Drug-Drug interactions and special considerations in breast cancer patients treated with CDK4/6 inhibitors: A comprehensive review

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have reshaped the treatment paradigm of hormone receptor positive (HR + )/HER2-negative breast cancer in both adjuvant and metastatic settings. However, their metabolism via the cytochrome P450 (CYP3A4) pathway poses a high risk of clinically relevant drug-drug interactions (DDIs), requiring vigilant therapeutic strategies. This review provides a comprehensive analysis of the pharmacokinetics, metabolism, and interaction profiles of palbociclib, ribociclib, and abemaciclib, emphasizing their differential DDI risks. Among these agents, ribociclib has been associated with a higher risk of QTc prolongation and CYP3A4-mediated interactions in some studies, whereas abemaciclib demonstrates a relatively favorable DDI profile. However, data remain limited and are largely derived from indirect comparisons or pharmacovigilance analyses. We further examine the clinical implications of drug-drug interactions with frequently co-prescribed agents, including proton pump inhibitors, antifungal medications, anticoagulants, and lipid-lowering therapies. Practical recommendations regarding drug selection, therapeutic drug monitoring, and dose adjustment are discussed with attention to the individual characteristics of each CDK4/6i. Dose modifications and monitoring in patients with renal or hepatic impairment are also discussed. Emerging pharmacogenomic data suggest that genetic polymorphisms in CYP3A4 and ABCG2 influence drug exposure and toxicity, reinforcing the need for personalized treatment approaches. As the use of CDK4/6i expands across different breast cancer settings, addressing DDIs through precision medicine strategies such as pharmacogenomic profiling, physiologically based pharmacokinetic modeling, and artificial intelligence-guided clinical support will be essential to personalize therapy and optimize safety.