Clopidogrel

Not to be confused with Clopidol.

Clopidogrel

Systematic (IUPAC) name
(+)-(S)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate
Clinical data
Trade names	Plavix
AHFS/Drugs.com	monograph
MedlinePlus	a601040
Licence data	US FDA:link
Pregnancy category	AU: B1 US: B (No risk in non-human studies)
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	>50%
Protein binding	94–98%
Metabolism	Hepatic
Biological half-life	7–8 hours (inactive metabolite)
Excretion	50% renal 46% biliary
Identifiers
CAS Number	113665-84-2 Y
ATC code	B01AC04 (WHO)
PubChem	CID: 60606
IUPHAR/BPS	7150
DrugBank	DB00758 Y
ChemSpider	54632 Y
UNII	A74586SNO7 Y
KEGG	D07729 Y
ChEBI	CHEBI:37941 Y
ChEMBL	CHEMBL1771 Y
Chemical data
Formula	C16H16ClNO2S
Molecular mass	321.82 g/mol
SMILES COC(=O)[C@H](c1ccccc1Cl)N2CCc3c(ccs3)C2
InChI InChI=1S/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1 Y Key:GKTWGGQPFAXNFI-HNNXBMFYSA-N Y
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Clopidogrel (INN) is an oral, thienopyridine-class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, cerebrovascular disease, and to prevent myocardial infarction (heart attack) and stroke. It is marketed by Bristol-Myers Squibb and Sanofi under the trade name Plavix. The drug works by irreversibly inhibiting a receptor called P2Y₁₂, an adenosine diphosphate (ADP) chemoreceptor on platelet cell membranes. Adverse effects include bleeding, severe neutropenia, and thrombotic thrombocytopenic purpura.

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system. Before the expiry of its patent, clopidogrel was the second best-selling drug in the world. In 2010, it grossed over US$9 billion in global sales.

Medical use

Clopidogrel is used to prevent heart attack and stroke in people who are at high risk of these events, including those with a history of myocardial infarction and other forms of acute coronary syndrome, stroke, and those with peripheral artery disease.

Treatment with clopidogrel or a related drug is recommended by the American Heart Association and the American College of Cardiology for people who:

• Present for treatment with a myocardial infarction with ST-elevation including

• A loading dose given in advance of percutaneous coronary intervention (PCI), followed by a full year of treatment for those receiving a vascular stent
• A loading dose given in advance of fibrinolytic therapy, continued for at least 14 days

• Present for treatment of a non-ST elevation myocardial infarction or unstable angina

• Including a loading dose and maintenance therapy in those receiving PCI and unable to tolerate aspirin therapy
• Maintenance therapy for up to 12 months in those at medium to high risk for which a noninvasive treatment strategy is chosen

• In those with stable ischemic heart disease, treatment with clopidogrel is described as a "reasonable" option for monotherapy in those who cannot tolerate aspirin, as is treatment with clopidogrel in combination with aspirin in certain high risk patients.

It is also used, along with acetylsalicylic acid (ASA, aspirin), for the prevention of thrombosis after placement of a coronary stent or as an alternative antiplatelet drug for people intolerant to aspirin.

Clopidogrel's benefit is primarily in those who smoke cigarettes, with only slight benefit in those who do not.

Consensus-based therapeutic guidelines also recommend the use of clopidogrel rather than ASA for antiplatelet therapy in people with a history of gastric ulceration, as inhibition of the synthesis of prostaglandins by ASA can exacerbate this condition. In people with healed ASA-induced ulcers, however, those receiving ASA plus the proton pump inhibitor esomeprazole had a lower incidence of recurrent ulcer bleeding than those receiving clopidogrel. However, prophylaxis with proton pump inhibitors along with clopidogrel following acute coronary syndrome may increase adverse cardiac outcomes, possibly due to inhibition of CYP2C19, which is required for the conversion of clopidogrel to its active form. The European Medicines Agency has issued a public statement on a possible interaction between clopidogrel and proton pump inhibitors. However, several cardiologists have voiced concern that the studies on which these warnings are based have many limitations and that it is not certain whether an interaction between clopidogrel and proton pump inhibitors is real.

Adverse effects

Serious adverse drug reactions associated with clopidogrel therapy include:

• Thrombotic thrombocytopenic purpura (incidence: four per million patients treated)
• Hemorrhage - the annual incidence of hemorrhage may be increased by the coadministration of aspirin.

In the CURE trial, people with acute coronary syndrome without ST elevation were treated with aspirin plus clopidogrel or placebo and followed for up to one year. The following rates of major bleed were seen:

• • Any major bleeding: clopidogrel 3.7%, placebo 2.7%
  • Life-threatening bleeding: clopidogrel 2.2%, placebo 1.8%
  • Hemorrhagic stroke: clopidogrel 0.1%, placebo 0.1%

The CAPRIE trial compared clopidogrel monotherapy to aspirin monotherapy for 1.6 years in people who had recently experienced a stroke or heart attack. In this trial the following rates of bleeding were observed.

