CDK 4/6 inhibitors, which include ribociclib, palbociclib, and abemaciclib, have become the standard of care for patients with hormone receptor–positive (HR+) and human epidermal growth factor receptor 2–negative (HER2-) BC. All three drugs are metabolized via CYP3A4, which metabolizes about 30% to 50% of drugs and is associated with numerous drug-drug interactions (DDIs).
Researchers conducted a retrospective study using electronic health records to determine the prevalence and significance of potential DDIs in BC patients receiving CDK 4/6 inhibitors. The study was performed in a medical outpatient oncology clinic between July 2021 and July 2023 and included all women receiving one of the CDK 4/6 inhibitors for BC. Patients’ profiles were screened using Drugs.com’s Drug Interaction Checker for potential interactions with the other drugs in their regimens. A major DDI was defined as a combination that should be avoided because the risk outweighs the benefit, whereas a moderate DDI is referred to as a combination that usually should be avoided or be used only under special circumstances.
The corrected QT interval (QTc; the QT interval is the time from the start of the Q wave to the end of the T wave made on an ECG) prolongation was based on the Common Terminology Criteria for Adverse Events or CTCAE Version 5.0, which utilized the Bazett’s formula. A normal QTc interval is 450 milliseconds (ms); Grade 1 is a QTc of 450-480 ms; Grade 2 is a QTc of 481-500 ms; Grade 3 is QTc >501 ms; and Grade 4 is torsades de pointes or polymorphic ventricular tachycardia—potentially fatal arrhythmias.
In total, 115 women were enrolled in the study (mean age: 58 years). Within this group, 73% (N = 84) received ribociclib and 27.0% were administered palbociclib (N = 31).
Of these 115 patients, 97.3% (N = 112) were receiving concomitant medications. The median number of medications in this group was 8 (range: 0-25). In the total group, 63.5% (N =73) had a potential DDI with a CDK 4/6 inhibitors. The median number of potential CDK 4/6 inhibitor DDIs was 1 with a range of 0 to 10.
A total of 170 DDIs were identified in the study group, of which 50.5% were considered a potential major DDI and 46.5% were a potential moderate DDI. The investigators examined the potential DDI event frequency and observed that 77 patients (45.2%) had prolongation of their QTc interval (i.e., long QT syndrome) and 44.1% had an increase in the plasma concentration of the second drug, thereby potentially increasing the toxicity of the additional drug (N = 75 patients). Much less common were the potential for an increase in toxicity of the CDK 4/6 inhibitor (nine patients [5.3%]); a decrease in the efficacy of the CDK 4/6 inhibitor (five patients [2.9%]); decrease in the plasma concentration of the additional drug (two patients [1.1%]); and serious potential infection risk (two patients [1.1%]).
Only 28.6% of the study population had a normal QTc interval, whereas evidence was present of grade 1 QTc prolongation in 12.1% (14 patients); grade 2 QTc prolongation in 4.3% (five patients); and grade 3 QTc prolongation in 1.7% (two patients).
DDIs were most likely to occur with the use of ribociclib. Ribociclib was also found to be associated with a higher risk of major DDIs compared with palbociclib. Among the drugs used concomitantly each in a single patient that were associated with grade 2 QTc prolongation were tramadol, granisetron, escitalopram, quetiapine, and hydroxyzine. Grade 3 QTc prolongation was also observed each in a single patient with tramadol and ondansetron.
The most frequent drugs/drug classes in those receiving CDK 4/6 inhibitors that were associated with a potential risk of DDIs were opioids (mostly tramadol and to a less extent, fentanyl), antiemetics (granisetron followed by dexamethasone), escitalopram, ciprofloxacin, amlodipine, and metformin. It is important to note that these associations were observational, and causality was not established.
Pharmacists who care for patients with advanced BC should be familiar with the findings of this study as this is the first report to raise awareness about the effect of polypharmacy on the potential for DDIs in patients receiving CDK 4/6 inhibitors.
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