Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models
Autor: | Amy Saari, Umesh S. Kestur, Balvinder S. Vig, Divyakant Desai, Yan Xu, Aditya U. Vanarase, John R. Crison, Munir A. Hussain, Neil Mathias |
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Rok vydání: | 2015 |
Předmět: |
Male
In vitro dissolution Pharmaceutical Science Pharmacology Models Biological Food-Drug Interactions Dogs Species Specificity Pharmacokinetics In vivo Animals Humans Computer Simulation Solubility Dissolution FOOD EFFECT Chromatography Chemistry Area under the curve Fasting Biopharmaceutics Classification System Pharmaceutical Preparations Area Under Curve Research Article |
Zdroj: | The AAPS Journal. 17:988-998 |
ISSN: | 1550-7416 |
DOI: | 10.1208/s12248-015-9759-z |
Popis: | In vitro and in vivo experimental models are frequently used to assess a new chemical entity’s (NCE) biopharmaceutical performance risk for food effect (FE) in humans. Their ability to predict human FE hinges on replicating key features of clinical FE studies and building an in vitro-in vivo relationship (IVIVR). In this study, 22 compounds that span a wide range of physicochemical properties, Biopharmaceutics Classification System (BCS) classes, and food sensitivity were evaluated for biorelevant dissolution in fasted- and fed-state intestinal media and the dog fed/fasted-state pharmacokinetic model. Using the area under the curve (AUC) as a performance measure, the ratio of the fed-to-fasted AUC (FE ratio) was used to correlate each experimental model to FE ratio in humans. A linear correlation was observed for the in vitro dissolution-human IVIVR (R 2 = 0.66, % mean square error 20.7%). Similarly, the dog FE ratio correlated linearly with the FE ratio in humans (R 2 = 0.74, % mean square error 16.25%) for 15 compounds. Data points near the correlation line indicate dissolution-driven mechanism for food effect, while deviations from the correlation line shed light on unique mechanisms that can come into play such as GI physiology or unusual physicochemical properties. In summary, fed/fasted dissolution studies and dog PK studies show a reasonable correlation to human FE, hence are useful tools to flag high-risk NCEs entering clinical development. Combining kinetic dissolution, dog FE model and in silico modeling one can study FE mechanism and formulation strategies to mitigate the FE risk. |
Databáze: | OpenAIRE |
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