骨肉瘤术前应用大剂量甲氨蝶呤化疗的药代动力学及临床分析

目的分析骨肉瘤患者术前应用大剂量甲氨蝶呤(HDMTX)化疗中药代动力学及临床疗效和不良反应。方法32例骨肉瘤患者术前应用大剂量HDMTX共37次化疗。HDMTX化疗方案:第1天水化碱化;第2天甲氨蝶呤8~12 g/m2静脉点滴,6~8 h后开始甲酰四氢叶酸钙9~15 mg肌肉注射。同时行MTX的血药浓度监测。第3天水化碱化。分别于MTX全部滴注后0、1、6、12、24、48及72 h采血,测量MTX的血药浓度。观察无瘤生存时间,MR I改变和不良反应。所得MTX血药浓度数据按照非房室模型进行药代动力学分析。结果AUC(药时曲线下面积)为(4 853.53±1 581.53)μmol/(L.h-1),Cm ax(最高血药浓度)为(947.79±333.45)μmol/L。EFS(无瘤生存时间)为(41.47±16.07)月,与AUC有明显相关性,与Cm ax无明显相关性。AUC<4 000μmol/(L.h-1)的EFS与AUC>4 000μmol/(L.h-1)的EFS生存率之间差异有统计学意义。32例中有11例出现白细胞下降,其AUC均值显著高于无白细胞下降者;4例出现化疗后肝功损害,1例出现口腔溃疡。结论在HDMTX化疗中,AUC可以作为一个预计远期和近期疗效的药代动力学指标,AUC>4 000μmol/(L.h-1)可以作为一个指导标准。白细胞的下降与较高的药时曲线下面积和最大药物浓度有关。

The Pharmacokinetics of High-dose Chemotherapy with Presperative Methotrexate for Osteosarcoma and the Clinical Analysis

Objective To evaluate the pharmacokinetics and clinical results in preoperative osteosarcoma patients with HDMTX chemotherapy.Methods The methotrexate pharmacokinetics of 32 osteosarcoma patients who were treated with 37 courses of preoperative HDMTX chemotherapy were analyzed.Chemotherapy protocol: all patients received HDMTX(at the dose of 8～12 g/m²) intravenously with folinic acid rescue(at the dose of 9～15 mg).Patients received hydration and alkalinization fluids starting 24 hr before the MTX administration and continuing 24 hrs after HDMTX administration was completed.Serial blood samples were obtained at 0,1,6,12,24,48 and 72 hours after the MTX infusion.The serum MTX concentrations were measured subsequently.The MTX data were treated with NCA(non-compartment analysis) model.The event free survival time(EFS),change of MR image and the adverse effects of the patients were recorded.Results AUC=4 853.53±1581.53 μmol/(L·h^-1),Cmax=947.79±333.45 μmol/(L·h^-1),EFS=(41.47±16.07)month.EFS has a close correlation with AUC and has none close correlation with the Cmax.Significant differences were detected in EFS considering the AUC of 4 000 μmol/(L·h^-1) as the cut-off point.According to the change of MRI,the cases are divided into two groups: good response group and poor response group,their AUCs and Cmaxs had significant differences.Eleven cases demonstrate marrow inhibition and their AUCs were significantly difference from those without.Four cases demonstrated hepatic impairment.One case complicated oral ulcer.Conclusion AUC has close correlations with the short and long term clinical results.AUC>4000 μmol/(L·h^-1) can be a criterion.Marrow inhibition is related to higher AUC or Cmax.