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Mechanism of Action
Clopidogrel (Plavix) is an inhibitor of platelet aggregation. A variety of drugs
that inhibit platelet function have been shown to decrease morbid events in
people with established atherosclerotic cardiovascular disease as evidenced by
stroke or transient ischemic attacks, myocardial infarction, or need for bypass
or angioplasty. This indicates that platelets participate in the initiation
and/or evolution of these events and that inhibiting them can reduce the event
Clopidogrel (Plavix) selectively inhibits the binding of adenosine diphosphate
(ADP) to its platelet receptor and the subsequent A.P. mediated activation of
the glycoprotein GPIIb/ IIIa complex, thereby inhibiting platelet aggregation.
Biotransformation of Clopidogrel (Plavix) is necessary to produce inhibition of
platelet aggregation, but an active metabolite responsible for the activity of
the drug has not been isolated. Clopidogrel (Plavix) also inhibits platelet
aggregation induced by agonists other than ADP by blocking the amplification of
platelet activation by released A.P. Clopidogrel (Plavix) does not inhibit
Clopidogrel (Plavix) acts by irreversibly modifying the platelet ADP receptor.
Consequently, platelets exposed to Clopidogrel (Plavix) are affected for the
remainder of their lifespan.
Dose dependent inhibition of platelet aggregation can be seen 2 hours after
single oral doses of PLAVIX. Repeated doses of 75 mg PLAVIX per day inhibit A.P.
induced platelet aggregation on the first day, and inhibition reaches steady
state between Day 3 and Day 7. At steady state, the average inhibition level
observed with a dose of 75 mg PLAVIX per day was between 40% and 60%. Platelet
aggregation and bleeding time gradually return to baseline values after
treatment is discontinued, generally in about 5 days.
Pharmacokinetics and Metabolism
After repeated 75- mg oral doses of Clopidogrel (Plavix) (base), plasma
concentrations of the parent compound, which has no platelet inhibiting effect,
are very low and are generally below the quantification limit (0.00025 mg/ L)
beyond 2 hours after dosing. Clopidogrel (Plavix) is extensively metabolized by
the liver. The main circulating metabolite is the carboxylic acid derivative,
and it too has no effect on platelet aggregation. It represents about 85% of the
circulating drugrelated compounds in plasma.
Following an oral dose of 14C- labeled Clopidogrel (Plavix) in humans,
approximately 50% was excreted in the urine and approximately 46% in the feces
in the 5 days after dosing. The elimination half- life of the main circulating
metabolite was 8 hours after single and repeated administration. Covalent
binding to platelets accounted for 2% of radiolabel with a half-life of 11 days.
Effect of Food: Administration of PLAVIX (Clopidogrel (Plavix) bisulfate)
with meals did not significantly modify the bioavailability of Clopidogrel (Plavix)
as assessed by the pharmacokinetics of the main circulating metabolite.
Absorption and Distribution: Clopidogrel (Plavix) is rapidly absorbed
after oral administration of repeated doses of 75 mg Clopidogrel (Plavix)
(base), with peak plasma levels (~/=3 mg/ L) of the main circulating metabolite
occurring approximately 1 hour after dosing. The pharmacokinetics of the main
circulating metabolite are linear (plasma concentrations increased in proportion
to dose) in the dose range of 50 to 150 mg of Clopidogrel (Plavix). Absorption
is at least 50% based on urinary excretion of Clopidogrel (Plavix)-related
Clopidogrel (Plavix) and the main circulating metabolite bind reversibly in
vitro to human plasma proteins (98% and 94%, respectively). The binding is
nonsaturable in vitro up to a concentration of 100mg/mL.
Metabolism and Elimination: In vitro and in vivo, Clopidogrel (Plavix)
undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and
urine, the glucuronide of the carboxylic acid derivative is also observed.
Geriatric Patients: Plasma concentrations of the main circulating
metabolite are significantly higher in elderly (>/=75 years) compared to young
healthy volunteers but these higher plasma levels were not associated with
differences in platelet aggregation and bleeding time. No dosage adjustment is
needed for the elderly.
Renally Impaired Patients: After repeated doses of 75 mg PLAVIX per day,
plasma levels of the main circulating metabolite were lower in patients with
severe renal impairment (creatinine clearance from 5 to 15 mL/ min) compared to
subjects with moderate renal impairment (creatinine clearance 30 to 60 mL/ min)
or healthy subjects. Although inhibition of ADP- induced platelet aggregation
was lower (25%) than that observed in healthy volunteers, the prolongation of
bleeding time was similar to healthy volunteers receiving 75 mg of PLAVIX per
day. No dosage adjustment is needed in renally impaired patients.
Gender: No significant difference was observed in the plasma levels of
the main circulating metabolite between males and females. In a small study
comparing men and women, less inhibition of A.P. induced platelet aggregation
was observed in women, but there was no difference in prolongation of bleeding
time. In the large, controlled clinical study (Clopidogrel (Plavix) vs. Aspirin
in Patients at Risk of Ischemic Events; CAPRIE), the incidence of clinical
outcome events, other adverse clinical events, and abnormal clinical laboratory
parameters was similar in men and women.
Race: Pharmacokinetic differences due to race have not been studied.