Personalized medicine: myth or reality? The position of Russian clinical pharmacologists
© Zhestovskaja et al.; licensee BioMed Central Ltd. 2013
Received: 18 February 2013
Accepted: 17 April 2013
Published: 11 May 2013
A personalized medicine, a recent trend of clinical pharmacology, makes possible the individual approach to the choice of the drugs and their dosage. According to the results of a study of the activity of different biomarkers, particularly the isoenzymes of the cytochrome P-450, they provide the efficiency and safety of the pharmacotherapy. The activity of the isoenzymes of the cytochrome P-450 determines an individual pharmacological response and depends on many factors, including genetic ones. The biomarkers of the activity of the isoenzymes of the cytochrome P-450 should be tested in the clinical practice settings using the simple and cheap methods, one of the most available is an immunofluorescent assay. The skilled staff and the centers of personalized medicine are necessary for this approach.
KeywordsPersonalized medicine Biotransformation Isoenzymes of the cytochrome P-450
Personalized pharmacotherapy: traditional approach or new perspectives
There is a long-standing opinion that pharmacotherapy should be personalized, but physicians did not have the method of choice of drugs and their dosage. The necessity of the individual approach to the choice of the drugs is determined by the efficiency of pharmacotherapy (not more than 60% (WHO)) and the increased frequency of the adverse drug reactions (up to fatal cases). In some clinical trials, while drug administration is in standard dosage, some patients had a high serum concentration and the adverse drug reactions developed; other ones had a low serum drug concentration, and as a result, the treatment was ineffective.
Why the efficiency of pharmacotherapy is not more than 60% in spite of the existence of concepts of evidence-based medicine?
Why the frequency of the adverse drug reactions is increasing?
Why when standard dosage of plenty of administered drugs, the range of drug serum concentration is so wide?
40% of drugs are metabolized with the involvement of the isoenzymes of the cytochrome P-450 (CYP450)
8% of drugs are prodrugs, and their active ‘drugs’ are active metabolites.
Role of genetic polymorphism and isoenzymes of the cytochrome P-450in drug metabolism
combined administered drugs (induction/inhibition)
severity and character of the main and associated conditions
qualitative composition of food
Such results of the genotyping tests let us conclude that when the genetic polymorphism of the enzyme that metabolizes the drug is more than 10% of the cases in the population, the genotyping tests are necessary. But if a drug is the prodrug, from which with the involvement of the isoenzymes of the cytochrome P-450, an active metabolite is formed, the genetic polymorphism may result not in the adverse drug reactions but in the inefficiency of the treatment.
Also, a patent example of the genetic polymorphism influence on the development of the adverse drug reactions is the phenomena of the development of Stevens–Johnson syndrome during carbamazepine treatment period in patients with carrier state of HLA-B*1502, and the development of bleedings occurs during warfarin (in standard doses) treatment period in patients with carrier state of allele CYP2C9.
The isoenzymes of the cytochrome P-450 activity in the range of personalized medicine
So, what should a physician do to make a pharmacotherapy effective and safe? A physician should know how to work in the range of personalized medicine. What is a personalized medicine? According to the Personalized Medicine Consortium (USA), personalized medicine is the use of new methods of molecular analysis for the improvement of prognosis, prophylaxis and treatment of the diseases. The personalized medicine should change the development and realization of measures on prophylaxis and treatment of the diseases. According to experts, the ‘instruments’ of the personalized medicine are genomics, transcriptomics, proteomics and metabolomics. The study of the activity of the isoenzymes of the cytochrome P-450 refers to metabolomics, and in spite of the key role of cytochrome P-450 nowadays, there are no activity tests for it.
The activity of the isoenzymes of the cytochrome P-450 examination
The isoenzymes of the cytochrome P-450
Drugs: the substrates of the isoenzymes
The activity examination
Slow channel-blocking agents, statins, H1-histamine receptor blockers, cytostatics
• Cortisol/6-beta-hydroxycortisol concentration ratio in the urine
• 5-Hydroxycholesterol concentration in the blood serum
Beta-blockers, antidepressants, antipsychotic drugs
• Concentration of the pinoline and its metabolite, hydroxyl-1,2,3,4-tetra-beta-hydrocarboline in the urine
Oral anticoagulant, NSAID, antidiabetic drugs
• Concentration of losartan and its metabolite, E-3174 in the urine
Proton-pump inhibitors, clopidogrel, anticonvulsant drugs
• Concentration of 6-hydroxyomeprazole and its metabolite in the blood serum
Thus, we demonstrated that the concentration of the drug in the blood serum depends on the activity of the metabolism enzymes, particularly on the isoenzymes of the cytochrome P-450. If we know the level of the activity of these isoenzymes, we can choose a proper drug and its dosage to achieve a clinical effect and a low percentage of the adverse drug reactions.
Centers of personalized medicine: implementation instruments of personalized medicine in clinical practice
For the workflow management skilled staff, laboratories of pharmacokinetics and pharmacodynamics, knowledge in the area of personalized medicine among the general practitioners and health professionals is needed.
The formation of a contract with FSBI Scientific Center of Assessment of Medical Products under MHSD of Russian Federation, I.M. Sechenov First Moscow State Medical University, P.A. Herzen Moscow Research Oncological Institute.
The information (in the form of methodical documents and lectures) about the drugs that are metabolized with the involvement of the isoenzymes of the cytochrome P-450 with the information about reasons that can enhance and weaken the isoenzymes activity should be given to the general practitioners of MPI.
The development of the working scheme between a general practitioner of the MPI and a coordinator (consultant of the center). At first, a general practitioner sends by e-mail case history and specific questions for the consultant of the center to answer, connected with pharmacotherapy (the choice of drug and dosage regimen). The consultant's work is compared with the duty in the hospital and should be paid in accordance with these principles.
Personalized medicine is an innovative and science-intensive instrument for the improvement of the effectiveness and safety of pharmacotherapy of the socially significant diseases
The first president of the European Association for Clinical Pharmacology and Therapeutics (EACPT), emeritus professor of the Karolinska University (Stockholm, Sweden) and a member of the Nobel Committee for medicine, Folke Sjöqvist: ‘The personalized medicine is a preferred direction in Europe nowadays’.
The ex-president of the European Association for Clinical Pharmacology and Therapeutics (EACPT) and the director of the Institute of Pharmacology (Kiel, Germany), professor Ingolf Cascorbi: ‘The personalized medicine is a rapidly developing discipline, aimed to the objective scientific basis for the studying the personal differences in drug reactions’.
A current paper follows the recommendations of the EPMA White Paper.
The authors would like to thank Prokofjev AB, Kukes IV, and Kazakov RE.
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