Abstracts

Rationale: Adjunctive use and monotherapy are no longer separate indications in FDA-approved labeling for antiepileptic drugs (AEDs) to treat partial-onset seizures (POS), with the proviso that recommended dosages and corresponding exposures with monotherapy are similar to those established for adjunctive therapy. Exposure-response modeling and simulations comparing QD Oxtellar XR (extended-release oxcarbazepine, Supernus Pharmaceuticals, Inc.) and BID Trileptal (immediate-release carbamazepine, Novartis) were performed to support the extrapolation of adjunctive Oxtellar XR efficacy in adults to monotherapy in adults and children.  Methods: Analyses used data from QD Oxtellar XR pharmacokinetic studies in healthy adults and children with POS, a double-blind, placebo-controlled study of QD Oxtellar XR as adjunctive therapy in adults with POS, and historical data for BID Trileptal. A model initially developed for extrapolating adjunctive BID Trileptal efficacy in adults with POS to monotherapy in children was used to establish exposure-response relationship for QD Oxtellar XR. The model was simulated (N=100) to predict % seizure frequency reduction from baseline normalized to 28 days (%SFR) at monohydroxylated derivative (MHD) concentrations (Cmin) achieved with 1200 and 2400 mg/day of both formulations in adults and children. Mean %SFR and 95% CI were generated and compared.  Results: Exposure-response analysis populations comprised 283 subjects for QD Oxtellar XR and 480 for BID Trileptal. The predicted response was not different (i.e., 95% CI of mean %SFR overlapped) for QD Oxtellar XR vs. BID Trileptal at mean MHD Cmin concentrations corresponding to 1200 and 2400 mg/day as Trileptal monotherapy (59.1 and 112 µmol/L) and adjunctive Oxtellar XR (47.4 and 76.4 µmol/L) in adults. Exposure-response model outcomes with QD Oxtellar XR and BID Trileptal were not different for adults vs. children. The predicted mean %SFR in adults ranged from -51.4% to -73.4% with QD Oxtellar XR and -53.2% to -78.5% with BID Trileptal. In children, predicted mean %SFR ranged from -54.3% to -58.1% (QD Oxtellar XR) and ‑32.5% to -70.4% (BID Trileptal).  Conclusions: A model-based analysis predicted comparable efficacy for QD Oxtellar XR vs. BID Trileptal, supporting the use of QD Oxtellar XR as monotherapy in adults and children >=6 years of age with partial-onset seizures.  Funding: Supernus Pharmaceuticals, Inc.