Kambayashi Atsushi, Yasuji Takehiko, Dressman Jennifer B
Pharmaceutical Research and Technology Labs, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan; Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max von Laue St. 9, D-60438 Frankfurt am Main, Germany.
Pharmaceutical Research and Technology Labs, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan.
Eur J Pharm Biopharm. 2016 Jun;103:95-103. doi: 10.1016/j.ejpb.2016.03.020. Epub 2016 Mar 21.
Precipitation of poorly soluble, weakly basic drugs upon entering the small intestine may lead to poor bioavailability. It would be useful to be able to predict the extent of in vivo precipitation so that formulation measures to counteract this problem can be taken.
The aim of this research was to characterize the precipitation kinetics of two representative weak base drugs, dipyridamole and ketoconazole in vitro using a simplified transfer model approach, and to establish a predictive model for the total and dissolved concentrations in the small intestine after oral administration using in silico modeling and simulation.
A simplified transfer ("dumping") method based on the USP paddle apparatus was used to obtain the precipitation profiles of the two weak base drugs by adding a solution of the drug in 0.02N hydrochloric acid to FaSSIF-V2. The observed precipitation curves obtained with various initial concentrations were fitted to first order kinetics. An in silico pharmacokinetic model for weak base drugs with precipitation in the small intestine was designed using STELLA® software and coupled with the precipitation profiles in order to simulate the total and dissolved drug concentrations in the small intestinal lumen in the fasted state in humans.
The predicted total and dissolved concentration curves in small intestine for the two weak base drugs were similar to the concentration profiles observed in vivo. The fraction precipitated of the drugs in the small intestine was also well predicted, although the precipitation of ketoconazole at higher initial concentrations was somewhat overestimated. A sensitivity analysis conducted on the simulation of the precipitation of the drugs indicated that a higher fraction precipitated when gastric emptying was faster and/or the concentration of the drug in the added solution was higher.
The dumping method provides a useful screen for precipitation in the small intestine, especially in the context of early development.
难溶性弱碱性药物进入小肠后可能会沉淀，导致生物利用度不佳。若能预测体内沉淀程度，便可采取制剂措施来解决此问题。
本研究旨在使用简化的转运模型方法体外表征两种代表性弱碱性药物双嘧达莫和酮康唑的沉淀动力学，并通过计算机模拟建立口服给药后小肠中总浓度和溶解浓度的预测模型。
基于美国药典桨法装置的简化转运（“倾倒”）方法，通过将药物在0.02N盐酸中的溶液加入到FaSSIF-V2中，获得两种弱碱性药物的沉淀曲线。将不同初始浓度下得到的观察沉淀曲线拟合为一级动力学。使用STELLA®软件设计了一个小肠中有沉淀的弱碱性药物的计算机药代动力学模型，并结合沉淀曲线来模拟空腹状态下人体小肠腔中的药物总浓度和溶解浓度。
两种弱碱性药物在小肠中的预测总浓度和溶解浓度曲线与体内观察到的浓度曲线相似。小肠中药物的沉淀分数也得到了较好的预测，尽管酮康唑在较高初始浓度下的沉淀被略微高估。对药物沉淀模拟进行的敏感性分析表明，当胃排空更快和/或添加溶液中药物浓度更高时，沉淀分数更高。
倾倒法为小肠中的沉淀提供了一种有用的筛选方法，尤其是在早期研发阶段。
