Clinical Implementation of Pharmacogenomics

Pharmacogenomics has the potential to influence clinically relevant outcomes in drug dosing, efficacy, and toxicity that can result in subsequent recommendations for testing. For many routinely used drugs, pharmacogenomics has provided inconclusive evidence for such testing. A probable reason could be the involvement of both genetic and nongenetic factors and their extent of contribution that determines the clinical relevance of some drugs. Therefore, identification of genetic markers associated with drug responses does not always link to clinically useful predictors of adverse outcomes, and most of the time require independent replication of genotypephenotype association before pursuing clinical implementation.

Lack of readily available resources, feasibility, utility, level of evidence, provider knowledge, cost effectiveness, and ethical, legal, and social issues further adds to the limitations and challenges to implementing pharmacogenomic testing in clinical practice. In order for a genetic marker to be implicated in clinical practice, an association of a genetic marker to a particular trait requires screening of tissues from several individuals, and corresponding functional studies are needed to establish probable association with the trait/phenotype. However, to overcome these challenges there are some pharmacogenomic tests for drugs currently used in clinical practice that have applied value in predicting ADRs and/or drug efficacy. Table 7.2 lists some of these clinically valuable pharmacogenomics tests. These tests are based on distinct genetic variants that have well-validated reproducible and significant impact on the drug therapy. These tests have a strong causal association between genetic polymorphisms and drug responses: a strong indication for clinical utility and high prognostic value. The tests are available both commercially and in academic settings, with many of these tests having clinical guidelines for dose adjustment and alternative medications (Wei et al., 2012). In addition, various international pharmacogenomic consortia have been developed recently to supervise drug response studies.

Table 7.2. Examples of Clinically Valuable Application of Pharmacogenomics Tests in Predicting Drug Response (Efficacy and Toxicity)

A list of current pharmacogenomic guidelines from these consortiums along with a well-annotated pharmacogenomic database has been consolidated into one curated database known as Pharmacogenomics Knowledge Base (PharmGKB) (Thorn et al., 2010). PharmGKB is available via an online portal where users can search on the website by gene, drug, metabolic pathway, and disease. To boost the clinical application of pharmacogenetics and address the barriers to implementation of pharmacogenetic tests into clinical practice CPIC was formed as a shared project between PharmGKB and the Pharmacogenomics Research Network (https://cpicpgx.org). CPIC provides freely available, peer-reviewed, updatable, and detailed gene/drug clinical practice guidelines that enable the translation of genetic laboratory test results into actionable prescribing decisions for specific drugs. The guidelines can focus on genes (e.g., thiopurine methyltransferase and its implications for thiopurines) or around drugs (e.g., warfarin and CYP2C9 and VKORC1). Efforts like PharmGKB and CPIC can help to overcome the confusion created about various pharmacogenetic tests and can help clinical decision making. In addition, the FDA has created a table of Pharmacogenomic Biomarkers in Drug Labeling that lists FDA-approved drugs with pharmacogenomic information in their labeling (http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm). This biomarker table provides up to date information on genomic markers that have been referred in FDA package inserts for different drugs. Various biomarkers are included in this table, e.g., germ-line or somatic gene variants, functional deficiencies, expression changes, and chromosomal abnormalities as well as selected protein biomarkers that need to be tested before starting treatment in a selected subset of patients. Moreover, with continued integration of pharmacogenomics in clinical trials and drug development, novel important genes and variants that can predict drug efficacy and toxicity will be identified and can be implemented in clinical practice.

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