CYP2C19 genotyping for clopidogrel dosing
The Food and Drug Administration recently issued a new black-box warning1 and updated prescribing information2 for clopidogrel (Plavix), indicating that the CYP2C19 genetic polymorphism plays a major role in its bioactivation and efficacy. The FDA stopped short of recommending how to use the test for patient management and dose recommendation. Considering that clopidogrel has been the second top-selling drug in the world for a few years, as of 2007, this black-box warning creates a new opportunity for clinical laboratory medicine—CYP2C19 genotyping in guided clopidogrel therapy. Bear in mind, though, that the issue in pharmacogenetic testing is not about the technical aspect but how to report the results and assist physicians in interpreting them. Physicians would like to receive a short report containing recommendations on what to do with the results.
Though pharmacogenetic testing is considered a molecular diagnostic test, it is a bit different from other molecular diagnostics in that it’s used in association with a drug. The reporting and interpretation of results are more complex for pharmacogenetic tests than for other molecular diagnostic tests. In this regard, the clinical laboratory can play a major role in making pharmacogenetic testing more useful to clinicians by putting recommendations into the reports. As examples, a number of possible interpretations and recommendations for clopidogrel pharmacogenetic testing are listed in Table 1. To make it less confusing, only the interpretation corresponding to the patient’s genotype should be reported. The reporting strategy in Table 1, or any similar strategy that includes interpretation and recommendation, will change the practice and enhance the use of pharmacogenetic tests for CYP2C19 in clopidogrel therapy.
Pharmacogenetic testing for CYP2C19 for clopidogrel makes sense, and use of CYP2C19 genotyping can be expected to increase for several reasons. First, the drug has been on the market for a while; therefore, a lot is known about its safety. Generally, it is safer to use a drug that we have more experience with than to use a new drug. Second, the generic version of clopidogrel will be available in a year or two because the clopidogrel patent will expire in November 2011. The cost of the pharmacogenetic test will be offset by the lower price of the generic version. Third, the majority of the tested patients, who will be normal metabolizers, will benefit from the test by remaining on an inexpensive drug when the generic version of clopidogrel becomes available. On the other hand, about two percent of whites, four percent of African-Americans, and 14 percent of Chinese are slow metabolizers for clopidogrel and at higher risk of cardiovascular events and stroke. This group may benefit from alternative medication or a larger dose of clopidogrel (Table 1).
Pharmacogenetic tests are available for both clopidogrel and warfarin. From a purely scientific perspective, implementing pharmacogenetic testing for these two drugs is beneficial to patients. However, CYP2C19 genotyping for clopidogrel will have a better chance for widespread uptake in clinical medicine than CYP2C9 and VKORC1 genetic testing for warfarin therapy for several practical reasons:
1. The pharmacogenetics of clopidogrel is less complex than that of warfarin because one gene (CYP2C19) is involved, whereas two genes (CYP2C9 and VKORC1) play a role in the pharmacogenetics of warfarin.
2. The interpretation of CYP2C19 genotyping is more straightforward for clopidogrel than is the interpretation of CYP2C9 and VKORC1 genotyping for warfarin.
3. Dose selection for clopidogrel is less complex (Table 1). Warfarin dosing is complex because it can be affected by many factors in addition to pharmacogenetic factors. It is not easy for clinical labs to interpret pharmacogenetic test results for warfarin, and make dose adjustment recommendations, because they need other non-laboratory information, such as age, gender, weight (body surface area), food-drug interactions, and medical history.
4. Clopidogrel in CYP2C19 slow metabolizers is not as efficacious as in CYP2C19 normal metabolizers, whereas warfarin is efficacious across the CYP2C9 genotypes. CYP2C19 slow metabolizers treated with clopidogrel at the recommended regular daily maintenance dose of 75 mg exhibit higher cardiovascular event rates than patients with normal CYP2C19 functions. This can lead to a decision to switch the patient to a different drug. Pharmacogenetic testing for warfarin affects only the dose adjustment for warfarin and a change in the drug may not be necessary.
5. From a cost analysis point of view, the CYP2C19 pharmacogenetic test benefits the majority of the patients on clopidogrel, whereas the genotyping for warfarin benefits a smaller group of patients who are at increased risk of developing severe side effects if started on a larger dose.
6. Though platelet aggregation assay is available as a functional test to assess the efficacy of clopidogrel, it is technically more challenging than INR, which is used widely in assessing the therapeutic effect of warfarin.
7. Platelet aggregation assay for clopidogrel monitoring is not used as widely as INR in warfarin monitoring.
- New boxed warning on Plavix, http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm204253.htm
- Updated label for clopidogrel, www.accessdata.fda.gov/drugsatfda_docs/label/2010/020839s042lbl.pdf
Majid Moridani, PharmD, PhD, DABCC, FACB
Department of Pharmaceutical Sciences, School of Pharmacy
Department of Pediatrics, School of Medicine
Texas Tech University
Health Sciences Center