Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2486175 | Journal of Pharmaceutical Sciences | 2011 | 10 Pages |
Abstract
Dogs are one of the most commonly used nonârodent species in toxicology studies and are known to have basal stomach pH ranging from 2 to 7 in the fasted state. Thus absorption and resulting plasma exposure of weakly basic compounds administered as crystalline suspensions to dogs are often variable. LY2157299 is a potent and selective transforming growth factor (TGF)âbeta receptor type 1 kinase (TGFâβRI) inhibitor that displayed variable absorption in early dog studies. This molecule is a weakly basic Biopharmaceutics Classification System (BCS)Class II compound, and depends on the rate and extent of dissolution to drive oral absorption. An artificial stomach and duodenum (ASD) dissolution model was utilized to evaluate potential effect of gastric pH on the absorption of suspension and buffered solution formulations. GastroPlus⢠was also employed to predict the magnitude of gastric pH changes on LY2157299 absorption. The ASD experiments demonstrated that administration of a buffered acidic solution could improve the potential for absorption by normalizing gastric pH and enabling supersaturation in the duodenum. GastroPlus⢠modeling suggested that direct modulation of gastric pH could lead to marked changes in bioavailability. Pharmacokinetic experiments were conducted in dogs to evaluate the effect of gastric pH modification on plasma exposure. The data were qualitatively consistent with the predictions. © 2011 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 100:4756-4765, 2011
Keywords
Related Topics
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Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Shobha N. Bhattachar, Everett J. Perkins, Jeffrey S. Tan, Lee J. Burns,