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Prediction of CYP down regulation after tusamitamab ravtansine administration (a DM4-conjugate), based on an in-vitro-in-vivo extrapolation approach #533
https://pubmed.ncbi.nlm.nih.gov/37964462/
Pouzin C, Teutonico D, Fagniez N, Ziti-Ljajic S, Perreard-Dumaine A, Pardon M, Klieber S, Nguyen L. Prediction of CYP down regulation after tusamitamab ravtansine administration (a DM4-conjugate), based on an in-vitro-in-vivo extrapolation approach. Clin Pharmacol Ther. 2023 Nov 14. doi: 10.1002/cpt.3102. Epub ahead of print. PMID: 37964462.
Abstract
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 (DDI) 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, 2B6). Since 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 down regulation, an in vitro in vivo extrapolation (IVIVE) PK based approach was developed. To mitigate model prediction errors and because of their similar inhibitory effect on tubulin polymerization, the same down regulation constants were used for DM4 and Me-DM4. This approach describes the time course of decreasing CYP3A4, 1A2, 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 less than 10% from baseline. The impact on midazolam exposure, as probe substrate of CYP3A, was then simulated based on a PBPK static method. The maximal CYP3A4 abundance reduction was associated with a predicted midazolam AUC ratio of 1.14. To conclude, the observed in vitro down regulation of CYPs by Me-DM4 is not expected to have relevant clinical impact.
This article is protected by copyright. All rights reserved.
https://pubmed.ncbi.nlm.nih.gov/37964462/ Pouzin C, Teutonico D, Fagniez N, Ziti-Ljajic S, Perreard-Dumaine A, Pardon M, Klieber S, Nguyen L. Prediction of CYP down regulation after tusamitamab ravtansine administration (a DM4-conjugate), based on an in-vitro-in-vivo extrapolation approach. Clin Pharmacol Ther. 2023 Nov 14. doi: 10.1002/cpt.3102. Epub ahead of print. PMID: 37964462.
Abstract 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 (DDI) 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, 2B6). Since 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 down regulation, an in vitro in vivo extrapolation (IVIVE) PK based approach was developed. To mitigate model prediction errors and because of their similar inhibitory effect on tubulin polymerization, the same down regulation constants were used for DM4 and Me-DM4. This approach describes the time course of decreasing CYP3A4, 1A2, 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 less than 10% from baseline. The impact on midazolam exposure, as probe substrate of CYP3A, was then simulated based on a PBPK static method. The maximal CYP3A4 abundance reduction was associated with a predicted midazolam AUC ratio of 1.14. To conclude, the observed in vitro down regulation of CYPs by Me-DM4 is not expected to have relevant clinical impact.
This article is protected by copyright. All rights reserved.