Contin Manuela, Riva Roberto, Albani Fiorenzo, Avoni Patrizia, Baruzzi Agostino
Laboratory of Clinical Neuropharmacology, Department of Neurological Sciences, University of Bologna, Via Foscolo 7, 40123 Bologna, Italy.
Ther Drug Monit. 2002 Jun;24(3):332-7. doi: 10.1097/00007691-200206000-00002.
The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new antiepileptic drug (AED) topiramate and the potential relation between topiramate plasma levels and side effects in a cohort of 116 patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two subgroups, otherwise comparable for age and weight-adjusted daily dose of topiramate. Group A (n = 73) received topiramate plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin. Group B (n = 43) received topiramate plus AEDs without inducing properties of CYP metabolism (namely valproic acid and lamotrigine). Weight-normalized topiramate clearance values, calculated as dosing rate/steady-state plasma drug concentration, were about 1.5-fold in patients receiving AED inducers compared with patients receiving AED noninducers. Topiramate plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 25 to 800 mg/d, although, at a given daily dose, a large interpatient variability was observed in matched plasma drug concentrations within each group of patients. Thirty-nine patients (34%) reported side effects associated with topiramate, mostly central nervous system effects. No consistent relation was observed between topiramate plasma concentrations and adverse effects, either in the cohort of patients as a whole or within each subgroup. From a clinical point of view, patients receiving concurrent treatment with enzyme-inducing AEDs can show twofold lower topiramate plasma concentrations compared with patients receiving valproic acid or lamotrigine, and appropriate topiramate dosage adjustments may be required when concomitant AED inducers are either added or withdrawn. Due to the observed variability in topiramate metabolic variables and the complex spectrum of possible pharmacokinetic and pharmacodynamic interactions with the most commonly coprescribed AEDs, monitoring of plasma topiramate concentrations may help the physician in the pharmacokinetic optimization of the drug dosage schedule in individual patients.
作者评估了在116例癫痫患者队列中，联合抗癫痫治疗对新型抗癫痫药物（AED）托吡酯稳态血药浓度的影响，以及托吡酯血药浓度与副作用之间的潜在关系。根据联合使用的AED，患者被分为两个亚组，这两组在年龄和托吡酯体重调整日剂量方面具有可比性。A组（n = 73）接受托吡酯加细胞色素P450（CYP）代谢的AED诱导剂，如卡马西平、苯巴比妥和苯妥英。B组（n = 43）接受托吡酯加无CYP代谢诱导特性的AED（即丙戊酸和拉莫三嗪）。以给药速率/稳态血药浓度计算的体重标准化托吡酯清除率值，接受AED诱导剂的患者约为接受AED非诱导剂患者的1.5倍。在25至800mg/d的剂量范围内，无论联合AED治疗如何，托吡酯血药浓度与每日药物剂量呈线性相关，尽管在给定的每日剂量下，每组患者的匹配血药浓度中观察到较大的患者间变异性。39例患者（34%）报告了与托吡酯相关的副作用，主要是中枢神经系统效应。在整个患者队列或每个亚组中，均未观察到托吡酯血药浓度与不良反应之间的一致关系。从临床角度来看，与接受丙戊酸或拉莫三嗪的患者相比，接受酶诱导AED联合治疗的患者托吡酯血药浓度可能低两倍，当添加或停用联合AED诱导剂时，可能需要适当调整托吡酯剂量。由于观察到托吡酯代谢变量的变异性以及与最常用的联合使用AED可能存在的复杂药代动力学和药效学相互作用谱，监测托吡酯血药浓度可能有助于医生对个体患者的药物剂量方案进行药代动力学优化。
