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This study aimed to evaluate the utility of physiologically\u2010based pharmacokinetic (PBPK) modeling in the prediction of gastric pH\u2010mediated drug exposure by using itraconazole, a weak base, as a case. An itraconazole PBPK model was developed on the mechanistic basis of its absorption kinetics in a middle\u2010out manner from a stepwise in vitro<jats:italic>\u2010<\/jats:italic>in vivo extrapolation to in vivo refinement. Afterward, an independent prospective clinical study evaluating gastric pH and itraconazole pharmacokinetics (PKs) under normal gastric acidity and esomeprazole\u2010induced gastric hypoacidity was conducted for model validation. Validation was performed by comparing the predicted data with the clinical observations, and the valid model was subsequently applied to predict PK changes under achlorhydria. The developed itraconazole PBPK model showed reasonable reproducibility for gastric pH\u2010mediated exposure observed in the clinical investigation. Based on the model\u2010based simulations, itraconazole exposure was expected to be decreased up to 65% under achlorhydria, and furthermore, gastric pH\u2010mediated exposure could be mechanistically interpreted according to sequential variation in total solubility, dissolution, and absorption. This study suggested the utility of PBPK modeling in the prediction of gastric pH\u2010mediated exposure, especially for drugs whose absorption is susceptible to gastric pH. Our findings will serve as a leading model for further mechanistic assessment of exposure depending on gastric pH for various drugs, ultimately contributing to personalized pharmacotherapy.<\/jats:p>","DOI":"10.1002\/psp4.12959","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T04:10:40Z","timestamp":1679890240000},"page":"865-877","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Prediction of gastric <scp>pH<\/scp>\u2010mediated drug exposure using physiologically\u2010based pharmacokinetic modeling: A case study of itraconazole"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2581-349X","authenticated-orcid":false,"given":"Eunsol","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics Seoul National University College of Medicine and Hospital  101 Daehak\u2010ro, Jongno\u2010gu Seoul 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