The Use of Global Sensitivity Analysis to Assess the Oral Absorption of Weakly Basic Compounds: A Case Example of Dipyridamole.

IF 3.5 3区医学 Q2 CHEMISTRY, MULTIDISCIPLINARY

Pharmaceutical Research Pub Date : 2024-05-01 Epub Date: 2024-03-27 DOI:10.1007/s11095-024-03688-0

Siddharth S Kesharwani, Guillaume Louit, Fady Ibrahim

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引用次数: 0

Abstract

Objective: 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.

Methods: 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_max) 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.

Results: 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_max, and AUC from the clinical studies.

Conclusions: 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.

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使用全局敏感性分析评估弱碱性化合物的口服吸收：以双嘧达莫为例。

目的利用全局系统分析（GSA）建立口服吸收模型，以深入了解系统行为，提高模型的准确性，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/或生理参数会对作为弱碱性化合物模型的双嘧达莫的血浆峰浓度（Cmax）和曲线下面积（AUC）产生影响。GSA 使用 FormulatedProducts v2202.1.0 指导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浓度胆盐中的溶解度和沉淀曲线。然后利用这些结果建立了一个机理口服吸收模型：GSA值得进一步研究沉淀动力学及其与胆盐浓度水平的联系。机理建模研究表明，沉淀整合建模方法可以适当预测临床研究中的平均血浆曲线、Cmax 和 AUC：这项工作显示了在早期开发中利用 GSA 指导体外实验的价值，并为确定数学模型的关键参数建立了更多信心。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmaceutical Research 医学-化学综合

CiteScore

6.60

自引率

5.40%

发文量

276

审稿时长

3.4 months

期刊介绍： Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.