统计学在临床前药物毒理学安全性评价中的应用

Application of the Statistical Methods in Toxicology Studies of Preclinical Safety Evaluation of Drugs

目的:介绍临床前药物毒理学安全性评价一般毒理学、遗传毒理学、生殖毒性实验、安全药理学和致癌性实验中的数据分析的统计学方法。方法:本文简要介绍了一般毒理实验、遗传毒理实验、生殖毒性实验、安全药理和致癌性实验的实验设计、动物种属、实验终点观察指标、结果判断,着重介绍了体内微核实验、慧星实验、器官重量分析、犬遥测实验、中枢神经系统实验以及致癌性实验的统计分析方法,进一步介绍了目前统计方法存在的问题和解决策略。结果:体内微核实验的统计方法包括一般线性模型、精确趋势检验、非参数趋势检验、配对检验和广义线性模型。彗星实验的统计方法包括汇总统计和广义线性模型。一般毒理实验的器官重量统计学方法包括协方差分析、器官绝对重量分析及器官相对重量分析。中枢神经系统评估定量数据的统计方法包括协方差分析、方差分析及Williams趋势检验或Dunnett-t检验。致癌性实验统计学方法包括Peto检验和poly-k趋势检验。结论:本文介绍了一般毒理学、遗传毒理学、生殖毒性实验、安全药理和致癌性实验常用的统计学方法,为我国临床前药物安全性评价毒理实验数据的统计学分析提供一些参考。

Objective： To introduce the statistical methods to analyze data of general toxicology, genetic toxicology, reproductive studies, safety pharmacology and carcinogenicity studies for preclinical safety evaluation of drugs. Methods： This paper briefly introduced the design, experimental animal species, endpoints, experimental unit, and checks for biologically relevant changes. In addition, we comprehensively reviewed statistical methods that used in data analysis of in vivo micronucleus study, comet study, organ weight analysis in general toxicology study, dog telemetry study, central nervous system study and carcinogenicity study. We further discussed the current issues and possible solutions of the statistical methods. Results： The statistical methods of in vivo micronucleus study include general linear model, exact trend tests, nonparametric trend tests, pairwise test, and generalized linear model. Summary of statistic（median of the log response） at the general level and general linear model to the animal data is adopted for comet study. Analysis of covariance（ANCOVA）, absolute organ weights, and relative organ weights are selected for organ weight analysis. The statistical methods used for quantitative data of CNS assay include ANCOVA, analysis of variance, Williams＇ trend test or Dunnett＇s t-test. Peto test and poly-k test are the statistical methods of carcinogenicity study. Conclusion： This paper introduced the statistical methods used in general toxicology, genetic toxicology, reproductive studies, safety pharmacology and carcinogenicity studies, which may provide references for data statistical analysis of toxicology studies in preclinical safety evaluation of drugs in China.