Petrakis Orestis, Vertzoni Maria, Angelou Alexandros, Kesisoglou Filippos, Bentz Kimberly, Goumas Konstantinos, Reppas Christos
Faculty of Pharmacy, National & Kapodistrian University of Athens, Athens, Greece.
J Pharm Pharmacol. 2015 Jan;67(1):56-67. doi: 10.1111/jphp.12320. Epub 2014 Sep 23.
Evaluate the ability of biorelevant media to adequately predict solubility in human gastrointestinal aspirates collected in the fasted state for the sodium salt of a highly dosed, Biopharmaceutics Classification System II (BCS II) compound with weakly acidic properties (L-870,810, pKa 7.3, HA (5-(1,1-dioxothiazinan-2-yl)-N-((4-fluorophenyl)methyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide)). Identify key luminal processes that dictate the behaviour of sodium salt of HA (NaA), after single-dose administrations of high (relatively to solubility limit) doses corresponding to 400 and 800 mg of HA in the fasted state.
Aspirates from stomach and upper small intestine were collected from eight healthy fasted adults, after administration of 240 ml of water. Solubilities of NaA and HA were measured in aspirated samples and biorelevant media. Dissolution experiments of NaA granules were performed in biorelevant media. Prediction of oral pharmacokinetics was evaluated in silico using Stella software.
Equilibrium solubility of NaA in fluids aspirated from the upper gastrointestinal tract is more transient than of HA. Solubility in upper gastrointestinal lumen was adequately estimated by data in biorelevant media. Supersaturation, followed by precipitation, which did not fully revert to the equilibrium solubility of HA, was observed during the dissolution of NaA granules in biorelevant media. Physiologically based pharmacokinetic modelling indicated that while intragastric processes had no significant impact on absorption kinetics, dissolution kinetics, kinetic solubility, radial transport rates and, for the 800-mg dose, precipitation kinetics in the small intestine had the greatest impact on absorption profiles.
Adequate prediction of the average plasma profile, after administration of NaA, required consideration of region-dependent dissolution rates and/or solubilisation.
评估生物相关介质对一种高剂量、具有弱酸性性质的生物药剂学分类系统II（BCS II）化合物（L-870,810，pKa 7.3，HA（5-(1,1-二氧代噻嗪烷-2-基)-N-((4-氟苯基)甲基)-8-羟基-1,6-萘啶-7-甲酰胺））钠盐在空腹状态下收集的人体胃肠道抽吸物中溶解度的充分预测能力。确定在空腹状态下单剂量给予相当于400和800 mg HA的高（相对于溶解度极限）剂量后，决定HA钠盐（NaA）行为的关键腔内过程。
在8名健康空腹成年人饮用240 ml水后，收集胃和上段小肠的抽吸物。测定NaA和HA在抽吸样品和生物相关介质中的溶解度。在生物相关介质中进行NaA颗粒的溶出实验。使用Stella软件通过计算机模拟评估口服药代动力学预测。
NaA在上胃肠道抽吸液中的平衡溶解度比HA更短暂。生物相关介质中的数据能够充分估计在上胃肠道腔内的溶解度。在生物相关介质中NaA颗粒溶解过程中观察到过饱和现象，随后发生沉淀，但沉淀并未完全恢复到HA的平衡溶解度。基于生理学的药代动力学模型表明，虽然胃内过程对吸收动力学没有显著影响，但溶解动力学、动力学溶解度、径向转运速率以及对于800 mg剂量，小肠中的沉淀动力学对吸收曲线影响最大。
给予NaA后，要充分预测平均血浆曲线，需要考虑区域依赖性溶解速率和/或增溶作用。
