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

Ningxia Liang; Sufeng Zhou; Tongtong Li; Zeru Zhang; Tangping Zhao; Run Li; Mingfeng Li; Feng Shao; Guangji Wang; Jianguo Sun

doi:10.1016/j.ejps.2023.106534

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

Eur J Pharm Sci. 2023 Oct 1:189:106534. doi: 10.1016/j.ejps.2023.106534. Epub 2023 Jul 20.

Authors

Ningxia Liang¹, Sufeng Zhou², Tongtong Li³, Zeru Zhang⁴, Tangping Zhao³, Run Li⁵, Mingfeng Li⁵, Feng Shao⁶, Guangji Wang⁷, Jianguo Sun⁸

Affiliations

¹ Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Clinical Pharmacology, School of Pharmacy College, Nanjing Medical University, Nanjing 211166, China.
² Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
³ Department of Clinical Pharmacology, School of Pharmacy College, Nanjing Medical University, Nanjing 211166, China; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
⁴ School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
⁵ Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
⁶ Department of Clinical Pharmacology, School of Pharmacy College, Nanjing Medical University, Nanjing 211166, China; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China. Electronic address: jsphshaofeng@hotmail.com.
⁷ Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: guangjiwang@hotmail.com.
⁸ Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jgsun@cpu.edu.cn.

PMID: 37480962
DOI: 10.1016/j.ejps.2023.106534

Abstract

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.

Keywords: Amoxicillin; Anaprazole; Clarithromycin; Drug-drug interactions; Physiologically based pharmacokinetics; Proton pump inhibitor.

MeSH terms

Amoxicillin / adverse effects
Amoxicillin / pharmacokinetics
Clarithromycin / adverse effects
Drug Interactions
Helicobacter Infections* / drug therapy
Helicobacter pylori*
Humans
Models, Biological

Substances

Clarithromycin
Amoxicillin