{"title":"每日一次缓释奥卡西平(Oxtellar XR®)单药治疗成人和儿童部分发作性癫痫的预测疗效:暴露-反应建模和模拟","authors":"Shamia Faison, Roberto Gomeni, Shannon Mendes, Welton O'Neal, Stefan Schwabe, Azmi Nasser","doi":"10.2147/CPAA.S256972","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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).</p><p><strong>Methods: </strong>Modeling assessed percent change from baseline 28-day seizure frequency (PCH) as a function of minimum concentration (C<sub>min</sub>) 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<sub>min</sub> 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.</p><p><strong>Results: </strong>Predicted efficacy was not different (ie, 95% CI of mean PCH overlapped) for OXC-XR qd vs OXC-IR bid at mean MHD C<sub>min</sub> concentrations achieved with 1200 and 2400 mg/day adjunctive OXC-XR (47.4 and 76.4 µmol/L) and at target MHD C<sub>min</sub> 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<sub>min</sub>, 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).</p><p><strong>Conclusion: </strong>This model-based analysis predicted comparable efficacy for OXC-XR qd vs OXC-IR bid at MHD C<sub>min</sub> 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.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"12 ","pages":"135-147"},"PeriodicalIF":3.1000,"publicationDate":"2020-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S256972","citationCount":"1","resultStr":"{\"title\":\"Predicted Efficacy of Once-Daily Extended-Release Oxcarbazepine (Oxtellar XR<sup>®</sup>) Monotherapy in Adults and Children with Partial-Onset Seizures: Exposure-Response Modeling and Simulation.\",\"authors\":\"Shamia Faison, Roberto Gomeni, Shannon Mendes, Welton O'Neal, Stefan Schwabe, Azmi Nasser\",\"doi\":\"10.2147/CPAA.S256972\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>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).</p><p><strong>Methods: </strong>Modeling assessed percent change from baseline 28-day seizure frequency (PCH) as a function of minimum concentration (C<sub>min</sub>) 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<sub>min</sub> 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.</p><p><strong>Results: </strong>Predicted efficacy was not different (ie, 95% CI of mean PCH overlapped) for OXC-XR qd vs OXC-IR bid at mean MHD C<sub>min</sub> concentrations achieved with 1200 and 2400 mg/day adjunctive OXC-XR (47.4 and 76.4 µmol/L) and at target MHD C<sub>min</sub> 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<sub>min</sub>, 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).</p><p><strong>Conclusion: </strong>This model-based analysis predicted comparable efficacy for OXC-XR qd vs OXC-IR bid at MHD C<sub>min</sub> 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.</p>\",\"PeriodicalId\":10406,\"journal\":{\"name\":\"Clinical Pharmacology : Advances and Applications\",\"volume\":\"12 \",\"pages\":\"135-147\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2020-09-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.2147/CPAA.S256972\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Pharmacology : Advances and Applications\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2147/CPAA.S256972\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2020/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Pharmacology : Advances and Applications","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2147/CPAA.S256972","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2020/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Predicted Efficacy of Once-Daily Extended-Release Oxcarbazepine (Oxtellar XR®) Monotherapy in Adults and Children with Partial-Onset Seizures: Exposure-Response Modeling and Simulation.
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 (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.
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