目的:在口服吸收模型中利用全局系统分析(GSA),以更深入地了解系统行为,提高模型精度,并在药物开发过程中做出明智的决定。
方法:使用GSA来深入了解哪种药物(DS),药品(DP),和/或生理参数将对作为模型弱碱性化合物的双嘧达莫的峰值血浆浓度(Cmax)和曲线下面积(AUC)产生影响。GSA使用FormulatedProductsv2202.1.0指导体外实验和口服吸收风险评估的设计。测量了双嘧达莫在不同胆汁盐浓度下的溶解度和沉淀曲线。然后将结果用于建立机械口服吸收模型。
结果:GSA有必要对沉淀动力学及其与胆汁盐浓度水平的联系进行进一步研究。力学建模研究表明,降水综合建模方法可以适当地预测平均等离子体分布,Cmax,和AUC来自临床研究。
结论:这项工作显示了GSA利用在早期开发中的价值,可以指导体外实验,并在确定数学模型的关键参数方面建立更多的信心。
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 (Cmax) 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, Cmax, 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.