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.
WARFARIN: IMPORTANCE OF CYP2C9, VKORC1
Warfarin is used for the long-term treatment and prevention of thromboembolic events.
This drug has a narrow therapeutic window and shows substantial interpatient dose variability. The start of warfarin therapy is associated with one of the highest rates of adverse events and emergency room visits of any single drug.12 More than 2 million patients start warfarin each year in the United States alone,13 and about 20% of them are hospitalized within the first 6 months because of bleeding due to overanticoagulation.14
The findings from a recent study suggest that pharmacogenomic testing may eventually allow more patients to safely benefit from warfarin therapy. In this large, nationwide, prospective study, hospitalization rates were 30% lower when pharmacogenomic testing was used.14 However, no reduction was seen in the time needed to reach the target international normalized ratio (INR) or in the need for INR checks at 6 months. Furthermore, this study used historical control data, and some or all of the reduction in hospitalization rates may be attributed to more frequent INR checks in the patients who underwent testing than in the historical control group.
A relationship between warfarin dose requirements and the genetic status of CYP2C9, which encodes a major drug-metabolizing enzyme, has been demonstrated in retrospective and prospective studies.15–17
S-warfarin is metabolized by CYP2C9, which is polymorphic
Warfarin contains equal amounts of two isomers, designated S and R. S-warfarin, which is more potent, is metabolized principally by CYP2C9, while R-warfarin is metabolized by CYP1A2, CYP2C19, and CYP3A4.
People who possess two copies of the wild type CYP2C9 gene CYP2C9*1 metabolize warfarin very well and so are called “extensive warfarin metabolizers.” Carriers of the allelic variants CYP2C9*2 and CYP2C9*3 (which have point mutations in exons 3 and 7 of CYP2C9, respectively), have less capacity. Compared with those who are homozygous for the wild-type gene, homozygous carriers of CYP2C9* 3 clear S-warfarin at a rate that is 90% lower, and those with the CYP2C9*1/*3, CYP2C9* 1/*2, CYP2C9*2/*2, or CYP2C9*2/*3 genotypes clear it at a rate 50% to 75% lower. A meta-analysis of 12 studies found that the CYP2C9 genotype accounted for 12% of the interindividual variability of warfarin dose requirements.18
About 8% of whites carry at least one copy of CYP2C9*2, as do 1% of African Americans; the allele is rare in Asian populations. The frequency of CYP2C9*3 is 6% in whites, 1% in African Americans, and 3% in Asians.19,20 People with CYP2C9*4 or CYP2C9*5 have a diminished capacity to clear warfarin; however, these variants occur so infrequently that their clinical relevance may be minimal.
Warfarin’s target, VKOR, is also polymorphic
Genetic variation in warfarin’s pharmacologic target, vitamin K 2,3-epoxide reductase (VKOR), also influences dose requirements. Warfarin decreases the synthesis of vitamin-K-dependent clotting factors by inhibiting VKOR. This inhibition depends on the patient’s C1 subunit gene, VKORC1. Patients with a guanine-to-adenine SNP 1,639 bases upstream of VKORC1 (−1639G>A) need lower warfarin doses—an average of 25% lower in those with the GA genotype (ie, one allele has guanine in the −1639 position and the other allele has adenine in that position) and 50% lower in those with the AA genotype compared with the wild-type genotype GG.21 This promoter SNP, positioned upstream (ie, before the gene-coding region), greatly influences VKORC1 expression.
A meta-analysis of 10 studies found that the VKORC1 polymorphism accounts for 25% of the interindividual variation in warfarin dose.18 In one study, the frequency of the AA genotype in a white population was 14%, AG 47%, and GG 39%; in a Chinese population the frequency of AA was 82%, AG 18%, and GG 0.35%.22
CYP4F2 and GGCX also affect warfarin’s dose requirements
Genetic variations in the enzymes CYP4F2 and gamma-glutamyl carboxylase (GGCX) also influence warfarin dose requirements. Although the data are limited and the effects are smaller than those of CYP2C9 and VKORC1, people with a SNP in CYP4F2 need 8% higher doses of warfarin, while those with a SNP in GGCX need 6% lower doses.23
CYP2C9 and VKORC1 testing is available
Currently, the clinical pharmacogenetic tests relevant for warfarin use are for CYP2C9 and VKORC1.10
The FDA has approved four warfarin pharmacogenetic test kits, but most third-party payers are reluctant to reimburse for testing because it is not currently considered a standard of care. Testing typically costs a few hundred dollars, but it should become less expensive as it becomes more commonplace. The current FDA-approved product label for warfarin does not recommend routine pharmacogenomic testing for determining initial or maintenance doses, but it does acknowledge that dose requirements are influenced by CYP2C9 and VKORC1 and states that genotype information, when available, can assist in selecting the starting dose.24
Clinical trials of warfarin pharmacogenomic testing are under way
Although genetic status can greatly influence an individual patient’s warfarin dosing requirement, routine prospective pharmacogenomic testing is not endorsed by the FDA or by other expert panels26 because there is currently insufficient evidence to recommend for or against it.
Several large prospective trials are under way. For example, the National Heart, Lung, and Blood Institute began a prospective trial in about 1,200 patients to evaluate the use of clinical plus genetic information to guide the initiation of warfarin therapy and to improve anticoagulation control for patients.27 The results, expected in September 2011, and those of other large prospective trials should provide adequate evidence for making recommendations about the clinical utility of routine pharmacogenetic testing for guiding warfarin therapy.
Several recent cost-utility and cost-effectiveness studies have attempted to quantify the value of pharmacogenomic testing for warfarin therapy,28–30 but their analyses are largely limited because the benefit (clinical utility) is yet to be sufficiently characterized.
The relevance of such analyses may soon be drastically diminished, as several non-vitamin-K-dependent blood thinners such as rivaroxaban (Xarelto), dabigatran (Pradaxa), and apixaban are poised to enter clinical practice.31
