{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T14:29:06Z","timestamp":1777991346246,"version":"3.51.4"},"reference-count":43,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T00:00:00Z","timestamp":1692576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100019081","name":"Science and Technology Program of Hunan Province","doi-asserted-by":"publisher","award":["2022RC1229"],"award-info":[{"award-number":["2022RC1229"]}],"id":[{"id":"10.13039\/501100019081","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82202398"],"award-info":[{"award-number":["82202398"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Methotrexate (MTX) is recognized for its potential to induce hepatotoxicity, commonly manifested by elevated alanine aminotransferase (ALT) levels. However, the quantitative relationship between the pharmacokinetics (PK) of MTX and ALT\u2010based hepatotoxicity remains unclear. This study aimed to develop a semimechanistic PK\/pharmacodynamic (PD) model to characterize the MTX\u2010induced hepatotoxicity based on ALT in paediatric patients with acute lymphoid leukaemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A retrospective study was conducted on paediatric patients who received high\u2010dose (3\u20135\u00a0g\/m<jats:sup>2<\/jats:sup>) MTX treatment. MTX concentrations were assessed at 24\u2010h intervals until the concentration dropped below 0.1\u00a0\u03bcmol\/L. ALT concentrations were measured both before and after MTX administration. A population PK model was initially developed, which was later connected to a semimechanistic hepatotoxicity model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The PK model was developed using 354 MTX concentrations obtained from 51 patients, while the PD model was constructed using 379 ALT concentrations collected from 48 patients. The optimal PK model for MTX consisted of a 2\u2010compartment structure, where body surface area served as a covariate for clearance and central volume of distribution. An indirect response model coupled to a liver injury signal transduction model was developed to describe the dynamics of ALT after MTX administration. The drug effect was adequately described by a linear model, exhibiting considerable interoccasion variability for each treatment session. No significant covariates were identified to have an impact on the PD parameters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A semimechanistic model was developed to describe ALT\u2010based hepatotoxicity of MTX, and it has the potential to serve as a valuable tool for characterizing drug\u2010induced hepatotoxicity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15868","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T08:49:30Z","timestamp":1691398170000},"page":"3637-3647","source":"Crossref","is-referenced-by-count":3,"title":["A semimechanistic pharmacokinetic\/pharmacodynamic model for alanine aminotransferase\u2010based hepatotoxicity of methotrexate in paediatric patients with acute lymphoid leukaemia"],"prefix":"10.1111","volume":"89","author":[{"given":"Qiufen","family":"Yin","sequence":"first","affiliation":[{"name":"Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences Central South University  Changsha China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeneng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences Central South University  Changsha China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minghua","family":"Yang","sequence":"additional","affiliation":[{"name":"Postdoctoral Research Station of Clinical Medicine and Department of Paediatrics, The Third Xiangya Hospital Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Postdoctoral Research Station of Clinical Medicine and Department of Paediatrics, The Third Xiangya Hospital Central South University  Changsha Hunan China"},{"name":"Department of Pharmacy, The Third Xiangya Hospital Central South University  Changsha 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