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The simulated plasma concentrations closely matched the observed data from non\u2010obese, morbidly obese, and post\u2010gastric bypass populations. Obesity significantly reduces CYP3A4 and CYP2C19 activities, as reflected by the metabolic ratio [omeprazole sulphone]\/[omeprazole] and [5\u2010hydroxy\u2010omeprazole]\/[omeprazole]. The morbidly obese model accounted for the down\u2010regulation of CYP2C19 and CYP3A4 to recapitulate the observed data. Sensitivity analysis showed that intestinal CYP3A4, gastric pH, small intestine bypass, and the delay in bile release do not have a major influence on omeprazole exposure. Hepatic CYP3A4 had a significant impact on the AUC of (<jats:italic>S<\/jats:italic>)\u2010omeprazole, while hepatic CYP2C19 affected both (<jats:italic>R<\/jats:italic>)\u2010 and (<jats:italic>S<\/jats:italic>)\u2010omeprazole AUC. After gastric bypass surgery, the activity of CYP3A4 and CYP2C19 is restored. The PBPK model was linked to a mechanism\u2010based PD model to assess the effect of omeprazole on intragastric pH. Following 40\u2009mg omeprazole, the mean intragastric pH was 4.3, 4.6, and 6.6 in non\u2010obese, obese, and post\u2010gastric bypass populations, and the daily time with pH &gt;4 was 14.7, 16.4, and 24\u2009h. Our PBPK\/PD approach provides a comprehensive understating of the impact of obesity and weight loss on CYP3A4 and CYP2C19 activity and omeprazole pharmacokinetics. Given that simulated intragastric pH is relatively high in post\u2010RYGB patients, irrespective of the dose of omeprazole, additional clinical outcomes are imperative to assess the effect of proton pump inhibitor in preventing marginal ulcers in this population.<\/jats:p>","DOI":"10.1002\/psp4.13189","type":"journal-article","created":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T03:44:14Z","timestamp":1719287054000},"page":"1528-1541","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Impact of obesity and roux\u2010en\u2010Y gastric bypass on the pharmacokinetics of (<i>R<\/i>)\u2010 and (<i>S<\/i>)\u2010omeprazole and intragastric <scp>pH<\/scp>"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2782-0389","authenticated-orcid":false,"given":"Leandro F.","family":"Pippa","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, Center for Pharmacometrics and 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