Introduction: We are initiating a study of the efficacy and safety of clobazam for pediatric patients ≥1 to ≤16 years of age with Dravet syndrome (DS). Lack of clobazam dosing information for patients <2 years makes this challenging. A published RCT of stiripentol with clobazam and valproate demonstrated the combination’s efficacy in DS.¹ However, as stiripentol substantially increases clobazam concentrations, clobazam’s contribution to efficacy was unclear.¹

Methods: We employed PK/PD modeling, using previous clobazam studies,^2‒4 to determine the appropriate clobazam dosage for patients 6 months to 2 years of age. Results from the stiripentol with clobazam and valproate study in DS⁴ were used to design the study.

Results: Maximum clobazam dosage was determined to be 1.5 mg/kg/day for patients 6 months to 2 years of age, similar to dosing for older patients. Based on statistical analysis, we estimated 54 patients would be needed to demonstrate clobazam’s efficacy (percentage decrease in seizure rate vs. placebo, 85% power) in a clinical study in DS. This estimate was with the assumption that 50% of stiripentol response in the previous study¹ was due to clobazam.

Conclusion: An innovative pharmacometrics modeling approach eliminated the need for a Phase I trial to justify Phase III study dosage and will provide supportive evidence of efficacy for clobazam in DS. This approach may facilitate other drug studies in ultra-orphan indications.