Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Product Development Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
J Pharm Sci. 2019 Aug;108(8):2728-2736. doi: 10.1016/j.xphs.2019.03.015. Epub 2019 Mar 21.
The purpose of the present study was to evaluate the prediction accuracy of a mechanism-based oral absorption model for the fraction of a dose absorbed (Fa) in dogs, focusing on poorly soluble drugs. As an open mechanism-based model, the gastrointestinal unified theoretical framework was used in this study. The prediction accuracy of the gastrointestinal unified theoretical framework was evaluated using Fa data in dogs (63 data sets for marketed drugs and proprietary compounds). For neutral compounds, Fa was accurately predicted, suggesting that the physiological parameters of dogs were appropriate except for gastrointestinal pH. An extensive literature survey on the small intestinal pH of dogs was then conducted. The result suggested that the pH value ranged between 6.5 and 7.5, with the midst value of 7.0, but there was a great variation among the literature. To confirm the appropriateness of this pH value, the Fa of free acid compounds was predicted by setting the small intestinal pH to 6.5, 7.0, and 7.5. The proportions of compounds with <2-fold error were 57%, 90%, and 76%, respectively. The results of the present study would enable an appropriate use of a mechanism-based model for drug discovery and development.
本研究旨在评估一种基于机制的口服吸收模型在犬中预测吸收分数 (Fa) 的准确性，重点关注难溶性药物。作为一种开放的基于机制的模型，胃肠道统一理论框架被用于本研究。使用犬的 Fa 数据（63 个已上市药物和专有化合物的数据）评估胃肠道统一理论框架的预测准确性。对于中性化合物，Fa 得到了准确的预测，这表明犬的生理参数是合适的，除了胃肠道 pH 值。随后对犬小肠 pH 值进行了广泛的文献调查。结果表明，pH 值在 6.5 到 7.5 之间，中间值为 7.0，但文献之间存在很大差异。为了确认该 pH 值的合理性，通过将小肠 pH 值设置为 6.5、7.0 和 7.5，预测了游离酸化合物的 Fa。化合物的<2 倍误差比例分别为 57%、90%和 76%。本研究的结果将有助于在药物发现和开发中合理使用基于机制的模型。
