甲氨蝶呤延迟消除的急性淋巴细胞白血病患儿的群体药动学研究

Population Pharmacokinetics of Delayed Methotrexate Elimination in Children with Acute Lymphoblastic Leukemia

目的建立符合甲氨蝶呤延迟消除的急性淋巴细胞白血病患儿的群体药动学模型,以定量探寻导致延迟消除的危险因素,取得模型群体特征。方法纳入147例甲氨蝶呤延迟消除的患儿,收集不同时间共606个稀疏血药浓度数据和临床资料,随机分成模型组和验证组。采用NLME软件进行模型拟合和群体参数的计算,考察协变量对甲氨蝶呤药动学相关参数的影响。采用拟合优度、Bootstrap内部验证及外部验证对最终模型进行评价。结果最终模型采用二房室模型拟合,患儿是否呕吐以及合并使用肾毒性药物显著影响外周室表观分布容积,而碱化量显著影响中央室清除率,水化量显著影响外周室清除率。中央室和外周室表观分布容积分别为51.16 L·m^(-2)(RSE=3.87%)和18.63 L·m^(-2)(RSE=5.73%),中央室和外周室清除率的群体典型值分别为9.62L·m^(-2)·h^(-1)(RSE=3.38%)和0.75 L·m^(-2)·h^(-1) (RSE=2.54%)。结论所建立的甲氨蝶呤延迟消除的急性淋巴细胞白血病患儿的群体药动学模型,可以较好地体现该特殊群体的群体特征。

OBJECTIVE To establish the population pharmacokinetics of delayed methotrexate elimination in children with acute lymphoblastic leukemia, and to quantitatively explore the risk factors on delayed elimination for population characteristics. METHODS A total of 606 sparse plasma concentrations and clinical data from 147 cases of acute lymphoblastic leukemia children with delayed methotrexate were included and randomly divided into model group and verification group. Model fitting and population parameters were calculated by using NLME software. The effects of covariates on methotrexate pharmacokinetic parameters were examined. The final model was evaluated and verified by using goodness of fit, Bootstrapping, and external validation. RESULTS The final model was fitted by a two-compartment model. Vomiting and combined use of nephrotoxic drugs were significant covariates on the apparent volume of distribution of the peripheral compartment, while the amount of alkalization significantly affected the clearance of the central compartment, and the amount of hydration significantly affected the clearance of the peripheral compartment(P<0.05). The population pharmacokinetics parameters were the apparent volume of distribution and the clearance of the central compartment and the peripheral compartment with values of 51.16 L·m-2(RSE=3.87%), 18.63 L·m-2(RSE=5.73%), 9.62 L·m-2·h-1(RSE=3.38%), 0.75 L·m-2·h-1(RSE=2.54%). CONCLUSION A population pharmacokinetic model of delayed methotrexate elimination in children with acute lymphoblastic leukemia is successfully established, which can provide a reference for individualized treatment.