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Pharmacogenomics

The development of genetic medicine and genetic testing have helped in the diagnosis of some rare and unusual diseases. Of potentially greater importance is the field of pharmacogenetics or pharmacogenomics, which represent the driving force for genetic medicine in primary care. In 1959 it has been coined the term “pharmacogenetics”, the study of variability in drug response based on inherited. Recently, the term pharmacogenomics was introduced in the broadest sense, it is the study of all the genes that may determine response to therapy. The distinction is very subtle, and both terms are often used interchangeably.

PHARMACOGENETICS, it is proposed to study the variations in sequence of genes (polymorphic variants) responsible for the effectiveness and tolerability of drug therapy in a single individual.

DNA tests, which identify these polymorphic variants are able to predict, at least in part, as a patient will respond to a given drug. The genetic test results will be used by the physician to choose which drug to use for the treatment of the patient, to optimize the dosage to be administered and minimize the risk of side effects.

The usefulness of Pharmacogenetic testing is the ability to assess the response of a patient to a certain drug on the basis of a genetic test routine, to achieve a customization of the therapy: “the right drug to the patient just”.

Pharmacogenomics: it is a branch of molecular biology that deals with investigating the effects of a drug based on genotype of the individual.

This type of research, however, is not based on the study of individual genes, but on the polymorphism (i.e. a change in the level of a nucleic acid sequence) at single nucleotide.

According to the observations made on several patients, it was noticed that everyone reacts differently to a particular drug depending on different polimorphisms Obviously the effective development of pharmacogenomics depends on the ability to identify genetic variations quickly and, possibly, economic.

Pharmacogenomics allows you to find new targets and everything starts with the identification of a susceptibility gene for a certain disease through genomic studies of pathological tissues and studies of transgenic animals.

The results are then verified by genetic studies in humans or differential gene expression studies and proteomics, in which one compares the levels of RNA or protein in a diseased tissue compared to normal tissue. Since susceptibility gene it is trying to trace the proteins encoded and their function and role in pathogenesis of the disease studied. This brings us to identify those molecules that can act as targets, if they hit with a suitable molecule they are able to stop or slow the disease process. The application of pharmacogenomics research has thus far allowed an increase of 5-10 times the number of drug targets identified.

The field is that of personalized medicine, in fact the purpose of pharmacogenomics is to enable the clinician to prescribe for each individual the drug or the dosage most suitable in order to achieve maximum clinical efficacy against the possible lower toxicity, based on a Genetic test.

DNA tests based on these genetic variations can predict how a patient will respond to that particular drug. Clinicians will use them to determine the optimal therapy and to customize the dosage, the benefits will include a reduced incidence of adverse reactions, in better clinical outcomes and reduced costs.

The first DNA-based tests are already available and pharmaceutical companies are developing specific tests to use with new drugs to market.

These tests represent the first step towards “patient-specific therapies”.

The customized drug therapies represent the reality of the coming years. Doctors will need to know if a drug is subject to genetic polymorphism that may influence the expression of drug metabolizing enzymes or drug receptors. Physicians should also know how to use this information to improve the care of their patients.

Variations in patient response to drugs represent a significant therapeutic problem. Although a generalization, has long been known that at least one third of people wanted to get the therapeutic benefit from prescribed drugs. In the remaining two thirds, or the drug does not work as intended or not well tolerated. The extraordinary appearance of responses is relatively frequent. In the U.S.A, adverse drug reactions in hospitalized patients is estimated at two million per year, with a hundred thousand of them fatal.

The Pharmacogenomics will have a major role in the individualization of treatment and in reducing adverse drug reactions. The short-term benefits may be underestimated because it often overshadowed by unrealistic expectations and probably the most remote of predictive medicine based on the study of genes.

The mapping and sequencing the complete human genome will lead to the discovery of genetic markers susceptibility to disease. But the great expectation that the human genome can reveal the genetic basis of common diseases and move the concept of health management from diagnosis and treatment of disease prevention and prediction remains a futuristic vision and perhaps impossible.

That the genetic revolution can not give rise to a new paradigm for the prevention of common diseases is very convincingly argued by Neil Holtzman and Theresa Marteau in a paper in The New England Journal of Medicine “The genetics will revolutionize medicine?” Although genomics identifies genes that cause “Mendelian disorders” such as “Huntington’s disease”, the genetic basis of common diseases are too complex to provide an accurate prediction of future disease based on genotype.

However, genetic differences influence the way individuals metabolize drugs. Polymorphisms have been identified in more than twenty drug-metabolizing human enzymes that can determine if an individual does not respond to a drug or manifest an exaggerated clinical response.

The Pharmacogenomics is making dramatic progress in the development of tests to predict which patients will benefit from a drug and which have toxic effects.

The DNA-based tests, designed for clinical use, will give the opportunity for physicians to predict patient response to a wide range of drug therapies.

Although the genome of individuals is identical for 99.9% of cases, the small difference of 0.1% can result in something like 3 million polymorphisms, the most common of them characterized by a single nucleotide polymorphism (SNP). Some polymorphisms in one hundred thousand and more genes of the human genome does not give effect. Many, however, affect the expression and function of proteins and result in phenotypes that affect disease or drug response.

