Sachdeo R C, Sachdeo S K, Walker S A, Kramer L D, Nayak R K, Doose D R
University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick 08903-0019, USA.
Epilepsia. 1996 Aug;37(8):774-80. doi: 10.1111/j.1528-1157.1996.tb00651.x.
We studied the steady-state pharmacokinetic profile of topiramate (TPM) as a function of dose and the effects of comedication with carbamazepine (CBZ).
We enrolled 12 patients with partial epilepsy receiving chronic stable doses of CBZ 300-800 mg every 8 h. In a 6-week period, TPM was added and doses were increased at approximately 2-week intervals from 100 to 200 to 400 mg every 12 h and stabilized at the highest tolerated dose to as high as 400 mg every 12 h. CBZ was tapered in the next 4 weeks when possible, and TPM was maintained as monotherapy at the highest stabilized dose for 2 more weeks. Plasma and urine samples were collected before TPM dosing, after each TPM dose increase, and during TPM monotherapy.
Dose-normalized results (n = 10) for TPM area under the curve from 0 to 12 h (AUC(0-12)), Cmin(0), and Cavg indicated that TPM exhibits linear plasma pharmacokinetics over the dose range of 100- to 400-mg every 12 h when administered with CBZ. Mean TPM AUC(0-12), Cmax, Cmin(0), and Cavg values were approximately 40% lower during CBZ treatment as compared with those during TPM monotherapy (n = 3). TPM oral and nonrenal clearance rates were approximately two- to threefold higher, whereas TPM renal clearance was unchanged during concomitant CBZ treatment (n = 3). There were no significant changes in total and unbound CBZ and CBZ-epoxide (CBZ-E) pharmacokinetics during TPM administration (n = 10). TPM pharmacokinetics during concomitant CBZ treatment were significantly different from those during TPM monotherapy, suggesting that metabolic clearance of TPM increases when CBZ is coadministered.
When CBZ is reduced or discontinued, TPM doses may need to be lowered to maintain equivalent plasma concentrations. Adjusting the CBZ dose for pharmacokinetic reasons when TPM is administered as adjunctive treatment does not appear to be necessary.
我们研究了托吡酯（TPM）的稳态药代动力学特征与剂量的关系以及与卡马西平（CBZ）联合用药的影响。
我们纳入了12例接受每8小时300 - 800毫克慢性稳定剂量CBZ治疗的部分性癫痫患者。在6周的时间里，添加TPM，并以大约2周的间隔将剂量从每12小时100毫克增加到200毫克再到400毫克，并在最高耐受剂量下稳定至每12小时高达400毫克。在接下来的4周内尽可能逐渐减少CBZ剂量，TPM则以最高稳定剂量作为单一疗法维持2周。在TPM给药前、每次TPM剂量增加后以及TPM单一疗法期间采集血浆和尿液样本。
TPM在0至12小时曲线下面积（AUC(0 - 12)）、Cmin(0)和Cavg的剂量标准化结果（n = 10）表明，当与CBZ联合给药时，TPM在每12小时100至400毫克的剂量范围内呈现线性血浆药代动力学特征。与TPM单一疗法期间（n = 3）相比，CBZ治疗期间TPM的平均AUC(0 - 12)、Cmax、Cmin(0)和Cavg值大约低40%。在联合使用CBZ治疗期间，TPM的口服和非肾清除率大约高出两到三倍，而TPM的肾清除率未发生变化（n = 3）。在TPM给药期间，总CBZ和未结合CBZ以及CBZ - 环氧化物（CBZ - E）的药代动力学没有显著变化（n = 10）。联合使用CBZ治疗期间TPM的药代动力学与TPM单一疗法期间显著不同，这表明联合使用CBZ时TPM的代谢清除增加。
当减少或停用CBZ时，可能需要降低TPM剂量以维持等效的血浆浓度。当TPM作为辅助治疗给药时，出于药代动力学原因调整CBZ剂量似乎没有必要。
