Assessment of CYP3A-mediated drug interaction via cytokine (IL-6) elevation for mosunetuzumab using physiologically-based pharmacokinetic modeling.
Autor: | Chen Y; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California, USA., Ma F; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California, USA., Jones N; Clinical Science, Genentech, Inc., South San Francisco, California, USA., Deng R; Clinical Pharmacology, Genentech, Inc., South San Francisco, California, USA., Li C; Clinical Pharmacology, Genentech, Inc., South San Francisco, California, USA., Li CC; Clinical Pharmacology, Genentech, Inc., South San Francisco, California, USA. |
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Jazyk: | angličtina |
Zdroj: | CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2024 Feb; Vol. 13 (2), pp. 234-246. Date of Electronic Publication: 2023 Dec 04. |
DOI: | 10.1002/psp4.13073 |
Abstrakt: | Mosunetuzumab is a CD3/CD20 bispecific antibody. As an on-target effect, transient elevation of interleukin-6 (IL-6) occurs in early treatment cycles. A physiologically-based pharmacokinetic (PBPK) model was developed to assess potential drug interaction caused by IL-6 enzyme suppression on cytochrome P450 3A (CYP3A) during mosunetuzumab treatment. The model's performance in predicting IL-6 CYP3A suppression and subsequent drug-drug interactions (DDIs) was verified using existing clinical data of DDIs caused by chronic and transient IL-6 elevation. Sensitivity analyses were performed for a complete DDI risk assessment. The IL-6 concentration- and time-dependent CYP3A suppression during mosunetuzumab treatment was simulated using PBPK model with incorporation of in vitro IL-6 inhibition data. At clinically approved doses/regimens, the DDI at maximum CYP3A suppression was predicted to be a midazolam maximum drug concentration in plasma (C (© 2023 Genentech. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.) |
Databáze: | MEDLINE |
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