{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T12:41:49Z","timestamp":1771332109608,"version":"3.50.1"},"reference-count":37,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,12,3]],"date-time":"2023-12-03T00:00:00Z","timestamp":1701561600000},"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":[[2024,2]]},"abstract":"<jats:p>Tusamitamab ravtansine is an antibody\u2010drug conjugate (ADC) composed of a humanized monoclonal antibody (IgG1) and DM4 payload. Even if DM4 and its main metabolite methyl\u2010DM4 (Me\u2010DM4) circulate at low concentrations after ADC administration, their potential as perpetrators of cytochrome P450 mediated drug\u2013drug interaction was assessed. <jats:italic>In vitro<\/jats:italic> studies in human hepatocytes indicated that Me\u2010DM4 elicited a clear concentration\u2010dependent down regulation of cytochrome P450 enzymes (CYP3A4, 1A2, and 2B6). Because DM4 was unstable under the incubation conditions studied, the <jats:italic>in vitro<\/jats:italic> constants could not be determined for this entity. Thus, to predict the clinical relevance of this observed downregulation, an <jats:italic>in vitro\u2010in vivo<\/jats:italic> extrapolation (IVIVE) pharmacokinetic (PK) based approach was developed. To mitigate model prediction errors and because of their similar inhibitory effect on tubulin polymerization, the same downregulation constants were used for DM4 and Me\u2010DM4. This approach describes the time course of decreasing CYP3A4, 1A2, and 2B6 enzyme amounts as a function of circulating concentrations of DM4 and Me\u2010DM4 predicted from a population PK model. The developed IVIVE\u2010PK model showed that the highest CYP abundance decrease was observed for CYP3A4, with a transient reduction of &lt;\u200910% from baseline. The impact on midazolam exposure, as probe substrate of CYP3A, was then simulated based on a physiologically\u2010based PK static method. The maximal CYP3A4 abundance reduction was associated with a predicted midazolam area under the curve (AUC) ratio of 1.14. To conclude, the observed <jats:italic>in vitro<\/jats:italic> downregulation of CYPs by Me\u2010DM4 is not expected to have relevant clinical impact.<\/jats:p>","DOI":"10.1002\/cpt.3102","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T17:27:38Z","timestamp":1700069258000},"page":"278-287","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Prediction of CYP Down Regulation after Tusamitamab Ravtansine Administration (a\u00a0DM4\u2010Conjugate), Based on an <i>In Vitro\u2013In Vivo<\/i> Extrapolation Approach"],"prefix":"10.1002","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3081-8201","authenticated-orcid":false,"given":"Clemence","family":"Pouzin","sequence":"first","affiliation":[{"name":"Sanofi R&amp;D, Pharmacokinetics Dynamics and Metabolism Department  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donato","family":"Teutonico","sequence":"additional","affiliation":[{"name":"Sanofi R&amp;D, Pharmacokinetics Dynamics and Metabolism Department  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie","family":"Fagniez","sequence":"additional","affiliation":[{"name":"Sanofi R&amp;D, Pharmacokinetics Dynamics and Metabolism Department  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samira","family":"Ziti\u2010Ljajic","sequence":"additional","affiliation":[{"name":"Sanofi R&amp;D, Pharmacokinetics Dynamics and Metabolism Department  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Perreard\u2010Dumaine","sequence":"additional","affiliation":[{"name":"Sanofi R&amp;D, Biomarkers and Clinical Bioanalysis  Paris 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