Drug–drug interactions in oncology: Why are they important and can they be minimized?

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Abstract

Adverse drug–drug interactions are a major cause of morbidity and mortality. Cancer patients are at particularly high risk of such interactions because they commonly receive multiple medications, including cytotoxic chemotherapy, hormonal agents and supportive care drugs. In addition, the majority of cancer patients are elderly, and so require medications for co-morbid conditions such as cardiovascular, gastrointestinal, and rheumatological diseases. Furthermore, the age-related decline in hepatic and renal function reduces their ability to metabolize and clear drugs and so increases the potential for toxicity. Not all drug–drug interactions can be predicted, and those that are predictable are not always avoidable. However, increased awareness of the potential for these interactions will allow healthcare providers to minimize the risk by choosing appropriate drugs and also by monitoring for signs of interaction. This review considers the basic principles of drug–drug interactions, and presents specific examples that are relevant to oncology.

Introduction

Patients with cancer are at considerable risk of drug–drug interactions. Typically, such patients will receive a large number of drugs during their treatment, including several different cytotoxic agents in multi-drug chemotherapy regimens, hormonal agents, and also supportive care with antiemetics, analgesics, and anti-infective agents, among others. Many patients may also self-administer alternative/complementary medicines without the knowledge of the prescribing physician [1]; a recent study found that 51.6% of patients with cancer were taking complementary alternative medicines, of which 12.2% were subsequently issued a health warning [2]. Commonly used complementary agents with the potential for drug–drug interactions include St. John's Wort and garlic [2], [3].

A further problem is that approximately 60% of patients with cancer are aged 65 years or over [4]. They are likely to have co-morbid conditions for which they also require medications. It has been reported that up to 80% of cancer patients aged over 65 years have co-morbid conditions [5], with the number of co-morbidities increasing with age. For example, one study of cancer and co-morbidity in the elderly found that the mean number of co-morbid conditions per patient increased from 2.9 for patients aged 55–64 years, to 3.6 in those aged 65–74 years and 4.2 in patients aged 75 years or older [6]. As a consequence, such patients may be expected to be taking several concomitant medications. Indeed, it is estimated that the majority (78%) of patients over 65 years of age are taking prescription medications, and that 39% regularly take five or more drugs [7], while up to 90% of patients in this age group are also reported to take over-the-counter medications [8]. As the risk of drug–drug interaction has been found to increase markedly with the number of concomitant medications (Table 1) [9], the risks of impaired treatment efficacy and/or increased drug-related toxicity will also increase. Elderly patients are also affected by age-related changes in hepatic [10] and renal [11] function that render them more susceptible to drug–drug interactions. The decline in hepatic blood flow and enzyme activity can contribute to impaired metabolism and elimination of drugs, while declining renal function contributes to reduced clearance of drugs and is a major contributor to drug toxicity in elderly patients. As a consequence of these changes, elderly patients are subject to a 3- to 10-fold increase in the incidence of adverse drug reactions compared with younger patients [11].

The problem for the physician is that physiological changes due to drug–drug interactions may be masked by, or confused with, the symptoms and signs of cancer or other co-morbid illnesses, as well as the adverse effects of antineoplastic agents. Furthermore, it can be difficult to determine which drugs are involved in any interactions. It is therefore essential that prescribing physicians are aware of all the medications that the patient is taking, including alternative/complementary remedies and over-the-counter preparations, and that they understand the potential for drug–drug interactions with each agent. Increased awareness of the potential for drug–drug interactions will allow physicians to minimize the risk by choosing appropriate drugs, and also by monitoring for any signs of interaction.

This article reviews the basic principles of drug–drug interactions and provides examples that are particularly relevant to oncology. Although this is not an exhaustive review, it is intended that the information provided will enable physicians to reduce the risk of some interactions by choosing appropriate drugs and monitoring for signs of drug–drug interactions. Three CME monographs have also been produced addressing drug–drug interaction issues in oncology and are an excellent source for additional information [12], [13], [14].

The recommended doses, indications and drug–drug interaction warnings/precautions listed in product labelling for the agents discussed in this review may differ between countries—it is important always to consult your local prescribing information before making treatment decisions. Product information can be obtained from the drug's manufacturer or distributor in your country. The Food and Drug Administration and European Medicines Agency websites (www.fda.gov and www.emea.eu.int) also hold useful, country-specific information on licensed products.

Section snippets

Principles of drug–drug interactions

Drug–drug interactions can have three possible outcomes: increased therapeutic and/or adverse effects, decreased therapeutic and/or adverse effects, or a unique response that does not occur with either agent alone [15].

Drug–drug interactions in oncology—antineoplastic agents

Cytotoxic drugs generally have a narrow therapeutic index. Even a slight increase or decrease in cytotoxic activity due to a drug–drug interaction could result in excessive toxicity or reduced efficacy.

Drug–drug interactions in oncology—supportive care medications

In addition to cytotoxic drugs, cancer patients will typically receive supportive care medications to treat the complications of cancer therapy or of the cancer itself. For example, patients with advanced cancer on palliative medicine services often receive five or more drugs for symptom relief [21]. These drugs all carry the potential for interactions—with antineoplastic agents, with each other, and with other medications that the patient may be receiving to treat co-morbid conditions.

