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Pharmacology: Pharmacodynamics: Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation by released ADP. Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan and recovery of normal platelet function occurs at a rate consistent with platelet turnover.
Repeated doses of 75 mg/day produced substantial inhibition of ADP-induced platelet aggregation from the 1st day; this increased progressively and reached steady state between days 3 and 7. At steady state, the average inhibition level observed with a dose of 75 mg/day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values, generally within 5 days after treatment was discontinued.
The safety and efficacy of clopidogrel in preventing vascular ischaemic events have been evaluated in 2 double-blind studies: The clopidogrel vs aspirin in patients at risk of ischaemic events (CAPRIE) study, a comparison of clopidogrel to acetylsalicylic acid (ASA), and the clopidogrel in unstable angina to prevent recurrent ischaemic events (CURE) study, a comparison of clopidogrel in combination with ASA, to placebo with ASA.
The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or ASA 325 mg/day, and were followed for 1-3 years. In the myocardial infarction subgroup, most of the patients received ASA for the first few days following the acute myocardial infarction.
Clopidogrel significantly reduced the incidence of new ischaemic events (combined endpoint of myocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the intention to treat analysis, 939 events were observed in the clopidogrel group and 1020 events with ASA [relative risk reduction (RRR) 8.7%, (95% CI: 0.2-16.4); p=0.045], which corresponds, for every 1000 patients treated for 2 years, to 10 (CI: 0-20) additional patients being prevented from experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show any significant difference between clopidogrel (5.8%) and ASA (6%).
In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke and PAD), the benefit appeared to be strongest (achieving statistical significance at p=0.003) in patients enrolled due to PAD (especially those who also had a history of myocardial infarction) (RRR=23.7%; CI: 8.9-36.2) and weaker (not significantly different from ASA) in stroke patients (RRR=7.3%; CI: -5.7 to 18.7). In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR=-4%; CI: -22.5 to 11.7). In addition, a subgroup analysis by age suggested that the benefit of clopidogrel in patients >75 years was less than that observed in patients ≤75 years.
Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear whether the differences in relative risk reduction across qualifying conditions are real or a result of chance.
The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), and presenting within 24 hrs of onset of the most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomized to clopidogrel (300 mg loading dose followed by 75 mg/day, N=6259) or placebo (N=6303), both given in combination with ASA (75-325 mg once daily) and other standard therapies. Patients were treated for up to 1 year. In CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins were administered in >90% of the patients and the relative rate of bleeding between clopidogrel and placebo was not significantly affected by the concomitant heparin therapy.
The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial infarction (MI) or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10-28%; p=0.00009) for the clopidogrel-treated group [17% relative risk reduction when patients were treated conservatively, 29% when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent and 10% when they underwent coronary artery bypass graft (CABG)]. New cardiovascular events (primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI:12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1, 1-3, 3-6, 6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the benefit observed in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage persisted (see Precautions).
The use of clopidogrel in CURE was associated with a decrease in the need of thrombolytic therapy (RRR=43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR=18.2%; CI: 6.5%, 28.3%).
The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory ischaemia) was 1035 (16.5%) in the clopidogrel-treated group and 1187 (18.8%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6-21%, p=0.0005) for the clopidogrel-treated group. This benefit was mostly driven by the statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel-treated group and 363 (5.8%) in the placebo-treated group]. There was no observed effect on the rate of re-hospitalisation for unstable angina.
The results obtained in populations with different characteristics (eg, unstable angina or non-Q-wave MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc) were consistent with the results of the primary analysis. The benefits observed with clopidogrel were independent of other acute and long-term cardiovascular therapies (eg, heparin/LMWH, GPIIb/IIIa antagonists, lipid-lowering drugs, β-blockers and ACE inhibitors). The efficacy of clopidogrel was observed independently of the dose of ASA (75-325 mg once daily).
Pharmacokinetics: After repeated oral doses of 75 mg/day, clopidogrel is rapidly absorbed. However, plasma concentrations of the parent compound are very low and below the quantification limit (0.00025 mg/L) beyond 2 hrs. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Clopidogrel is extensively metabolised by the liver and the main metabolite, which is inactive, is the carboxylic acid derivative which represents about 85% of the circulating compound in plasma. Peak plasma levels of this metabolite (approximately 3 mg/L after repeated 75-mg oral doses) occurred approximately 1 hr after dosing.
Clopidogrel is a prodrug. The active metabolite, a thiol derivative, is formed by oxidation of clopidogrel to 2-oxo-clopidogrel and subsequent hydrolysis. The oxidative step is regulated primarily by cytochrome P-450 isoenzymes 2B6 and 3A4 and to a lesser extent by 1A1, 1A2 and 2C19. The active thiol metabolite, which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation. This metabolite has not been detected in plasma.
The kinetics of the main circulating metabolite were linear (plasma concentrations increased in proportion to dose) in the dose range of 50-150 mg of clopidogrel.
Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro over a wide concentration range.
Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hr interval after dosing. The elimination half-life of the main circulating metabolite was 8 hrs after single and repeated administration. After repeated doses of 75 mg clopidogrel/day, plasma levels of the main circulating metabolite were lower in subjects with severe renal disease (creatinine clearance 5-15 mL/min) compared to subjects with moderate renal disease (creatinine clearance 30-60 mL/min) and to levels observed in other studies with healthy subjects. Although inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, the prolongation of bleeding was similar to that seen in healthy subjects receiving 75 mg clopidogrel/day. In addition, clinical tolerance was good in all patients.
The pharmacokinetics and pharmacodynamics of clopidogrel were assessed in a single- and multiple-dose study in both healthy subjects and those with cirrhosis (Child-Pugh class A or B). Daily dosing for 10 days with clopidogrel 75 mg/day was safe and well-tolerated. Clopidogrel Cmax for both single dose and steady state for cirrhotics was many fold higher than in normal subjects. However, plasma levels of the main circulating metabolite together with the effect of clopidogrel on ADP-induced platelet aggregation and bleeding time were comparable between these groups.
Pharmacogenetics: Several polymorphic CYP450 enzymes activate clopidogrel. CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles correspond to reduced metabolism. The CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced function alleles in whites and 99% in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but these are less frequent in the general population.
Pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity.
There may be genetic variants of other CYP450 enzymes with effects on the ability to form the active metabolite of clopidogrel.
Toxicology: Preclinical Safety Data: During preclinical studies in rat and baboon, the most frequently observed effects were liver changes. These occurred at doses representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No effect on hepatic metabolising enzymes were observed in humans receiving clopidogrel at the therapeutic dose.
At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of clopidogrel was also reported in rat and baboon.
There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats when given at doses up to 77 mg/kg/day (representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day).
Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies, and showed no genotoxic activity.
Clopidogrel was found to have no effect on the fertility of male and female rats and was not teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in the development of the offspring. Specific pharmacokinetic studies performed with radiolabelled clopidogrel have shown that the parent compound or its metabolites are excreted in the milk. Consequently, a direct effect (slight toxicity) or an indirect effect (low palatability) cannot be excluded.
