Faison Shamia, Gomeni Roberto, Mendes Shannon, O'Neal Welton, Schwabe Stefan, Nasser Azmi
Supernus Pharmaceuticals, Inc., Rockville, MD, USA.
PharmacoMetrica, La Fouillade, France.
Clin Pharmacol. 2020 Sep 23;12:135-147. doi: 10.2147/CPAA.S256972. eCollection 2020.
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).
Modeling assessed percent change from baseline 28-day seizure frequency (PCH) as a function of minimum concentration (C) 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 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.
Predicted efficacy was not different (ie, 95% CI of mean PCH overlapped) for OXC-XR qd vs OXC-IR bid at mean MHD C concentrations achieved with 1200 and 2400 mg/day adjunctive OXC-XR (47.4 and 76.4 µmol/L) and at target MHD C 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, 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).
This model-based analysis predicted comparable efficacy for OXC-XR qd vs OXC-IR bid at MHD C 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.
我们进行了暴露-反应建模与模拟，以比较缓释奥卡西平（OXC-XR，一种每日口服一次的抗癫痫药物）与即释型奥卡西平（OXC-IR，每日口服两次）在以部分性发作（POS）为特征的癫痫患者中作为单药治疗或辅助治疗时的预测疗效。
建模评估了单羟基衍生物（MHD，奥卡西平的临床相关代谢物）最低浓度（C）与基线28天癫痫发作频率百分比变化（PCH）之间的函数关系。对于OXC-IR，模型使用历史数据；OXC-XR的值来自观察数据。对模型进行模拟（N = 100），以预测接受每日一次OXC-XR或每日两次OXC-IR的成人和儿童在1200和2400毫克/天剂量下达到的MHD C浓度时的PCH。生成并比较平均PCH和95%置信区间（CI）。
在成人中，当辅助使用OXC-XR剂量为1200和2400毫克/天达到的平均MHD C浓度（47.4和76.4微摩尔/升）以及OXC-IR单药治疗的目标MHD C浓度（59.1和112微摩尔/升）时，OXC-XR每日一次与OXC-IR每日两次的预测疗效无差异（即平均PCH的95%CI重叠）。两种剂型在成人与儿童中的预测疗效无差异。根据MHD C，成人中OXC-XR每日一次的预测平均PCH范围为-51.4%至-73.4%，OXC-IR每日两次为-53.2%至-78.5%。在儿童中，预测平均PCH范围为-48.4%至-58.1%（OXC-XR每日一次）和-32.5%至-70.4%（OXC-IR每日两次）。
基于该模型的分析预测，在对应于1200和2400毫克/天作为单药治疗或辅助治疗的MHD C浓度下，OXC-XR每日一次与OXC-IR每日两次的疗效相当。基于该分析，美国食品药品监督管理局批准OXC-XR用于≥6岁患有POS的成人和儿童的单药治疗。
