Clopidogrel/ASK-Teva, tablets 100 mg+75 mg 28 pcs

Pharmacotherapeutic group: anti-aggregant.

ATX code: B01AC30

Pharmacological properties.

Pharmacodynamics

p> Clopidogrel is a prodrug with one of its active metabolites being a platelet aggregation inhibitor. To form an active metabolite that inhibits platelet aggregation, clopidogrel must be metabolized by cytochrome P450 (CYP450) isoenzymes.

The active metabolite of clopidogrel selectively inhibits adenosine diphosphate (ADP) binding to the P2Y₁₂ receptor of platelets and subsequent ADP-mediated activation of the GPIIb/IIIa complex, leading to suppression of platelet aggregation.

With 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.

Since formation of the active metabolite occurs via cytochrome P450 system isoenzymes, some of which may be polymorphic or inhibited by other drugs, not all patients may have adequate inhibition of platelet aggregation.

When clopidogrel is taken daily in 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 the initial level, on average within 5 days.

Acetylsalicylic acid (ASA) has a different and complementary mechanism of antiaggregative action to clopidogrel. ASA suppresses platelet aggregation through irreversible inhibition of prostaglandin cyclooxygenase-1 and, consequently, reduction of formation of thromboxane A₂, which is an inducer of platelet aggregation and vasoconstriction. This effect persists throughout the life of the platelets.

ASK does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, whereas clopidogrel increases the effect of ASK on collagen-induced platelet aggregation.

The two active agents in monotherapy and when used concomitantly can prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, particularly in cerebral, coronary or peripheral arterial lesions.

. The ACTIVE-A clinical trial showed that patients with atrial fibrillation who had at least one risk factor for vascular complications but were unable to take indirect anticoagulants, clopidogrel combined with ASA (compared with taking ASA alone) reduced the incidence of combined stroke, myocardial infarction, systemic thromboembolism outside central nervous system (CNS) vessels, or death from vascular causes, more by reducing the risk of stroke.

The benefit of taking clopidogrel in combination with ASA compared with taking ASA in combination with placebo was detected early and persisted throughout the study period (up to 5 years). The reduction in the risk of major vascular complications in the group of patients taking clopidogrel in combination with ASA was mainly due to a greater reduction in the incidence of strokes.

The risk of stroke of any severity decreased when clopidogrel was used in combination with ASA, and there was a tendency to a decrease in the incidence of myocardial infarction in the group of patients who took clopidogrel in combination with ASA, but there were no differences in the incidence of thromboembolism outside CNS vessels or death from vascular causes. In addition, the use of clopidogrel in combination with ASA reduced the total number of days of hospitalization for cardiovascular disease.

Pharmacokinetics

p> absorption

Klopidogrel

In a single and course oral dose of 75 mg per day, clopidogrel is rapidly absorbed in the gut.

The mean maximum plasma concentrations (C_max) of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after an oral single dose of 75 mg) are reached approximately 45 minutes after a single dose. According to the excretion of clopidogrel metabolites by the kidneys, its absorption is approximately 50%.

Acetylsalicylic acid

After absorption, ASK undergoes hydrolysis to form salicylic acid, C_max of which in plasma are reached 1 hour after ASK ingestion. Due to rapid hydrolysis 1.5-3 hours after oral administration of Clopidogrel/ASK-Teva ASK is practically not detected in blood plasma.

Radistribution

p> Klopidogrel

In vitro in is in vitro is unsaturated up to a concentration of 100 mg/L.

Acetylsalicylic acid

ASC binds weakly to plasma proteins and has a low volume of distribution (10L). Its metabolite, salicylic acid, binds well to plasma proteins, but its binding to plasma proteins depends on its concentration in blood plasma (non-linear relationship). At low concentrations (< 100 µg/ml) about 90% of salicylic acid binds to plasma albumin. Salicylic acid is well distributed in tissues and body fluids, including the CNS, breast milk and fetal tissues.

Metabolism

Klopidogrel

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo clopidogrel is metabolized via two metabolic pathways: The first pathway, metabolism by enzymes (esterases), which leads to hydrolysis to form an inactive metabolite, a carboxylic acid derivative (accounts for 85% of the metabolites circulating in the systemic bloodstream); the second pathway, metabolism by several isoenzymes of the cytochrome P450 system.

In this case, clopidogrel is first 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.

The active metabolite is formed primarily by CYP2C19 with the participation of several other isoenzymes, including CYP1A2, CYP2B6 and CYP3A4. The active thiol metabolite of clopidogrel, which has been isolated in in vitro studies, binds rapidly and irreversibly to platelet receptors, inhibiting platelet aggregation.

After a loading dose of clopidogrel 300 mg, the C_max of the active metabolite is 2 times greater than after a 4-day maintenance dose of clopidogrel 75 mg, and its C_max is reached approximately 30-60 minutes after clopidogrel administration.

Acetylsalicylic acid

ASA when taken in combination with clopidogrel undergoes rapid plasma hydrolysis to salicylic acid with a half-life (T_1/2) of 0.3-0.4 h for ASA doses of 75-100 mg. Salicylic acid mainly undergoes conjugation in the liver to form salicyluric acid, phenolic glucuronide and acyl glucuronide, as well as a large number of minor metabolites.

