US Early Development Biopharmacy, Synthetics Platform, Sanofi, 350 Water St, Cambridge, MA, 02141, USA.
Siemens K.K, DI SW Division, 1-6-1 Miyahara, Osaka, 532-0003, Japan.
Pharm Res. 2024 May;41(5):877-890. doi: 10.1007/s11095-024-03688-0. Epub 2024 Mar 27.
To utilize the global system analysis (GSA) in oral absorption modeling to gain a deeper understanding of system behavior, improve model accuracy, and make informed decisions during drug development.
GSA was utilized to give insight into which drug substance (DS), drug product (DP), and/or physiological parameter would have an impact on peak plasma concentration (C) and area under the curve (AUC) of dipyridamole as a model weakly basic compound. GSA guided the design of in vitro experiments and oral absorption risk assessment using FormulatedProducts v2202.1.0. The solubility and precipitation profiles of dipyridamole in different bile salt concentrations were measured. The results were then used to build a mechanistic oral absorption model.
GSA warranted further investigation into the precipitation kinetics and its link to the levels of bile salt concentrations. Mechanistic modeling studies demonstrated that a precipitation-integrated modeling approach appropriately predicted the mean plasma profiles, C, and AUC from the clinical studies.
This work shows the value of GSA utilization in early development to guide in vitro experimentation and build more confidence in identifying the critical parameters for the mathematical models.
利用全局系统分析（GSA）进行口服吸收建模，以更深入地了解系统行为，提高模型准确性，并在药物开发过程中做出明智的决策。
利用 GSA 深入了解哪些药物物质（DS）、药物产品（DP）和/或生理参数会对双嘧达莫（作为模型弱碱性化合物）的峰血浆浓度（C）和曲线下面积（AUC）产生影响。GSA 指导了使用 FormulatedProducts v2202.1.0 进行体外实验设计和口服吸收风险评估。测量了双嘧达莫在不同胆盐浓度下的溶解度和沉淀曲线。然后将结果用于构建机制口服吸收模型。
GSA 保证进一步研究沉淀动力学及其与胆盐浓度水平的关系。机制建模研究表明，沉淀整合建模方法能够适当预测来自临床研究的平均血浆曲线、C 和 AUC。
这项工作表明，在早期开发中利用 GSA 的价值在于指导体外实验，并建立更多信心，以确定数学模型的关键参数。
