Genetic polymorphisms in the CYP2C19 gene that decrease active metabolite formation and consequently reduce the drug’s antiplatelet activity are associated with variability in response to clopidogrel. Carriers of the reduced function CYP2C19 *2 alleles taking clopidogrel are at increased risk for serious adverse cardiovascular events, particularly in acute coronary syndrome managed with percutaneous coronary intervention (PCI); the hazard ratios (HR) are 1.76 for *2/*2 genotype and 1.55 for *2 heterozygotes compared to noncarriers. The risk associated with stent thrombosis is even greater (HR 3.97 for *2/*2 genotype and 2.67 for *2 heterozygotes compared to *1 homozygotes). However, for other indications, eg, atrial fibrillation and stroke, the effects of the CYP2C19*2 allele are less dramatic. Thus, current clinical recommendations from CPIC are specific for acute coronary syndrome with PCI: Standard starting doses are recommended in EMs and UMs, and CPIC recommends use of an alternative antiplatelet agent, eg, prasugrel or ticagrelor, in PMs and IMs (Table 5–2). The US Food and Drug Administration (FDA)-approved label for clopidogrel recommends alternative antiplatelet drugs for patients who are poor metabolizers of clopidogrel.
Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) is the first and rate-limiting step in pyrimidine catabolism, as well as a major elimination route for fluoropyrimidine chemotherapy agents (Chapter 54). Considerable intergroup and intragroup variation exists in DPD enzyme activity. Many of the alleles identified in the DPYD gene either are too rare to sufficiently characterize or have shown conflicting associations with DPD activity. Three nonfunctional alleles have been identified, ie, DPYD *2A, *13, and rs67376798. All three of these variants are rare; however, the *2A allele is the most commonly observed allele and is often the only variant tested in commercial genotyping platforms (see National Institutes of Health Genetic Testing Registry, http://www.ncbi.nlm.nih.gov/gtr/conditions/C2720286/ or http://www.ncbi.nlm.nih.gov/gtr/conditions/CN077983/). Frequencies of the *2A allele range from less than 0.005 in most European, African, and Asian populations to 3.5% in a Swedish population (see Table 5–1).
Example: Three fluoropyrimidine drugs are used clinically, namely 5-fluorouracil (5-FU), capecitabine, and tegafur (only approved in Europe). 5-FU is the pharmacologically active compound of each drug, and all are approved to treat solid tumors including colorectal and breast cancer (Chapter 54). 5-FU must be administered intravenously, while both capecitabine and tegafur are oral prodrugs that are rapidly converted to 5-FU in the body. Only 1–3% of an administered dose of the prodrug is converted to the active cytotoxic metabolites, ie, 5-fluorouridine 5′-monophosphate (5-FUMP) and 5-fluoro-2′-deoxyuridine-5′monophosphate (5-FdUMP), which effectively target rapidly dividing cancer cells and inhibit DNA synthesis. The majority of an administered dose (∼80%) is subjected to pyrimidine catabolism via DPD and is excreted in the urine. Complete or
TABLE 5–2 Gene-based dosing recommendations for selected drugs.