Di Paolo Antonello, Danesi Romano, Vannozzi Francesca, Falcone Alfredo, Mini Enrico, Cionini Luca, Ibrahim Toni, Amadori Dino, Del Tacca Mario
Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Italy.
Clin Pharmacol Ther. 2002 Dec;72(6):627-37. doi: 10.1067/mcp.2002.128867.
Administration of 5-fluorouracil may be associated with life-threatening toxicities, resulting from a reduced drug biotransformation to the inactive metabolite 5-fluoro-5,6-dihydrouracil. Patients with severe toxicities display significant alterations of 5-fluorouracil pharmacokinetics, the monitoring of which may be made easier by the availability of a limited sampling model (LSM).
LSMs for 5-fluorouracil and 5-fluoro-5,6-dihydrouracil therapeutic monitoring have been developed in 80 patients with colorectal cancer (training set) given 5-fluorouracil, 370 mg/m(2) per day as an intravenous bolus, plus leucovorin, 100 mg/m(2) per day, for 5 days every 4 weeks. Pharmacokinetic analysis was performed on plasma levels of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil obtained on day 1 of the first cycle of chemotherapy, and backward stepwise regression analysis was used to determine the optimal LSM on the basis of bias (percentage mean prediction error [MPE]) and precision (percentage root mean square prediction error [RMSE]).
An optimal model based on 2 time points was obtained (percentage MPE = 1.99% +/- 1.41%; percentage RMSE = 12.70% +/- 1.27%), and the predicted area under the time versus plasma concentration curve (AUC) was calculated as follows: predicted AUC (h x microg/mL) = 0.119 x C(5) + 1.436 x C(45) + 2.066, in which C(5) and C(45) are plasma concentrations of 5-fluorouracil at 5 and 45 minutes after drug administration, respectively. The application of this algorithm to pharmacokinetic analysis of plasma levels of 5-fluorouracil in 80 patients (test set) allowed a precise estimation of AUC (percentage MPE = -0.09% +/- 1.37%; percentage RMSE = 12.17% +/- 1.23%). The best LSM for 5-fluoro-5,6-dihydrouracil was characterized by a percentage MPE of -0.64% +/- 0.86% and a percentage RMSE of 7.64% +/- 0.81%, and the optimal sampling time points were 45 and 180 minutes.
The current LSM allows a reliable assessment of drug exposure and improves the use of therapeutic drug monitoring for treatment optimization of 5-fluorouracil in patients with cancer.
5-氟尿嘧啶的给药可能会导致危及生命的毒性反应，这是由于药物向无活性代谢物5-氟-5,6-二氢尿嘧啶的生物转化减少所致。发生严重毒性反应的患者会出现5-氟尿嘧啶药代动力学的显著改变，而有限采样模型（LSM）的应用可能会使5-氟尿嘧啶药代动力学的监测变得更加容易。
已在80例接受5-氟尿嘧啶治疗的结直肠癌患者（训练集）中建立了用于5-氟尿嘧啶和5-氟-5,6-二氢尿嘧啶治疗监测的LSM。患者接受5-氟尿嘧啶，每日370mg/m²静脉推注，加亚叶酸，每日100mg/m²，每4周给药5天。在化疗第一个周期的第1天对所获得的5-氟尿嘧啶和5-氟-5,6-二氢尿嘧啶的血浆水平进行药代动力学分析，并采用向后逐步回归分析，根据偏倚（平均预测误差百分比[MPE]）和精密度（均方根预测误差百分比[RMSE]）确定最佳LSM。
获得了基于2个时间点的最佳模型（MPE百分比=1.99%±1.41%；RMSE百分比=12.70%±1.27%），时间-血浆浓度曲线下的预测面积（AUC）计算如下：预测AUC（h×μg/mL）=0.119×C(5)+1.436×C(45)+2.066，其中C(5)和C(45)分别是给药后5分钟和45分钟时5-氟尿嘧啶的血浆浓度。将该算法应用于80例患者（测试集）的5-氟尿嘧啶血浆水平药代动力学分析，能够精确估计AUC（MPE百分比=-0.09%±1.37%；RMSE百分比=12.17%±1.23%）。5-氟-5,6-二氢尿嘧啶的最佳LSM的特征为MPE百分比为-0.64%±0.86%，RMSE百分比为7.64%±0.81%，最佳采样时间点为45分钟和180分钟。
当前的LSM能够可靠地评估药物暴露情况，并改善治疗药物监测在癌症患者5-氟尿嘧啶治疗优化中的应用。
