Clopidogrel

  Clopidogrel is a potent oral antiplatelet agent often used in the treatment of coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. It works by blocking a receptor called P2Y12. Adverse effects include hemorrhage.

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Pharmacology

The mechanism of action of clopidogrel is irreversible blockade of the adenosine diphosphate (ADP) receptor on platelet cell membranes. This receptor is named P2Y12 and is important in platelet aggregation, the cross-linking of platelets by fibrin. The blockade of this receptor inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa pathway.

Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so that a loading-dose of 300-600 mg is usually administered.

Clinical use

Indications

Clopidogrel is indicated for:^[1]

• Prevention of vascular ischaemic events in patients with symptomatic atherosclerosis
• Acute coronary syndrome without ST-segment elevation (NSTEMI), along with aspirin
• ST elevation MI (STEMI)

It is also used, along with aspirin, for the prevention of thromboembolism after placement of intracoronary stent. ^[1]

International guidelines granted the highest grade of recommendation for NSTE-ACS, PCI and stent, for Clopidogrel in addition to Aspirin. Consensus-based therapeutic guidelines recommend also the use of clopidogrel, instead of aspirin, in patients requiring antiplatelet therapy but with a history of gastric ulceration, as inhibition of the synthesis of prostaglandins by aspirin (acetylsalicylic acid) can exacerbate this condition. A recent study has shown that in patients with healed aspirin-induced ulcers, however, patients receiving aspirin plus the proton pump inhibitor esomeprazole had a lower incidence of recurrent ulcer bleeding than patients receiving clopidogrel. ^[2]

Dosage forms

Clopidogrel is marketed as clopidogrel bisulfate (clopidogrel hydrogen sulfate), most commonly under the trade names Plavix or Iscover, as 75 mg oral tablets.

Pharmacokinetics and Metabolism

After repeated 75-mg oral doses of clopidogrel (base), plasma concentrations of the parent compound, which has no platelet inhibiting effect, are very low and are generally below the quantification limit (0.000258 mg/L) beyond 2 hours after dosing. Clopidogrel 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 represent about 85% of the circulating drug-related compound in plasma.

Following an oral dose of ¹⁴C-labeled clopidogrel 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 bisulfate) with meals did not significantly modify the bioavailability of clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite.

Absorption and Distribution: Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg clopidogrel (base), with peak plasma levels (appx. 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 does) in the dose range of 50 to 150 mg of clopidogrel. Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites. Clopidogrel 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 110 μg/mL.

Metabolism and Elimination: In vitro and in vivo, clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.

Adverse effects

Serious adverse drug reactions associated with clopidogrel therapy include:

• Severe neutropenia (Incidence: 5/10,000)
• Thrombotic thrombocytopenic purpura (TTP) (Incidence: 4/1,000,000 patients treated)
• Hemorrhage - The incidence of hemorrhage may be increased by the co-administration of aspirin.
  • Gastrointestinal Hemorrhage (Incidence: 2.0%)
  • Cerebral Hemorrhage (Incidence: 0.1 to 0.4%)
• Erectile Dyfunction (Incidence as yet unknown)

Marketing

In 2006, generic clopidogrel was briefly marketed by Apotex, a Canadian generic pharmaceutical company before a court order halted further production until resolution of a patent infringement case brought by Bristol-Myers Squibb.^[3] The court ruled that Bristol-Myers Squibb's patent was valid and has patent protection until November 2011.^[4] In 2007, the production was halted to many retail pharmacies and will be changing back to Plavix. In 2005 it was reported that Plavix was the world's second highest selling pharmaceutical with sales of US$5.9 billion.^[5]

Research into migraine treatment

Dr. John Chambers, a cardiologist in London, recently reported that the use of clopidogrel in patients with a history of migraines worked "spectacularly well" in some cases. A wider study is planned and has received considerable support from within the British medical community. ^[6]

References

1. ^ ^{a b} Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
2. ^ Chan FK, Ching JY, Hung LC, et al (2005). "Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding". N. Engl. J. Med. 352 (3): 238-44. doi:10.1056/NEJMoa042087. PMID 15659723.
3. ^ Preliminary Injunction Against Apotex Upheld on Appeal - Press Release. Retrieved on 2007-09-05.
4. ^ U.S. judge upholds Bristol, Sanofi patent on Plavix. Retrieved on 2007-09-05.
5. ^ IMS HEALTH. Retrieved on 2007-09-05.
6. ^ Jeremy, Laurance. "Drug promises end to migraine misery", Independent Online Edition, Independent News and Media Limited, 2007-12-26. Retrieved on 2007-12-26.