CDK 4/6 inhibitors, which include palbociclib, ribociclib, and ademaciclib, are a new class of agents indicated for the treatment of hormone receptor–positive and human epidermal growth factor receptor–negative breast cancer. A recent paper published in Cancer Treatment Review examined the propensity for these drugs to be involved in drug interactions, as well as the significance of these interactions.
Pharmacokinetic interactions for CDK 4/6 inhibitors involve CYP3A4 or P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). All of the CDK 4/6 inhibitors are metabolized by CYP3A4, with palbociclib also undergoing biotransformation via SULT2A1 (sulfotransferase 2A1). When these drugs are administered with strong CYP3A4 inducers, treatment failure can result. Conversely, when these medications are given concomitantly with
CYP3A4 inhibitors, toxicity may occur.
The authors recommend avoiding the use of CDK 4/6 inhibitors with drugs that produce strong CYP3A4 inhibition, including clarithromycin, telithromycin, itraconazole, ketoconazole, posaconazole, and ritonavir as well as with drugs that are known to be strong inducers of CYP3A4, such as rifampin. Among the macrolides, azithromycin does not interact with CYP3A4 and may be used in place of clarithromycin. The use of alternative antifungals such as echinocandins should be considered in patients receiving CDK 4/6 inhibitors.
P-gp and BCRP-based drug interactions can affect a drug’s intestinal absorption or distribution across the blood-brain barrier. CDK 4/6 inhibitors are substrates of P-gp, and rifampin is known to be a strong inducer of intestinal P-gp, possibly reducing the bioavailability of these chemotherapeutic agents. As a result, concomitant use with CDK 4/6 inhibitors should be avoided. To further complicate this interaction, abemaciclib inhibits P-gp and BCRP activities. The azole antifungals, in particular isavuconazole, ketoconazole, and itraconazole, are strong P-gp inhibitors and may markedly increase the bioavailability of CDK 4/6 inhibitors; they should also not be used in combination with these anticancer drugs. Azole antifungals may compete with P-gp at the blood-brain barrier and enhance central nervous system penetration of CDK 4/6 inhibitors.
Pharmacodynamic drug interactions may manifest as QTc prolongation, especially with the use of ribociclib and other QTc-prolonging drugs, leading to torsades de pointes (TdP). Among the medications associated with QT-interval prolongation are anticancer drugs (e.g., tamoxifen, 5-fluorouracil, capecitabine, anthracyclines), antiemetic drugs (e.g., 5-HT3 receptor antagonists), analgesics (e.g., propoxyphene, methadone), psychiatric drugs (e.g., citalopram, escitalopram), and antimicrobial agents (e.g., macrolides, fluroquinolones, fluconazole).
Drugs that should not be used in combination with CDK 4/6 inhibitors are ondansetron, dolasetron, domperidone, chlorpromazine, metoclopramide, methadone, oxycodone, erythromycin, clarithromycin, ciprofloxacin, levofloxacin, moxifoxacin, fluconazole, propofol, sevoflurane, citalopram, and escitalopram. Genetic and epigenetic factors should also be evaluated when the risk of developing TdP is being considered.
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