10-29-2012, 12:04 AM
Importance of pharmacogenomic testing
Different people react differently to a prescribed drug. The reason is genetic polymorphism resulting in interindividual variability in a drug response. More than half of the drug metabolizing enzymes are polymorphic, and when they fail to “digest” the drug properly – toxic effect is inevitable. Luckily, a lot of examples of genetic polymorphism are already well known and they could be tested using various methods.
Drug application could result in severe adverse effects and those are the leading cause of death in USA hospitals (hundreds of thousands patients annually), plus hundred billion dollars are spent as additional cost. However, testing patients before prescribing drugs is not a common practice as it’s still expensive. Insurance companies are not covering costs for genetic polymorphism testing since clinical trials are lacking evidence that tests would benefit both patient and the health system.
Most common type of genetic polymorphism is single nucleotide polymorphisms (SNPs) resulting in different gene product. Single DNA base substitutes could alter mRNA processing and translation (structural RNA polymorphisms), transcription (regulatory polymorphisms) or protein sequence and function (polymorphisms in coding regions). Genome wide association study or GWAS is project whose purpose is to discover connection between single nucleotide polymorphism (in the large group of people) and their clinical traits. However, just couple proved to be clinically relevant our of the numerous SNPs candidates. Several key factors need to be fulfilled before genetic testing becomes routine procedure. First, genetic variant candidate needs to be identified. It’s important to confirm how often allelic variant is present in the population. If it’s rare, there’s no point wasting time and money on the research that will not be beneficial to a large group of patients. Association between genetic candidate and phenotype needs to be precisely determined. Clinical trials will determine whether genetic testing could improve current health care system. Cost effectiveness will show how profitable genetic testing could be, can it save or improve patient life, how it will affect clinical events….Finally, when all those steps prove that genetic tests are important, they could become a standard in a health care. FDA will recommend genetic testing through product labels or demand testing prior prescribing drugs to a patient at a high genetic risk.
Why all this is so important?
Warfarin is used to prevent thromboembolic events but it has one of the highest rates of the adverse effects compared to other single used drugs. Out of 2 million patients starting Warfarin therapy each year, around 20% are hospitalized due to bleeding in the first 6 mounts of the treatment. Problem lays in the polymorphism of CYP2C9 and VKORC1 genes. First one is metabolizing the drug, and other is drug’s target. Polymorphism in CYP4F2 and GGCX genes could also influence drug metabolism and activity. Tests for CYP2C9 and VKORC1 genetic polymorphisms are available, but due to lack of clinical evidence of their importance they are not used routinely prior prescribing the drug. When SNPs are determined precisely - Warfarin dose can be adjusted and adverse effects could be avoided. Alternatively, several other marketed drug thinners should be prescribed instead of Warfarin.
Clopidogrel protects against atherothrombotic events and could be combined with aspirin to prevent cardiac stent thrombosis. That is a pro-drug undergoing transformation by CYP2C19 when ingested. People having non functional CYP2C19 allele can’t convert prodrug into chemically active form and they are dealing with recurrent cardiovascular disorders. In a one year study, 21% of patients taking Clopidogrel have experienced cardiac ischemia or died during the study due to inability to convert pro-drug into drug. Routine genetic testing or dose adjustment is still not recommended, but FDA stated in the box warning section that CYP2C19 poor metabolizers could lack positive effect of a drug.
Codeine is an opiate showing analgesic, antitussive, anti-hypertensive and sedative effects. It’s converted into more active form by CYP2D6. In 2006, 14 days long Codeine therapy in the breastfeeding mother resulted in a death of her baby. Both mother and baby were rapid CYP2D6 metabolizers which resulted in extensive conversion of the Codeine to a Morphine and death due to overdose. This case is considered to be a rare genetic variation that resulted fatally and genetic testing is not considered important before Codeine is prescribed.
All people are different and unique and will react differently to a prescribed drug. Genetic testing could help determine appropriate dose or type of medication, but due to high price it’s not economical at the moment. Hopefully, greater demand and need for this kind of tests would reduce the price and ensure more efficient and safe future treatments.
