Pharmacogenetics of clopidogrel and its significance for the clinic

The purpose of a brief review for the pharmacogenetics of clopidogrel and its significance for the clinic. The results of some studies conducted on the basis of pharmacogenetic testing are presented. Bedside aggregatometry can be recommended for patients on dual antiplatelet therapy in order to reduce the risk of fatal complications thrombosis and bleeding, identify cases of resistance and compliance problems, which will significantly improve the quality of medical care, allow to personalize the antiplatelet therapy, reduce the cost of treatment, the number and duration of hospitalizations. In the treatment of patients, the results of pharmacogenetic studies should be considered, taking into account the populations of different nationalities, for the doctors to be confident in the safety and efficacy of drugs.

The problem of effedive and safe pharmacоtherapy in the wоrld is actualized in eonneGtion with the growth of the number of drugs (D).

At the present time, the still face the problems of piUc^s &еа№еМ, сіюісс of the most safe and effedive D, adjustment of drug dosage taking into consideration their cоmpatibility and interadion with other D, prevention of adverse events and ^гассИт when they o^ur.

We cannot but ^^g^ze the development of standards and сііпісіі guidelines for patients’ &еа№еМ, based on the prindples of evidence-based medidne and the results оf сіітсаі studies is the achievements of the past сспИігу. But in the ^urse of this approach the individual features of piUc^s ^t inOue^e the nutrnme of the drug therapy were not taken into account. [1].

The results of foreign s^endf^ studies [2,3,4,5,6,7] showed ^t piUc^s Iivc different pharmacological responses to the standard drug dose. Some patients have Іоо high concentratiоn of MA in blnnd, whidi lends to the deve^me^ of side гоасіо^; dllicrs have ton tow concentration and the йтайміП beromes meffert^e. The third group of patients has а paradoxical response, whidi сап lend to fatal outcome. According to the data of the World НөаіЛ Organization (2009), the effediveness of patients’ treatment is, оп average, опіу 60%. In the United States, up to 100,000 people die from inappropriate use of drugs, wh^h occupies the 6th place among the causes of death. Мого іНап 2 іпііііоп adverse drug гоасйо^ (ADR) аго rerorded. The economic damage increased from 76.6 (1997) to 177.4 Ьііііоп dollars (2001) [7].

The results of pharmacogenetic studies differ in different national affiliations of people. Ғог example, the work of Professor Yu.N. Chernov shows ^t the frequences of сИтсаПу signif^m: аМіс variants of the biotransformation system genes of Russians аго comparable to theisc of dtlicr European rountries. But among the Chutazhi living in the Far Nr>rth, these frequences аго higher. GenetK characteristics of а person affecting the pharmacological response аго determined during pharmacogenetic testing [8, 9].

Genet^l^ determined features of the enzymes and receptors of patients, non-compliance with the drug regimen by patients, presence of aurait infіammatory processes, obesity, diabetes and smoking аго causes of clopidogrel resistance.

Ғог overcoming resistance sGme authors (B. Aleil and coauthors) suggest increasing the dose of clopidogrel ог гаріас^ it with another antiplatelet agent. In this connection, ай^г increasing the dose ой clopidogrel from 75 mg / day to 150 mg / day the number ой resistant patients with percutaneous coronary intcrvcntir>n decreased from 33% to 12% withr>Lit an increase in the number ой bleeding [10].

The data from а systematic review ой 15 studies indite ^t ассо^^ to ^огайгу testing 25% ой patients have clopidogrel resistance [8].

Studies ой CAPRIE (Clopidogrel versus Aspirin in Patients at Risk ой Is^em^ Events), CURE (Clopidogrel in Unstable angina ой ReGuiTent Events), CREDO (Clopidogrel йог the ReduCton ой Events during Observation) герои an unambiguously positive effeC ой clopidogrel оп the reduCton ой total поИ^ійу from heart diseases. [11-13].

It is ако кпоѵп іНаІ during these studies from 5 to 44% ой patients with согопагу heart disease show insuffident effeciveness йог clopidogrel арріісайоп, wh^h is "resistance'' [14-15].

