紫杉醇种属间药动学相关性的荟萃分析

Model-Based Meta-Analysis of Population Pharmacokinetic Models for Paclitaxel in Humans,Rats and Mice

目的应用基于模型化的荟萃分析的方法,建立紫杉醇种属间相关性的定量评价方法,为新药研发的种属间外推与剂量确定提供参考。方法以紫杉醇药动学为关键词,检索Pub-Med、中国知网(CNKI)、万方等数据库建库相关文献。按照纳入排除标准对检索文献进行筛选,并按种属进行分类,摘录每篇文献的血药浓度数据,应用非线性混合效应模型法(NONMEM)分别对人、大鼠、小鼠进行建模。采用正态化预测分布误差(normalized prediction distribution errors,NPDE)法对建立的模型进行验证,并依据相关生长规律法对药物种属间相关系数进行计算。结果通过非线性混合效应模型法法模型化,人、大鼠、小鼠的药动学行为均符合二室模型,与文献检索结果一致。正态化预测分布误差对最终模型结果进行可视化检验,模型结果准确可靠。依据相关生长规律法(allometric scaling)对3个种属的清除率CL和总表观分布容积Vtotal的相关系数进行计算,结果分别为r2=0.997 4和r2=0.937 2,种属间相关系数的线性关系良好。结论以紫杉醇为例,成功地建立了基于模型的Meta分析方法,能够定量的评价和预测种属间相关性。

OBJECTIVE To establish a quantitative method to evaluate the relationship on the PK parameters of paclitaxel among different species by using the model-based Meta-analysis, and provide a reference for species extrapolation and dose determination of new drug research and development. METHODS Relevant literatures were searched in Pub-Med, CNKI, WanFang and other data- bases, and all search results were filtrated with the criteria and classified according to species. Using NONMEM to construct the model for human, rats and mice, respectively. Evaluating the performance of the model with normalized prediction distribution errors （ NP- DE） , and calculating the correlation coefficient of species with allometric scaling method. RESULTS The nonlinear mixed-effects model （NONMEM） was developed to describe the paclitaxel PK profiles for mice, rats and humans. A two-compartment pharmacoki- netic model fitted the data well, and consistent with the reported results. The models were evaluated by NDPE, the final model was ac- curate and reliable. The allometric scaling of CL and V_total among three different species for paclitaxel was r^2 = 0. 997 4 and r^2 = 0. 937 2, respectively. CONCLUSION Take paelitaxel for example, established the model-based meta-analysis, successfully, and evaluated the correlation on the PK parameters of paclitaxel among different species quantitatively.