{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T03:07:58Z","timestamp":1788404878394,"version":"build-2803163510"},"reference-count":28,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T00:00:00Z","timestamp":1704672000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T00:00:00Z","timestamp":1704672000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:p>\n                    In the past, rifampicin was well\u2010established as strong index CYP3A inducer in clinical drug\u2013drug interaction (DDI) studies. However, due to identified potentially genotoxic nitrosamine impurities, it should not any longer be used in healthy volunteer studies. Available clinical data suggest\u00a0carbamazepine as an alternative to rifampicin as strong index CYP3A4 inducer in clinical DDI studies. Further, physiologically\u2010based pharmacokinetic (PBPK) modeling is a tool with increasing importance to support the DDI risk assessment of drugs during drug development. CYP3A4 induction properties and the safety profile of carbamazepine were investigated in two open\u2010label, fixed sequence, crossover clinical pharmacology studies in healthy volunteers using midazolam as a sensitive index CYP3A4 substrate. Carbamazepine was up\u2010titrated from 100\u2009mg twice daily (b.i.d.) to 200\u2009mg b.i.d., and to a final dose of 300\u2009mg b.i.d. for 10 consecutive days. Mean area under plasma concentration\u2010time curve from zero to infinity (AUC(\n                    <jats:sub>0\u2010\u221e<\/jats:sub>\n                    )) of midazolam consistently decreased by 71.8% (ratio: 0.282, 90% confidence interval (CI): 0.235\u20130.340) and 67.7% (ratio: 0.323, 90% CI: 0.256\u20130.407) in study 1 and study 2, respectively. The effect was adequately described by an internally developed PBPK model for carbamazepine which has been made freely available to the scientific community. Further, carbamazepine was safe and well\u2010tolerated in the investigated dosing regimen in healthy participants. The results demonstrated that the presented design is appropriate for the use of carbamazepine as alternative inducer to rifampicin in DDI studies acknowledging its CYP3A4 inductive potency and safety profile.\n                  <\/jats:p>","DOI":"10.1002\/cpt.3151","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:18:05Z","timestamp":1702858685000},"page":"1025-1032","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Assessment of the CYP3A4 Induction Potential by Carbamazepine: Insights from Two Clinical DDI Studies and PBPK Modeling"],"prefix":"10.1002","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1346-9336","authenticated-orcid":false,"given":"Friederike","family":"Kanefendt","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1108-5719","authenticated-orcid":false,"given":"Andr\u00e9","family":"Dallmann","sequence":"additional","affiliation":[{"name":"Bayer HealthCare SAS, Loos, France, on behalf of Bayer AG, Pharmacometrics\/Modeling and Simulation Systems Pharmacology &amp; Medicine \u2013 PBPK  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0268-2976","authenticated-orcid":false,"given":"Huijun","family":"Chen","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Asia Bayer AG  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Francke","sequence":"additional","affiliation":[{"name":"Translational Medicine Bayer AG  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3462-2163","authenticated-orcid":false,"given":"Tianxing","family":"Liu","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Asia Bayer AG  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Brase","sequence":"additional","affiliation":[{"name":"Translational Medicine Bayer AG  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1170-9392","authenticated-orcid":false,"given":"Sebastian","family":"Frechen","sequence":"additional","affiliation":[{"name":"Systems Pharmacology &amp; Medicine \u2013 PBPK Bayer AG  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4424-6339","authenticated-orcid":false,"given":"Marcus\u2010Hillert","family":"Schultze\u2010Mosgau","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,8]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2018.10.033"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-022-03250-w"},{"issue":"1","key":"e_1_2_10_3_1","first-page":"S160","article-title":"Application of PBPK modeling and simulation for regulatory decision making and its impact on US prescribing information: an update on the 2018\u20102019 submissions to the US FDA's Office of Clinical Pharmacology","volume":"60","author":"Zhang X.","year":"2020","journal-title":"J. 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