The prescription ой P2Y12 inhibitors ой receptors and acetylsalicylic acid as а dual anti-thrombocytic Йіотару is ап integral ран ой the treatment ой patients with acute согопагу syndrome (ACS). ^weve^ depending оп а variety ой genetic сііпісаі, demographic, ЬЪогаЮгу, and ойіст Іасіоге, the patients’ response to clopidogrel may vary ronsiderably. Clopidogrel is ап тасйуө prodrug and йог the йотайоп ой ап асйуѳ metabolite, its oxidation by cytochrome Р-450 (CYP) enzymes is required. There аго variants ой this gene ^t enrode the йотайоп ой ап enzyme with redded ог absent fundim. Polymorphisms rontributing to the toss ой enzyme Ьпсйоп аго defined as CYP2C19 * 2 and CYP2C19 * 3, while опИпау polymorphism is defined as CYP2C19 * 1. CYP2C19 * 2 and CYP2C19 * 3 аік^ do wt have ап effecive metabolism ой clopidogrel [18]. These :ѵо аік^ аго responsible йог the majority ой аііө^ with redded ріай^ Ьпсйоп among patients ой Asian (99%) and Caucasoid (85%) origin [19]. Лссогеіііір to numerous studies оп patients’ clopidogrel resistance with а homozygous mutation by CYP2C19

• 2 (G681A) а^к [20] t^grelm should be prescribed instead ой clopidogrel. There аго signif^M ethn^ and гасіаі differences in the h^que^y ой the CUR2C19 * 2 а^к. It is established ^t the frequemy ой occurrence ой сагеіст ой the CUR2C19 * 2 (G681A) аі^^ is about 15% among Caucasians and ЛІгісаі^ and 29-35% among Asians. It йollows ^t up to 35% ой Asians have а high risk ой ЛгошЬойс ^прі^Но^ аііот PCI. Based оп the identified SUR2C19 genotypes, people аго classiйied as йast metabolisers (EMs; * 1 / * 1), intermediate metabolisers (IMs; * 1 / * 2 and * 1 / * 3) and роог metabolisers (PMs, * 2 / * 2 and * 2 /
• 3). The frequences ой SUR2S19 PMs аго ~ 2-5% among Caucasians and ЛІгісаі^ and ~ 15% among Asians [21]. Amrng patients сагеісге ой а genets variant with toss ой fundim ой the CYP2C19 * 2 enzyme (* 2 / * 2) during the treatment with clopidogrel the risk ой stent thrombosis is 3-6 times higher. Taking into account the data ой numerous studies оп clopidogrel resistance, patients with а homozygous mutation by the CYP2C19
• 2 (G681A) а^к ог роог metabolisers, should be prescribed

t^grelm instead ой clopidogrel [20]. In а study conducted by W.P.Zhrng and cithers, new variants in the genes (SLC14A2, ABCA1, N6AMT1) ^t aййect clopidogrel's antiplatelet response were identified among Chinese patients. These new variants have signif^M^ improved the predictability ой the variability ой the residual ріай^ гоаскйу (ORT) to 37.7%. In addition, the association ой the above ment^ned genets variants with the deve^me^ ой the main adverse cardiovascular events айөг PCI was identified. From recommendations ой the European Society ой Cardiology (ESC) and the European Association ой Cardiothoracic Surge'diis (EACTS) оп myocardial revascularization ой 2014, platelet fundim testing ог genets testing сап be ronsidered in high-risk situations. Today, genets testing in routine ргасйсө is wt rerommended because there аго insufficent prospective data [22]. ^weve^ genets characteristics аго the cause from 20 to 95% ой аіі adverse responses ой the human body, the аНг^й ой wh^h is their constancy throughout life. Availability ой various огаі inhibitors P2Y12 allowed physicians to ronsider the possibility ой switohing ^гару depending оп the speciйic сііпісаі situations. This decsim сап be йacilitated by many йаСога: the patient's сііпісаі characteristics, concomitant іЬсгару, social problems, deve^me^ ой side effeCs, adherence to treatment, and patient and / ог physician preйerence. Thereйore, if necessary, the P2Y12 inhibitor сап be replaced [16].

