O'Dwyer Patrick J, Imanidis Georgios, Box Karl J, Reppas Christos
Pion Inc. (UK) Ltd., Forest Row, East Sussex RH18 5DW, UK.
Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, GR 157 84 Zografou, Greece.
Pharmaceutics. 2020 Mar 16;12(3):272. doi: 10.3390/pharmaceutics12030272.
A small-scale biphasic dissolution setup and a small-scale dissolution-permeation (D-P) setup were evaluated for their usefulness in simulating the luminal precipitation of three lipophilic weak bases-dipyridamole, ketoconazole and itraconazole. The transition from the gastric to intestinal environment was incorporated into both experimental procedures. Emulsification during the biphasic dissolution experiments had a minimal impact on the data, when appropriate risk mitigation steps were incorporated. Precipitation parameters estimated from the in vitro data were inputted into the Simcyp® physiologically based pharmacokinetic (PBPK) modelling software and simulated human plasma profiles were compared with previously published pharmacokinetic data. Average C and AUC values estimated using experimentally derived precipitation parameters from the biphasic experiments deviated from corresponding published actual values less than values estimated using the default simulator parameters for precipitation. The slow rate of transport through the biomimetic membrane in the D-P setup limited its usefulness in forecasting the rates of in vivo precipitation used in the modelling of average plasma profiles.
评估了小规模双相溶出装置和小规模溶出-渗透（D-P）装置在模拟三种亲脂性弱碱（双嘧达莫、酮康唑和伊曲康唑）的腔内沉淀方面的实用性。两种实验方法都纳入了从胃环境到肠道环境的转变。在双相溶出实验中，当纳入适当的风险缓解措施时，乳化对数据的影响最小。将从体外数据估计的沉淀参数输入到Simcyp®基于生理的药代动力学（PBPK）建模软件中，并将模拟的人体血浆曲线与先前发表的药代动力学数据进行比较。使用双相实验中实验得出的沉淀参数估计的平均C和AUC值与相应公布的实际值的偏差小于使用沉淀默认模拟器参数估计的值。D-P装置中通过仿生膜的传输速率较慢，限制了其在预测用于平均血浆曲线建模的体内沉淀速率方面的实用性。