Extract

Klopidogrel

For 120 h after human oral administration ¹⁴C-labeled clopidogrel, about 50% of the radioactivity is excreted by the kidneys and about 46% of the radioactivity is excreted through the intestine. After a single oral dose of 75 mg, the T_1/2 of clopidogrel is approximately 6 hours. After a single and course dose of clopidogrel, the T_1/2 of the main circulating inactive metabolite in blood is 8 hours.

Acetylsalicylic acid

. Salicylic acid has a T_1/2 from blood plasma of approximately 2 h when administered with Clopidogrel/ASC-Teva. The metabolism of salicylate is saturable and total clearance is reduced at higher serum concentrations due to the limited ability of the liver to form salicylic acid and phenolic glucuronide.

The plasma T_1/2 may increase up to 20 h after toxic doses of ASA (10-20 g). At high doses of ASA, elimination of salicylic acid follows a zero-order kinetics (that is, the rate of elimination depends on plasma concentration) with a T_1/2 of 6 h or more.

The renal excretion of unchanged active substance depends on the urine pH. When the pH exceeds 6.5, the renal clearance of free salicylate increases from < 5% to > 80%. After therapeutic doses, approximately 10% of the dose taken is detected in the urine as salicylic acid, 75% of the dose taken as salicyluric acid, 10% of the dose taken as phenolic glucuronides, and 5% of the dose taken as acyl glucuronides.

Farmakogenetics

. Both the active metabolite and the intermediate metabolite 2-oxo-clopidogrel are formed via the CYP2C19 isoenzyme. Pharmacokinetics and antiaggregant effect of the active metabolite clopidogrel in platelet aggregation studies ex vivo (in vitroro study of platelet aggregation in blood taken from a patient who took clopidogrel orally, that is, after clopidogrel is metabolized in the body) vary depending on the genotype of the CYP2C19 isoenzyme.

The CYP2C19*1 isoenzyme gene allele corresponds to fully functional metabolism, whereas the CYP2C19*2 and CYP2C19*3 isoenzyme gene alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 isoenzyme gene alleles are responsible for reduced metabolism in the majority of Caucasoid (85%) and Mongoloid races (99%).

The other alleles that are associated with absence or reduced metabolism are less common and include, but are not limited to, the CYP2C19*4, *5, *6, *7, and *8 isoenzyme gene alleles. A patient with low CYP2C19 isoenzyme activity will have the two loss-of-function gene alleles listed above.

The published frequencies of occurrence in general populations of people with a phenotype with low CYP2C19 isoenzyme activity are: in Caucasoid patients 2%, in Negroid patients 4%, and in Mongoloid patients 14%. There are appropriate tests to determine the CYP2C19 isoenzyme genotype of a patient.

. According to data from a cross-sectional study (40 healthy volunteers) and from a meta-analysis of six studies (335 volunteers taking clopidogrel) that included healthy volunteers with very high, high, intermediate, and low CYP2C19 isoenzyme activity, No significant differences were found in the exposure of the active metabolite and in the mean values of platelet aggregation inhibition (PIA) (induced by ADP) in healthy volunteers with very high, high, and intermediate CYP2C19 isoenzyme activity.

In healthy volunteers with low CYP2C19 isoenzyme activity, compared with healthy volunteers with high CYP2C19 isoenzyme activity, exposure to the active metabolite was decreased.

When volunteers with low CYP2C19 isoenzyme activity took clopidogrel on a regimen of: 600 mg loading dose/150 mg maintenance dose (600 mg/150 mg), exposure to the active metabolite was higher than when clopidogrel was taken on the regimen: 300 mg/75 mg.

In addition, IAT was similar to that in groups of patients with higher metabolism rates by the CYP2C19 isoenzyme who were taking clopidogrel on the regimen: 300 mg/75 mg. However, the dosing regimen of clopidogrel for patients in this group (patients with low CYP2C19 isoenzyme activity) has not yet been established in studies with regard to clinical outcomes.

This is because the clinical studies conducted to date have not had sufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme activity.

Otseparate patient groups

The pharmacokinetics of the active metabolite clopidogrel in selected patient groups have not been studied.

Patients over 75 years

There were no differences in platelet aggregation and bleeding time in elderly volunteers (over 75 years) when compared to younger volunteers. No dose adjustment is required for the elderly.

Dchildren younger than 18 years

Data not available.

Pacandpatients with impaired renal function

. After repeated doses of clopidogrel at 75 mg/day, patients with severe renal impairment (creatinine clearance of 5 to 15 mL/min) had lower (25%) inhibition of ADP-induced platelet aggregation compared with healthy volunteers, but prolongation of bleeding time was similar to that in healthy volunteers taking clopidogrel at 75 mg/day.

Pacandpatients with impaired liver function

. After 10 days of daily clopidogrel administration at a daily dose of 75 mg in patients with severe hepatic impairment (greater than 9 points on the Child-Pugh scale), inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups.

Etpecificity

The prevalence of CYP2C19 isoenzyme gene alleles responsible for intermediate and reduced metabolism varies among different ethnic groups. There are limited literature data on their prevalence among members of the Mongoloid race, which does not allow an assessment of the clinical significance of the influence of CYP2C19 isoenzyme genotypes on clinical outcomes.

Based on the pharmacokinetics and metabolic features of both active ingredients of Clopidogrel/ASC-Teva, no clinically significant pharmacokinetic interactions are expected between them.