Clinical Pharmacology, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
Small Molecule Pharmaceutical Sciences, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
J Pharm Sci. 2021 Mar;110(3):1427-1430. doi: 10.1016/j.xphs.2020.12.023. Epub 2020 Dec 24.
Absorption via the intestinal lymphatic system is known to be important for some highly lipophilic compounds, and can be associated with unique pharmacokinetic properties due to evasion of hepatic first-pass metabolism. This work aimed to develop a physiologically-based pharmacokinetic model incorporating the role of lymphatic transport in a physiologically-based, mechanistic oral absorption model, using halofantrine as a model compound. Simcyp V19 was used for model development; oral absorption was characterized using the multi-layer gut wall (M-ADAM) model, and the model was constructed and verified using parameters derived from in vitro experiments and clinical PK data. The final model appeared to adequately capture halofantrine pharmacokinetics in the fasted state and the magnitude of the effect of food on halofantrine total exposure; the effect of food on peak exposure was slightly underpredicted, which may be due to transient post-prandial changes in protein binding. The model simulated halofantrine fraction absorbed (f) via the lymph in the fed state was 0.26, representing 62% of the increase in f in the fed state over fasting. This work demonstrates that a PBPK modeling approach can be used to mechanistically describe oral absorption incorporating intestinal lymphatic transport.
肠淋巴系统吸收对于一些高度亲脂性化合物是很重要的，并且由于可以逃避肝脏首过代谢，因此可能具有独特的药代动力学特性。本工作旨在开发一种基于生理的药代动力学模型，该模型将淋巴转运的作用纳入基于生理的口服吸收模型中，以卤泛群作为模型化合物。使用 Simcyp V19 进行模型开发；使用多层肠壁（M-ADAM）模型来描述口服吸收，并且使用从体外实验和临床 PK 数据中得出的参数来构建和验证模型。最终模型似乎能够充分捕获禁食状态下卤泛群的药代动力学和食物对卤泛群总暴露量的影响程度；食物对峰暴露量的影响略有低估，这可能是由于餐后蛋白质结合的短暂变化。该模型模拟了进食状态下经肠淋巴吸收的卤泛群分数（f）为 0.26，这代表了进食状态下 f 相对于禁食状态的增加的 62%。这项工作表明，可以使用基于生理的建模方法来机械地描述包含肠淋巴转运的口服吸收。
