Because of the complexities of cardio-oncology medication regimens, pharmacists are vital to assess drug-drug interactions using multiple resources, such as databases, case reports, FDA and National Institutes of Health guidelines, and package inserts.
With complex treatment regimens and countless potential drug interactions, pharmacists’ perspectives are crucial on cardio-oncology care teams, according to a panel of experts at the American College of Cardiology 2023 Scientific Session.
Jo Ellen Rodgers, PharmD, a clinical professor at the UNC Eshelman School of Pharmacy, first reviewed key points about pharmacodynamics and pharmacokinetics. Whereas pharmacodynamics are defined as “what the drug does to the body,” pharmacokinetics involve what the body does to the drug. Three potential outcomes of pharmacodynamics are synergistic effect, antagonistic effect, and additive effect.
Similarly, the 4 mechanisms of pharmacokinetics are absorption, distribution, metabolism, and elimination. Although all 4 play important roles, Rodgers noted that most pharmacokinetic issues are associated with metabolism. The bulk of her presentation focused on metabolism through the CYP3A4/5 enzymes, which is responsible for approximately 30% of interactions.
Many cardiovascular drugs and anti-cancer drugs are metabolized through CYP3A4/5. For example, some cardiology drugs that are substrates of CYP3A4 include amiodarone, apixaban, dofetilide, dronedarone, and rivaroxaban. Inhibitors of CYP3A4 include amiodarone, diltiazem, dronedarone, and verapamil.
Additionally, Rodgers said many commonly used oncology drugs, and particularly TKIs, are substrates of CYP3A4, including acalabrutinib, ibrutinib, imatinib, and neratinib. TKI inhibitors of CYP3A4 include capmatinib, ceritinib, and encorafenib, whereas inducers of CYP3A4 include dabrafenib, encorafenib, and others.
Because of the complexities of cardio-oncology medication regimens, Rodgers urged pharmacists to assess drug-drug interactions using multiple resources, such as databases, case reports, FDA and National Institutes of Health guidelines, and package inserts. Additionally, she said interdisciplinary collaboration is crucial to ensure optimal care for these patients.
“I think that this is where medicine is going to go, is more multidisciplinary care involving more advanced practitioners who can supplement what our cardiologists and oncologists are doing,” Rodgers said in an interview with Pharmacy Times. “It simply takes a village these days to get really complex patients safely through our health care system.”
Hypertension can be a major concern when managing cardio-oncology patients, particularly with vascular endothelial growth factor (VEGF) inhibitors. Presenter Nicolas Palaskas, MD, FACC, focused his presentation on VEGF-inhibiting monoclonal antibodies and small molecule TKIs, in particular.
The incidence of hypertension with VEGF inhibitors is highly variable, Palaskas said. There are several proposed mechanisms of action, including decreased nitric oxide production leading to increased vasoconstriction; stimulation of the endothelin-1 pathway leading to increased vasoconstriction; and capillary rarefaction and decreased capillary bed density.
Risk factors for VEGF inhibitor-associated hypertension include previous hypertension with a systolic blood pressure greater than 160 mmHg and a diastolic greater than 100 mmHg; diabetes; established cardiac or renal disease; older age; smoking; dyslipidemia; family history of premature coronary artery disease; obesity; and elevated fasting plasma glucose levels.
After starting therapy with TKIs, Palaskas said approximately 30% of patients develop hypertension. It is typically early onset within months after therapy initiation but can occur as early as after the first dose, particularly with small molecule TKIs.
Monitoring and management are crucial, with weekly office blood pressure monitoring during the initial cycle with TKIs, followed by every 3 to 4 weeks. This can be challenging for patients, but Palaskas said technology can help. He has worked with a virtual hypertension clinic in which providers conduct virtual visits and help patients monitor their blood pressure with TKIs.
“I think this is one of the disease entities that is very well suited for virtual visits,” Palaskas said.
Finally, Aaron Bagnola, PharmD, BCPS, BCCP, reviewed bleeding and clotting risks with cancer therapies for patients with cardiovascular disease. Cancer and its associated treatments can enhance thrombotic and bleeding risks, and venous thromboembolism remains one of the leading causes of death in cancer patients, Bagnola said.
Approximately 10% of patients with advanced cancer have at least 1 bleeding episode, and this increases up to 30% in hematologic malignancies. Consequences include worsening morbidity and mortality, increased health care utilization and cost, delayed treatments, and worsening quality of life.
In particular, treatment with ibrutinib has heightened risks for cardiovascular toxicities, including hypertension, arrhythmias, and bleeding. Between 3% and 16% of patients on ibrutinib are estimated to develop thrombotic issues, and one systematic review showed that the incidence of atrial fibrillation in patients on ibrutinib was 5.77 per 100 person-years, most of which occurred 2 to 3 months after initiation. These risks extend to other Bruton tyrosine kinase (BTK) inhibitors, but to a lesser extent.
When managing these concerns, Bagnola said clinicians should utilize the HAS-BLED and CHA2DS2-VASc scores to risk-stratify patients. However, he added that it is important to remember that these do not adequately capture cancer-associated risks of bleeding and clotting. Additionally, he said a multidisciplinary approach is crucial to navigating the complexities of cancer-associated bleeding and clotting, cardiovascular risk management, and the interactions of therapies used in all of these conditions.
Bagnola A, Palaskas N, Rodgers J. Pharmacology I: Pharmacists Are Your BFFs in Cardio-Oncology – CV Drug Interactions to Be Aware of in Oncology Patients. Presented at American College of Cardiology 2023 Scientific Session. March 5, 2023.