Лссогеііпр to A.I. Akhmetov's study ой pharmacogenetic testing ой patients with ACS was а signif^M predictor ой antiplatelet іЬсгару соггоСіоп. The соггоСіоп induded the replacement ой clopidogrel with t^grelm ог ап increase in the maintenance dose ой clopidogrel up to 150 mg / day, wh^h did wt aййect the signif^M сііпісаі outcomes [17].

Pharmacogenetic testing ой CYP2C19 gene polymorphisms is desdibed in the thesis research by D.A. Mansurov. In the study ой 101 patients айст percutaneous согопагу intervenUm, genotyping was perйormed by the аМіс variants ой CYP2C19 * 2 (G681A) and CYP2C19 * 3 (T^^Ter). The average age ой аіі patients was 58.5 (+10.2), minimum 36 and maximum 87. 77 ой them were men (76.2%) and 24 ѵопсп (23.8%). By пайопаійу 75 (74.3%) were Kazakhs and 26 (25.7%) were Caucasians.

As а result ой genets analysis by the CYP2C19 * 2 аПэк (G681A) the йоМоѵ^ distribute was received:

• 44 (43.6%) patients had погшаі CYP2C19 * 1 / * 1 genotype, 32 ой them (41.6%) were men and 12 (50%) were ѵопсп (р = 757); 32 (42.7%) were ой Kazakh пайопаійу and 12 (46.2%) were ой the Caucasian race (р = 0.466);
• -51 (50.5%) patients were heterozygous сагеісге ой CYP2C19 * 1 / * 2, 39 (50.6%) ой them were men and 12 (50%) were ѵопсп (р = 0.953); 38 (50.7%) were ой Kazakh пайопаійу and 13 (50%) were ой the Caucasian race (р = 0.956);
• 6 (5.9%) men (7,8%) (р=0,331) were homozygous сагеісге ой CYP2C19 * 2 / * 2 ^^аМ homozygote); 5 (6.7%) were ой Kazakh пайопаійу and 1 (3.8%) was ой the Caucasian race (р = 0.600).

By the аМіс variant ой CYP2C19 * 3 (Trp212Ter), the studied patients were distributed as йollows:

• 94 (93.1%) patients had the потаі genotype CYP2C19 * 1 / * 1; 72 (93.5%) ой them were men and 22 (91.7%) were ѵопсп (р = 0.669); by their пайопаійу 69 (92%) were Kazakhs and 25 (96.2%) were Caucasians (р = 0.674);
• 7 (6.9%) patients were heterozygous сагеісге ой CYP2C19 * 1 /
• 3, 5 (6.4%) ой them were men and 2 (8.3%) were ѵопсп (р = 0.669); by пайопаійу 6 (7.9%) were Kazakhs and 1 (3.8%) were Caucasians (р = 0.472);
• patients with homozygous carriage ой CYP2C19 * 2 / * 3, * 3 / * 3 were wt defined.

Thus, as а result ой genotyping ой the CYP2C19 polymorphism * 2, there were defined 43.6% ой patients with потаі genotype CYP2C19 * 1 / * 1, 50.5% with heterozygous CYP2C19 * 1 / * 2 and 5.9% with homozygous CYP2C19 * 2 / * 2 carriership. By theCYP2C19 * 3 allele: 6, 9% of patients were heterozygous carriers of CYP2C19 * 1 / * 3, patients with homozygous carrier of CYP2C19 * 2 / * 3, * 3 / * 3 were not identified. The carriership rate for CYP2C19 * 2 is 49.5% higher than that for CYP2C19 * 3 [23].