Different people react differently to a prescribed drug. The reason is genetic polymorphism resulting in interindividual variability in a drug response. More than half of the drug metabolizing enzymes are polymorphic, and when they fail to “digest” the drug properly – toxic effect is inevitable. Luckily, a lot of examples of genetic polymorphism are already well known and they could be tested using various methods.
Drug application could result in severe adverse effects and those are the leading cause of death in USA hospitals (hundreds of thousands patients annually), plus hundred billion dollars are spent as additional cost. However, testing patients before prescribing drugs is not a common practice as it’s still expensive. Insurance companies are not covering costs for genetic polymorphism testing since clinical trials are lacking evidence that tests would benefit both patient and the health system.
Most common type of genetic polymorphism is single nucleotide polymorphisms (SNPs) resulting in different gene product. Single DNA base substitutes could alter mRNA processing and translation (structural RNA polymorphisms), transcription (regulatory polymorphisms) or protein sequence and function (polymorphisms in coding regions). Genome wide association study or GWAS is project whose purpose is to discover connection between single nucleotide polymorphism (in the large group of people) and their clinical traits. However, just couple proved to be clinically relevant our of the numerous SNPs candidates. Several key factors need to be fulfilled before genetic testing becomes routine procedure. First, genetic variant candidate needs to be identified. It’s important to confirm how often allelic variant is present in the population. If it’s rare, there’s no point wasting time and money on the research that will not be beneficial to a large group of patients. Association between genetic candidate and phenotype needs to be precisely determined. Clinical trials will determine whether genetic testing could improve current health care system. Cost effectiveness will show how profitable genetic testing could be, can it save or improve patient life, how it will affect clinical events….Finally, when all those steps prove that genetic tests are important, they could become a standard in a health care. FDA will recommend genetic testing through product labels or demand testing prior prescribing drugs to a patient at a high genetic risk.
Why all this is so important?
Warfarin is used to prevent thromboembolic events but it has one of the highest rates of the adverse effects compared to other single used drugs. Out of 2 million patients starting Warfarin therapy each year, around 20% are hospitalized due to bleeding in the first 6 mounts of the treatment. Problem lays in the polymorphism of CYP2C9 and VKORC1 genes. First one is metabolizing the drug, and other is drug’s target. Polymorphism in CYP4F2 and GGCX genes could also influence drug metabolism and activity. Tests for CYP2C9 and VKORC1 genetic polymorphisms are available, but due to lack of clinical evidence of their importance they are not used routinely prior prescribing the drug. When SNPs are determined precisely - Warfarin dose can be adjusted and adverse effects could be avoided. Alternatively, several other marketed drug thinners should be prescribed instead of Warfarin.
Clopidogrel protects against atherothrombotic events and could be combined with aspirin to prevent cardiac stent thrombosis. That is a pro-drug undergoing transformation by CYP2C19 when ingested. People having non functional CYP2C19 allele can’t convert prodrug into chemically active form and they are dealing with recurrent cardiovascular disorders. In a one year study, 21% of patients taking Clopidogrel have experienced cardiac ischemia or died during the study due to inability to convert pro-drug into drug. Routine genetic testing or dose adjustment is still not recommended, but FDA stated in the box warning section that CYP2C19 poor metabolizers could lack positive effect of a drug.
Codeine is an opiate showing analgesic, antitussive, anti-hypertensive and sedative effects. It’s converted into more active form by CYP2D6. In 2006, 14 days long Codeine therapy in the breastfeeding mother resulted in a death of her baby. Both mother and baby were rapid CYP2D6 metabolizers which resulted in extensive conversion of the Codeine to a Morphine and death due to overdose. This case is considered to be a rare genetic variation that resulted fatally and genetic testing is not considered important before Codeine is prescribed.
All people are different and unique and will react differently to a prescribed drug. Genetic testing could help determine appropriate dose or type of medication, but due to high price it’s not economical at the moment. Hopefully, greater demand and need for this kind of tests would reduce the price and ensure more efficient and safe future treatments.
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