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.
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 max ) and area under the plasma drug concentration-time curve (AUC) ratio of 1.17 and 1.37, respectively. At the 95th percentile of IL-6 concentration level or when gut CYP3A suppression was considered, the predicted DDI risk for mosunetuzumab remained low (<2-fold). The PBPK-based DDI predictions informed the mosunetuzumab product label to monitor, in early cycles, the concentrations and toxicities for sensitive CYP3A substrates with narrow therapeutic windows.
(© 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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