Center for Pharmacology, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
Cancer Chemother Pharmacol. 2022 May;89(5):617-627. doi: 10.1007/s00280-022-04424-4. Epub 2022 Mar 30.
Although temozolomide is widely used in the treatment of childhood central nervous system (CNS) tumors, information on its pharmacokinetic profile in the brain or cerebrospinal fluid (CSF) is sparse. This study aimed at investigating whether measurable and clinically relevant concentrations of temozolomide are reached and maintained in CSF for continuous oral administration in pediatric patients. A population pharmacokinetic model was developed to quantify CSF penetration of temozolomide.
Eleven pediatric CNS tumor patients (aged 4-14 years) treated with oral temozolomide using a metronomic schedule (24-77 mg/m/day) were included. Temozolomide concentrations in 28 plasma samples and 64 CSF samples were analyzed by high-performance liquid chromatography. Population pharmacokinetic modeling and simulations were performed using non-linear mixed effects modeling (NONMEM 7.4.2).
Median temozolomide concentrations in plasma and CSF were 0.96 (range 0.24-5.99) µg/ml and 0.37 (0.06-1.76) µg/ml, respectively. A two-compartment model (central/plasma [1], CSF [2]) with first-order absorption, first-order elimination, and a transit compartment between CSF and plasma adequately described the data. Population mean estimates for clearance (CL) and the volume of distribution in the central compartment (V) were 3.29 L/h (95% confidence interval (CI) 2.58-3.95) and 10.5 L (8.17-14.32), respectively. Based on simulations, we found a median area under the concentration vs. time curve ratio (AUC / AUC ratio) of 37%.
Metronomic oral temozolomide penetrates into the CSF in pediatric patients, with even higher concentration levels compared to adults.
替莫唑胺在儿童中枢神经系统（CNS）肿瘤的治疗中被广泛应用，但关于其在脑或脑脊液（CSF）中的药代动力学特征的信息却很少。本研究旨在探讨连续口服替莫唑胺时，其在 CSF 中是否能够达到并维持可测量的、具有临床相关性的浓度。我们建立了一个群体药代动力学模型来量化替莫唑胺在 CSF 中的渗透情况。
纳入 11 例接受按节拍方案（24-77mg/m/天）口服替莫唑胺治疗的儿童 CNS 肿瘤患者（年龄 4-14 岁）。采用高效液相色谱法对 28 份血浆样本和 64 份 CSF 样本中的替莫唑胺浓度进行分析。采用非线性混合效应模型（NONMEM 7.4.2）进行群体药代动力学建模和模拟。
血浆和 CSF 中的替莫唑胺中位数浓度分别为 0.96（范围 0.24-5.99）µg/ml 和 0.37（0.06-1.76）µg/ml。一个两室模型（中央/血浆 [1]，CSF [2]），具有一级吸收、一级消除和 CSF 与血浆之间的转运室，能够很好地描述数据。群体平均估计的清除率（CL）和中央室分布容积（V）分别为 3.29 L/h（95%置信区间（CI）2.58-3.95）和 10.5 L（8.17-14.32）。基于模拟，我们发现浓度-时间曲线下面积比（AUC/AUC 比）的中位数为 37%。
节拍式口服替莫唑胺在儿科患者中渗透进入 CSF，其浓度水平甚至高于成人。
