| CYP2C9, VKORC1 |
Warfarin |
Numerous studies have shown that the CYP2C9*2, *3, *5, *6, *8, *11 and VKORC1 -1639A alleles are associated with lower warfarin dose requirements. CPIC guidelines recommend use of pharmacogenetic dosing algorithms to assist with warfarin dosing based on CYP2C9 and VKORC1 genotypes plus clinical factors.6 The FDA approved warfarin labeling contains a dosing table based on genotype based on the CYP2C9 and VKORC1 genotypes that may be used when dosing algorithms are inaccessible. While warfarin elimination is almost entirely by hepatic metabolism, data show that moderate to severe kidney dysfunction reduces warfarin dose requirements by 10% to 20%, respectively. 26 Most pharmacogenetic algorithms do not account for kidney dysfunction, but reducing the dose estimated by pharmacogenetic algorithms (or the FDA dosing table) by 10% to 20% for patients with moderate to severe kidney dysfunction, respectively, may prevent warfarin over-dosing in these subgroups.
|
| CYP2C19 |
Clopidogrel |
CYP2C19 poor and intermediate metabolizer phenotypes are associated with reduced response to clopidogrel and an increased risk for major adverse cardiovascular events with clopidogrel treatment after PCI compared to the extensive and ultra-rapid metabolizer phenotypes. CPIC guidelines recommend alternative treatment with prasugrel or ticagrelor after acute coronary syndrome and PCI in CYP2C19 poor and intermediate metabolizers in the absence of contraindications.8 The FDA approved clopidogrel label contains a boxed warning about reduced clopidogrel efficacy with the poor metabolizer phenotype. Though no dose adjustment is necessary for prasugrel or ticagrelor in patients with kidney disease, patients with end-stage kidney disease may be at higher risk for bleeding with these agents and thus need close monitoring. 76
|
| SLCO1B1 |
Simvastatin |
The SLCO1B1 521C allele is associated with an increased risk of myopathy with simvastatin. CPIC guidelines recommend avoiding simvastatin doses >20 mg or prescribing an alternative statin and consideration of creatinine kinase surveillance in patients with a 521C allele. CPIC guidelines do not address simvastatin pharmacogenetics in patients with kidney disease. In patients with severe kidney dysfunction, the simvastatin labeling recommends an initial dose of 5 mg. Kidney dysfunction is a risk factor for myopathy and may could potentially further increase risk for statin-induced myopathy in patients with the 521C allele.
|
| ADRB1 |
β-blockers |
There is evidence supporting associations between genes involved in β-blocker pharmacodynamics (ADRB1, ADRA2C, GRK5) and response to β-blockers in hypertension and coronary heart disease and response to bucindolol (not available in the U.S.), in heart failure. No CPIC guidelines are available at present. Atenolol is excreted by the kidneys and should be used cautiously in lower than usual doses in patients with kidney dysfunction regardless of genotype.
|
