Clapitax, 75 mg 28 pcs

Pharmacological group:

anti-aggregant

ATX code: B01AC04

Pharmacological action

Pharmacodynamics

Clopidogrel is a prodrug, one of whose active metabolites is a platelet aggregation inhibitor. Active metabolite of clopidogrel selectively inhibits binding of ADP (adenosine diphosphate) to P2Y12 receptor of platelets and subsequent ADP-mediated activation of GPIIb/IIIa complex, resulting in suppression of platelet aggregation. Through irreversible binding, platelets remain immune to ADP stimulation for the remainder of their lives (approximately 7-10 days), and recovery of normal platelet function occurs at a rate consistent with the rate of platelet renewal.

The aggregation of platelets caused by agonists other than ADP is also inhibited by blocking enhanced platelet activation by the released ADP. Because formation of the active metabolite occurs via cytochrome P450 isoenzymes, some of which may be polymorphic or may be inhibited by other drugs, adequate platelet suppression is not possible in all patients.

When clopidogrel is taken daily at a dose of 75 mg, significant suppression of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases over 3-7 days and then reaches a constant level (when an equilibrium state is reached). In the equilibrium state, platelet aggregation is suppressed by an average of 40-60%. After stopping clopidogrel administration, platelet aggregation and bleeding time gradually return to baseline within an average of 5 days.

When studying the pharmacodynamics of clopidogrel, less inhibition of ADP-induced platelet aggregation was observed in women. However, no differences were found between men and women in prolongation of bleeding time.

Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular, in lesions of the cerebral, coronary or peripheral arteries.

In patients with recent myocardial infarction, ischemic stroke and/or diagnosed peripheral arterial occlusive disease, administration of clopidogrel at a dose of 75 mg daily significantly reduces the risk of vascular complications (myocardial infarction, stroke, cardiovascular mortality)

. In acute coronary syndrome without ST-segment elevation on ECG (unstable angina pectoris, myocardial infarction) the use of clopidogrel (loading dose of 300 mg once and then 75 mg/day) in combination with acetylsalicylic acid 75-325 mg/day and other standard therapy significantly and independently of other treatments reduces risk of vascular complications.

. In ST-segment elevation myocardial infarction on ECG, administration of clopidogrel (loading dose of 300 mg once during the first 12 hours of the disease, then 75 mg/day) in combination with acetylsalicylic acid (loading dose of 150-325 mg, then 75-162 mg/day) fibrinolytic therapy and, when indicated, heparin, reduces the incidence of infarct-related coronary artery occlusion (according to coronary angiography at discharge from hospital), recurrent myocardial infarction and fatal outcomes. In patients who did not undergo coronary angiography at discharge, clopidogrel administration according to the specified scheme reduces the rate of fatal outcomes and recurrent myocardial infarction until day 8 of the disease or until discharge from the hospital.

In general, in myocardial infarction, regardless of ECG changes (ST-segment elevation, ST-segment depression, or first-time complete left bundle branch block), clopidogrel at a dose of 75 mg/day combined with acetylsalicylic acid 162 mg/day reduces overall mortality and cumulative recurrent myocardial infarction, ischemic stroke and fatal outcomes.

. In patients with atrial fibrillation who have at least one risk factor for vascular complications and are not taking indirect anticoagulants for any reason, clopidogrel at 75 mg/day in combination with acetylsalicylic acid (compared with taking acetylsalicylic acid alone) reduces the cumulative incidence of stroke, myocardial infarction, systemic thromboembolism outside the central nervous system, and cardiovascular mortality, primarily by reducing the risk of nonfatal stroke. This effect of clopidogrel has been observed in studies lasting up to 5 years.

Pharmacokinetics

Eabsorption

Clopidogrel is rapidly absorbed at a single and course oral dose of 75 mg daily. Thus the mean maximum concentration (Cmax) of unchanged clopidogrel in plasma is very low (approximately 2.2-2.5 ng/ml after a single oral dose of 75 mg) is reached approximately 45 minutes after intake. According to the urinary excretion of clopidogrel metabolites, its absorption is approximately 50%.

The concentration of the unchanged substance in plasma decreases rapidly and does not reach the limit of measurement (0.025 µg/L) within 2 hours after administration.

Distribution

In vitro clopidogrel and its main circulating inactive metabolite are reversibly bound to plasma proteins (98% and 94%, respectively) and this binding is unsaturated in a wide concentration range.

Metabolism

As a prodrug, clopidogrel is extensively metabolized in the liver. The active metabolite is not detected in the blood.

In vitro and in vivo clopidogrel is metabolized in two ways:

• through esterases and subsequent hydrolysis to form an inactive carboxylic acid derivative (85% of circulating metabolites);
• through the cytochrome P450 system. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel – thiol derivative of clopidogrel. In vitro metabolism through this pathway occurs via the cytochrome P450 isoenzymes CYP3A4, CYP2C19, CYP1A2, and CYP2B6. The active thiol metabolite of clopidogrel, which has been isolated in in vitro studies, binds rapidly and irreversibly to platelet receptors under in vivo conditions, blocking platelet aggregation.

The Cmax of the active metabolite clopidogrel after a loading dose of 300 mg is twice the Cmax after a maintenance dose of clopidogrel 75 mg for 4 days. When clopidogrel 300 mg is taken, the TCmax is approximately 30-60 min.

