Abstracts

Rationale: The objective of this research project was to determine whether the exposure-response relationship for antiepileptic drugs (AEDs) known to be effective for the treatment of partial onset seizure (POS) both in adult and pediatric patients is sufficiently similar between both groups to allow an extrapolation of efficacy from adults to children for other drugs known to be effective for the treatment of POS in adults. Methods: Patient-level data were obtained from the efficacy trials of 8 drugs with varying presumed mechanisms of action (levetiracetam, oxcarbazepine, topiramate, lamotrigine, gabapentin, perampanel, tiagabine and vigabatrin) that are FDA-approved for the treatment of POS in both adult and pediatric patients. Information from 26 placebo-controlled trials conducted in over 6000 patients (1400 children) was used. The percent change from baseline in seizure frequency/28 days (%CFB) was the response metric, while Cmin, Caverage, or area under the drug concentration versus time curve (AUC) was the exposure metric. The following analyses were conducted in adults and children ?- 4 years of age: comparison of a) responses at the approved doses; b) exposures at the approved doses; c) exposures and responses in different pediatric age subgroups; d) exposure-response (E-R) relationships using graphical and model-based analyses. The ?- 4 years of age criterion was based on a presumed difference in pathophysiology of POS in younger patients. Results: For all 8 AEDs, the placebo-corrected responses (median %CFB) and exposures were consistent between adults and children at the approved doses. Furthermore, the exposures and responses across pediatric age subgroups were similar. E-R analyses performed using graphical and model-based comparisons showed that the slopes of the E-R relationship were similar between adults and children. Conclusions: Based on the totality of evidence, including evidence of similarity of disease pathophysiology, similar response to intervention, consistent exposures and response in all pediatric age subgroups, and similar E-R in adults and children, extrapolation of efficacy from adults to pediatric patients ?- 4 years of age appears justified, as targeting drug concentrations in children that are similar to those obtained at doses known to be effective in adults can be expected to result in similar clinical responses. In the setting of extrapolation of efficacy based on this analysis, long-term open-label safety studies are necessary to support the use of AEDs in pediatric patients. Funding: FDA Critical Path