Predicted Efficacy of Once-Daily Extended-Release Oxcarbazepine (Oxtellar XR?) Monotherapy in Adults and Children with Partial-Onset Seizures: Exposure-Response Modeling and Simulation

摘要

Purpose: We conducted exposure-response modeling and simulations to compare the predicted efficacy of extended-release oxcarbazepine (OXC-XR), an oral once-daily (qd) antiepileptic drug, with that of immediate-release (IR) OXC twice-daily (bid) when the agents are used as monotherapy or adjunctive therapy in patients with epilepsy characterized by partial-onset seizures (POS). Methods: Modeling assessed percent change from baseline 28-day seizure frequency (PCH) as a function of minimum concentration (C min ) of monohydroxy derivative (MHD), the clinically relevant metabolite of OXC. For OXC-IR, the model used historical data; values for OXC-XR were derived from observed data. The model was simulated (N=100) to predict PCH at MHD C min concentrations achieved with 1200 and 2400 mg/day in adults and children receiving OXC-XR qd or OXC-IR bid. Mean PCH and 95% confidence intervals (CIs) were generated and compared. Results: Predicted efficacy was not different (ie, 95% CI of mean PCH overlapped) for OXC-XR qd vs OXC-IR bid at mean MHD C min concentrations achieved with 1200 and 2400 mg/day adjunctive OXC-XR (47.4 and 76.4 μmol/L) and at target MHD C min concentrations for OXC-IR monotherapy (59.1 and 112 μmol/L) in adults. Predicted efficacy in adults vs children was not different between formulations. Depending on MHD C min , the predicted mean PCH in adults ranged from ? 51.4% to ? 73.4% with OXC-XR qd and ? 53.2% to ? 78.5% with OXC-IR bid. In children, the predicted mean PCH ranged from ? 48.4% to ? 58.1% (OXC-XR qd) and ? 32.5% to ? 70.4% (OXC-IR bid). Conclusion: This model-based analysis predicted comparable efficacy for OXC-XR qd vs OXC-IR bid at MHD C min concentrations corresponding to 1200 and 2400 mg/day as monotherapy or adjunctive therapy. Based on this analysis, the US Food & Drug Administration approved OXC-XR for use as monotherapy in adults and children ≥ 6 years of age with POS.