Chabot G G
Laboratory of Pharmacotoxicology and Pharmacogenetics (URA 147 CNRS), Gustave-Roussy Institute, Villejuif, France.
Cancer Chemother Pharmacol. 1995;36(6):463-72. doi: 10.1007/BF00685795.
Irinotecan (CPT-11) is a novel topoisomerase I inhibitor with clinical activity in human malignancies. The objective of this study was to develop efficient limited sampling models (LSMs) to estimate simulataneously the area under the plasma concentration versus time curves (AUC) for both CPT-11 and its active metabolite SN-38. A total of 64 pharmacokinetic sets (> or = 24-h sampling) were obtained in phase I studies at doses ranging from 50 to 750 mg/m2 (0.5-h i.v. infusion). The patients were randomly assigned to a training data set (n = 32) and a test set (n = 32). Multiple linear regression analyses were used to determine the optimal LSMs based on the correlation coefficient (r), bias (MPE%, percentage of mean prediction error), and precision (RMSE%, percentage of root mean squared prediction error). Of these LSMs, the ones including maximal concentrations of CPT-11 (0.5 h, the end of the i.v. infusion) and metabolite SN-38 (approximately 1 h) were favored along with predictive precision and clinical constraints. Several bivariate models including a 6-h time point as the last sampling time (or 7 h) were found to be highly predictive of either the CPT-11 AUC or the SN-38 AUC. The chosen sampling time points were the ones that allowed the best compromise between the accurate determination of either compound alone with the same sampling times. The simultaneously best prediction of both CPT-11 and SN-38 AUCs was obtained with sampling time points harvested at 0.5, 1, and 6 h (or 7 h). With these sampling time points a trivariate model was selected for the determination of CPT-11 AUC namely, CPT-11 AUC (ng h ml-1) = 0.820 x C0.5h + 0.402 x C1h + 15.47 x C6h + 928, and a corresponding model was selected for the determination of metabolite AUC, i.e., SN-38 AUC (ng h ml-1) = 4.05 x C0.5h -0.81 x C1h + 23.01 x C6h - 69.78, where C(t) is the concentration in nanograms per milliliter of either compound at a given time t. These models performed well with the test data sets for CPT-11 AUC (r = 0.98, MPE% = -1.4, RMSE% = 13.9) and for SN-38 AUC (r = 0.95, MPE% = -6.5, RMSE% = 37.7). In addition to the determination of AUCs (and hence clearance), these models also allow the determination of the maximal concentrations of both compounds, which might be needed for pharmacodynamics studies.(ABSTRACT TRUNCATED AT 400 WORDS)
伊立替康（CPT-11）是一种新型拓扑异构酶I抑制剂，对人类恶性肿瘤具有临床活性。本研究的目的是建立有效的有限采样模型（LSM），以同时估算CPT-11及其活性代谢产物SN-38的血浆浓度-时间曲线下面积（AUC）。在I期研究中，以50至750mg/m²的剂量（0.5小时静脉输注）共获得了64组药代动力学数据（采样时间≥24小时）。患者被随机分为训练数据集（n = 32）和测试数据集（n = 32）。基于相关系数（r）、偏差（MPE%，平均预测误差百分比）和精密度（RMSE%，均方根预测误差百分比），采用多元线性回归分析来确定最佳LSM。在这些LSM中，包括CPT-11（0.5小时，静脉输注结束时）和代谢产物SN-38（约1小时）的最大浓度的模型，因其预测精度和临床限制而受到青睐。发现几个以6小时时间点作为最后采样时间（或7小时）的双变量模型对CPT-11 AUC或SN-38 AUC具有高度预测性。所选的采样时间点是在相同采样时间下，能在单独准确测定任一化合物之间实现最佳折衷的时间点。在0.5、1和6小时（或7小时）采集的采样时间点，能同时对CPT-11和SN-38的AUC进行最佳预测。利用这些采样时间点，选择了一个三变量模型来测定CPT-11 AUC，即CPT-11 AUC（ng h ml⁻¹）= 0.820×C0.5h + 0.402×C1h + 15.47×C6h + 928，以及一个相应的模型来测定代谢产物AUC，即SN-38 AUC（ng h ml⁻¹）= 4.05×C0.5h - 0.81×C1h + 23.01×C6h - 69.78，其中C(t)是给定时间t时任一化合物每毫升的纳克浓度。这些模型在CPT-11 AUC（r = 0.98，MPE% = -1.4，RMSE% = 13.9）和SN-38 AUC（r = 0.95，MPE% = -6.5，RMSE% = 37.7）的测试数据集中表现良好。除了测定AUC（从而确定清除率）外，这些模型还能确定两种化合物的最大浓度，这可能是药效学研究所需的。（摘要截断于400字）
