Utility of preclinical species for uncertainty assessment and correction of prediction of human volume of distribution using the Rodgers-Lukacova model

Prediction of rat, dog, monkey, and human volume of distribution (VD_ss) by Rodgers-Lukacova model was evaluated using a data set of more than 100 compounds.The prediction accuracy was best for humans followed by monkeys and dogs with 59, 52, and 41% of compounds within 2-fold, respectively.The accuracy of predictions in preclinical species was indicative of the human situation. This was particularly true for monkeys, where 87% of the compounds that were predicted within 2-fold in monkeys were also predicted within 2-fold in humans.The model's tendency to underestimate VD_ss was higher in rats and dogs compared to humans and monkeys for all ion classes but zwitterions. Hence, correction of human predictions using prediction errors in rats and dogs resulted in overestimation of VD_ss.The model had a similar degree of underestimation in humans and monkeys. Correction using monkeys improved the accuracy of the human estimate, especially for basic and zwitterion compounds.A strategy is proposed based on the accuracy of prediction in monkey and monkey scalars for prediction and prospective assessment of the accuracy of human VD_ss. Prediction of rat, dog, monkey, and human volume of distribution (VD_ss) by Rodgers-Lukacova model was evaluated using a data set of more than 100 compounds. The prediction accuracy was best for humans followed by monkeys and dogs with 59, 52, and 41% of compounds within 2-fold, respectively. The accuracy of predictions in preclinical species was indicative of the human situation. This was particularly true for monkeys, where 87% of the compounds that were predicted within 2-fold in monkeys were also predicted within 2-fold in humans. The model's tendency to underestimate VD_ss was higher in rats and dogs compared to humans and monkeys for all ion classes but zwitterions. Hence, correction of human predictions using prediction errors in rats and dogs resulted in overestimation of VD_ss. The model had a similar degree of underestimation in humans and monkeys. Correction using monkeys improved the accuracy of the human estimate, especially for basic and zwitterion compounds. A strategy is proposed based on the accuracy of prediction in monkey and monkey scalars for prediction and prospective assessment of the accuracy of human VD_ss.

本研究采用包含100余种化合物的数据集，对Rodgers-Lukacova模型预测大鼠、犬、猴及人稳态分布容积（VDss）的性能开展了评估。该模型的预测精度以人类最优，其次依次为猴与犬，分别有59%、52%、41%的化合物的预测偏差处于2倍以内。临床前实验动物的预测精度可反映人类的预测表现，这一相关性在猴身上尤为显著：若某化合物在猴的预测中偏差在2倍以内，则其中87%的化合物在人类的预测中同样满足该精度要求。除两性离子（zwitterions）外，所有离子类别的化合物中，该模型在大鼠与犬中对VDss的低估倾向均显著高于人类与猴。因此，若利用大鼠和犬的预测误差对人类的预测结果进行校正，反而会导致VDss的预测值被高估。该模型在人类与猴中表现出相近的低估程度。借助猴的预测结果开展校正，可提升人类VDss的预测精度，对于碱性化合物及两性离子化合物效果尤为明显。本研究提出了一种基于猴的预测精度及猴标度因子的策略，用于人类VDss预测精度的预估与前瞻性评估。
本研究采用包含100余种化合物的数据集，对Rodgers-Lukacova模型预测大鼠、犬、猴及人稳态分布容积（VDss）的性能开展了评估。该模型的预测精度以人类最优，其次依次为猴与犬，分别有59%、52%、41%的化合物的预测偏差处于2倍以内。临床前实验动物的预测精度可反映人类的预测表现，这一相关性在猴身上尤为显著：若某化合物在猴的预测中偏差在2倍以内，则其中87%的化合物在人类的预测中同样满足该精度要求。除两性离子（zwitterions）外，所有离子类别的化合物中，该模型在大鼠与犬中对VDss的低估倾向均显著高于人类与猴。因此，若利用大鼠和犬的预测误差对人类的预测结果进行校正，反而会导致VDss的预测值被高估。该模型在人类与猴中表现出相近的低估程度。借助猴的预测结果开展校正，可提升人类VDss的预测精度，对于碱性化合物及两性离子化合物效果尤为明显。本研究提出了一种基于猴的预测精度及猴标度因子的策略，用于人类VDss预测精度的预估与前瞻性评估。