Prediction of food effects on the absorption of celecoxib based on biorelevant dissolution testing coupled with physiologically based pharmacokinetic modeling
Prediction of food effects on the absorption of celecoxib based on biorelevant dissolution testing coupled with physiologically based pharmacokinetic modeling
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DOI：
10.1016/j.ejpb.2009.05.009
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发表时间：
2009-09-01
影响因子：
4.9
通讯作者：
Dressman, Jennifer B.
中科院分区：
文献类型：
--
作者：
Shono, Yasushi;Jantratid, Ekarat;Dressman, Jennifer B.
由于难溶药物在肠道吸收的速率决定步骤是胃肠道的溶解，因此餐后胃肠道生理的变化，除了药物和食物之间的任何特定相互作用外，预计还会影响这些药物的药代动力学和生物利用度。在这项研究中，使用生物释放介质的体外溶出度测试与基于硅生理学的药代动力学(PBPK)模型相结合，用于预测食物对难溶药物塞来昔布从200 mg胶囊中的吸收的影响。基于Stella(R)软件，利用溶出动力学、溶解度、标准GI参数和吸收后处置参数建立了PBPK模型。测定了塞来昔布200 mg胶囊在生物缓释剂和药典介质中的溶出度、溶出度和初始溶出度。标准GI参数(胃排空率和液体容量)根据给药条件而不同。由于塞来昔布的静脉注射数据不可用，因此处置参数是通过将间隔模型与口服PK数据拟合来估计的。使用AUC和C-max和差值因子(f(1))来评估食物效应和平均血浆分布的预测。在代表进食和禁食状态的体外溶出试验中，观察到最大溶解百分比大约相差7倍。相比之下，用PBPK模型模拟血浆谱估计的食物效应只预测了峰值血浆水平的轻微延迟(类似于1h)，C-max和AUC分别温和地增加了1.9倍和1.3倍。因此，结合电子计算机模拟和生物释放试验结果的PBPK方法，更好地符合体内观察到的塞来昔布的食物效应。此外，AUC和Cmax的点估计以及f(1)计算表明，在PBPK模型中使用生物悬浮介质而不是药典介质的结果具有明显的优势。(C)2009爱思唯尔B.V.保留所有权利。
Since the rate-determining step to the intestinal absorption of poorly soluble drugs is the dissolution in the gastrointestinal (GI) tract, postprandial changes in GI physiology, in addition to any specific interactions between drug and food, are expected to affect the pharmacokinetics and bioavailability of such drugs. In this study, in vitro dissolution testing using biorelevant media coupled with in silico physiologically based pharmacokinetic (PBPK) modeling was applied to the prediction of food effects on the absorption of a poorly soluble drug, celecoxib, from 200 mg capsules. A PBPK model was developed based on STELLA (R) software using dissolution kinetics, Solubility, standard GI parameters and post-absorptive disposition parameters. Solubility, dissolution profiles and initial dissolution rate from celecoxib 200 mg capsules were measured in biorelevant and compendial media. Standard GI parameters (gastric emptying rate and fluid volume) were varied according to the dosing conditions. Disposition parameters were estimated by fitting compartmental models to the oral PK data, since intravenous data are not available for celecoxib. Predictions of food effects and average plasma profiles were evaluated using the AUC and C-max and the difference factor (f(1)). An approximately 7-fold difference in the maximum percentage dissolved was observed in in vitro dissolution tests designed to represent the fed and fasted states. By contrast, the food effect estimated by simulating the plasma profiles with the PBPK model predicted only a slight delay in the peak plasma level (similar to 1 h), and modest increases in the C-max and AUC of similar to 1.9-fold and 1.3-fold in the fed state, respectively. The PBPK approach, combining in silico simulation coupled with biorelevant dissolution test results, thus corresponds much better to the food effect observed for celecoxib in vivo. Additionally, point estimates of AUC and Cmax as well as f(1) calculations demonstrated clear advantages of using results in biorelevant rather than compendial media in the PBPK model. (c) 2009 Elsevier B.V. All rights reserved.