Evaluating the impact of acid-reducing agents on drug absorption using biorelevant in vitro tools and PBPK modeling - Case example dipyridamole.
Evaluating the impact of acid-reducing agents on drug absorption using biorelevant in vitro tools and PBPK modeling - Case example dipyridamole.
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使用生物相关体外工具和 PBPK 模型评估酸还原剂对药物吸收的影响 - 案例示例双嘧达莫。
DOI：
10.1016/j.ejps.2021.105750
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
J. Dressman
中科院分区：
文献类型：
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作者：
Domagoj Segregur;Ric Barker;J. Mann;Andrea Moir;Eva M. Karlsson;D. Turner;S. Arora;J. Dressman
研究背景体外硅方法已成为评价代谢性药物相互作用（DDI）和避免疗效降低和副作用增加的重要工具。DDI的另一个重要类型是酸还原剂（ARA）的共同治疗对药物药代动力学的影响，由于胃pH值的变化，特别是对于难溶性弱碱性drugs. MethodsOne阶段，两个阶段和转移溶出度实验与双嘧达莫片使用新的生物相关介质代表ARA的效果进行，结果再加上PBPK模型。临床药代动力学数据进行了比较，从PBPK模型的模拟和TIM-1实验，一个evolvedin vitrosystem，旨在模拟生理学在上消化道。ResultsTwo-stage和转移实验证实，thesin vitrosetups往往高估的程度，双嘧达莫沉淀中发生的pepsinesin体内。因此，在升高的胃pH条件下的一阶段溶出试验的数据被用作ARA/双嘧达莫相互作用的PBPK建模的输入。使用代表ARA效应的培养基结合PBPK模型，成功地将ARA效应纳入体内试验。作为一种替代方案，TIM-1系统与胃pH值调整，以模拟ARA预处理可以用来预测ARA对双嘧达莫的药代动力学的影响。ConclusionDrug-drug interactions of dipyridamole with ARA were simulated well with a combination of dissolution experiment using bioreactive media representing the gastric environment after a ARA treatment with the PBPK model.调整TIM-1模型，以反映ARA相关的胃pH值的变化也成功地预测了相互作用。应使用更广泛的药物对这两种预测ARA相关DDI的方法进行进一步测试，以验证其在此方面的实用性。
BackgroundIn vitroandin silicomethods have become an essential tool in assessing metabolic drug-drug interactions (DDI) and avoiding reduced efficacy and increased side-effects. Another important type of DDI is the impact of acid-reducing agent (ARA) co-therapy on drug pharmacokinetics due to changes in gastric pH, especially for poorly soluble weakly basic drugs.MethodsOne-stage, two-stage and transfer dissolution experiments with dipyridamole tablets using novel biorelevant media representing the ARA effect were conducted and the results were coupled with a PBPK model. Clinical pharmacokinetic data were compared with the simulations from the PBPK model and with output from TIM-1 experiments, an evolvedin vitrosystem which aims to simulate the physiology in the upper GI tract.ResultsTwo-stage and transfer experiments confirmed that thesein vitroset-ups tend to overestimate the extent of dipyridamole precipitation occurring in the intestinesin vivo. Consequently, data from one-stage dissolution testing under elevated gastric pH conditions were used as an input for PBPK modeling of the ARA/dipyridamole interaction. Using media representing the ARA effect in conjunction with the PBPK model, the ARA effect observedin vivowas successfully bracketed. As an alternative, the TIM-1 system with gastric pH values adjusted to simulate ARA pre-treatment can be used to forecast the ARA effect on dipyridamole pharmacokinetics.ConclusionDrug-drug interactions of dipyridamole with ARA were simulated well with a combination of dissolution experiments using biorelevant media representing the gastric environment after an ARA treatment together with the PBPK model. Adjustment of the TIM-1 model to reflect ARA-related changes in gastric pH was also successful in forecasting the interaction. Further testing of both approaches for predicting ARA-related DDIs using a wider range of drugs should be conducted to verify their utility for this purpose.