Purpose

A dataset of fraction excreted unchanged in the urine (fe) values was developed and used to evaluate the ability of preclinical animal species to predict high urinary excretion, and corresponding poor metabolism, in humans.

Methods

A literature review of fe values in rats, dogs, and monkeys was conducted for all Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3 and 4 drugs (n=352) and a set of Class 1 and 2 drugs (n=80). The final dataset consisted of 202 total fe values for 135 unique drugs. Human and animal data were compared through correlations, two-fold analysis, and binary classifications of high (fe ≥30%) versus low (<30%) urinary excretion in humans. Receiver Operating Characteristic curves were plotted to optimize animal fe thresholds.

Results

Significant correlations were found between fe values for each animal species and human fe (p<0.05). Sixty-five percent of all fe values were within two-fold of human fe with animals more likely to underpredict human urinary excretion as opposed to overpredict. Dogs were the most reliable predictors of human fe of the three animal species examined with 72% of fe values within two-fold of human fe and the greatest accuracy in predicting human fe ≥30%. ROC determined thresholds of ≥25% in rats, ≥19% in dogs, and ≥10% in monkeys had improved accuracies in predicting human fe of ≥30%.

Conclusions

Drugs with high urinary excretion in animals are likely to have high urinary excretion in humans. Animal models tend to underpredict the urinary excretion of unchanged drug in humans.

中文翻译：

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人体未改变药物尿液排泄和临床前动物模型的检查：增加人体代谢不良的可预测性

目的

开发了尿液 (fe) 值不变排泄分数的数据集，并用于评估临床前动物物种预测人类高尿排泄和相应代谢不良的能力。

方法

对所有生物药剂学药物处置分类系统 (BDDCS) 第 3 类和第 4 类药物 (n=352) 以及一组第 1 类和第 2 类药物 (n=80) 的大鼠、狗和猴子的 fe 值进行了文献综述。最终数据集包含 135 种独特药物的 202 个总 fe 值。通过相关性、双重分析和人类高（fe ≥30%）与低（<30%）尿液排泄的二元分类来比较人类和动物数据。绘制接受者操作特征曲线以优化动物 fe 阈值。

结果

每个动物物种的 fe 值与人类 fe 值之间存在显着相关性 ( p <0.05)。所有 fe 值的 65% 在人类 fe 的两倍以内，动物更有可能低估人类尿液排泄而不是高估。在所检查的三种动物物种中，狗是最可靠的人类 fe 预测因子，其 fe 值的 72% 在人类 fe 的两倍以内，并且预测人类 fe 的最准确度≥30%。ROC 确定的阈值在大鼠中≥25%，在狗中≥19%，在猴子中≥10% 提高了预测人类 fe ≥30% 的准确性。

结论

在动物中具有高尿排泄的药物可能在人类中具有高尿排泄。动物模型往往低估人体未变化药物的尿液排泄。