The thesis of K. B. Mirzaeva gives a profound interpretatfon of the pharmarogenetic testing and rerommendatfons оп the tactics of patients management. Depending оп the catalytic activity of the CYP2C19 isoenzyme, the folfowing phenotypes are distinguished in the human population (Figure 1):

"Extensive metabolisers" (EM; carriers of CYP2C19 * 1 / * 1 genotype), “Intermediate metabolisers'' (IM; carriers of CYP2C19 * 1 / * 2, * 1 / * 3, * 2 / * 17, * 3 / * 17), “sfow metabolizers'' (PM; carriers of CYP2C19 * 2 / * 2 genotypes, * 2 / * 3, * 3 / * 3) and "ultrafast metabolisers" (UM; carriers of CYP2C19 * 1 / * 17, * 17 / * 17 genotypes) (http://www.pharmgkb.org/). Individuals with PM and IM phenotypes produce CYP2C19 with reduced enzymatic activity, which leads to an increase in the concentration of drugs in the plasma (the transformatfon of drugs into an inactive metabolite stows down), despite the delivery of therapy in the standard dose. If the medicinal agent is a prodrug and it requires bfoactivatfon in humans, then patients with PM and IM phenotypes show insufficient effectiveness of pharmarotherapy (sfowing in formatfon of the active metabolite).

It is observed that patients with UM phenotype produce CYP2C19 with an increased enzymatic activity and, as a ronsequence, there is a decrease in the pharmarofogical effect of drugs taken in the standard dose (in the case of prodrugs, the risk of undesirable drug reactfons, оп the rontrary, increases).

Figure 1 Patient groups accordiпg to the metabolic ratto of the coпceпtratioп of omeprazole to 5-OH-omeprazole 4 hours after 20 mg of omeprazole, metabolized by CYP2C19 isoeпzyme. (Adapted from: Scott SA, 51 Sangkuhl K, Stein CM, et al; Clinical Pha^a^ge^^cs

Implementatfon Consortium. Clinical Pharmarogenetics Implementatfon Guide for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmarol 2013 2013; 94 (3): 317323).

In 2010 US Food and Drug Administratfon (FDA) amended the instructfons for medical use of the original drug, with a warning that the drug may be ineffective for carriers of functfonally defective alleys of the CYP2C19 gene. In 2011, the Guidelines of the European Society of Cardfofogy (ESC) for the treatment of patients with ACS included the possibility of pharmarogenetic testing in order to select an antiaggregant drug for certain categories of patients (level of evidence IIB). Acrording to the rerommendatfons of the American Heart Association (AHA) / American Cnllege of Cardfofogy (ACC), pharmarogenetic testing is justified опіу for patients from the risk group of devefoping stent thrombosis (level of evidence IIIC). Acrording to the rerommendatfons of the Internatfonal Consortium оп the introductfon of pharmarogenetics into clinical practice, and the European Society of Cardfofogy, when detecting sfow allelic variants of the CYP2C19 gene, it is rerommended to choose an antiplatelet drug not metabolizable (ticagrefor) ог less metabolizable (prasugrel) by this isozyme (Srott, 2013) (Figure 2).

Indications for

DAT:

patients with ACS,

< • -I- —У

Genotyping

byCYP2C19

\ /

1/*2, *1/*3, 2/*17

Assign another blocker P2Y12receptors: ticagrelor, prasugrel

*1/*17,*17/*17

Prescribe a standard dose of clopidogrel

Figure 2 Recommeпdatioпs оп the tactics of patients management with ACS and PCI acrording to the results of pharmarogenetic testing. (Adapted from: Srott SA, Sangkuhl K, Stein CM, et al; Clinical Pharmarogenetics Implementatton Coпsortium. Clinical Pharmarogenetics

Implementation Guide for CYP2C19 genotype and clopidogrelotherapy: 2013 update. Clin Pharmacol 2013; 94 (3): 317323).

Indications for pharmacogenetic for CYP2C19 testing for prediction of clopidogrel resistance.

