Abstract
Purpose
Iberdomide is a cereblon E3 ligase modulator capable of redirecting the protein degradation machinery of the cell towards the elimination of target proteins potentially driving therapeutic effects. In vitro studies demonstrated that iberdomide predominantly undergoes oxidative metabolism mediated by cytochrome P450 (CYP) 3A4/5 but had no notable inhibition or induction of CYP enzymes. Consequently, the potential of iberdomide as a victim of drug-drug interactions (DDI) was evaluated in a clinical study with healthy subjects.
Methods
A total of 33 males and 5 females with 19 subjects per part were enrolled. Part 1 evaluated the pharmacokinetics (PK) of iberdomide alone (0.6 mg) and when administered with the CYP3A and P-gp inhibitor itraconazole (200 mg twice daily on day 1 and 200 once daily on days 2 through 9). Part 2 evaluated the PK of iberdomide alone (0.6 mg) and with CYP3A4 inducer rifampin (600 mg QD days 1 through 13). Plasma concentrations of iberdomide and the active metabolite M12 were determined by validated liquid chromatography-tandem mass spectrometry assay.
Results
Coadministration of iberdomide with itraconazole increased iberdomide peak plasma concentration (Cmax) 17% and area under the concentration curve (AUC) approximately 2.4-fold relative to administration of iberdomide alone. The Cmax and AUC of iberdomide were reduced by approximately 70% and 82%, respectively, when iberdomide was administered with rifampin compared with iberdomide administered alone. Exploratory assessment of metabolite M12 concentrations demonstrated that CYP3A is responsible for M12 formation.
Conclusions
Caution should be taken when coadministering iberdomide with strong CYP3A inhibitors. Coadministration of iberdomide with strong CYP3A inducers is not advised.
Clinical trial registration
Clinical trial identification number is NCT02820935 and was registered in July 2016.
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Acknowledgments
The authors gratefully acknowledge Lisa Liu for the conduct of in vitro CYP inhibition studies described in this manuscript.
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Data requests may be submitted to Celgene, A Bristol-Myers Squibb Company at https://vivli.org/ourmember/celgene/ and must include a description of the research proposal.
Funding
Support for this study and preparation of this manuscript was provided by Bristol-Myers Squibb Company.
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Allison Gaudy wrote the paper, analyzed PK data, and contributed to study design. Christian Atsriku analyzed the in vitro DDI studies data and contributed to study design. Ying Ye contributed to study design and study conduct. Kimberly MacGorman was the sponsor trial manager responsible for study design, conduct, and execution. Liangang Liu was the biostatistician responsible for statistical analysis. Yongjun Xue contributed to bioanalysis of the PK samples. Sekhar Surapaneni managed in vitro DDI studies and bioanalytical analysis. Maria Palmisano was the sponsor medical monitor for the trial.
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Allison Gaudy, Ying Ye, Kimberly MacGorman, Christian Atsriku, Liangang Liu, Yongjun Xue, Sekhar Surapaneni and Maria Palmisano are all full-time employees of Bristol Myers Squibb, and own stock in the company.
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Gaudy, A., Atsriku, C., Ye, Y. et al. Evaluation of iberdomide and cytochrome p450 drug-drug interaction potential in vitro and in a phase 1 study in healthy subjects. Eur J Clin Pharmacol 77, 223–231 (2021). https://doi.org/10.1007/s00228-020-03004-w
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DOI: https://doi.org/10.1007/s00228-020-03004-w