Rosenfeld W E, Liao S, Kramer L D, Anderson G, Palmer M, Levy R H, Nayak R K
The Comprehensive Epilepsy Care Center for Children and Adults at St. Luke's Hospital, St. Louis, Missouri 63017, USA.
Epilepsia. 1997 Mar;38(3):324-33. doi: 10.1111/j.1528-1157.1997.tb01124.x.
The steady-state pharmacokinetics of valproate (VPA) and topiramate (TPM) were compared during VPA monotherapy, concomitant VPA and TPM therapy, and TPM monotherapy to evaluate pharmacokinetic interactions.
After a 3-week baseline period, 12 patients receiving VPA monotherapy (500 to 2,250 mg every 12 h) received TPM at three escalating doses (from 100 to 200 to 400 mg every 12 h), each for 2 weeks. Thereafter, the VPA dose was tapered by 25% weekly. Blood and urine samples were collected over 12-h intervals during VPA monotherapy and at the end of each stage of TPM dose escalation and TPM monotherapy.
All patients reached TPM monotherapy, and nine achieved satisfactory seizure control for > or = 2 weeks without VPA. TPM plasma peak concentration (C(max)) and area under the concentration-versus-time curve during a 12-h dosing interval (AUC(0-12)) were slightly higher (17%; n = 8) during TPM monotherapy than during concomitant VPA therapy. TPM oral and renal clearances (n = 8) were 25.9 +/- 4.6 and 11.6 +/- 3.2 ml/min during TPM monotherapy and were 29.8 +/- 4.2 and 12.4 +/- 2.7 ml/min during VPA concomitant therapy. VPA AUC(0-12) decreased (11.3%; n = 10) with the addition of TPM 400 mg every 12 h. VPA oral clearance was 12.8 +/- 4.1 ml/min during monotherapy and was 13.8 +/- 4.0, 14.1 +/- 3.9, and 14.5 +/- 5.2 ml/min during coadministration of TPM 100, 200, and 400 mg every 12 h, respectively. Cognitive dysfunction, observed in some patients receiving high doses of VPA with TPM, reversed or improved with VPA dose reduction and discontinuation. The lower-than-normal prestudy platelet count measured in one patient increased to normal levels when VPA was discontinued.
Because changes in TPM and VPA pharmacokinetics were small, it is unlikely that their concomitant use will have a significant impact on the clinical condition of the patient.
比较丙戊酸盐（VPA）单药治疗、VPA与托吡酯（TPM）联合治疗以及TPM单药治疗期间VPA和TPM的稳态药代动力学，以评估药代动力学相互作用。
在为期3周的基线期后，12例接受VPA单药治疗（每12小时500至2250毫克）的患者接受了三个递增剂量的TPM（每12小时从100毫克增至200毫克再增至400毫克），每个剂量治疗2周。此后，VPA剂量每周递减25%。在VPA单药治疗期间以及TPM剂量递增的每个阶段结束时和TPM单药治疗结束时，每隔12小时采集血液和尿液样本。
所有患者均进入TPM单药治疗阶段，9例患者在不使用VPA的情况下实现了≥2周的满意癫痫控制。TPM单药治疗期间的血浆峰浓度（C(max)）和12小时给药间隔内的浓度-时间曲线下面积（AUC(0-12)）比VPA联合治疗期间略高（17%；n = 8）。TPM单药治疗期间的口服清除率和肾清除率（n = 8）分别为25.9±4.6和11.6±3.2毫升/分钟，VPA联合治疗期间分别为29.8±4.2和12.4±2.7毫升/分钟。每12小时加用400毫克TPM后，VPA的AUC(0-12)降低（11.3%；n = 10）。VPA单药治疗期间的口服清除率为12.8±4.1毫升/分钟，在每12小时联合使用100毫克、200毫克和400毫克TPM时，分别为13.8±4.0、14.1±3.9和14.5±5.2毫升/分钟。在一些接受高剂量VPA联合TPM治疗的患者中观察到的认知功能障碍，随着VPA剂量的减少和停用而逆转或改善。一名患者在研究前测得的血小板计数低于正常水平，在停用VPA后升至正常水平。
由于TPM和VPA的药代动力学变化较小，它们联合使用不太可能对患者的临床状况产生重大影响。
