Pharmacogenetics and the Genetic Basis of ADRs

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Chapter: Pharmacovigilance: Pharmacogenetics and the Genetic Basis of ADRs

Health care providers and patients have long recog-nized that people often respond differently to the same medicine, both in terms of efficacy and ‘side effects’, or adverse drug reactions (ADRs).


Pharmacogenetics and the Genetic Basis of ADRs

INTRODUCTION

Health care providers and patients have long recog-nized that people often respond differently to the same medicine, both in terms of efficacy and ‘side effects’, or adverse drug reactions (ADRs). There are many factors that contribute to this inter-individual variability in response to medications, including the pathogenesis and severity of the disease being treated; concomitant medications and drug interactions; and the patient’s age, renal and liver function, concomitant illnesses, nutrition and lifestyle (smoking, alcohol use, weight and fitness) (Meyer, 2000). Genetic factors that affect the kinetics and dynamics of drugs play an even greater role in determining an individual’s risk of non-response or toxicity (Evans and Relling, 1999). Although it is difficult to define the relative contribution of genetic and environmental effects in an individual, it is clear that variation in genes coding for drug-metabolizing enzymes, drug transporters and drug receptors and targets accounts for a significant portion of the observed heterogeneity in drug response across populations.

The study of ADRs has been hampered by the use of ambiguous and inconsistent terminology and reporting. Edwards and Aronson (2000) proposed the following definition of an ADR: ‘an apprecia-bly harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future admin-istration and warrants prevention or specific treat-ment, alteration of the dosage regimen, or withdrawal of the product’. ADRs may result from health care provider, pharmacy or patient error or from a variety of genetic and environmental factors. Although defi-nitions and figures vary, it is clear that ADRs are a significant cause of morbidity, mortality and health care expense. Lazarou, Pomeranz and Corey (1998) performed a meta-analysis of 39 prospective studies from US hospitals and found that 6.7% of inpatients have a serious ADR while hospitalized, resulting in 106 000 deaths per year. Johnson and Bootman (1995) used a cost of illness model to address the drug-related morbidity and mortality in the ambulatory care setting in the US from data collected in the early 1990s. Their estimate of the costs of adverse events was $76B/year. Ernst and Grizzle (2001) updated the estimates using data published since the 1995 study and updated values for May 2000 in dollars. Their estimates for the cost of drug-related morbidity and mortality exceeded $177.4B in 2000. Pirmohammed et al. (2004) conducted a prospective analysis of all admissions to two general hospitals in the United Kingdom. They found that 6.5% of all hospital admis-sions were due to an adverse event and that the adverse event directly led to the hospitalization in 80% of the cases. They projected the annual cost of such admis-sions to the National Health Services to be $847M. The overall fatality rate was 0.15% and the most common drugs implicated were aspirin, diuretics, warfarin and non-steroidal anti-inflammatory drugs. GI bleeding was the most common reaction.

The number, severity and cost of ADRs is now recognized as a significant public health issue and has triggered interest in discovering what causes them and if and how their occurrence can be predicted and prevented. In this chapter, we will focus on the current state of knowledge regarding the genetic basis of ADRs and the important role that pharmacogenet-ics will play in meeting the ultimate goal of providing safer, more effective medicines.

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