Using pharmacogenetics guidelines when prescribing: What’s available
As well as working on the CPIC guidelines, PGRN investigators also provide numerous free online educational resources related to the principles behind pharmacogenomics, including additional resources necessary for systematic implementation. Examples include tables that outline all possible diplotypes (genotypes) for genes in the guidelines and how these are related to the metabolic phenotypes.2,4 Drug metabolizing phenotypes, for example, often are described as poor, intermediate, extensive, and ultra-rapid; in this system, metabolizing ability labeled as poor is less-than-average, and ultra-rapid describes greater-than-average ability. The extensive phenotype is considered average. The data files on the CPIC Web site also can be used as resources to “double check” interpretation results for the diplotype phenotype combinations currently available from various pharmacogenomics companies.7
Based on Ms. C’s presentation, as well as information from the CPIC guidelines, we expect that she might experience substantial adverse effects from most selective serotonin reuptake inhibitors and tricycle antidepressants because of her intermediate metabolizer status for CYP2D6 and poor metabolizer status for CYP2C19. The CPIC’s recommendation for using paroxetine and fluvoxamine in patients with a CYP2D6 intermediate metabolism phenotype is to initiate the recommend starting dose, but acknowledge that reduced metabolic capacity through CYP2D6 may result in higher blood levels and greater probability of adverse drug reactions. For a patient with the CYP2C19 poor metabolizer phenotype, the recommendation is to reduce the starting dose of citalopram or sertraline by 50%, or to prescribe a drug that is not metabolized by CYP2C19.8 Therefore, this pharmacogenomic information may help us understand why Ms. C is unable to tolerate these medications.
Although the CPIC guidelines do not address venlafaxine, the PharmGKB Web site contains literature supporting CYP2D6 as important in venlafaxine metabolism. Current recommendations from the Dutch Pharmacogenetics Working Group Guidelines9 are to either use a non–CYP2D6 metabolized medication or to adjust the dose to clinical response. Because Ms. C has been taking venlafaxine ER for the last 6 weeks and is taking a relatively low but effective dose, our recommendation is to continue current therapy.
It is also important to consider drug interactions when interpreting pharmacogenomic test results. In Ms. C’s case, the impact of a CYP2D6 intermediate metabolism phenotype would be increased if she also was taking a strong CYP2D6 inhibitor such as bupropion. Pharmacogenomics is another clinical tool and discontinuation of an effective treatment that is adequately tolerated should not be done based on pharmacogenomics recommendations alone.
