Battino Dina, Croci Danilo, Rossini Alessandro, Messina Sara, Mamoli Daniela, Perucca Emilio
Carlo Besta National Neurological Institute, Milan, Italy.
Clin Pharmacokinet. 2005;44(4):407-16. doi: 10.2165/00003088-200544040-00005.
To compare the steady-state pharmacokinetics of topiramate in a large population of children and adults with epilepsy in a therapeutic drug monitoring setting.
Retrospective, case-matched pharmacokinetic evaluation.
Seventy children (aged 1-17 years) with epilepsy and 70 adult controls (aged 18-65 years) with epilepsy, matched for sex and comedication.
Topiramate apparent oral clearance (CL/F) values were calculated from steady-state serum concentrations in children and compared with those determined in controls. Comparisons were made by means of the Mann-Whitney's U-test, or the Kruskal-Wallis test in the case of multiple comparisons. A linear regression model was used to assess potential correlation of CL/F values with age. To investigate the influence of different variables on the variability in topiramate CL/F values, a multiple regression model was developed.
In the absence of enzyme-inducing comedication, mean topiramate CL/F was 42% higher in children than in adults (40.3 +/- 21.0 vs 28.4 +/- 15.3 mL/h/kg; p < 0.01). In children and adults comedicated with enzyme-inducing antiepileptic drugs (AEDs), topiramate CL/F values were approximately 1.5- to 2-fold higher than those observed in the absence of enzyme inducers, and the elevation in topiramate CL/F in children compared with adults was also present in the subgroups receiving enzyme inducers (66%; 76.6 +/- 35.1 vs 46.1 +/- 16.7 mL/h/kg; p < 0.0001). In the paediatric population, a negative correlation between CL/F and age was demonstrated, both in the absence (p < 0.01) and in the presence (p < 0.001) of enzyme induction. The independent influence of age and enzyme-inducing AEDs on topiramate CL/F was confirmed by multiple regression analysis.
Topiramate CL/F is highest in young children and decreases progressively with age until puberty, presumably due to age-dependent changes in the rate of drug metabolism. As a result of this, younger patients require higher dosages to achieve serum topiramate concentrations comparable with those found in older children and adults. Enzyme-inducing comedication decreases serum topiramate concentration by approximately one-half and one-third in children and adults, respectively.
在治疗药物监测环境中，比较托吡酯在大量癫痫儿童和成人中的稳态药代动力学。
回顾性、病例匹配的药代动力学评估。
70例癫痫儿童（年龄1 - 17岁）和70例癫痫成人对照（年龄18 - 65岁），按性别和合并用药情况匹配。
根据儿童稳态血清浓度计算托吡酯的表观口服清除率（CL/F）值，并与对照组中测定的值进行比较。通过Mann-Whitney U检验进行比较，对于多重比较则采用Kruskal-Wallis检验。使用线性回归模型评估CL/F值与年龄的潜在相关性。为研究不同变量对托吡酯CL/F值变异性的影响，建立了多元回归模型。
在未使用酶诱导性合并用药的情况下，儿童托吡酯的平均CL/F比成人高42%（40.3±21.0 vs 28.4±15.3 mL/h/kg；p < 0.01）。在使用酶诱导性抗癫痫药物（AEDs）的儿童和成人中，托吡酯的CL/F值比未使用酶诱导剂时观察到的值高约1.5至2倍，并且在接受酶诱导剂的亚组中，儿童与成人相比托吡酯CL/F的升高也存在（66%；76.6±35.1 vs 46.1±16.7 mL/h/kg；p < 0.0001）。在儿科人群中，无论是否存在酶诱导作用，CL/F与年龄之间均显示出负相关（无酶诱导时p < 0.01，有酶诱导时p < 0.001）。多元回归分析证实了年龄和酶诱导性AEDs对托吡酯CL/F的独立影响。
托吡酯的CL/F在幼儿中最高，并随着年龄增长逐渐下降直至青春期，这可能是由于药物代谢速率随年龄变化所致。因此，较年轻的患者需要更高的剂量才能达到与较大儿童和成人相当的血清托吡酯浓度。酶诱导性合并用药分别使儿童和成人的血清托吡酯浓度降低约二分之一和三分之一。