The mechanism of action of most drugs depends on the interaction of the drug to specific target proteins such as receptors, transporters, and cellular transmission routes. Many of these drug targets have polymorphisms that may influence the response to specific drugs. In addition, polymorphisms in known pathological pathways can predict the effectiveness of a specific drug.

There are numerous examples in which the genotype studies have identified associations clinically relevant between genetic polymorphisms in drug targets and disease.

• A polymorphism of the protein that transfers cholesterol ester (CETP) determines the effectiveness of pravastatin in patients with diagnosed coronary atherosclerosis. The absence of polymorphism is associated with decreased efficacy. This finding was based on a study of Kuivenhoven, but has not been reproduced.

• Recently it was reported that the polymorphism of the beta-adrenergic receptor may influence the sensitivity of beta-adrenergic agonists such as albuterol. Asthmatic patients carrying the polymorphism Gly 16 (glycine at codon 16) show an increased response to beta-agonists compared with carriers of the polymorphism Arg 16 (arginine at codon 16).

• The 5HT2A receptor polymorphisms of the neurotransmitter serotonin are associated with efficacy of the antipsychotic drug clozapine. Patients with conversion of thymine-cytosine in position 102 are particularly predisposed to respond to clozapine.

• Other reported associations with alleged drug targets include converting enzymes of the angiotensyne and sensitivity to ACE inhibitors and apolipoprotein E (Apo-E) in response to tacrine therapy in patients with Alzheimer’s disease.

Currently, however, the greatest opportunity for clinical application of the genetic variations are related to enzymes involved in drug metabolism.

Polymorphisms in the drug-metabolizing enzymes

A relatively small number of drug-metabolizing enzymes (DMEs) is responsible for the metabolism of most drug therapies applied in clinical use today. There is a small number of relevant polymorphisms in these enzymes, and many of them give rise to a lack of therapeutic effect or an exaggerated clinical response to drug.

The genetic polymorphisms in DMEs gives rise to the formation of three subgroups of individuals who have appreciable differences in their ability to metabolize drugs for each active or inactive metabolite. People with an efficient drug metabolism are called “extensive metabolizers” (EMs). People with deficiencies in the metabolism, requiring mutation or deletion of both alleles of the gene are called poor metabolizers (PMs). Conversely, an increased expression due to gene amplification giving rise to ultrarapid metabolizers (UMS).

Standard doses of drug with a steep dose-response curve or a narrow therapeutic range may produce adverse drug reactions, toxicity or reduced efficacy in PMs. Standard doses of the drug, when taken by UMS, may be unable to produce the desired effect.

Two examples of polymorphism in drug-metabolizing enzyme, which have considerable clinical importance, include the important family of cytochrome P450, CYP2D6, and the enzyme thiopurine methyltransferase (TPMT). These genetic variations involve a significant proportion of the population and affect the therapeutic outcome of drugs commonly used to treat cardiovascular diseases, cancer, central nervous system disorders and pain.

Pharmacogenomic testing in cancer therapy: TPMT and HER2

TPMT is responsible for the metabolism of drugs containing thiopurine: the antileukaemic 6-mercaptopurine and 6-thioguanine and the immunosuppressant azathioprine. The activity of TPMT is essential for normal metabolism of these drugs and determine both the effectiveness and toxicity. Patients with a congenital deficiency of TPMT are suffering from severe and potentially fatal hematopoietic toxicity when exposed to standard doses of drugs containing thiopurine.

Pharmacogenomics test, developed at St. Jude Children’s Research Hospital, gives doctors the opportunity to predetermine the levels of TPMT activity of patients based on the presence or not of the same alleles associated with TPMT deficiency. The test classifies patients according to the level of normal, intermediate, and deficient in TPMT activity. The correlation between genotype and phenotype approaches 100%.

Patients classified as a normal activity, approximately 90% of whites and blacks are treated with conventional doses. In patients with poor and intermediate activities, which represent about 10% of each of these populations, lower doses are chosen to avoid toxicity.

Approximately 1 in 300 whites and blacks is deficient in TPMT. Although this polymorphism is relatively rare, patients with TPMT deficiency undergo a toxic response, exaggerated and potentially life-threatening to the normal dose of azathioprine and drugs containing thiopurine.

Genetic testing of TPMT have shown their effectiveness in the clinical management of patients with acute lymphoblastic leukemia (ALL). The reduction of the dose of 6-mercaptopurine 10-15 times compared with conventional thiopurine has made it tolerable in patients with TPMT deficiency and effective as the normal dose in patients with normal levels of enzymatic activity.

In the treatment of ALL, now this pharmacogenomics test is used extensively. At St. Jude Children’s Research Hospital, for example, patients with ALL are tested periodically for the activity of TPMT in order to optimize therapy. It is now considering the possibility of applying this test to azathioprine treatment of Crohn’s disease, rheumatoid arthritis and kidney transplants.

