Pharmaceutical Sciences Research and Development, Eli Lilly & Company, 1223 W. Morris St. Lilly Technology Center, Indianapolis, Indiana 46221, USA.
AAPS J. 2012 Dec;14(4):895-903. doi: 10.1208/s12248-012-9402-1. Epub 2012 Sep 11.
Absorption modeling is an excellent strategic fit to perform a risk assessment for relative bioavailability (RBA) studies as it provides direct input into the question that is at the core of the RBA decision, namely, how does the absorption of the test drug product compare to the reference and is it likely to be different enough to justify an RBA study. The main limitation to absorption modeling in risk assessment is the inherent uncertainty associated with modeling. The extent to which the absorption modeling is integrated into the risk assessment should depend on the level of confidence in the modeling. It is difficult, however, to quantify the level of confidence on a case by case basis. The effective application of absorption modeling for RBA risk assessment therefore requires a general understanding of when modeling is expected to be reliable and also how to build reliability directly into the modeling. This paper describes a framework for effective modeling in RBA risk assessment that is based on four fundamental building blocks: (1) relate severity of drug product change and API properties to reliability of modeling, (2) use critical model variables to express the critical differences in the drug products, (3) generate a fraction-absorbed response surface expressed in terms of the critical model variables to evaluate the relative performance of the drug products, and (4) tie the first three building blocks together by following good model building practices that assure the highest quality model is built. The building blocks are demonstrated by a simple but common example of a change in solid state from free base to HCl salt.
吸收模型是进行相对生物利用度（RBA）研究风险评估的绝佳策略，因为它为核心 RBA 决策问题提供了直接的输入，即受试药物产品的吸收与参比药物相比如何，是否存在足够的差异需要进行 RBA 研究。吸收模型在风险评估中的主要局限性在于建模固有的不确定性。吸收模型在风险评估中的集成程度应取决于对模型的置信度水平。然而，很难在逐个案例的基础上量化置信度水平。因此，为了有效地将吸收模型应用于 RBA 风险评估，需要对建模何时有望可靠以及如何直接将可靠性构建到建模中有一个全面的了解。本文描述了一种基于四个基本构建块的 RBA 风险评估中有效建模的框架：（1）将药物产品变化和 API 性质的严重程度与建模的可靠性联系起来，（2）使用关键模型变量来表达药物产品的关键差异，（3）生成以关键模型变量表示的吸收分数响应曲面，以评估药物产品的相对性能，以及（4）通过遵循良好的模型构建实践，将前三个构建块联系在一起，以确保构建出最高质量的模型。通过一个简单但常见的从游离碱到 HCl 盐的固体状态变化的示例来演示构建块。
