التفاصيل البيبلوغرافية
| العنوان: |
Prediction of CYP Down Regulation after Tusamitamab Ravtansine Administration (a DM4‐Conjugate), Based on an In Vitro–In Vivo Extrapolation Approach. |
| المؤلفون: |
Pouzin, Clemence, Teutonico, Donato, Fagniez, Nathalie, Ziti‐Ljajic, Samira, Perreard‐Dumaine, Anne, Pardon, Magalie, Klieber, Sylvie, Nguyen, Laurent |
| المصدر: |
Clinical Pharmacology & Therapeutics; Feb2024, Vol. 115 Issue 2, p278-287, 10p |
| مصطلحات موضوعية: |
CYTOCHROME P-450, EXTRAPOLATION, ANTIBODY-drug conjugates, CYTOCHROME P-450 CYP3A, DRUG interactions, TUBULINS, CYTOCHROME c |
| مستخلص: |
Tusamitamab ravtansine is an antibody‐drug conjugate (ADC) composed of a humanized monoclonal antibody (IgG1) and DM4 payload. Even if DM4 and its main metabolite methyl‐DM4 (Me‐DM4) circulate at low concentrations after ADC administration, their potential as perpetrators of cytochrome P450 mediated drug–drug interaction was assessed. In vitro studies in human hepatocytes indicated that Me‐DM4 elicited a clear concentration‐dependent down regulation of cytochrome P450 enzymes (CYP3A4, 1A2, and 2B6). Because DM4 was unstable under the incubation conditions studied, the in vitro constants could not be determined for this entity. Thus, to predict the clinical relevance of this observed downregulation, an in vitro‐in vivo 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‐DM4. This approach describes the time course of decreasing CYP3A4, 1A2, and 2B6 enzyme amounts as a function of circulating concentrations of DM4 and Me‐DM4 predicted from a population PK model. The developed IVIVE‐PK model showed that the highest CYP abundance decrease was observed for CYP3A4, with a transient reduction of < 10% from baseline. The impact on midazolam exposure, as probe substrate of CYP3A, was then simulated based on a physiologically‐based 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 in vitro downregulation of CYPs by Me‐DM4 is not expected to have relevant clinical impact. [ABSTRACT FROM AUTHOR] |
|
Copyright of Clinical Pharmacology & Therapeutics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
Full Text Finder