Physiologically based pharmacokinetic modeling to assess the drug-drug interactions of anaprazole with clarithromycin and amoxicillin in patients undergoing eradication therapy of H. pylori infection,European Journal of Pharmaceutical Sciences

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Physiologically based pharmacokinetic modeling to assess the drug-drug interactions of anaprazole with clarithromycin and amoxicillin in patients undergoing eradication therapy of H. pylori infection
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2023-07-20 , DOI: 10.1016/j.ejps.2023.106534
Ningxia Liang ₁ , Sufeng Zhou ₂ , Tongtong Li ₃ , Zeru Zhang ₄ , Tangping Zhao ₃ , Run Li ₅ , Mingfeng Li ₅ , Feng Shao ₃ , Guangji Wang ₅ , Jianguo Sun ₅

Affiliation

Objective

This study aimed to assess the pharmacokinetic (PK) interactions of anaprazole, clarithromycin, and amoxicillin using physiologically based pharmacokinetic (PBPK) models.

Methods

The PBPK models for anaprazole, clarithromycin, and amoxicillin were constructed using the GastroPlus™ software (Version 9.7) based on the physicochemical data and PK parameters obtained from literature, then were optimized and validated in healthy subjects to predict the plasma concentration-time profiles of these three drugs and assess the predictive performance of each model. According to the analysis of the properties of each drug, the developed and validated models were applied to evaluate potential drug-drug interactions (DDIs) of anaprazole, clarithromycin, and amoxicillin.

Results

The developed PBPK models properly described the pharmacokinetics of anaprazole, clarithromycin, and amoxicillin well, and all predicted PK parameters (C_max,ss, AUC_0-τ,ss) ratios were within 2.0-fold of the observed values. Furthermore, the application of these models to predict the anaprazole-clarithromycin and anaprazole-amoxicillin DDIs demonstrates their good performance, with the predicted DDI C_max,ss ratios and DDI AUC_0-τ,ss ratios within 1.25-fold of the observed values, and all predicted DDI C_max,ss, and AUC_0-τ,ss ratios within 2.0-fold. The simulated results show no need to adjust the dosage when co-administered with anaprazole in patients undergoing eradication therapy of H. pylori infection since the dose remained in the therapeutic range.

Conclusion

The whole-body PBPK models of anaprazole, clarithromycin, and amoxicillin were built and qualified, which can predict DDIs that are mediated by gastric pH change and inhibition of metabolic enzymes, providing a mechanistic understanding of the DDIs observed in the clinic of clarithromycin, amoxicillin with anaprazole.

中文翻译：

基于生理学的药代动力学模型，用于评估接受幽门螺杆菌感染根除治疗的患者中阿纳拉唑与克拉霉素和阿莫西林的药物相互作用

客观的

本研究旨在使用基于生理的药代动力学 (PBPK) 模型评估阿纳拉唑、克拉霉素和阿莫西林的药代动力学 (PK) 相互作用。

方法

根据文献中获得的理化数据和 PK 参数，使用 GastroPlus™ 软件（版本 9.7）构建阿纳拉唑、克拉霉素和阿莫西林的 PBPK 模型，然后在健康受试者中进行优化和验证，以预测这些药物的血浆浓度-时间曲线。这三种药物并评估每个模型的预测性能。根据对每种药物特性的分析，开发和验证的模型用于评估阿纳拉唑、克拉霉素和阿莫西林的潜在药物相互作用（DDI）。

结果

开发的 PBPK 模型很好地描述了阿纳拉唑、克拉霉素和阿莫西林的药代动力学，所有预测的 PK 参数（C _max,ss、AUC _0-τ,ss）比率均在观察值的 2.0 倍以内。此外，应用这些模型来预测阿纳拉唑-克拉霉素和阿纳拉唑-阿莫西林 DDI 表现出良好的性能，预测的 DDI C _max,ss比率和 DDI AUC _0-τ,ss比率在观测值的 1.25 倍以内，所有预测的 DDI C _max,ss和 AUC _0-τ,ss比率均在 2.0 倍以内。模拟结果表明，在接受幽门螺杆菌感染根除治疗的患者中与阿纳拉唑联合给药时无需调整剂量，因为剂量仍在治疗范围内。