应用群体药动学-药效学结合模型评估大剂量甲氨蝶呤化疗后的骨髓抑制

发布时间：2018-09-14 13:01

【摘要】：目的:建立群体药动学(PPK)-药效学(PD)模型评估大剂量甲氨蝶呤(HDMTX)化疗后的骨髓抑制效应,促进个体化用药。方法:收集144例急性淋巴细胞白血病(ALL)患儿行HDMTX化疗的临床资料。以MTX血清药物浓度作为药动学指标,化疗5 d后的白细胞计数减少率作为药效学指标,采用非线性混合效应建模法进行数据分析。药动学模型选用二房室开放式模型,药效学模型选用带效应室的SigmoidEmax模型。用拟合优度(goodness-of-fit)、自举法(Bootstrap)和正态化预测分布误差(NPDE)对最终模型的预测性能进行验证。结果:PPK-PD最终模型参数的群体典型值分别为:V_1(中央室分布容积)=15.46 L,V_2(周边室分布容积)=1.95 L,CL(表观清除率)=4.76 L·h~(-1),CL_2(周边室清除率)=0.11 L·h~(-1),k_(e0)(效应室消除速率常数)=0.003 6 h~(-1),EC50(达最大效应一半时效应室浓度)=0.87 mg·L~(-1),γ(陡度因子)=1.91,E_(max)(最大效应参数)=79.87%。化疗期间的总碱化量(碳酸氢钠)对MTX的表观清除率有显著影响。拟合优度、自举验证和NPDE结果表明,最终模型稳定,预测结果可靠。结论:本研究成功建立了用于评估HDMTX化疗后骨髓抑制程度的PPK-PD模型,可为临床优化给药方案提供帮助。
[Abstract]:Aim: to establish a colony pharmacokinetic (PPK)-pharmacodynamics (PD) model to evaluate the bone marrow suppression effect of high dose methotrexate (HDMTX) chemotherapy and to promote individualized drug use. Methods: the clinical data of 144 children with acute lymphoblastic leukemia (ALL) undergoing HDMTX chemotherapy were collected. The serum concentration of MTX was used as the pharmacokinetic index, and the leukocyte count reduction rate after 5 days of chemotherapy was used as the pharmacodynamics index. The data were analyzed by nonlinear mixed effect modeling method. The pharmacokinetic model was two-compartment open model and the pharmacodynamics model was SigmoidEmax model with effect chamber. The prediction performance of the final model is verified by goodness-of-fit, bootstrap (Bootstrap) and normal prediction distribution error (NPDE). Results the population typical values of the parameters of the final model of the: PPK-PD were as follows: VStub1 (Central Chamber Distribution Volume) / 15.46L / V / L (Peripheral Ventricular Distribution Volume) / 1.95L / L / L (apparent clearance) / 4.76L / h-1 / CL2 (peripheral ventricular clearance) / 0.11L / h-1 / (e0) (rate constant of elimination rate of the effect chamber) / 0.0036h-1 / EC50 Half-time effect chamber concentration) 0.87 mg L ~ (-1), 纬 (steepness factor) ~ (1.91) E _ (max) (maximum effect parameter) ~ (79.87). The total alkalinity (sodium bicarbonate) during chemotherapy had a significant effect on the apparent clearance of MTX. The results of goodness of fit, bootstrap verification and NPDE show that the final model is stable and the prediction results are reliable. Conclusion: this study successfully established a PPK-PD model for evaluating the degree of bone marrow suppression after HDMTX chemotherapy, which may be helpful for clinical optimization of drug administration.
【作者单位】：华中科技大学同济医学院附属武汉儿童医院药学部;华中科技大学同济医学院附属武汉儿童医院血液肿瘤科;
【基金】：国家自然基金青年基金资助项目(81600123) 湖北省卫生厅2011—2012年度科研项目(JX5B74)
【分类号】：R969

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