van Warmerdam L J, Verweij J, Rosing H, Schellens J H, Maes R A, Beijnen J H
Dept of Clinical Pharmacy, Slotervaart Hospital, Amsterdam, The Netherlands.
Ann Oncol. 1994 Mar;5(3):259-64. doi: 10.1093/oxfordjournals.annonc.a058804.
Limited sampling models for the estimation of the topotecan Area Under the concentration versus time Curve (AUC) and its lactone ring opened form (AUC Tm), from one or more plasma concentration determinations, are desired for further population-kinetic studies.
The models were developed and validated using 34 pharmacokinetic curves in 19 patients who participated in a phase I study.
A single point model was selected as optimal: AUC (mumol/L.min) = 499 (min).C2h (mumol/L) +0.85 (m2/mg.mumol/L.min).dose(mg/m2), and for topotecan-metabolite (Tm), AUC Tm (mumol/L.min) = 55.1 (min).CTm2h (mumol/L) -0.011 (m2/mg.mg.mumol/L.min).dose (mg/m2), where C2h is the plasma concentration (mumol/L) of topotecan at 2 h after the end of a 30-min infusion, and CTm2h the concentration of the opened form at the same time point. The models are valid for dosages ranging from 0.5 to 1.5 mg/m2/day and proved to be unbiased (MPE% = -1.8% and -9.3%, respectively) and precise (RMSE% = 17.9% and 22.7%, respectively). From the predicted AUCs, the clearance (Cl = dose (mumol)/AUC(mumol/L.min)) could also reliably be predicted, as well as the total AUC (AUC+AUC Tm) RMSE% = 17.1% and MPE% = -0.02%). Half-life values could not be predicted with acceptable precision and accuracy.
The limited sampling models presented may useful for future studies focused on pharmacokinetic/pharmacodynamic relationships of topotecan in large populations.
为进一步开展群体药代动力学研究，需要建立有限采样模型，通过一次或多次血浆浓度测定来估算拓扑替康的浓度-时间曲线下面积（AUC）及其开环形式（AUC Tm）。
使用参与一项I期研究的19例患者的34条药代动力学曲线建立并验证模型。
选择单点模型为最优模型：AUC（μmol/L·min）=499（min）·C2h（μmol/L）+0.85（m²/mg·μmol/L·min）·剂量（mg/m²），对于拓扑替康代谢物（Tm），AUC Tm（μmol/L·min）=55.1（min）·CTm2h（μmol/L）-0.011（m²/mg·mg·μmol/L·min）·剂量（mg/m²），其中C2h是30分钟输注结束后2小时拓扑替康的血浆浓度（μmol/L），CTm2h是同一时间点开环形式的浓度。这些模型在0.5至1.5mg/m²/天的剂量范围内有效，且被证明无偏倚（MPE%分别为-1.8%和-9.3%）且精确（RMSE%分别为17.9%和22.7%）。根据预测的AUC，也可以可靠地预测清除率（Cl = 剂量（μmol）/AUC（μmol/L·min））以及总AUC（AUC+AUC Tm）（RMSE% = 17.1%，MPE% = -0.02%）。半衰期值无法以可接受的精度和准确性进行预测。
所提出的有限采样模型可能对未来聚焦于大群体中拓扑替康药代动力学/药效学关系的研究有用。
