Pharmacogenetics and Pharmacogenomics
Optimizing Drug Response
The impact of the genome on our ability to predict drug response is one of the most promising and fertile areas of genomic and personalized medicine. Pharmacogenetics is the study of genetic variation that ultimately gives rise to the variable responses in individuals to any given drug treatment. More recently, pharmacogenetics has provided an explanation as to why certain individuals do not respond, or respond differently, to a given drug treatment. Pharmacogenomics uses genomic technology to understand the effects of all relevant genes on the behavior of a drug or conversely the effect of a drug on gene expression. Pharmacogenomics, like pharmacogenetics, has rapidly embraced genomic technologies to identify molecular patterns of response, drug disposition, and drug targets. Both approaches have great potential to positively affect the field of medicine.
Pharmacogenomic Tests: Promise on the Horizon
Perhaps the best example of a successful pharmacogenetic association for which the clinical relevance is clear is the management of warfarin therapy.[43] The oral anticoagulant warfarin (a derivative of coumarin) is commonly prescribed for the long-term treatment and prevention of thromboembolic events. However, because of the drug's narrow therapeutic index, a variety of complications are associated with its treatment, even after dose adjustment according to age, gender, weight, disease state, diet, and concomitant medications. Investigation of pharmacokinetic and pharmacodynamic drug properties indicated the additive involvement of 2 genes in determination of warfarin maintenance dose. One of these genes encodes CYP2C9, which is responsible for most of the metabolic clearance of the more pharmacologically potent S-enantiomer of warfarin. Both CYP2C9*2 and *3 cause a reduction in S-warfarin clearance, with the lowest activity variant (CYP2C9*3) showing 3% to 11% of the activity of the most active (wild type) variant, CYP2C9*1. Numerous studies have associated these genotypes with initial dose sensitivity, delayed stabilization of maintenance dose, delays in hospital discharge and increased bleeding complications.[44] However, it is estimated that CYP2C9 variants account for only 6% to 10 % of the total variation in warfarin dose,[45] with additional genetic and environmental factors playing larger roles in dose determination. The second gene identified as a predictor of dosing is the vitamin K epoxide reductase complex protein 1 (VKORC1), targeted by warfarin and accounting for 21% to 25% of dosage variance.[45] According to new product labeling, consideration of VKORC1 genotype or haplotype together with CYP2C9 genotype and factors such as age and body size are estimated to account for about 55% of the variability in warfarin dosing requirements.
Despite the fact that multiple independent groups have reproduced these data, prospective clinical studies are required to establish whether initial dose may be tailored to patients by CYP2C9 and VKORC1 genotyping coupled with known clinical variables.[46] These studies are currently underway, however, the Food and Drug Administration acknowledged the importance and potential for genotyping of CYP2C9 and VKORC1 during the early phase of warfarin therapy, and the drug label was amended accordingly in August 2007.
More than 50 years ago, 6-mercaptopurine was marketed for the treatment of acute lymphoblastic leukemia. Despite great expectations, fatal bone marrow suppression was found in 0.3% of treated children. There were similar findings for azathioprine several years later. It was later discovered that polymorphisms within the thiopurine methyltransferase (TPMT) gene underlie the large interindividual differences in the enzyme's activity, leading to a high risk for thiopurine-induced toxicity in homozygotes for the defective alleles and inadequate therapeutic efficacy in patients with high-activity TPMT.[47] Tests for TPMT activity (genotype, enzyme activity, and metabolite screening) are available in the United States and throughout Europe; however, clinical implementation of these tests is very low. This is contrary to expectations based on cost-effectiveness analysis of TPMT testing in children with acute lymphoblastic leukemia showing high savings per life-year.[48] Current clinical practice for the management of leukemia using thiopurines dictates careful monitoring of white blood cell counts and clinical outcomes. It is expected, however, that as genetic tests become generally accepted for a variety of conditions, it will become progressively acceptable to use TPMT genetic testing as a prognostic tool for adverse drug response.
A forme fruste of pharmacogenomics is the notion of targeted therapies.[49] Trastuzumab therapy (a monoclonal antibody specifically targeting HER2/neu-overexpressing breast tumors) for the treatment of breast cancer is an example of a protein therapeutic for which an obligatory biomarker assay and diagnostic test has been developed to identify the patients most likely to benefit from this drug. Trastuzumab is marketed solely for the subset of patients who have overexpression of HER2/neu.Given the low prevalence of marker-positive breast cancers, it is conceivable that if it were not for the use of the diagnostic marker in clinical development, the drug would not have been successfully developed. Cancer is not the only field of medicine with a targeted pharmacogenomic approach to giving therapeutics. In cardiovascular medicine, a targeted approach to acute coronary syndromes has been practiced for more than a decade with the use of cTnI measurements to dictate the beneficial use of glycoprotein IIb/IIIa inhibitors.
To assist clinicians in the practice of pharmacogenetics across a broad number of medications, the first microarray-based gene chip, approved both in the United States and Europe, was released in 2003 as the AmpliChip CYP450.[50] The product was designed to identify key genetic polymorphisms in 2 CYP450 enzymes, CYP2D6 and CYP2C19, cumulatively responsible for much of the first-pass metabolism of many currently prescribed drugs. The regulatory agencies indicated that its utility as a stand-alone test remained unproven.[51] Thus clinicians, as well as patients, are unclear about the impact of these tests on clinical decision-making guidelines. Until unambiguous evidence proves the clinical use of this and other genetic tests, caution is advised in their interpretation and application in healthcare management.
Can interpatient variability in somatic tissues such as a tumor be used in treatment planning? Recently, a series of gene expression signatures have been developed that predict response and resistance to conventional cytotoxic chemotherapeutic agents, portending the advent of personalized cancer treatment based on a tumor's gene expression pattern. Using in vitro drug sensitivity data combined with microarray gene expression data publicly available for the NCI-60 set of cell lines, signatures of response to , docetaxel, paclitaxel, topotecan, doxorubicin, cyclophosphamide, and etoposide were developed using logistic regression modeling.[52] Using independent sets of human tumors with known clinical outcome and for which expression data were available, the authors went on to demonstrate that these signatures could predict response to chemotherapy in these tumors in both the neoadjuvant and adjuvant chemotherapy settings. These genomic signatures now form the basis for a series of first-of-their-kind clinical studies in which treatment assignments in the trials are being made based on the pharmacogenomic molecular signatures from a patient's tumor. This is one of the clearest examples of a genomic technology paving the way for truly personalized medical treatment.
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