Department of Biopharmaceutics and Pharmaceutical Technology , Center of Drug Absorption and Transport, University of Greifswald , D-17487 Greifswald , Germany.
HEXAL AG , Industriestraße 25 , D-83607 Holzkirchen , Germany.
Mol Pharm. 2019 Nov 4;16(11):4651-4660. doi: 10.1021/acs.molpharmaceut.9b00799. Epub 2019 Oct 22.
In the postprandial stomach, processes such as secretion, digestion, and gastric emptying all occur simultaneously. Therefore, the system is highly heterogeneous and dynamically changing, for instance, in terms of various physicochemical parameters such as pH value or viscosity. Thus, the administration of a drug together with food can result in highly variable drug plasma concentrations, which may affect the efficacy and safety of the pharmacotherapy. In this work, the pharmacokinetic (PK) data obtained from two fed-state bioequivalence studies with the immediate release (IR) drug products Viagra (sildenafil) and Adenuric (febuxostat) have been analyzed. This evaluation revealed that basically three characteristic types of onset behaviors of drug plasma concentration can be distinguished. It was hypothesized that the different types of onset behaviors were mainly caused by the interplay between gastric drug dissolution and gastric emptying. To study this interplay in vitro, a biopredictive dissolution tool-GastroDuo-was developed and used for both drug products. Therefore, three different test programs have been applied to simulate certain aspects of the postprandial human stomach, which included dynamic pH changes, gastric peristalsis, and the kinetics of gastric emptying. Specifically, the behavior of noncaloric fluids by the so-called "Magenstrasse" was taken into deeper consideration. The experiments revealed that the dissolution and emptying behavior of the two drug products were affected in different ways by the three test programs. The in vitro data nicely explained the tendencies of the drug products for certain types of onset behaviors observed in the PK data. While Viagra was strongly affected by simulated peristalsis, Adenuric was more sensitive to the simulated emptying kinetics. This work clearly demonstrated the important role of gastric fluid emptying for the onset of drug plasma concentration after oral administration of IR formulations in the fed state. Moreover, this was the first study in which GastroDuo was applied as a biopredictive in vitro model which is able to simulate crucial parameters of the human stomach (e.g., pH profiles and gastric emptying) in a realistic manner.
在餐后胃中，分泌、消化和胃排空等过程同时发生。因此，该系统具有高度的异质性和动态变化，例如在 pH 值或粘度等各种物理化学参数方面。因此，将药物与食物一起给药可能会导致药物血浆浓度高度变化，从而影响药物治疗的疗效和安全性。在这项工作中，分析了两种与进食状态生物等效性研究的药代动力学 (PK) 数据，这些研究使用了即时释放 (IR) 药物产品 Viagra（西地那非）和 Adenuric（非布司他）。评估结果表明，基本上可以区分药物血浆浓度出现的三种特征类型。假设不同类型的发作行为主要是由胃药物溶解和胃排空之间的相互作用引起的。为了在体外研究这种相互作用，开发了一种生物预测性溶解工具-GastroDuo-并用于两种药物产品。因此，应用了三种不同的测试程序来模拟餐后人体胃的某些方面，包括动态 pH 值变化、胃蠕动和胃排空动力学。具体而言，通过所谓的“Magenstrasse”进一步考虑了非热量液体的行为。实验表明，两种药物产品的溶解和排空行为受到三种测试程序的不同影响。体外数据很好地解释了 PK 数据中观察到的某些药物产品发作行为的趋势。虽然 Viagra 受到模拟蠕动的强烈影响，但 Adenuric 对模拟排空动力学更敏感。这项工作清楚地表明，在进食状态下口服 IR 制剂后，胃排空对药物血浆浓度出现的重要作用。此外，这是首次应用 GastroDuo 作为生物预测性体外模型的研究，该模型能够以现实的方式模拟人体胃的关键参数（例如，pH 曲线和胃排空）。
