All drugs entering clinical trials are expected to undergo a series of in vitro and in vivo genotoxicity tests as outlined in the International Council on Harmonization (ICH) S2 (R1) guidance. Among the standard battery of genotoxicity tests used for pharmaceuticals, the in vivo micronucleus assay, which measures the frequency of micronucleated cells mostly from blood or bone marrow, is recommended for detecting clastogens and aneugens. (Quantitative) structure-activity relationship [(Q)SAR] models may be used as early screening tools by pharmaceutical companies to assess genetic toxicity risk during drug candidate selection. Models can also provide decision support information during regulatory review as part of the weight-of-evidence when experimental data are insufficient. In the present study, two commercial (Q)SAR platforms were used to construct in vivo micronucleus models from a recently enhanced in-house database of non-proprietary study findings in mice. Cross-validated performance statistics for the new models showed sensitivity of up to 74% and negative predictivity of up to 86%. In addition, the models demonstrated cross-validated specificity of up to 77% and coverage of up to 94%. These new models will provide more reliable predictions and offer an investigational approach for drug safety assessment with regards to identifying potentially genotoxic compounds.

中文翻译：

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开发改进的QSAR模型以预测体内微核遗传毒性测定的结果。

如国际协调委员会（ICH）S2（R1）指南所述，所有进入临床试验的药物均应进行一系列体外和体内遗传毒性测试。在用于药物的标准遗传毒性试验中，建议使用体内微核试验（主要测量血液或骨髓中的微核细胞的频率）来检测胶体来源和中性原。（定量）结构-活性关系[（Q）SAR]模型可被制药公司用作早期筛选工具，以评估候选药物选择过程中的遗传毒性风险。当实验数据不足时，模型还可以在监管审查期间提供决策支持信息，作为证据权重的一部分。在目前的研究中，两个商业（Q）SAR平台用于从最近增强的小鼠非专有研究发现的内部数据库中构建体内微核模型。对新模型进行交叉验证的性能统计数据显示，灵敏度高达74％，阴性预测率高达86％。此外，这些模型显示出高达77％的交叉验证特异性和高达94％的覆盖率。这些新模型将提供更可靠的预测，并为鉴定潜在的遗传毒性化合物提供药物安全性评估的研究方法。这些模型显示出交叉验证的特异性高达77％，覆盖率高达94％。这些新模型将提供更可靠的预测，并为鉴定潜在的遗传毒性化合物提供药物安全性评估的研究方法。这些模型显示出交叉验证的特异性高达77％，覆盖率高达94％。这些新模型将提供更可靠的预测，并为鉴定潜在的遗传毒性化合物提供药物安全性评估的研究方法。