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3 drug regimens expand to 11 regimens

FIGURE 4-8 Potential impact of incorporation of pharmacogenetics into dosing of drugs for a relatively simple therapeutic regimen. The traditional approach to treatment for a disease (A), in this case a cancer, is based purely on stage of the cancer. Up to three different drugs are used in combination, with intensity of dosing dependent on the stage of the cancer. With this strategy, some with stage II disease are not receiving as much drug as they could tolerate; some patients with stage III or IV disease are undertreated and some are overtreated. Panel B illustrates a hypothetical patient population with eight different multilocus genotypes. It is assumed that each of the three drugs is affected by just one genetic polymorphism (TYMS for methotrexate [MTX], MDR1 for paclitaxel, and GSTM1 for cyclophosphamide), and each polymorphism has just two important genotypes (one coding for low and one for high activity). The possible multilocus genotypes are designated by the letters A to H, and the combinations of TYMS, MDR1 and GSTM1 genotypes giving rise to those multilocus genotypes are indicated in the table. If these three genotypes, along with stage of cancer, are used to individualize dosages (C), so that those with low activity receive lower doses and those with higher activity receive higher doses of the relevant drug, what began as a total of three drug regimens in the absence of pharmacogenetics becomes 11 regimens (distinguished by different backgrounds and font colors) by using pharmacogenetics for dosage individualization.

complexity could be large. Many individuals take multiple drugs simultaneously for different diseases, while many therapeutic regimens for a single disease include multiple agents. All of this translates into a plethora of possible drug-dose combinations. The promise of human genomics has emphasized the potential to discover individualized "magic bullets", while ignoring the reality of the added complexity of additional testing and need for interpretation of results to capitalize on individualized dosing. This is illustrated in Figure 4-8. In this case, a traditional anticancer treatment regimen is replaced with one that incorporates pharmacogenetic information with the stage of the cancer determined by a variety of standardized pathological criteria. Assuming just one important genetic polymorphism for each of the three different anticancer drugs, 11 individual drug regimens are generated.

The potential utility of pharmacogenetics in drug therapy is great. Once adequate genotype/ phenotype studies have been conducted, molecular diagnostic tests will be developed that detect >95% of the important genetic variants for the most polymorphisms; such genetic tests have the advantage that they need only be conducted once in a given individual. Continued incorporation of pharmacogenetics into clinical trials will identify important genes and polymorphisms demonstrate whether dosage individualization can improve outcomes and decrease adverse effects. Significant covariates will be identified to refine dosing in the context of drug interactions and disease influences. Although the challenges are substantial, accounting for the genetic basis of variability in response to medications is likely to be a fundamental component of disease diagnosis and pharmacotherapy.

For a complete Bibliographical listing see Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed., or Goodman & Gilman Online at www.accessmedicine.com.

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