Summary And Future Directions

The occurrence of an ADR is clearly dependent on both genetic and environmental factors; the contribution of both will vary between drugs and individuals. Importantly, there may also be an interaction between the genetic and environmental factors, which has not been really studied to any great extent. The nature of the genetic predisposition is also likely to vary; for some there might be a major genetic predisposing factor (the so called "low-hanging fruit"), with minor contributions from other genes, whereas for other adverse reactions (perhaps the majority), the situation might be much more complex with multiple genetic factors, each contributing to a small extent, but none of which by itself is necessary nor sufficient to lead to the adverse reaction, that is, the situation is similar to a polygenic disease with many susceptibility genes.

The challenge for researchers and clinicians is to incorporate pharmacogenetics of drug safety into clinical practice. To date, only phenotyping (and genotyping in some centers) for thiopurine methyltransferase (TPMT) has had substantial (but not complete) clinical uptake. Approximately 10% of the population has low enzyme activity (heterozygous patients), while one in 300 patients have no detectable TPMT activity (188). These patients are likely to develop severe hemopoietic toxicity with conventional doses of drugs, such as 6-mercaptopurine and azathioprine, and particularly for the former, recommendations for dose modifications have been suggested (189). This is covered in greater detail in the other chapters in this book.

Many factors will determine whether a genotyping test is taken up into clinical practice, which will include patient and clinician acceptance. The value of a pharmacogenetic test in preventing ADRs is dependent on three criteria, as defined by Phillips et al. (7). These are medical needs, clinical utility, and ease of use. In order to fulfill medical needs, the incidence of the ADR, the prevalence of the variant allele, and the use of the drug have to be high enough to warrant the use of genetic information. However, if the prevalence of the ADR and/or the variant allele is low, a genetic test may still be warranted if the ADR has severe clinical consequences. The clinical utility of a test depends on whether there is sufficient evidence to link the variant allele to the drug response, and the test criteria, that is, sensitivity, specificity, positive, and negative predictive values. Finally, the assay has to be easy to use, relatively inexpensive and reliable, and most importantly, clinicians should be able to interpret the results and use the information appropriately. How the latter would be implemented and the format it would take is unclear at present and needs further research.

An important aspect to consider is whether pre-prescription genotyping will be cost-effective. Danzon et al. (190) examined the potential impact of pharmacogenetic testing from societal, payer, and company perspectives. They concluded that testing was worthwhile for the payer if the ratio of nonresponders to the total population exceeds the ratio of the price of the test to the price of the drug. From the perspective of a drug company, pretreatment genetic tests are likely to be developed if they can yield a net saving to the payer. This happens when the cost of testing the entire patient population is less than the savings from avoiding treatment of nonresponders plus any savings from averting harm. This has recently been tackled in relation to abacavir hypersensitivity (113). Using data from three cohorts, it was possible to develop test characteristics, and by applying them into a decision analysis framework, it was shown that the cost-effectiveness of a test was largely dictated not by the cost of the genotyping test but by the costs of the alternative treatments that would have to be used should the patient prove to be positive for HLA-B*5701, a genetic determinant of abacavir hyper-sensitivity. Perhaps, one also needs to put into perspective the overall impact that the ADRs have on the health service and on the economy as a whole. For instance, the cost of drug-related morbidity and mortality in the United States has been estimated to be $76.6 billion (4). Clearly, this is a huge burden and anything that can help in reducing this burden has to be seriously considered and investigated, and if the relevant criteria are met, implemented into clinical practice. This is the challenge facing researchers in this area as they attempt to reduce the burden of ADR on the patient, the health care system, and the economy.

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