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University","award":["XKTJ-XK202406"],"award-info":[{"award-number":["XKTJ-XK202406"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Objective: This study assessed the pharmacokinetic (PK) interactions between clarithromycin (a P-glycoprotein [P-gp] inhibitor) and four direct oral anticoagulants (DOACs) (P-gp substrates) using physiologically based PK (PBPK) models to elucidate the influence of P-gp in the interaction between them. Methods: PBPK models for clarithromycin, DABE\u2013dabigatran (DAB), rivaroxaban, apixaban, and edoxaban were constructed using GastroPlus\u2122 (version 9.9), based on physicochemical data and PK parameters from the literature. The models were optimized and validated in healthy subjects. We evaluated the predictive performance of the established model and further assessed the impact of P-gp on the PK of the four DOACs. Successfully validated models were then used to evaluate potential drug\u2013drug interactions (DDIs) between clarithromycin and the DOACs. Results: The established PBPK models accurately described the PK of clarithromycin, DABE\u2013DAB, rivaroxaban, apixaban, and edoxaban. The predicted PK parameters (Cmax, Tmax, AUC0-t) were within 0.5\u20132 times the observed values. A sensitivity analysis of P-gp parameters indicated that an increase in P-gp expression was reduced by in vivo exposure to DOACs. The models demonstrated good predictive ability for DDIs between clarithromycin and the anticoagulants, and the ratio of the predicted values to the observed values of Cmax and the area under the curve (AUC) in the DDI state was within the range of 0.5\u20132. Conclusions: Comprehensive PBPK models for clarithromycin, DABE\u2013DAB, rivaroxaban, apixaban, and edoxaban were developed, which can effectively predict DDIs mediated by P-gp\u2019s function. These models provide theoretical support for clinical dose adjustments and serve as a foundation for future PBPK model development for DOACs under specific pathological conditions.<\/jats:p>","DOI":"10.3390\/pharmaceutics16111449","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T12:49:56Z","timestamp":1731415796000},"page":"1449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Evaluation of Drug\u2013Drug Interactions Between Clarithromycin and Direct Oral Anticoagulants Using Physiologically Based Pharmacokinetic Models"],"prefix":"10.3390","volume":"16","author":[{"given":"Zhuan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"College of Pharmaceutical Science, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0649-3147","authenticated-orcid":false,"given":"Yuchen","family":"Qu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yewen","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"College of Pharmaceutical Science, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0811-3267","authenticated-orcid":false,"given":"Yunli","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1093\/eurheartj\/eht280","article-title":"Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060","volume":"34","author":"Krijthe","year":"2013","journal-title":"Eur. 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