Clopidogrel

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Clopidogrel
Systematic (IUPAC) name
(+)-(S)-methyl 2-(2-chlorophenyl)- 2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate
Identifiers
CAS number	113665-84-2
ATC code	B01AC04
PubChem	60606
DrugBank	APRD00444
ChemSpider	54632
Chemical data
Formula	C16H16ClNO2S
Mol. mass	321.82 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	>50%
Protein binding	94–98%
Metabolism	Hepatic
Half life	7–8 hours (inactive metabolite)
Excretion	50% renal 46% biliary
Therapeutic considerations
Pregnancy cat.	B1(AU) B(US)
Legal status	Prescription Only (S4)(AU) POM(UK) ℞-only(US)
Routes	Oral
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Clopidogrel is an oral antiplatelet agent (thienopyridine class) to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix, by Sun Pharmaceuticals under the trade name Clopilet, by Ranbaxy Laboratories under the trade name Ceruvin, and under the name "Clavix" by Intas Pharmaceuticals. It works by irreversibly inhibiting a receptor called P2Y₁₂. Adverse effects include hemorrhage.

Pharmacology

Clopidogrel is a pro-drug whose action may be related to adenosine diphosphate (ADP) receptor on platelet cell membranes. The specific subtype of ADP receptor that clopidogrel irreversibly inhibits is P2Y₁₂ and is important in platelet aggregation and the cross-linking of platelets by fibrin.^[1] The blockade of this receptor inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa pathway. The IIb/IIIa complex functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor. Activation of this receptor complex is the "final common pathway" for platelet aggregation, and is important in the cross-linking of platelets by fibrin.

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:^[2]

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

It is also used, along with aspirin, for the prevention of thrombosis after placement of intracoronary stent. ^[2]

International guidelines granted the highest grade of recommendation for NSTE-ACS, PCI and stent,^{[clarification needed]} 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 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. ^[3] However, a more recent study suggested that prophylaxis with proton pump inhibitors along with clopidogrel following acute coronary syndrome may increase adverse outcomes, possibly due to inhibition of CYP2C19 which is required for activation of clopidogrel, itself a pro-drug.^[4]

Dosage forms

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

Pharmacokinetics and metabolism

The active metabolite of clopidogrel ^[5]

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 a pro-drug activated in the liver by cytochrome P450 enzymes, including CYP2C19. The active metabolite has an elimination half-life of about 8 hours and acts by forming a disulfide bridge with the platelet ADP receptor. Patients with a variant allele of CYP2C19 are 1.5 to 3.5 times more likely to die or have complications than patients with the high-functioning allele.^[6][7][8]

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.

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 dose) 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.

Pharmacogenetics

CYP2C19 is an important drug-metabolizing enzyme that catalyzes the biotransformation of many clinically useful drugs including antidepressants, barbiturates, proton pump inhibitors, antimalarial and antitumor drugs. Clopidogrel is one of the drugs metabolized by this enzyme.

Several recent landmark studies have proven the importance of 2C19 genotyping in treatment using clopidogrel or Plavix. Researchers have found that patients with variants in cytochrome P-450 2C19 (CYP2C19) have lower levels of the active metabolite of clopidogrel, less inhibition of platelets, and a 3.58 times greater risk for major adverse cardiovascular events such as death, heart attack, and stroke; the risk was greatest in CYP2C19 poor metabolizers.^[9]

Adverse effects

Serious adverse drug reactions associated with clopidogrel therapy include:

• Severe neutropenia (low white blood cells) (Incidence: 1/2,000)
• Thrombotic thrombocytopenic purpura (TTP) (Incidence: 4/1,000,000 patients treated)^{[citation needed]}
• Hemorrhage - The annual incidence of hemorrhage may be increased by the co-administration of aspirin.^[10]
  • Gastrointestinal Hemorrhage (Incidence: 2.0% annually)
  • Cerebral Hemorrhage (Incidence: 0.1 to 0.4% annually)
  • Use of non-steroidal anti-inflammatory drugs is discouraged in those taking clopidogrel due to increased risk of digestive tract hemorrhage

Interactions

Clopidogrel is interacted with following drugs: phenytoin (Dilantin); tamoxifen (Nolvadex); tolbutamide (Orinase); torsemide (Demadex); fluvastatin (Lescol); a blood thinner such as warfarin (Coumadin), heparin, ardeparin (Normiflo), dalteparin (Fragmin), danaparoid (Orgaran), enoxaparin (Lovenox), or tinzaparin (Innohep); (Activase), anistreplase (Eminase), dipyridamole (Persantine), streptokinase (Kabikinase, Streptase), ticlopidine (Ticlid), and urokinase (Abbokinase). If you are using any of these drugs, you may not be able to take Plavix, or you may need dosage adjustments or special tests during treatment.

Marketing and litigation

A box of Plavix

Plavix is marketed worldwide in nearly 110 countries, with sales of US$5.9 billion in 2005.^[11] It had been the 2nd top selling drug in the world for a few years as of 2007^[12] and was still growing by over 20% in 2007.

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.^[13] The court ruled that Bristol-Myers Squibb's patent was valid and provided protection until November 2011.^[14]

Generic clopidogrel is also produced by several pharmaceutical companies in India at significantly lower retail prices, up to 1/30th of the price.

Counterfeit Plavix is in circulation, as with many popular medicines.

References

External links

• 3418 drug label/data at Daily Med from U.S. National Library of Medicine, National Institutes of Health.
• Plavix : Information for the General Public
• Plavix, Aspirin and Stents : Patients' Forum : Angioplasty.Org
• Drug promises end to migraine misery