Use of the pentagastrin dog model to explore the food effects on formulations in early drug development

被引:19
作者
Zane, P. [1 ]
Guo, Z. [1 ]
MacGerorge, D. [1 ]
Vicat, P. [2 ]
Oilier, C. [3 ]
机构
[1] Sanofi US, Bridgewater, NJ 08807 USA
[2] Sanofi Rech, F-94140 Alfortville, France
[3] Sanofi Rech, F-34184 Montpellier, France
关键词
Dog; Pentagastrin; Pharmacokinetics; Food effect;
D O I
10.1016/j.ejps.2013.09.018
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The ability to extrapolate dosage performance from in vitro to in vivo situations has an important role in early drug development. In parallel, the Beagle dog has come to represent a useful animal model for extrapolation to humans especially when drugs formulated for humans are to be tested. In this article, the pentagastrin-induced Beagle dog model was validated internally to show that in the colony the dogs were generally responsive to known doses of pentagastrin that produces effects similar to gastrin in the stomach, i.e., increasing gastric acid production and lowering gastric pH. The effect was observed with a short time course, maximum pH lowering was observed between 0.5 and 1 h with return to baseline at 2 4 h. The dog stomach pH is a better representative of the human fasted stomach with this pretreatment. The ultimate goal was to use these animals in a food effect studies to predict the behavior of formulations in humans. The results for 4 compounds were provided in the dog and a clear relationship between the effect of food in the dog and the effect of food in humans was observed. While the directionality (positive or negative) of the effect could be adequately predicted, the extent of the effect could not be predicted for all the tested formulations of the 4 compounds. The data will be used to generate a database of known compounds from which a correlation can be drawn to make future predictions using the pentagastrin dog model. (C) 2013 Elsevier B.V. All rights reserved.
引用
收藏
页码:207 / 213
页数:7
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