Pharmacogenetic tests have become an integral part of the treatment of metastatic breast cancer with trastuzumab (Herceptin). In this case there is no genetic variation in DME but a variation of the gene for the HER2 receptor, which influences the patient’s response to trastuzumab. HER2, a receptor for the hormone that stimulates tumor growth, is “overexpressed” in approximately one quarter of patients with breast cancer. The HER2/neu oncogene overexpression is correlated with a malignant prognosis, increased tumor formation and metastasis, and resistance to chemotherapeutic agents. Trastuzumab, a cloned antibody that blocks the receptor, gives a significant benefit when used as an adjuvant to conventional chemotherapy. Testing for HER2 identifies patients who iper-express HER2 and respond to the Trastuzumab.

2D6 genomic tests for specific classes of drugs

CYP2D6, or 2D6, is responsible for the metabolism of approximately 25% of all drugs. There are over 20 known drugs that are substrates of CYP2D6 (table). They include cardiovascular agents, antidepressants, antipsychotics, and derivatives from morphine; for example amitriptyline, fluoxetine, perphenazine, timolol, propaphenone, codein and dextromethorphan. Genetic variations in the levels of expression or function of 2D6 cause profound effects on the efficacy and toxicity of these drugs.

In 7-10% of whites and 1-2% of Asians were no mutations that lead to a deficiency of the enzyme 2D6. In the context of treatment, these changes can affect the correct determination of the initial dose of many drugs. For drugs with a narrow therapeutic profile and steep dose-response curve, this deficiency can lead to an overdose or to an inability to maintain therapeutic efficacy. Because many psychotropic drugs have a narrow therapeutic profile and adverse reactions are common, being able to predetermine the activity levels of the 2D6 for patients treated with these agents may have a significant clinical benefit.

The CYP2D6 may also influence the effectiveness of the pro-drug. Ingleman-Sundberg and his colleagues in their analysis of the effects in ultra-rapid metabolizers, they claim that high doses of the pro-drug codeine can give rise to the massive formation of morphine and trigger adverse effects. The absence of the 2D6 in poor metabolizers may reduce the effectiveness of pro-drugs that require activation of 2D6, such as, for example, the analgesic tramadol.

Until recently, pharmacogenomics tests were used primarily in a limited number of academic centers and teaching hospitals. Examples include the laboratory of pharmacology at Georgetown University (Washington, DC), which provided analysis for the 2D6 .The CYP gene family can offer many opportunities to explore the clinical validity of genomic testing. At the top of the list are the polymorphisms of CYP2C19, which affect a significant percentage of Asian population and allow you to predict the metabolism of commonly prescribed drugs.

Mutations in the gene CYP2C19, which gives rise to a compromise drug metabolism, have been found in 18-23% of Asians and 2-5% of whites. 75% of all PMs is due to a single allele. There is only one allele in Asians which is responsible for 25% of PMs in that population.

There are correlations between CYP2C19 polymorphism and pharmacokinetics and pharmacodynamics of drugs such as citalopram, clomipramine, diazepam, propranolol, omeprazole, and tricyclic antidepressants.

Emerging patient-specific therapy

One day we will consider today’s era as primitive as regards the choice of drug and dose.

In the future, will be considered unethical to expose patients to the risk of adverse reactions without first having made these rapid and simple DNA test. Improve outcomes in patients and adverse reactions will be reduced by avoiding the costs of hospitalization, the number of office visits and the great waste for ineffective therapies.

The selection of patients who respond to treatment is the most effective and economical solution to the growing problem that is driving governments and industries to deny effective drugs just because some patients do not respond to treatment. The policy of possible effectiveness, limited side effects, the reduction of complications due to a targeted therapy, as well as a cost-effective drugs, improve treatment of health and eliminate the need for “expenditure restraint”.

Whatever the future will be, pharmacogenomics tests there are and there are now. And it is proven that they represent an important tool in the evolution of drug therapy from an empirical art to a clinical science.

The FDA (Federal and Drug Admnistration), who chairs the American agency for approval of medical devices, in 2006 began to require pharmaceutical companies the obligation to accompany the registration dossier to the data of pharmacogenomics and to cite these same data in the drug information leaflet.

In concert, the EMEA (European Medicines Agency), the European equivalent of the FDA, has created commissions for pharmacogenetics and requires the prior execution of pharmacogenetic tests, such as the treatment of metastatic colorectal cancer with monoclonal antibodies.

And in Italy?

The AIFA (Italian Agency for the drug) is issuing guidelines for the execution of tests to investigate specific genes prior to therapy with certain drugs in order to predict the toxicity and / or efficacy. An example of a “general warning” of the toxicity associated with one of the most popular drugs in cancer therapy such as irinotecan is UGT1A1.

It was observed, in fact, that patients with a particular change to the DNA of the gene UGT1A1, if treated with irinotecan, were subjected to severe forms of toxicity. For this reason, the Food and Drug Administration has decided to include in the booklet that accompanies the irinotecan a pharmacogenetics indication that recommended the dose adjustment based on the sequence of the UGT1A1 gene.

In the future, as already happens in the United States, all of us have a genetic identity card, with which we’ll have access to highly customized treatments. By priority we started from cancer treatments, but in the future we’ll have costumized counter drugs.