Application of Physiologically-Based Pharmacokinetic Modeling to Predict Gastric pH-Dependent Drug-Drug Interactions for Weak Base Drugs
Application of Physiologically-Based Pharmacokinetic Modeling to Predict Gastric pH-Dependent Drug-Drug Interactions for Weak Base Drugs
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DOI：
10.1002/psp4.12541
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发表时间：
2020-07-31
影响因子：
3.5
通讯作者：
Zhang, Lei
中科院分区：
文献类型：
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作者：
Dong, Zhongqi;Li, Jia;Zhang, Lei
当弱碱性药物与胃酸降解剂(ARAs)联合应用时，易发生药物间相互作用(DDiS)。我们开发了PBPK模型来评估这种pH依赖的DDiS对四种弱碱性药物的潜力，即Tapentadol，darunavir，erlotinib和saxagliptin。这些药物的基于生理的药代动力学(PBPK)模型首先使用口服给药后的药代动力学(PK)数据进行优化，然后用有无食物的其他PK研究的数据进行验证。这些模型随后被用来预测ARA联合给药的DDIS的程度。通过敏感性分析，探讨在ARA存在的情况下，胃pH值对药物暴露的定量预测的影响。结果表明，所建立的PBPK模型可以较好地描述ARA对替替卡那多、达鲁那韦和沙格列汀的PK缺乏的影响，并可以定性地预测ARA减少厄洛替尼吸收的作用。需要更多pH依赖性DDI阳性药物的进一步研究来证实这些发现，并拓宽我们的知识库，以进一步提高PBPK模型在评估pH依赖性DDI潜力方面的应用。
Weak-base drugs are susceptible to drug-drug interactions (DDIs) when coadministered with gastric acid-reducing agents (ARAs). We developed PBPK models to evaluate the potential of such pH-dependent DDIs for four weak-base drugs, i.e., tapentadol, darunavir, erlotinib, and saxagliptin. The physiologically-based pharmacokinetic (PBPK) models of these drugs were first optimized using pharmacokinetic (PK) data following oral administration without ARAs, which were then verified with data from additional PK studies in the presence and absence of food. The models were subsequently used to predict the extent of DDIs with ARA coadministration. Sensitivity analysis was conducted to explore the impact of gastric pH on quantitative prediction of drug exposure in the presence of ARA. The results suggested that the PBPK models developed could adequately describe the lack of the effect of ARA on the PK of tapentadol, darunavir, and saxagliptin and could qualitatively predict the effect of ARA in reducing the absorption of erlotinib. Further studies involving more drugs with positive pH-dependent DDIs are needed to confirm the findings and broaden our knowledge base to further improve the utilization of PBPK modeling to evaluate pH-dependent DDI potential.