on data from 21 subjects with valid profiles for both Treatment A and Treatment B. Each timepoint is the mean of predicted concentrations from 16-21 subjects. Error bars are standard error of the mean.