Cyclin-dependent kinase (CDK)4/6 inhibitors have transformed the treatment of patients with locally advanced or metastatic hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2–) breast cancer. There are currently 3 CDK4/6 inhibitors approved by the US Food and Drug Administration and European Medicines Agency: ribociclib, palbociclib, and abemaciclib. While shown to be effective, these treatments are associated with drug-drug interaction (DDI) risks, which increase with long-term use. Polypharmacy and drug interactions are not uncommon among patients with breast cancer, especially those who are older, and may limit the therapeutic value of medicines prescribed for the primary disease. Among patients with locally advanced or metastatic breast cancer, opioid analgesics are the most frequently used concomitant medications, followed by antiemetics. Others include additional medications for side effect management, over-the-counter agents, and natural supplements.
Polypharmacy is associated with increased risk for DDIs, medication errors, poor adherence, pill burden, increased toxicity, suboptimal surgical outcomes, and potentially negative clinical outcomes. A study published in late 2023 (N = 115) identified potential DDI risks in 63.5% of patients with HR+, HER2– breast cancer treated with CDK4/6 inhibitors, with over half of these having a major potential DDI. QT prolongation and increased toxicity of the additional drug were the most frequent drug interactions. For patients with locally advanced or metastatic breast cancer, concomitant use of more than 1 drug that prolongs QT further increases the risk of myocardial dysfunction or arrhythmias. An article by Dr Justin Cheng and colleagues suggested that baseline cardiac function be assessed before initiating medications that may contribute to QTc prolongation in patients with breast cancer to help manage this risk.
A recent review article published in Expert Opinion on Drug Metabolism & Toxicology also highlighted cardiac toxicity, as well as hepatotoxicity, with CDK4/6 inhibitors, suggesting that concomitant use of other medications with similar toxicity profiles should be avoided. The authors proposed that toxicity and clinical outcomes with CDK4/6 inhibitors may also be influenced by body mass index, but further research is needed to establish a prognostic relationship between body weight and treatment. The review also discussed the importance of considering the potential interactions of CDK4/6 inhibitors with proton pump inhibitors and CYP3A4 inducers and inhibitors when developing individual treatment plans. To optimize treatment outcomes and minimize risks, regular monitoring and dose adjustments may be necessary.
High level
Increasing awareness of the potential for increased cardiac side effects, decreased efficacy, and increased toxicity with concomitant use of CDK4/6 inhibitors and other treatments can help improve outcomes for patients with breast cancer. Therapeutic drug monitoring and medication therapy management are proposed methods for mitigating DDIs. Involving pharmacists in treatment plan development can play a crucial role in reducing polypharmacy and drug interactions, particularly for older patients who may be more likely to receive concomitant medications.
Ground level
Clinicians prescribing CDK4/6 inhibitors should be aware of polypharmacy and drug interactions, including QT prolongation and increase or decrease in plasma concentration of CDK4/6 inhibitors or additional drugs. Medications such as proton pump inhibitors may interfere with drug absorption, and CYP3A4 inhibitors and inducers may interfere with drug metabolism. When developing individual treatment plans, special consideration should be given to populations at higher risk for polypharmacy, such as older patients with comorbidities.
