Institut für Pharmazeutische und Medizinische Chemie - Klinische Pharmazie-, Westfälische Wilhelms-Universität Münster, Germany.
Br J Haematol. 2010 Jan;148(1):119-25. doi: 10.1111/j.1365-2141.2009.07923.x. Epub 2009 Oct 11.
We analysed 1221 serum activity measurements in 168 children from the Berlin-Frankfürt-Münster acute lymphoblastic leukaemia studies, ALL-BFM (Berlin-Frankfürt-Münster) 95 and ALL-BFM REZ, in order to develop a pharmacokinetic model describing the activity-time course of pegylated (PEG)-asparaginase for all dose levels. Patients received 500, 750, 1000 or 2500 U/m(2) PEG-asparaginase on up to nine occasions. Serum samples were analysed for asparaginase activity and data analysis was done using nonlinear mixed effects modelling (NONMEM Vers. VI, Globomax, Hanouet, MD, USA). Different linear and nonlinear models were tested. The best model applicable to all dosing groups was a one-compartmental model with clearance (Cl) increasing with time according to the formula: Cl=Cl(i) *e((0.0793 *t)) where Cl(i) = initial clearance and t = time after dose. The parameters found were: volume of distribution (V) 1.02 +/- 26% l/m(2), Cl(i) 59.9 +/- 59% ml/d per m(2) (mean +/- interindividual variability). Interoccasion variability was substantial with 0.183 l/m(2) for V and 44.7 ml/d per m(2) for Cl, respectively. A subgroup of the patients showed a high clearance, probably due to the development of inactivating antibodies. This is the first model able to predict the activity-time course of PEG-asparaginase at different dosing levels and can therefore be used for developing new dosing regimens.
我们分析了来自柏林-法兰克福-明斯特儿童急性淋巴细胞白血病研究（ALL-BFM）95 和 ALL-BFM REZ 的 168 名儿童的 1221 份血清活性测量值，以开发一种描述聚乙二醇（PEG）-天冬酰胺酶活性随时间变化的药代动力学模型，适用于所有剂量水平。患者接受了多达 9 次 500、750、1000 或 2500 U/m²PEG-天冬酰胺酶的治疗。分析了血清样本中的天冬酰胺酶活性，并使用非线性混合效应建模（NONMEM Vers. VI，Globomax，Hanouet，MD，USA）进行数据分析。测试了不同的线性和非线性模型。适用于所有给药组的最佳模型是一个具有清除率（Cl）随时间增加的单室模型，根据公式：Cl=Cl(i) *e((0.0793 *t))，其中 Cl(i) =初始清除率，t =给药后时间。发现的参数为：分布容积（V）为 1.02 +/- 26% l/m²，初始清除率 Cl(i)为 59.9 +/- 59% ml/d per m²（平均值 +/- 个体间变异性）。变异性较大，V 为 0.183 l/m²，Cl 为 44.7 ml/d per m²。一部分患者的清除率较高，可能是由于产生了失活抗体。这是第一个能够预测不同剂量水平下 PEG-天冬酰胺酶活性随时间变化的模型，因此可用于开发新的给药方案。
