Abstract PS3-09-15: Ribociclib drug-drug interaction and concomitant medication management in early and advanced breast cancer patients

Abstract Background: Ribociclib is approved for the treatment of HR+/HER2- advanced or metastatic breast cancer (ABC) in combination with an aromatase inhibitor or fulvestrant, and more recently, for the adjuvant treatment of HR+/HER2- stage II and III early breast cancer (EBC) at high risk of recurrence, with the starting dose of 600 mg in ABC and 400mg in EBC. The DDI profile of ribociclib has been previously characterized 1,2. Ribociclib is a strong to moderate cytochrome P450 (CYP) CYP3A4 inhibitor at 600 mg and 400 mg, respectively, and thus caution is recommended for concomitant use with sensitive CYP3A4 substrates with a narrow therapeutic index. Ribociclib is also a CYP3A4 substrate, and concomitant use with strong inhibitors or inducers of CYP3A4 should be avoided. Methods: The DDI profile of ribociclib and physiology-based pharmacokinetic modeling (PBPK) modeling were utilized to assess the DDI between ribociclib and the commonly used concomitant medications that are statins, antidepressants/antipsychotics, and corticosteroids. Results: There is no overall DDI risk for the class of statins with ribociclib. The effect of ribociclib on rosuvastatin, pravastatin, pitavastatin, and fluvastatin is considered minor with no clinical relevance, since these statins are not sensitive CYP3A4 substrates. Only the statins with substantial metabolism by CYP3A4, such as simvastatin, lovastatin and atorvastatin, may have increased exposure upon co-medication with ribociclib 400 or 600 mg. No clinically relevant DDI is expected for commonly used antidepressants/antipsychotics, such as citalopram, escitalopram, fluoxetine, mirtazapine, sertraline, trazodone, venlafaxine, aripiprazole, olanzapine and cariprazine, when co-administered with ribociclib 400 mg or 600 mg. Quetiapine is a CYP3A4 substrate and its exposure may increase approximately 2-3-fold when co-administered with ribociclib 400 or 600 mg. Systemically administered corticosteroids which induce CYP3A4, such as dexamethasone, may reduce ribociclib exposure if they are used chronically. The extent of the decrease of ribociclib exposure depends on the dexamethasone dose and doses of 5 mg or lower are not expected to have clinically relevant DDI. Dexamethasone is also a CYP3A4 substrate, and its exposure may be increased (2-fold) when co-administered with 400 or 600 mg ribociclib. DDI with ribociclib is not expected for corticosteroids that are administered non-systemically (e.g. topical, inhaled, eye drop, or local injection). Conclusion: No clinically relevant DDI with ribocicilib is anticipated for commonly used statins or antidepressants/antipsychotics, except simvastatin, lovastatin, atorvastatin and quetiapine, which are substantially metabolized by CYP3A4. Systemic corticosteroids that are CYP3A inducers and/or substrates such as dexamethasone should be used for a short duration and monitored for their adverse effects when co-administrated with ribociclib. References: 1. Untch M. et al, Ribociclib in Early Breast Cancer: Drug-Drug Interaction and Organ Impairment Assessments, European Society for Medical Oncology (ESMO) Breast Cancer Conference, Munich, Germany, May 14-17, 2025 2. Samant T. et al, Ribociclib Drug-Drug Interactions - Clinical Evaluations and PBPK Modeling Guiding Current Drug Labeling, Clin Pharmacol Ther. 2020, 108 (3): 575-585. Citation Format: Y. Ji, F. Huth, L. Santarsiero, J. P. Zarate, H. Schiller. Ribociclib drug-drug interaction and concomitant medication management in early and advanced breast cancer patients abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-09-15.