Minami H, Beijnen J H, Verweij J, Ratain M J
Department of Medicine, Committee on Clinical Pharmacology, and Cancer Research Center, University of Chicago, Chicago, Illinois 60637-1470, USA.
Clin Cancer Res. 1996 Jan;2(1):43-6.
Antitumor activity of topotecan, a new derivative of camptothecin, has been documented in many tumors. The active lactone form of topotecan is in equilibrium with the inactive hydroxyacid form. However, dose-limiting toxicity, neutropenia, is correlated to the area under the concentration time curve (AUC) of not only the lactone form but also total (lactone + hydroxyacid) topotecan. Because the determination of the total topotecan plasma concentration is technically much easier than the lactone, we sought to establish a limited sampling model for the AUC of total topotecan. Thirty-four pharmacokinetic profiles were obtained in 19 patients in a Phase I study of topotecan, which was infused over 30 min for 5 days. Multiple regression models predicting the AUC were developed using 17 profiles and validated using the rest of the data. The best model was: AUCpred (ng x h/ml) = 1.75 x C15m (ng/ml) + 11.2 x C6h (ng/ml) + 7.90 x dose (mg/m2), where AUCpred was the AUC predicted by the model, and C15m and C6h were the measured concentrations of total topotecan at 15 min and 6 h after the end of infusion, respectively. When this model was validated, it was unbiased (percentage of mean predicted error +/- SE, -1.0 +/- 3.3%) and precise (percentage of root mean square error, 11%). Because this model requires only two concentrations of total topotecan to estimate the AUC, it will be useful for further pharmacodynamic evaluation of topotecan in multi-institutional studies.
喜树碱的一种新衍生物拓扑替康的抗肿瘤活性已在多种肿瘤中得到证实。拓扑替康的活性内酯形式与无活性的羟基酸形式处于平衡状态。然而，剂量限制性毒性中性粒细胞减少不仅与内酯形式的浓度时间曲线下面积（AUC）相关，还与总拓扑替康（内酯+羟基酸）的AUC相关。由于测定总拓扑替康血浆浓度在技术上比测定内酯形式容易得多，我们试图建立一个总拓扑替康AUC的有限采样模型。在一项拓扑替康的I期研究中，对19名患者进行了34次药代动力学分析，拓扑替康在30分钟内输注，持续5天。使用17次分析结果建立了预测AUC的多元回归模型，并使用其余数据进行验证。最佳模型为：AUCpred（ng×h/ml）=1.75×C15m（ng/ml）+11.2×C6h（ng/ml）+7.90×剂量（mg/m2），其中AUCpred是模型预测的AUC，C15m和C6h分别是输注结束后15分钟和6小时时总拓扑替康的测定浓度。当对该模型进行验证时，它无偏倚（平均预测误差百分比±标准误差，-1.0±3.3%）且精确（均方根误差百分比，11%）。由于该模型仅需总拓扑替康的两个浓度来估算AUC，它将有助于在多机构研究中对拓扑替康进行进一步的药效学评估。
