{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:51:43Z","timestamp":1791438703998,"version":"4.3.3"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T00:00:00Z","timestamp":1681948800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:p>Failure to perform adequate dose adjustment in patients with liver cirrhosis may be associated with increased toxicity. We compared the prediction of area under the curve (AUC) and clearance for the six compounds of the Basel phenotyping cocktail (caffeine, efavirenz, flurbiprofen, omeprazole, metoprolol, and midazolam) using a well\u2010known physiology\u2010based pharmacokinetic approach (physiologically\u2010based pharmacokinetic [PBPK] approach, Simcyp) and a novel top\u2010down method based on the systemic clearance in healthy volunteers adjusted for markers of liver and renal dysfunction (\u201ctop\u2010down approach\u201d). With few exceptions, plasma concentration\u2010time curves were accurately predicted by the PBPK approach. In comparison to the measured AUC and clearance of these drugs in patients with liver cirrhosis and healthy controls, except for efavirenz, the estimates of both approaches were within two standard deviations of the mean for total and free drug concentrations. For both approaches, a correction factor for dose adjustment in patients with liver cirrhosis could be calculated for the drugs administered. AUCs calculated using the adjusted doses were comparable to the AUCs measured in control subjects, with slightly more accurate predictions generated by the PBPK approach. For drugs with a free fraction &lt;\u200950%, predictions using free drug concentrations were more accurate than with total drug concentrations. In conclusion, both methods provided good qualitative predictions of the changes by liver cirrhosis in the pharmacokinetics of the six compounds investigated. The top\u2010down approach is easier to implement but the PBPK approach predicted changes in drug exposure more accurately than the top\u2010down approach and provided reliable estimates for plasma concentrations.<\/jats:p>","DOI":"10.1002\/cpt.2897","type":"journal-article","created":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T14:40:20Z","timestamp":1680705620000},"page":"1346-1358","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Dose Adjustment in Patients with Liver Cirrhosis \u2013 Comparison of Two Different Modeling Approaches"],"prefix":"10.1111","volume":"113","author":[{"given":"Agustos C.","family":"Ozbey","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences, Roche Pharma Research and Early Development Roche Innovation Center Basel  Basel Switzerland"},{"name":"Department of Drug Delivery and Disposition KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2789-4377","authenticated-orcid":false,"given":"Fabio","family":"Bachmann","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology &amp; Toxicology University Hospital Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7811-3932","authenticated-orcid":false,"given":"Urs","family":"Duthaler","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology &amp; Toxicology University Hospital Basel  Basel Switzerland"},{"name":"Department of Clinical Research University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3525-7351","authenticated-orcid":false,"given":"Pieter","family":"Annaert","sequence":"additional","affiliation":[{"name":"Department of Drug Delivery and Disposition KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7331-3559","authenticated-orcid":false,"given":"Stephen","family":"Fowler","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences, Roche Pharma Research and Early Development Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Umehara","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences, Roche Pharma Research and Early Development Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Parrott","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences, Roche Pharma Research and Early Development Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Kr\u00e4henb\u00fchl","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology &amp; Toxicology University Hospital Basel  Basel Switzerland"},{"name":"Department of Clinical Research University of Basel  Basel Switzerland"},{"name":"Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,20]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200528060-00005"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-013-1502-z"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199529050-00005"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-022-01119-0"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1989.tb03327.x"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.27.2.190"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-015-0288-9"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2125"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.2165\/11318160-000000000-00000"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-013-0115-0"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2016.08.043"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840010617"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-150-9-200905050-00006"},{"key":"e_1_2_9_14_1","first-page":"36","article-title":"Foreign substances as indicators of liver function","volume":"19","author":"Preisig R.","year":"1985","journal-title":"Schweiz. 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