Egorin M J, Forrest A, Belani C P, Ratain M J, Abrams J S, Van Echo D A
Division of Developmental Therapeutics, University of Maryland Cancer Center, Baltimore, Maryland 21201.
Cancer Res. 1989 Jun 1;49(11):3129-33.
A limited sampling strategy was developed to estimate the total area under the curve of plasma cyclophosphamide concentrations versus time (AUC). The strategy was developed with a training set consisting of 29 pharmacokinetic studies in 16 patients who received 1-h i.v. infusions of cyclophosphamide at a dosage of 1000 mg/m2. The strategy was developed by applying stepwise forward multiple regression analysis to cyclophosphamide concentrations observed at each time in the training set (independent variables) versus the AUC (dependent variable). It was confirmed by applying stepwise backward elimination regression analysis to the same data set. The final sampling strategy, which utilized three time points, was: AUC = 40.18C24 + 8.79C4 + 0.83C1 - 28 (dosage/1000), where C24, C4, and C1 represent plasma cyclophosphamide concentrations at 24, 4, and 1 h, respectively, and the dosage is in mg/m2 (r = 0.98). The strategy was validated prospectively with a test data set consisting of 14 pharmacokinetic studies in 11 patients who received 1-h i.v. infusions of cyclophosphamide at dosages of 300, 600, or 1200 mg/m2. The strategy proved highly predictive, with correlation coefficient between predicted and actual AUC of 0.94. The strategy also proved unbiased, with mean percentage of error (+/- SE) of 3.3 +/- 3.6%, and precise, with mean absolute percentage of error of 9.3 +/- 2.7%. The sampling strategy developed is being used in a multiinstitution trial of cyclophosphamide in an effort to relate cyclophosphamide pharmacokinetics, as expressed by AUC, with the toxic or therapeutic pharmacodynamic responses of the drug.
已制定一种有限采样策略，用于估算血浆环磷酰胺浓度随时间变化的曲线下总面积（AUC）。该策略是根据一个训练集制定的，该训练集包含对16例患者进行的29项药代动力学研究，这些患者接受了剂量为1000mg/m²的环磷酰胺1小时静脉输注。通过对训练集中每个时间点观察到的环磷酰胺浓度（自变量）与AUC（因变量）应用逐步向前多元回归分析来制定该策略。通过对同一数据集应用逐步向后剔除法回归分析对其进行了验证。最终的采样策略使用三个时间点，即：AUC = 40.18C24 + 8.79C4 + 0.83C1 - 28（剂量/1000），其中C24、C4和C1分别代表24、4和1小时时的血浆环磷酰胺浓度，剂量单位为mg/m²（r = 0.98）。该策略通过一个测试数据集进行了前瞻性验证，该测试数据集包含对11例患者进行的14项药代动力学研究，这些患者接受了剂量为300、600或1200mg/m²的环磷酰胺1小时静脉输注。该策略具有高度预测性，预测AUC与实际AUC之间的相关系数为0.94。该策略还被证明无偏差，平均误差百分比（±SE）为3.3±3.6%，且精确，平均绝对误差百分比为9.3±2.7%。所制定的采样策略正在用于一项环磷酰胺的多机构试验中，以努力将以AUC表示的环磷酰胺药代动力学与该药物的毒性或治疗药效学反应联系起来。
