大剂量甲氨蝶呤消除相末端药时曲线下面积的相关因素分析

目的：研究大剂量甲氨蝶呤（HD-MTX）治疗儿童急性淋巴细胞白血病后其消除相末端的药时曲线下面积（AUC_48-∞）与患儿病理生理因素的相关性，探讨AUC_48-∞与化疗中发生严重不良反应的关系，为临床治疗提供依据。方法：采用回顾性调查方法在某院收集2014年4月至2015年5月急性淋巴细胞白血病患儿使用大剂量MTX化疗的病历资料，记录患儿的年龄、身高、体质量、性别、病程、MTX剂量、亚叶酸钙（CF）解救剂量、水化量、碱化量、血药浓度及相应的生化检验值等数据，观察给药后不良反应并进行评级，计算AUC_48-∞并应用SPSS19.0统计软件对数据进行多元线性回归分析，绘制ROC曲线以评估AUC_48-∞、C_{48 h}和C_{72 h}对于严重不良反应的预测效力。结果：MTX的AUC_48-∞与血清肌酐（CRE）、γ-谷氨酰胺转肽酶（γ-GT）及合并使用奥美拉唑之间存在明显正相关性（P<0.05），以AUC_48-∞作为预测因子绘制的ROC曲线下面积（95% CI）为0.819（0.734~0.904），具有诊断意义（P<0.001），且AUC_48-∞对严重不良反应的预测灵敏度比C_{48 h}、C_{72 h}更高。结论：AUC_48-∞可能对HD-MTX化疗中严重不良反应的发生有较好的预测效力，当化疗期间患儿出现γ-GT、CRE值升高或联用奥美拉唑时临床医师需加以重视并采取相应措施。

Analysis of correlation factors on AUC at terminal elimination phase of high dose methotrexate

OBJECTIVE To study correlation between AUC of high dose methotrexate (HD-MTX) at terminal elimination phase (AUC_48-∞) and pathological and physiological factors of children with acute lymphoblastic leukemia (ALL), investigate relationship between AUC_48-∞ and severe adverse events during HD-MTX chemotherapy and provide basis for clinical treatment.METHODS Medical records of pediatric ALL patients hospitalized between April 2014 and May 2015 and treated with high dose MTX were reviewed retrospectively for records of patient age, height, body weight, sex, course of disease, dosage of MTX and calcium folinate (CF), hydration volume, alkalization volume, serum drug concentration and corresponding biochemical indexes etc. Adverse events after HD-MTX administration were observed and graded. AUC_48-∞ of MTX was calculated and data were analyzed with multiple linear regression method by SPSS (19.0) software. Receiver operating characteristic (ROC) curves were drawn to evaluate predictive capacity of AUC_48-∞, C_{48 h}and C_{72 h}.RESULTS AUC_48-∞ of MTX was positively correlated with CRE, γ-GT and combination with omeprazole (P<0.05). With AUC_48-∞ as the predictor, area under ROC (95% confidence interval) was 0.819 (0.734-0.904), and AUC_48-∞ could predict better than C_{48 h} and C_{72 h}.CONCLUSION AUC_48-∞ may be a good predictor of severe adverse events during HD-MTX chemotherapy. Clinician should be careful and take appropriate measures when value of γ-GT or CRE rises or omeprazole is combined during the therapy.