Clinical Pharmacology: Advances and Applications (Sep 2020)
Predicted Efficacy of Once-Daily Extended-Release Oxcarbazepine (Oxtellar XR®) Monotherapy in Adults and Children with Partial-Onset Seizures: Exposure-Response Modeling and Simulation
Abstract
Shamia Faison,1 Roberto Gomeni,2 Shannon Mendes,1 Welton O’Neal,1 Stefan Schwabe,1 Azmi Nasser1 1Supernus Pharmaceuticals, Inc., Rockville, MD, USA; 2PharmacoMetrica, La Fouillade, FranceCorrespondence: Azmi NasserSupernus Pharmaceuticals, Inc., 9715 Key West Avenue, Rockville, MD 20850, USATel +1 301 838 2500Fax +1 240 403 0065Email [email protected]: 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 (Cmin) 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 Cmin 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 Cmin concentrations achieved with 1200 and 2400 mg/day adjunctive OXC-XR (47.4 and 76.4 μmol/L) and at target MHD Cmin 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 Cmin, 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 Cmin 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.Keywords: oxcarbazepine, monotherapy, Oxtellar, monohydroxy derivative, adjunctive therapy
