Pharmacokinetic Drug Interactions in Cancer Therapy
Identifying drug interactions, ensuring patient safety
Patient safety constitutes a fundamental goal shared by clinicians and pharmaceutical scientists. When it comes to complex medical conditions, the intersection between patient safety and drug interactions becomes evident. The probability of interactions increases with the number of drugs taken, and while some can have desired effects, in many cases drug interactions can be predicted and avoided so as to prevent reduced or unwanted effects in the patient. Thus, studying and understanding clinically relevant drug interactions is essential to ensuring patient safety. Between 20 and 30 percent of all adverse reactions to drugs occur as a consequence of interactions between drugs.
More often than not, we refer to drug-drug interactions when we say ‘drug interaction;’ however, substances and other factors may also alter the pharmacokinetics and/or pharmacodynamics of medications. Food, nutritional supplements, formulation excipients and even behaviors (such as cigarette smoking) may cause a drug interaction.
Oncologic pharmacotherapies frequently carry a narrow therapeutic index, and anticancer agents’ characteristic toxicity means interactions with other medications could have a significant impact on a chemotherapy agent’s efficacy or toxicity.
Prevalence and Significance of DDIs in Cancer Therapy
Several studies have evaluated drug interactions in general medicine, but only a handful have examined pharmacological interactions in patients with cancer. As mentioned above, the higher the number of prescribed medications, the higher the likelihood of drug interactions, and the higher the risk these interactions may result in hospitalization. Studies have looked at elderly patients (65-year-old patients take an average of five drugs) and their risk of complications due to drug interactions. Cancer patients, regardless of age, often find themselves in a similar situation. “Patients with cancer are particularly at risk of drug interactions as they could be taking many different medications as part of their cancer treatment or for the management of other illnesses” (Scripture & Figg, 2006).
A 2020 study by Ismail et al. found an overall prevalence of 78 percent of potential drug-drug interactions among patients receiving chemotherapy—a majority of patients had 1–2 potential DDIs (39.2%). Major potential DDIs were most frequent (67.3%) whereas, a significant association of potential DDIs was found between > 7 all prescribed drugs and ≥ 3 anti-cancer drugs.
Approximately 60 percent of patients receiving cancer therapy (regardless of mode of administration) are estimated to have had at least one potential drug-drug interaction. Sixteen percent of patients on oral anticancer therapy experienced a major event. Approximately 30 percent of DDIs linked to antineoplastic therapy required medical intervention, and DDIs are estimated to have caused the death of approximately four percent of cancer patients.
Pharmacokinetic DDIs in Cancer Treatment
Establishing systematic knowledge of how one drug alters the absorption, distribution, metabolism or elimination of another drug or substance in the context of chemotherapy may help to prevent adverse effects or reduced efficacy.
Pharmacokinetic interactions: absorption
As more anticancer agents are developed for oral delivery, more attention must be paid to factors that affect drug absorption, such as the type and quantity of food consumed by the patient.
Food–drug interactions can have four pharmacokinetic effects on the bioavailability of the orally administered anticancer agent: delayed, decreased, increased or unaffected absorption.
Antacids that contain aluminium and magnesium can increase the bioavailability of capecitabine. Co-administration of ondansetron with cisplatin and cyclophosphamide can result in a decrease in systemic exposure to both cisplatin and cyclophosphamide.
Pharmacokinetic interactions: distribution
After absorption, drug distribution to the target site is mostly determined by blood flow to the area and how much the antineoplastic agent binds to blood components.
The unbound portion of the drug is thought to be biologically active. Nevertheless, while the free fraction of the agent is more available for its target, it is also more available for metabolic and renal clearance. For instance, cytotoxic drugs, which are often highly protein-bound, could theoretically interact with other highly protein-bound drugs such as warfarin. This DDI could produce a displacement of the anticancer drug from its protein-bound state, though the therapeutic implications of such displacement have not yet been shown to be significant.
Pharmacokinetic interactions: metabolism
Adverse effects that occur when two anticancer agents are administered as part of the same therapeutic regimen could be due to metabolic DDIs.
Potential drug interactions between antineoplastic therapy agents and anti-emetics (most commonly, serotonin antagonists) have been documented. Metabolic drug interactions can also be observed when an isoenzyme substrate is given with an inhibitor or inducer that is specific to the same isoenzyme.
In recent years cancer patients have increased their use of herbal products and nutritional supplements, so the potential effect on drug metabolism by these substances when taken in combination with anticancer agents must be considered.
Pharmacokinetic interactions: excretion
Because irinotecan is transported across the cell membrane by several members of the ATP-binding cassette (ABC) drug transporter family, substrates and/or inhibitors of these transporters could interfere with its renal and/or biliary excretion, which could result in increased plasma concentrations and toxicity.
Are you ready to delve into DDIs?
The pharmacokinetic interactions listed above are just a sample of possible DDIs in cancer therapy. The complex nature of cancer and oncology therapies makes it imperative to acquire proper knowledge of clinically significant drug interactions. Cancer patients often take a large number of drugs to manage their condition(s). This circumstance poses a threat of undesired adverse events, or of decreased efficacy of antineoplastic agents. Clinicians and pharmaceutical scientists have a responsibility to learn and stay up-to-date on DDIs and how they may impact patients.
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References
Carpenter, M., Berry, H., & Pelletier, A. L. (2019). Clinically relevant drug-drug interactions in primary care. American family physician, 99(9), 558-564.
Cascorbi, I. (2012). Drug interactions—principles, examples and clinical consequences. Deutsches Ärzteblatt International, 109(33-34), 546.
Gelderblom, H., Köhne, C. H., Launay-Vacher, V., & van Leeuwen, R. W. F. (2016). Drug–drug interactions associated with kinase inhibitors: highlighting a new resource for oncologists and clinical pharmacists. Annals of Oncology, 27(4), 752.
Ismail, M., Khan, S., Khan, F., Noor, S., Sajid, H., Yar, S., & Rasheed, I. (2020). Prevalence and significance of potential drug-drug interactions among cancer patients receiving chemotherapy. BMC cancer, 20, 1-9.
Riechelmann, R., & Girardi, D. (2016). Drug interactions in cancer patients: A hidden risk?. Journal of research in pharmacy practice, 5(2), 77.
Saha, N. (2018). Clinical pharmacokinetics and drug interactions. In Pharmaceutical Medicine and Translational Clinical Research (pp. 81-106). Academic Press.
Scripture, C. D., & Figg, W. D. (2006). Drug interactions in cancer therapy. Nature Reviews Cancer, 6(7), 546-558.