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The PBPK DDI analysis was conducted using the U.S. Food and Drug Administration (FDA) DDI index drugs (probe substrates) midazolam, omeprazole and digoxin for CYP3A4, CYP2C19 and P\u2010gp, respectively. Qualified and documented PBPK models of the probe substrates have been adopted from an open\u2010source online model database.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The PBPK model for treosulfan, based on both in vitro and in vivo data, was able to predict the plasma concentration\u2010time profiles and exposure levels of treosulfan applied for a standard conditioning treatment. Medium and low potentials for DDI on CYP3A4 (maximum area under the concentration\u2010time curve ratio (AUCR<jats:sub>max<\/jats:sub>\u2009=\u20092.23) and CYP2C19 (AUCR<jats:sub>max<\/jats:sub>\u2009=\u20091.6) were predicted, respectively, using probe substrates midazolam and omeprazole. Treosulfan was not predicted to cause a DDI on P\u2010gp.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Medicinal products with a narrow therapeutic index (eg, digoxin) that are substrates for CYP3A4, CYP2C19 or P\u2010gp should not be given during treatment with treosulfan. However, considering the comprehensive treosulfan\u2010based conditioning treatment schedule and the respective pharmacokinetic properties of the concomitantly used drugs (eg, half\u2010life), the potential for interaction on all evaluated mechanisms would be low (AUCR\u2009&lt;\u20091.25), if concomitantly administered drugs are dosed either 2\u00a0hours before or 8\u00a0hours after the 2\u2010hour intravenous infusion of treosulfan.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15081","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T02:09:46Z","timestamp":1631585386000},"page":"1722-1734","source":"Crossref","is-referenced-by-count":3,"title":["Evaluation of the drug\u2010drug interaction potential of treosulfan using a physiologically\u2010based pharmacokinetic modelling approach"],"prefix":"10.1111","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1046-7651","authenticated-orcid":false,"given":"Stephan","family":"Schaller","sequence":"first","affiliation":[{"name":"esqLABS GmbH  Saterland Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5555-8771","authenticated-orcid":false,"given":"Frederico S.","family":"Martins","sequence":"additional","affiliation":[{"name":"esqLABS GmbH  Saterland Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8199-9869","authenticated-orcid":false,"given":"Pavel","family":"Balazki","sequence":"additional","affiliation":[{"name":"esqLABS GmbH  Saterland Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4214-1816","authenticated-orcid":false,"given":"Sonja","family":"B\u00f6hm","sequence":"additional","affiliation":[{"name":"medac Gesellschaft f\u00fcr klinische Spezialpr\u00e4parate mbH  Wedel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4502-2847","authenticated-orcid":false,"given":"Joachim","family":"Baumgart","sequence":"additional","affiliation":[{"name":"medac Gesellschaft f\u00fcr klinische Spezialpr\u00e4parate mbH  Wedel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralf A.","family":"Hilger","sequence":"additional","affiliation":[{"name":"West German Cancer Centre University Hospital Essen  Essen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5050-220X","authenticated-orcid":false,"given":"Dietrich W.","family":"Beelen","sequence":"additional","affiliation":[{"name":"West German Cancer Centre University Hospital Essen  Essen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Hemmelmann","sequence":"additional","affiliation":[{"name":"medac Gesellschaft f\u00fcr klinische Spezialpr\u00e4parate mbH  Wedel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4324-5820","authenticated-orcid":false,"given":"Arne","family":"Ring","sequence":"additional","affiliation":[{"name":"medac Gesellschaft f\u00fcr klinische Spezialpr\u00e4parate mbH  Wedel Germany"},{"name":"Department for Mathematical Statistics and Actuarial Science University of the Free State Nelson Mandela Drive  Bloemfontein South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"Public Health \u2013 European Commission.Union Register of medicinal products. 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