Sachdeo R, Narang-Sachdeo S K, Shumaker R C, Perhach J L, Lyness W H, Rosenberg A
Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick 08903, USA.
Epilepsia. 1997 Aug;38(8):887-92. doi: 10.1111/j.1528-1157.1997.tb01253.x.
Felbamate (FBM) pharmacokinetic parameters, safety and tolerability in the dose range of 1,200-6,000 mg/day were assessed in two open-label studies with similar designs.
In study A, newly diagnosed subjects with epilepsy receiving FBM monotherapy at a starting dose of 1,200 mg/day (400 mg/three times daily, t.i.d.) and increased 1,200 mg/day, if tolerated, at 14-day intervals to 3,600 mg/day were investigated. In study B, epilepsy subjects with prior FBM monotherapy exposure received ascending FBM doses in five consecutive 14-day periods with a starting dose of 3,600 mg/day (1,200 mg t.i.d.) FBM. In each successive period, if FBM was well tolerated, the dose was increased by 600 mg/day to a maximum of 6,000 mg/day (2,000 mg t.i.d.).
The pharmacokinetic parameter estimates maximum observed concentration (Cmax), area under the concentration-time curve (AUCtau) Ctrough, and Cav showed a linear dependence to dose above the 1,200-6,000 mg/day FBM dose range (F-tests; p < 0.0001) with apparent clearance (Cl/kg) and Tmax (time to Cmax) independent of dose. When AUCtau, Cmax and Ctrough were adjusted for dose, there were no significant differences between the dosing periods.
The data establish that plasma concentrations of FBM are linear with respect to dose to 6,000 mg/day. In addition, FBM was safely administered at these doses for periods as long as 14 days to epileptic subjects with prior exposure to FBM. FBM-naive subjects appeared to report more adverse experiences (generally of mild to moderate severity) than did subjects with prior FBM exposure.
在两项设计相似的开放标签研究中，评估了非氨酯（FBM）在1200 - 6000毫克/天剂量范围内的药代动力学参数、安全性和耐受性。
在研究A中，对新诊断的癫痫患者进行研究，这些患者接受FBM单药治疗，起始剂量为1200毫克/天（400毫克/每日三次，tid），如果耐受，则每隔14天增加1200毫克/天，直至3600毫克/天。在研究B中，先前接受过FBM单药治疗的癫痫患者在连续五个14天周期内接受递增的FBM剂量，起始剂量为3600毫克/天（1200毫克tid）FBM。在每个连续周期中，如果FBM耐受性良好，剂量每天增加600毫克，最大剂量为6000毫克/天（2000毫克tid）。
药代动力学参数估计值，即最大观察浓度（Cmax）、浓度 - 时间曲线下面积（AUCtau）、谷浓度（Ctrough）和平均浓度（Cav），在1200 - 6000毫克/天FBM剂量范围以上与剂量呈线性相关（F检验；p < 0.0001），表观清除率（Cl/kg）和达峰时间（Tmax，达到Cmax的时间）与剂量无关。当对AUCtau、Cmax和Ctrough进行剂量调整后，各给药周期之间无显著差异。
数据表明，FBM的血浆浓度在剂量达到6000毫克/天时与剂量呈线性关系。此外，在这些剂量下，FBM对先前接触过FBM的癫痫患者安全给药长达14天。与先前接触过FBM的患者相比，未接触过FBM的患者似乎报告了更多不良事件（一般为轻度至中度严重程度）。
