Riccardi Keith, Cawley Shannon, Yates Phillip D, Chang Cheng, Funk Carrie, Niosi Mark, Lin Jian, Di Li
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, 06340.
J Pharm Sci. 2015 Aug;104(8):2627-36. doi: 10.1002/jps.24506. Epub 2015 Jun 2.
Accurately determining fraction unbound (fu ) with currently available methods has been challenging for certain compounds. Inaccurate fu values can lead to the misinterpretation of important attributes of a drug candidate. Our analysis of over 2000 Pfizer drug discovery compounds showed no systematic bias in low or high fu precision using the equilibrium dialysis method. However, the accuracy of the plasma protein binding (PPB) estimate for highly bound compounds may be poor, should equilibrium not be fully achieved in the equilibrium dialysis assay. Here, a dilution method and a presaturation method were applied to accelerate equilibration for a set of challenging compounds. These improved methods demonstrate the ability to provide an accurate measurement of PPB for highly bound compounds with fu values much less than 1%. Therefore, we recommend that the actual experimental fu value be used for the prediction of drug-drug interaction potential and for the characterization of important drug candidate properties. Our recommendation calls into question the need for current regulatory guidelines that restrict the reporting of fu values below 1%.
使用现有方法准确测定游离分数（fu）对于某些化合物而言一直具有挑战性。不准确的fu值可能导致对候选药物重要属性的错误解读。我们对辉瑞公司2000多种药物发现化合物的分析表明，使用平衡透析法在低fu或高fu精度方面没有系统偏差。然而，如果在平衡透析测定中未完全达到平衡，对于高结合化合物的血浆蛋白结合（PPB）估计的准确性可能较差。在此，应用稀释法和预饱和法来加速一组具有挑战性的化合物的平衡。这些改进方法证明能够为fu值远低于1%的高结合化合物提供准确的PPB测量。因此，我们建议将实际实验fu值用于预测药物相互作用潜力以及表征候选药物的重要属性。我们的建议对当前限制报告低于1%的fu值的监管指南的必要性提出了质疑。
