监管机构最近发布了药物-药物相互作用指南,这需要测定血浆蛋白结合(PPB)。保守方面的错误,机构建议0.01下限未结合的馏分(FU)用于高度结合的化合物(>99%),与实际测量值无关。虽然这可以避免假阴性,该建议可能会导致高比例的假阳性预测,导致不必要的临床研究和更严格的纳入/排除标准,这可能会增加向患者提供新药的成本和时间。从这个角度来看,我们对当前测量PPB的方法进行了综述,以及实现这些测量的准确性和精确度的重要决定因素。华法林和伊曲康唑的PPB的跨公司数据比较进一步说明了测量fu的能力,证明测量的fu值具有良好的一致性。数据表明,当使用适当的方法时,可以在实验室中准确确定≤0.01的fu值。这些数据,连同文献中提出的许多其他例子,支持使用实验测量的Fu值进行药物-药物相互作用预测,而不是使用当前监管指南中建议的0.01的任意截止值。
Regulatory agencies have recently issued drug-drug interaction
guidelines, which require determination of plasma protein binding (PPB). To err on the conservative side, the agencies recommend that a 0.01 lower limit of fraction unbound (fu) be used for highly bound compounds (>99%), irrespective of the actual measured values. While this may avoid false negatives, the recommendation would likely result in a high rate of false positive predictions, resulting in unnecessary clinical studies and more stringent inclusion/exclusion criteria, which may add cost and time in delivery of new medicines to patients. In this perspective, we provide a review of current approaches to measure PPB, and important determinants in enabling the accuracy and precision in these measurements. The ability to measure fu is further illustrated by a cross-company data comparison of PPB for warfarin and itraconazole, demonstrating good concordance of the measured fu values. The data indicate that fu values of ≤0.01 may be determined accurately across laboratories when appropriate methods are used. These data, along with numerous other examples presented in the literature, support the use of experimentally measured fu values for drug-drug interaction predictions, rather than using the arbitrary cutoff value of 0.01 as recommended in current regulatory
guidelines.