{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:34:57Z","timestamp":1791480897936,"version":"4.3.4"},"reference-count":49,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T00:00:00Z","timestamp":1694217600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:p>Patho\u2010physiological changes in liver cirrhosis create portacaval shunts that allow blood flow to bypass the hepatic portal vein into the systemic circulation affecting drug pharmacokinetics (PKs). The objectives of this work were to implement a physiologically\u2010based pharmacokinetic (PBPK) framework describing shunted blood flows in virtual patients with differing degrees of liver cirrhosis; and to assess the minimal and full PBPK model's performance using drugs with intermediate to high hepatic extraction. Single dose concentration\u2010time profiles and PK parameters for oral ibrutinib, midazolam, propranolol, and buspirone were simulated in healthy volunteers (HVs) and subjects with cirrhosis (Child\u2010Pugh severity score (CP\u2010A, CP\u2010B, or CP\u2010C)). Model performance was verified by comparing predicted to observed fold\u2010changes in PK parameters between HVs and cirrhotic subjects. The verified model was used to simulate the PK changes for simvastatin in patients with cirrhosis. The predicted area under the curve ratios (AUC<jats:sub>Cirr<\/jats:sub>:AUC<jats:sub>HV<\/jats:sub>) for ibrutinib were 3.38, 6.87, and 11.46 using the minimal PBPK model with shunt and 1.61, 2.58, and 4.33 without the shunt, these compared with observed values of 4.33, 8.14, and 9.04, respectively. For ibrutinib, propranolol, and buspirone, including a shunt in the PBPK model improved the prediction of the AUC<jats:sub>Cirr<\/jats:sub>:AUC<jats:sub>HV<\/jats:sub> and maximum plasma concentration ratios (C<jats:sub>maxCirr<\/jats:sub>:C<jats:sub>maxHV<\/jats:sub>). For midazolam, an intermediate extraction drug, the differences were less clear. Simulated simvastatin dose adjustments in cirrhosis suggested that 20\u2009mg in CP\u2010A and 10\u2009mg in CP\u2010B could be used clinically. A mechanistic model\u2010informed understanding of the anatomic and pathophysiology of cirrhosis will facilitate improved dose prediction and adjustment in this vulnerable population.<\/jats:p>","DOI":"10.1002\/cpt.3032","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T02:48:46Z","timestamp":1692931726000},"page":"1264-1273","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Incorporation and Performance Verification of Hepatic Portal Blood Flow Shunting in Minimal and Full PBPK Models of Liver Cirrhosis"],"prefix":"10.1002","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4387-5689","authenticated-orcid":false,"given":"Ben G.","family":"Small","sequence":"first","affiliation":[{"name":"Certara UK Limited (Simcyp Division)  Sheffield 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