Abstracts

Rationale: Clobazam (CLB) is a 1,5 benzodiazepine approved for the treatment of Lennox–Gastaut syndrome (LGS) in patients 2 years and older. CLB is metabolized via CYP3A4 to over 20 metabolites in humans, with N-desmethylclobazam (N-CLB) considered the main, active metabolite in systemic circulation. The effect of weight and ontogeny in the characterization of CLB pharmacokinetics (PK) in pediatrics, as well as the distribution exposures of CLB and N-CLB, were investigated by simulation to predict doses that would be effective in reducing seizures in patients with Dravet syndrome, a rare form of intractable epilepsy. Methods: CLB plasma concentrations from three studies (OV-1017, OV-1012 and Study 301) were combined to generate a population PK (PopPK) model, which was validated using a prediction-corrected visual predictive check (pcVPC). Simulations from the PopPK model predicted distributions of CLB and N-CLB after daily doses of 1.5 and 2 mg/kg in children. Results: The PopPK model appropriately predicted the PK of CLB and N-CLB when patient age and weight were included. Based on distributions of steady-state Cmin (Figure), simulated mean concentrations of CLB and N-CLB for participants ≥3 years receiving CLB 1.5 mg/kg were 654 ng/mL and 4780 ng/mL, respectively, resulting in a CLB:N-CLB ratio of 0.14. In participants < 3 years receiving the 1.5 mg/kg dose, mean concentrations of 645 ng/mL and 2822 ng/mL resulted in a CLB:N-CLB ratio of 0.23. Ratios were maintained at the 2 mg/kg dose, consistent with linear PK profiles. Conclusions: A pediatric PopPK model was developed that accounts for weight and ontogeny in the metabolism of CLB. Simulated data suggest concentrations of CLB that would be efficacious against Dravet syndrome, as well as potential CLB dosing strategies for LGS patients < 3 years. Funding: Funded by Lundbeck