The Procter & Gamble Company, 8700 Mason Montgomery Road, Cincinnati, OH, 45040, USA.
Regul Toxicol Pharmacol. 2018 Nov;99:61-77. doi: 10.1016/j.yrtph.2018.09.008. Epub 2018 Sep 8.
Physiologically based pharmacokinetic (PBPK) models enable simulations of absorption, distribution, metabolism, and elimination of chemicals from the body. Model evaluation is a key step in the PBPK model development processes whereby model predictions are compared to pharmacokinetic (PK) data. A prerequisite for PBPK model evaluation has always been the availability of PK data for the modeled compound, a requirement which has limited the use and acceptance of PBPK models since PK data is often limited or not available. The current work tests the hypothesis that an adequately developed PBPK model for a target chemical (chemical with no PK data) can be evaluated using PK data from a source chemical (chemical with existing PK data). Two different approaches for identifying the source chemical, a structural PK analog and functional PK analog technique, are used to evaluate a series of oral human PBPK models. Results show that both analog approaches can identify PK analogs which display similar PK as the target chemical and can be used as alternative ways for evaluating PBPK models. As animal free safety assessment strategies continue to develop, it's important to develop alternative approaches for PBPK model evaluation which does not rely on generating new PK data.
基于生理学的药代动力学（PBPK）模型可用于模拟化学物质在体内的吸收、分布、代谢和消除。模型评估是 PBPK 模型开发过程中的关键步骤，通过该步骤可以将模型预测与药代动力学（PK）数据进行比较。PBPK 模型评估的一个前提条件一直是需要有被建模化合物的 PK 数据，由于 PK 数据通常有限或不可用，这一要求限制了 PBPK 模型的使用和接受程度。本研究旨在检验以下假设，即对于目标化学物质（无 PK 数据的化学物质），如果其 PBPK 模型开发得足够完善，则可以使用源化学物质（具有现有 PK 数据的化学物质）的 PK 数据对其进行评估。本研究使用两种不同的方法来识别源化学物质，即结构 PK 类似物和功能 PK 类似物技术，以评估一系列口服人体 PBPK 模型。结果表明，这两种类似物方法都可以识别出与目标化学物质具有相似 PK 的 PK 类似物，并可作为评估 PBPK 模型的替代方法。随着动物免费安全评估策略的不断发展，开发不依赖于生成新 PK 数据的 PBPK 模型评估替代方法非常重要。