Not all

Drug–drug interactions in oncology—drugs to treat co-morbid conditions

Cancer patients are typically over 65 years of age, and consequently may have a number of pre-existing conditions, including cardiovascular or respiratory disorders and arthritis, in addition to cancer [4], [6], [137]. Indeed, it has been estimated that such patients have an average of three co-morbid conditions [6], [138], [139], [140]. For example, one study of patients aged over 70 years with non-small-cell lung cancer found that 60% of patients had a pre-existing cardiovascular condition,

Conclusions

This review has presented examples of important, or potentially important, drug–drug interactions involving antineoplastic agents and some of the other drugs that are typically prescribed for cancer patients. However, this information is intended to be illustrative and not comprehensive, and not all antineoplastic agents or other classes of agents have been included. Furthermore, many documented or potential interactions of those drugs that are included have also been omitted—in part due to

Reviewers

Balant Luc P. (Ph.D.), Prof., Chairman, COST Technical Committee “Medicine & Health”, Department of Psychiatry, University of Geneva, 2 ch. du Petit-Bel-Air, CH-1225 Chêne-Bourg, Switzerland.

Martin Jennifer H., Dr., Clinical Pharmacology Unit, Monash Medical School/Alfred Hospital, Prahran, Vic., Australia.

Andrews Paul L.R., Prof., Department of Physiology, St. George's Hospital Medical School, Cranner Terrace, Tooting, London SW17 0RE, UK.

Peter Blower, Ph.D., D.Sc., C.Biol., F.I.Biol.; Dr. Blower has worked in pharmaceutical R&D for 35 years. In 1977 he received his Ph.D. in pharmacology from Aston University, Birmingham, UK. Dr. Blower led drug discovery research and development teams for SmithKline Beecham in the therapeutic areas of oncology, inflammation, gastrointestinal disorders and neuroscience, and has served as a governor of the University of East London, including a time as Chairman of Governors (1994–1997). In 2000,

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    Peter Blower, Ph.D., D.Sc., C.Biol., F.I.Biol.; Dr. Blower has worked in pharmaceutical R&D for 35 years. In 1977 he received his Ph.D. in pharmacology from Aston University, Birmingham, UK. Dr. Blower led drug discovery research and development teams for SmithKline Beecham in the therapeutic areas of oncology, inflammation, gastrointestinal disorders and neuroscience, and has served as a governor of the University of East London, including a time as Chairman of Governors (1994–1997). In 2000, Dr. Blower founded Biophar Consulting Ltd., a pharmaceutical and biological consultancy firm. He has authored more than 60 publications and lives in a small village near Cambridge in the UK.

    Dr. De Wit is Medical Oncologist, Senior Staff member of the Erasmus University Medical Center and the Rotterdam Cancer Institute (Daniel den Hoed Cancer Center) in The Netherlands. He is Faculty Member of the American Society of Clinical Oncology (ASCO), member of the American Association of Cancer Research (AACR), Faculty Member of the European Society of Medical Oncology (ESMO) and the European Cancer Conference (ECCO). His main focus is on genito-urinary oncology, new drug development, and cancer supportive care issues. He is the former chairman of the EORTC-Genitourinary Group Chemotherapy Subcommittee (1994–2002) and currently consultant medical oncologist for the EORTC-Genitourinary Group.

    Dr. Susan Goodin is a board certified Oncology Pharmacist and is licensed in New Jersey and Kentucky, USA. She is Associate Professor of Medicine in the Division of Medical Oncology at the University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School in New Brunswick, and Adjunct Associate Professor of Pharmacy Practice and Administration at Rutgers University College of Pharmacy in Piscataway, New Jersey. She is also Director of Pharmaceutical Services, and Co-Director of the Symptom Management–Supportive Care Group at The Cancer Institute of New Jersey.

    After earning her doctorate in pharmacy from the University of Kentucky College of Pharmacy in Lexington, Dr. Goodin completed an Internship at COSTEP–United States Public Health Service at the Federal Bureau of Prisons–Federal Correctional Institution in Lexington, Kentucky. She undertook her Pharmacy Practice Residency at the University of Kentucky Medical Center in Lexington, and Oncology Pharmacy at the Lucille P. Markey Cancer Center in conjunction with the University of Kentucky Medical Center.

    Dr. Goodin is a member of several professional societies, including the American Society of Health-System Pharmacists, for which she is presently Chair-Elect for the ASHP Section of Clinical Specialists and Scientists, the American College of Clinical Pharmacy, the American Society of Clinical Oncologists, and the International Society of Oncology Pharmacy Practice, for which she is the US Delegate and a member of the research committee. As an active researcher, Dr. Goodin is well published and a well respected national and international speaker. She is currently a reviewer for Clinical Cancer Research, American Journal of Health-System Pharmacy, Drugs, and The Oncologist.

    Dr. Matti Aapro received his medical degree from the Faculty of Medicine, University of Geneva, Switzerland. He was a fellow at the Arizona Cancer Center in Tucson and was the founding chair of the Medical and Radiation Therapy Department at the European Institute of Oncology in Milano. He is presently Dean of the Multidisciplinary Oncology Institute, Genolier, Switzerland. Dr. Aapro serves as Executive Director of the International Society for Geriatric Oncology (SIOG). In addition to being a member of the Board of the European Organization for Research and Treatment of Cancer (EORTC), he chairs the EORTC Cancer in the Elderly Task Force. Dr. Aapro is President of the Multinational Association for Supportive Care in Cancer (MASCC). Dr. Aapro is Editor-in-Chief of Critical Reviews in Oncology/Hematology, and www.cancerworld.org, as well as Associate Editor of Annals of Oncology, Section Editor for The Oncologist. He has authored more than 180 publications and his major interests are new drug development, breast cancer, cancer in the elderly, and supportive care.

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