After repeated oral administration of clopidogrel at a dose of 75 mg per day, the Cmax of the main inactive metabolite is approximately 3 mg/L, the TCmax of the inactive metabolite is reached in 1 hour.

Elimation

In 120 hours after human oral administration of 14C-labeled clopidogrel, approximately 50% of the radioactivity is excreted in the urine and approximately 46% of the radioactivity in the feces.

The elimination half-life (T1/2) of the main circulating inactive metabolite (carboxylic acid derivative) is 8 hours after a single dose and repeated doses.

Pharmacogenetics

A few polymorphic isoenzymes of the cytochrome P450 system are involved in the activation of clopidogrel. CYP2C19 isoenzyme is involved in the formation of both the active metabolite and the intermediate metabolite, 2-oxo-clopidogrel. Pharmacokinetics and antiaggregant effect of the active metabolite clopidogrel studied by ex vivo platelet aggregation differ depending on the genotype of CYP2C19 isoenzyme.

The CYP2C19*1 gene allele is responsible for normally functioning metabolism, whereas the CYP2C19*2 and CYP2C19*3 gene alleles are nonfunctional. These alleles are responsible for reduced metabolism in about 85% of Caucasoid races and in 99% of Mongoloid races. Other alleles associated with no or reduced metabolism are CYP2C19*4, *5, *6, *7, and *8, but these are rare in the general population. Patients with low CYP2C19 isoenzyme activity, must have the above two loss-of-function gene alleles.

The published incidence of phenotypes of individuals with low CYP2C19 isoenzyme activity in Caucasoid individuals is 2%, in non-Hispanic individuals 4%, and in Chinese individuals 14%.

Tests exist to determine a patient’s CYP2C19 genotype; these tests can be used as an adjunctive tool in determining treatment tactics.

A cross-sectional study involving 40 healthy volunteers (10 volunteers each with very fast, extensive, intermediate, and delayed metabolism) examined the pharmacokinetics and antiaggregant effects of clopidogrel when used in two regimens:

• 300 mg once followed by a dose of 75 mg daily for 5 days and
• 600 mg once followed by a dose of 150 mg daily for 5 days (until equilibrium is reached)

.

There were no significant differences in active metabolite exposure and mean platelet aggregation inhibition (IAT) between the very fast, extensive, and intermediate metabolism groups of volunteers. Volunteers with reduced metabolic rate had 63-71% lower exposure to the active metabolite compared to volunteers extensively metabolizing clopidogrel.

When the drug was administered on a 300 mg once / 75 mg daily regimen, platelet response (when stimulated by 5 μm ADP) was reduced in volunteers with delayed clopidogrel metabolism: IAT was 24% (after 24 hours) and 37% (Day 5). In comparison, volunteers with extensive metabolism had an IAT of 39% (after 24 hours) and 60% (Day 5).

When clopidogrel was administered at 600 mg once / 150 mg daily in volunteers with decreased clopidogrel metabolic rate, the effects of the drug were more pronounced than when the drug was used at 300 mg once / 75 mg daily: IAT was 32% (after 24 hours) and 61% (Day 5), which was comparable to IAT in groups of volunteers with other clopidogrel metabolic rates who received the drug at the 300 mg / 75 mg regimen. A suitable dosing regimen for the patient population with a reduced clopidogrel metabolic rate has not been established in clinical trials.

Similarly, a meta-analysis of six studies that included data from 335 healthy volunteers who received clopidogrel and were at equilibrium concentration reached showed that intermediate metabolizers had a 28% reduction in active metabolite exposure and weak metabolizers had a 72% reduction. Compared to extensive metabolizers, platelet aggregation inhibition was reduced by 5.9% and 21.4% in intermediate and weak metabolizers, respectively.

The effect of CYP2C19 genotype on clinical outcomes in patients receiving clopidogrel has not been evaluated in prospective randomized controlled trials. Existing data from retrospective analyses of clinical trials for which patient genotyping results are available do not have sufficient power to assess differences in clinical outcomes in weak clopidogrel metabolizers compared with extensive and intermediate metabolizers.

Separate patient groups

Elderly persons

There were no differences in platelet aggregation and bleeding time in elderly volunteers (over 75 years of age) when compared with younger volunteers. No dose adjustment of clopidogrel in elderly persons is required

Age under 18 years

The pharmacokinetics of clopidogrel in children has not been studied.

Kidney function impairment

. After repeated doses of clopidogrel at a dose of 75 mg/day in patients with severe chronic renal impairment (creatinine clearance (CK) 5-15 ml/min), inhibition of ADP-induced platelet aggregation was 25% lower than in healthy volunteers, but no prolongation of bleeding time was observed.

Hepatic impairment

After administration of clopidogrel at a dose of 75 mg daily for 10 days in patients with severe liver injury, inhibition of ADP-induced platelet aggregation did not differ from that in healthy volunteers. The mean bleeding time in patients with severe liver injury and in healthy volunteers was comparable.

Raciality

The prevalence of CYP2C19 isoenzyme gene alleles responsible for intermediate or reduced metabolism differs among racial groups. The available literature is insufficient to assess the value of CYP2C19 isoenzyme genotyping for predicting the development of ischemic complications.