Pharmacogenomic testing: Relevance in medical practice
ABSTRACTGenetics may account for much of the variability in our patients’ responses to drug therapies. This article offers the clinician an up-to-date overview of pharmacogenomic testing, discussing implications and limitations of emerging validated tests relevant to the use of warfarin (Coumadin), clopidogrel (Plavix), statins, tamoxifen (Nolvadex), codeine, and psychotropic drugs. It also discusses the future role of pharmacogenomic testing in medicine.
KEY POINTS
- Polymorphisms that affect the pharmacokinetics and pharmacodynamics of specific drugs are common.
- Testing for certain polymorphisms before prescribing certain drugs could help avoid adverse drug effects and improve efficacy.
- Pharmacogenomic testing has only recently begun to enter clinical practice, and routine testing is currently limited to a few clinical scenarios. However, additional applications may be just around the corner.
- Many pharmacogenomic tests are available, but testing has not yet been recommended for most drugs. Needed are large-scale trials to show that routine testing improves patient outcomes.
TAMOXIFEN IS ACTIVATED BY CYP2D6
Tamoxifen is prescribed to prevent the recurrence of estrogen-receptor-positive breast cancer, to treat metastatic breast cancer, to prevent cancer in high-risk populations, and to treat ductal carcinoma in situ.
Tamoxifen is metabolized to form endoxifen, which has much higher potency and higher systemic levels than tamoxifen.45 Both CYP2D6 and CYP3A4/5 are required to produce endoxifen via two intermediates, but CYP2D6 catalyzes the critical step leading to metabolic activation.
The CYP2D6 gene is highly polymorphic, with more than 75 allelic variants identified. Extensive literature is available describing the influence of CYP2D6 polymorphisms on tamoxifen metabolism and therapy outcomes.46–52 Several CYP2D6 variants result in reduced or no enzyme activity, and people who have more than two normally functioning alleles have exaggerated enzyme activity (gene amplification).
Classification of CYP2D6 status
Several systems have been developed to categorize the phenotypic activity of CYP2D6 based on genotype.
A genetic basis for the observed diversity in the metabolism of cytochrome P450 substrates was recognized more than 30 years ago. People were categorized as either extensive or poor metabolizers, reflecting normal vs impaired ability to metabolize the CYP2D6 substrates sparteine and debrisoquine. Later work expanded this system to include categories for intermediate (between poor and extensive) and ultra-rapid (better than extensive) metabolizers.
The genetic basis for these categories includes homozygosity for dysfunctional variants (the poor-metabolizer group) or extra copies of normal functioning variants (the ultra-rapid-metabolizer group).
Newer systems have been described for characterizing the CYP2D6 activity phenotype whereby CYP2D6 variants are assigned activity scores.53–56 The various scoring systems have been reviewed by Kirchheiner.57
A recent version of the activity scoring system also takes into consideration the many drugs that inhibit CYP2D6, such as amiodarone (Cordarone) and fluoxetine (Prozac) that can reduce the action of tamoxifen if given with it (Table 4).58 For example, the tamoxifen exposure (as predicted by the CYP2D6-activity score) experienced by a CYP2D6 extensive metabolizer taking a CYP2D6-inhibiting drug may be similar to the exposure experienced by a CYP2D6 poor metabolizer receiving the same tamoxifen dose but not taking a CYP2D6-inhibiting drug.
Likewise, the activity score of a CYP2D6 intermediate metabolizer taking a CYP2D6-inducing drug may be similar to that of a CYP2D6 ultra-rapid metabolizer not taking a CYP2D6-inducing drug. Examples of CYP2D6 inducers are dexamethasone, rifampin, and hyperforin (St. John’s wort).
While the newer systems are reported to provide better correlations between genotype and phenotype scores, the older scoring systems and the categorical names are still widely used (eg, in the FDA-approved AmpliChip CYP450 test from Roche,59 which includes genotype data for CYP2D6 and CYP2C19).
No firm recommendations for CYP2D6 testing in tamoxifen users
The different genotypes and phenotypes vary in prevalence in different ethnic groups, and significantly different activity levels for endoxifen formation are observed. Tamoxifen lacks efficacy in those who are poor CYP2D6 metabolizers—ie, about 7% of the white population.
However, the FDA has not made firm recommendations about CYP2D6 testing for prescribing tamoxifen because the evidence of benefit, although suggestive, has been considered insufficient.
Clinicians should be aware that tamoxifen’s efficacy is greatly reduced by concomitant therapy with CYP2D6-inhibiting drugs (Table 4).
Other genes affecting tamoxifen: CYP3A4/5, SULT1A1, and UGT2B15
Some investigators propose that polymorphisms in additional genes encoding enzymes in the tamoxifen metabolic and elimination pathways (eg, CYP3A4/5, SULT1A1, and UGT2B15) also need to be considered to account adequately for interindividual variation in drug response.
For example, CYP3A4 and CYP3A5 are also polymorphic, and large interindividual variation exists in their enzyme activities. These enzymes have overlapping substrate specificities, represent the most abundant drug-metabolizing enzymes in the human liver, and are involved in the biotransformation of a broad range of endogenous substrates and most drugs.60
Clinical studies evaluating the impact of CYP3A4/5 polymorphisms have been inconsistent in their conclusions, which is generally attributed to the relatively low functional impact or the low prevalence of the SNPs evaluated. Many of the nearly 100 CYP3A4/5 polymorphisms identified have not yet been characterized regarding their functional impact on enzyme expression or activity. CYP-3A4/5 enzyme activity is highly variable between individuals and warrants further study of its role in outcomes of tamoxifen therapy. Ongoing and future prospective clinical trials evaluating CYP2D6, CYP3A4/5, and other relevant polymorphisms are necessary to define their clinical relevance before routine genetic testing for tamoxifen can be justified.
CODEINE IS ALSO ACTIVATED BY CYP2D6
Codeine also depends on the CYP2D6 gene, as it must be activated to its more potent opioid metabolites, including morphine. Poor CYP2D6 metabolizers do not benefit from codeine therapy.
The pharmacogenomics of codeine has become a hot topic, especially regarding breast-feeding mothers. The debate was ignited with the publication in 2006 of a case report of an infant’s death, apparently the result of metabolic polymorphisms.61 The evolution of this debate and the outcome of the case may be noteworthy to clinicians, as they illustrate the gravity of public and patient interest in pharmacogenomic testing. In this case, the breast-feeding mother had taken codeine regularly for about 14 days when her 13-day-old infant died from toxic levels of morphine. Unknown to her and the prescriber, both the mother and infant were ultra-rapid CYP2D6 metabolizers, resulting in a more rapid and extensive conversion of codeine to morphine.
A logical strategy for preventing similar deaths would be routine CYP2D6 genotyping when prescribing codeine to breast-feeding mothers. However, after several investigations examined the metabolic and excretion pathways of codeine in their entirety, the FDA did not recommend routine CYP2D6 testing when prescribing codeine to breastfeeding mothers because several other factors, including rare genetic variations of other enzymes, proved necessary for reaching the opioid toxicity leading to the infant’s death.62