• • Gastrointestinal hemorrhage: clopidogrel 2.0%, aspirin 2.7%
  • Intracranial bleeding: clopidogrel 0.4%, aspirin 0.5%

In CAPRIE, itching was the only adverse effect seen more frequently with clopidogrel than aspirin. In CURE, there was no difference in the rate of non-bleeding adverse events.

Interactions

Clopidogrel interacts with: 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), anistreplase (Eminase), dipyridamole (Persantine), streptokinase (Kabikinase, Streptase), ticlopidine (Ticlid), and urokinase (Abbokinase).

In November 2009, the FDA announced that clopidogrel should be used with caution in patients using the proton pump inhibitors omeprazole or esomeprazole, but pantoprazole appears to be safe. The newer antiplatelet agent prasugrel has minimal interaction with (es)omeprazole, hence might be a better antiplatelet agent (if no other contraindications are present) in patients who are on these proton pump inhibitors.

Mechanism of action

Clopidogrel acts by inhibiting the ADP receptor on platelet cell membranes. It is a prodrug, which requires CYP2C19 for its activation. The drug specifically and irreversibly inhibits the P2Y₁₂ subtype of ADP receptor, which is important in activation of platelets and eventual cross-linking by the protein fibrin. Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so a loading dose of either 600 or 300 mg is administered when a rapid effect is needed.

Pharmacokinetics and metabolism

Clopidogrel (top left) being activated: The first step is an oxidation mediated (mainly) by CYP2C19, unlike the activation of the related drug prasugrel. The two structures at the bottom are tautomers of each other; and the final step is a hydrolysis. The active metabolite (top right) has Z configuration at the double bond C3–C16 and possibly R configuration at the newly asymmetric C4.

After repeated oral doses of 75 mg of clopidogrel (base), plasma concentrations of the parent compound, which has no platelet-inhibiting effect, are very low and, in general, are below the quantification limit (0.258 µg/l) beyond two hours after dosing.

Clopidogrel is activated in the liver by cytochrome P450 enzymes, including CYP2C19. Due to opening of the thiophene ring, the chemical structure of the active metabolite has three sites that are stereochemically relevant, making a total of eight possible isomers. These are: a stereocentre at C4 (attached to the —SH thiol group), a double bond at C3—C16, and the original stereocentre at C7. Only one of the eight structures is an active antiplatelet drug. This has the following configuration: Z configuration at the C3—C16 double bond, the original S configuration at C7, and, although the stereocentre at C4 cannot be directly determined, as the thiol group is too reactive, work with the active metabolite of the related drug prasugrel suggests the R-configuration of the C4 group is critical for P2Y₁₂ and platelet-inhibitory activity.

The active metabolite has an elimination half-life of about 0.5 to 1.0 h, 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.

Following an oral dose of ¹⁴C-labeled clopidogrel in humans, about 50% was excreted in the urine and 46% in the feces in the five days after dosing.

• Effect of food: Administration of 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-milligram clopidogrel (base), with peak plasma levels (about 3 mg/l) of the main circulating metabolite occurring around one 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 not saturable 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.

In March 2010, the U.S. FDA added a boxed warning to Plavix alerting that the drug can be less effective in people unable to metabolize the drug to convert it to its active form.

Pharmacogenetics

CYP2C19 is an important drug-metabolizing enzyme that catalyzes the biotransformation of many clinically useful drugs, including antidepressants, barbiturates, proton pump inhibitors, and 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. In March 2010, the FDA put a black box warning on Plavix to make patients and healthcare providers aware that CYP2C19-poor metabolizers, representing up to 14% of patients, are at high risk of treatment failure and that testing is available. 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.

Marketing and litigation

A box of Plavix

Plavix is marketed worldwide in nearly 110 countries, with sales of US$6.6 billion in 2009. It had been the second-top-selling drug in the world for a few years as of 2007 and was still growing by over 20% in 2007. U.S. sales were US$3.8 billion in 2008.

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. The court ruled that Bristol-Myers Squibb's patent was valid and provided protection until November 2011. The FDA extended the patent protection of clopidogrel by six months, giving exclusivity that would expire on May 17, 2012. The FDA approved generic versions of Plavix on May 17, 2012.

In June 2009, the European Medicines Agency gave authorisation to six generic versions of clopidogrel bisulfate, and the drug is now available in several European countries, including the United Kingdom.

Generic clopidogrel is produced by many companies worldwide, under many brand names.

Use in cats

Clopidogrel has also been shown to be effective at decreasing platelet aggregation in cats, so its use in prevention of feline aortic thromboembolism has been advocated.

External links

• Bristol-Myers Squibb official website Bristol-Myers Squibb/Sanofi
• Plavix prescribing information Bristol-Myers Squibb/Sanofi
• Plavix, Aspirin and Stents : Patients' Forum : Angioplasty.Org
• Drug promises end to migraine misery
• U.S. National Library of Medicine: Drug Information Portal - Clopidogrel
• Krka official website