Clinical pharmacogenetics: a promising tool for personalized medicine

Clinic

Department of Clinical Pharmacology of I.M. Sechenov MMA,
Institute of Clinical Pharmacology of the NC ESMP Roszdravnadzor.
The journal "Remedium" No. 3-2008.

The use of medicines in clinical practice, the effectiveness of which has been proven in randomized trials performed in accordance with the methodology of evidence-based medicine, is one of the largest achievements of medical science and practice of the late twentieth century. Indeed, the methodology of evidence-based medicine implies that a doctor makes a decision on the use of drugs in a patient based on the results of the best clinical studies, thus determining the strategy of drug therapy for a particular disease. These strategies are reflected in the standards and clinical guidelines of various professional societies. However, the tactics of choosing and using drugs in a particular patient, taking into account all his individual characteristics, are still poorly developed, and doctors often prescribe medications by trial and error and by eye. Therefore, the problem of insufficient safety and effectiveness of drugs remains relevant at the beginning of the XXI century.

Indeed, all patients are different, therefore, the tactics of using drugs should be different, and the use of technologies that allow individualizing pharmacotherapy will contribute to its optimization, making it as effective and safe as possible. Among other things, it is economically advantageous, because it allows you to reduce the cost of purchasing ineffective drugs and correcting undesirable drug reactions (NLR).

The use of such technologies in clinical practice is the basis of personalized medicine. Based on the fact that the genetic characteristics of the patient can determine an inadequate pharmacological response by more than 50%, i.e. what we do not expect from drugs (inefficiency or development of NLR), personalization of the use of drugs based on genetic studies is the most promising direction. The study of the influence of genetic features on the development of the pharmacological response in patients with the use of certain drugs deals with the section of clinical pharmacology, called clinical pharmacogenetics, the foundations of which were laid in the middle of the last century.

Currently, the number of publications devoted to clinical pharmacogenetics is growing like a snowball. There is even a resource on the Internet where the results of pharmacogenetic studies are concentrated (www.pharmgkb.org ). However, while a single number of pharmacogenetic tests have been approved for use by the relevant regulatory authorities abroad, pharmacogenetic testing is rarely used in real clinical practice. For example, in Australia and New Zealand in 2005, only about 1,000 pharmacogenetic tests were conducted. At the same time, allelic variants of the TRMT (sensitivity to the cytostatic mercaptopurine) and VSNE (sensitivity to the muscle relaxant suxamethonium) genes are most often determined. And the definition of "slow" allelic variants of genes encoding cytochrome P-450 isoenzymes and acetyltransferase was never used at all in 2005. Russia, unfortunately, does not have such statistics. But if you look on the Internet, you can easily find several commercial medical centers and laboratories that offer pharmacogenetic testing. These are mainly polymorphisms of genes of biotransformation enzymes, in particular CYP2C9 (sensitivity to indirect anticoagulants), CYP2D6 (sensitivity to antidepressants and neuroleptics), etc.

In Russia, the need for pharmacogenetic testing was regulated by an order of the Ministry of Health of the Russian Federation back in 2003, but it is used extremely rarely. In our opinion, this is due to the fact that not every identified association between the polymorphism of a particular gene and an inadequate pharmacological response can form the basis of a pharmacogenetic test suitable for real clinical practice. We have formulated the basic conditions for the introduction of pharmacogenetic testing in practical healthcare. However, it should be borne in mind that pharmacogenetic testing is necessary to personalize the use of, first of all, "problematic" drugs, which are characterized by a large range of NLR and high variability in effectiveness.

It should be noted that the number of pharmacogenetic tests that the FDA has approved for use in the United States can be counted on the fingers. These include:

• Identification of polymorphisms of the CYP2D6 and CYP2C19 genes for the selection of antidepressants and neuroleptics, as well as their doses.
• Identification of polymorphisms of the CYP2D6 gene for choosing the dose of atomoxetine in children with attention deficit disorder.
• Identification of TPMT polymorphisms for dose selection of 6-mercaptoputrin in children with leukemia.
• Determination of the expression of the HER2 gene for the selection of trastuzumab (herceptin) in women with breast cancer.
• Identification of CYP2C9 gene polymorphisms for warfarin dose selection (approved in August 2007).

It is also worth mentioning the problem associated with the fact that not all gene polymorphisms that determine the pharmacological response to drugs are currently known, therefore, while our tests do not reveal all genetic features, and therefore there will be both false positive and false negative results of the study. Moreover, other non-genetic factors (interaction, impaired liver and kidney function, food, etc.) also affect the pharmacological response. There is confidence that in the future new models of drug dosing will appear, taking into account many other individual characteristics of a person.

The list of drugs, in the application of which it is necessary to use pharmacogenetic testing, will be rapidly expanding. Basically, these are drugs, when using which there may be problems of efficiency and safety. Pharmacogenetic tests are on the way to implementation, allowing to choose the most effective antihypertensive agents, statins, adrenomimetics for a particular patient, and in minimal doses. In addition, in our opinion, the use of pharmacogenetic testing gives greater confidence to the doctor when using drugs. For example, the same warfarin in Russia is rarely prescribed, not only because of the inability to control INR, but also because doctors are afraid of bleeding. A doctor who selects a dose of warfarin using pharmacogenetic testing is confident in the safety of this treatment. By the way, the use of pharmacogenetic testing can increase the patient's adherence to treatment, since he knows that the doctor prescribed him a drug in a dose that is suitable only for him.

It is very important to equip doctors with knowledge in the field of pharmacogenetics and skills of practical use of pharmacogenetic testing, for which it is necessary to organize training of personnel of pharmacogenetic laboratories. At the same time, in our opinion, the main specialists in the field of applied pharmacogenetic testing should be clinical pharmacologists, because they should become assistants to doctors in solving problems arising from the use of drugs, and it is on their "pay-off" according to the already mentioned order of the Ministry of Health of the Russian Federation "On improving the activities of clinical pharmacologists" pharmacogenetics has been given away. The basics of clinical pharmacogenetics should be studied both at the pre-graduate and postgraduate stages of training doctors, and of all specialties. And the only Department of Pharmacogenetics in Russia at RSMU (head of the Department, Academician of the Russian Academy of Medical Sciences, prof. S.B.Seredenin) is not enough. So far, students have little idea what clinical pharmacogenetics is and why it is needed: only 21% of 6th-year students studying in the specialty "medicine" gave the correct definition of pharmacogenetics during the survey.

So, personalized medicine and its main tool at present – clinical pharmacogenetics are actively developing and have already come close to being introduced into real clinical practice, including in Russia. Pharmacogenetic testing may well be a high medical technology in the field of pharmacotherapy. Yes, there are many unresolved problems in Russian healthcare, but the opportunities provided by clinical pharmacogenetics should be used for the benefit of patients right now. Both doctors and pharmaceutical companies should be interested in this. It is not for nothing that the issues of clinical pharmacogenetics are constantly discussed at almost all major medical symposia, and in 2005 a seminar on personalized medicine was even organized at the World Economic Forum in Davos. It should also be said that pharmacogenetic research is officially supported in the EU countries. This is reflected in a document developed 2 years ago: "25 recommendations on the ethical, legal and social consequences of genetic testing." These recommendations emphasize the need for state support for the active introduction of pharmacogenetic testing into clinical practice. We hope that in the future, when coming to a doctor's appointment, the patient will receive clear personalized recommendations on drug therapy, both taking into account the results of pharmacogenetic studies reflected in his "genetic passport", and in accordance with the methodology of evidence-based medicine.

Portal "Eternal youth" www.vechnayamolodost.ru
27.11.2008