Clinical situations in which it is desirable to conduct pharmacogenetic testing for CYP2C19 (AHA 2012: class IIb, level of evidence C. ESC 2011: class IIb, level of evidence B)

• intervention on an unprotected LCA trunk (AHA 2012),
• bifurcation stenosis of the left coronary artery trunk (AHA 2012),
• stenosis of the only passable coronary artery (AHA 2012),
• repeated PCI (AHA 2012),
• history of stent thrombosis (CPIC 2013),
• clinical high risk factors (ACS, diabetes, chronic renal failure) (CPIC 2013)

The problem of predicting the antiplatelet effect of clopidogrel, considering genetic polymorphism and catalytic activity of isoenzymes, clinical, laboratory and demographic features of the patient remains relevant at the present time.

A promising direction for solving this problem is the development of complex algorithms with the integration of the results of genotyping, phenotyping, patient's individual characteristics, which makes it possible to take a step towards a more complete adaptation and personalization of antiplatelet therapy compared to the traditional practice of isоlated assessment of factors affecting the pharmacological response to clopidogrel. Currently, there is an active development of such forecasting algorithms and the study of the possibility of their use by patients of different ethnic groups and race. The factor stimulating the development of various algorithms for predicting antiplatelet activity is also gaining more and more evidence the concept of a “therapeutic window” for the use of P2Y12 receptor blockers (Malhotra N, 2015)) [24].

High residual platelet reactivity is a proven factor of increasing the risk of adverse cardiovascular events, while low platelet reactivity is associated with the risk of bleeding. According to the results of clinical studies, numerous domestic and foreign standards and clinical guidelines determine the indications for aggregometry. Testing platelets function may be recommended for patients on a dual antiplatelet therapy in the following clinical situations:

1. High risk of stent thrombosis in the following cases: repeated ACS, non-cardioembolic strokes, episodes of acute lower limb ischemia; stent thrombosis in history; the patient underwent multiple stenting; a lesion of the left main coronary artery or a lesion of the only remaining vessel supplying the myocardium was diagnosed;
2. High risk of bleeding;
3. Suspected resistance to one of the components of DAT (including the identification of genotypes, the carriership of which is associated with clopidogrel resistance);
4. Suspected adherence to treatment problems;
5. Preparation for conducting CABG or other, including noncardiac surgical intervention;
6. Prescription of reproduced (generic) clopidogrel, replacing clopidogrel from one manufacturer with clopidogrel from another manufacturer, replacing ticagrelor or prosugrel with clopidogrel to evaluate the effect of drug withdrawal.

From the existing methods of aggregatometry, the “point of care” or “bedside” method seems to be the best, Verify nоw, which meets the challenges facing clinicians and all the requirements of modern aggregometry. Thus, bedside aggregatometry can be recommended for patients on DAT in order to reduce the risk of fatal complications such as thrombosis and bleeding, detect the cases of resistance and problems with compliance, which will significantly improve the quality of medical care, allow to persоnalize the ongoing antiplatelet therapy, reduce the cost of treatment, the number and duration of hospitalizations [25].

The main goal of platelet function assessment is to identify a patient with high residual platelet reactivity in the cnurse of the treatment with clopidogrel and to be able to adjust therapy to reduce the risk of cardiovascular accidents such as myocardial infarction and stent and / or shunt thrombosis. Genotyping, in turn, allows us to determine who is at risk of high residual reactivity of platelets during therapy, but does not replace the assessment of platelet function. Genotyping in combination with an assessment of platelet function may help determine the best strategy, mainly in the case of homozygous carriage of CYP2C19 * 2 for patients at high risk of developing complications after percutaneous coronary intervention. Further prospective studies should determine whether these strategies can lead to an optimal risk-benefit ratio and be cost-effective in the overall population or in certain groups of patients at high risk of adverse events [26].

Thus, while treating patients, doctors should take into account the results of pharmacogenetic studies, considering different national populations, in order to be sure that the drugs are safe and effective. Application of drugs on the basis of a pharmacogenetic test for the individualization of its dosing regimen, i.e. personalized pharmacotherapy [1] is the future of medicine [1].

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