Friday, 29 August 2014

Clopidogrel

S-Clopidogrel structure.svg


Clopidogrel (INN) is an oral, thienopyridine-class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. 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 hemorrhage, severe neutropenia, and thrombotic thrombocytopenic purpura.
Before the expiry of its patent, clopidogrel was the second-most prescribed drug in the world. In 2010, it grossed over US$9 billion in global sales.[1]

Medical use

Clopidogrel is used to prevent myocardial infarction (heart attack) and stroke in people who are at high risk in certain people at elevated risk of these events, including those with unstable angina, myocardial infarction (heart attack) with or without ST elevation, and those with established peripheral artery disease, recent heart attack, or ischemic stroke.
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 heart attack with ST-elevation,[2] including
  • A loading dose given in advance of percutaneous coronary intervention, 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 heart attack or unstable angina without ST-elevation .[3]
  • 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 non-invasive treatment strategy is chosen
  • In those with stable ischemic heart disease,[4] treatment with clopidogrel is described a 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 aspirin (ASA), for the prevention of thrombosis after placement of an intracoronary stent[5] or as an alternative antiplatelet drug for people intolerant to aspirin.[6]
Clopidogrel's benefit is primarily in those who smoke cigarettes, with only slight benefit in those who do not.[7]
International guidelines granted the highest grade of recommendation for NSTE-ACS, PCI and stent,[] for clopidogrel in addition to ASA. 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.[8] 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.[9][10][11] The European Medicines Agency has issued a public statement on a possible interaction between clopidogrel and proton pump inhibitors.[12] 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.[13]

Adverse effects

Serious adverse drug reactions associated with clopidogrel therapy include:
  • Severe neutropenia (low white blood cells) (incidence: one in 2,000)
  • Thrombotic thrombocytopenic purpura (incidence: four per million patients treated)[14][15]
  • Hemorrhage - the annual incidence of hemorrhage may be increased by the coadministration of aspirin.[16]
    • Gastrointestinal hemorrhage (incidence: 2.0% annually)
    • Cerebral hemorrhage (incidence: 0.1 to 0.4% annually)
    • Use of nonsteroidal anti-inflammatory drugs is discouraged in those taking clopidogrel due to increased risk of digestive tract hemorrhage
    • Bleeding in the postoperative period is especially problematic for patients after heart surgery, where clopidogrel is associated with a more than double the take-back for bleeding rate, as well as other complications. The take-back for bleeding occurs when chest tube clogging occurs in the setting of ongoing bleeding in early postoperative period. Often, if chest tube clogging can be avoided, and the chest tubes drain, the patient can be given platelets until the platelet defect is corrected and the bleeding ceases. But, if the bleeding continues, and the chest tubes occlude, then the patient will become hemodynamically unstable and may require an emergency take-back to the operating room. This affects outcomes and costs of care.[citation needed]
  • Most studies researching clopidogrel do not compare patients on clopidogrel to patients taking placebo; rather, clopidogrel use is compared to aspirin use. Thus, attributing side effects directly to clopidogrel is difficult. Other side effects may include:
    • Other gastrointestinal side effects
      • Upper GI discomfort (27% vs 29% in patients taking aspirin alone)
      • Gastric or duodenal ulcer, gastritis
      • Diarrhea (4.5% of patients in the CAPRIE trial)[17]
    • Rash (6% overall, 0.33% severe)[18]
    • Respiratory (infrequent)
      • Upper respiratory infections, rhinitis, shortness of breath, cough
    • Cardiovascular
      • chest pain
      • edema (generalized swelling)
    • Thrombocytopenia (reduction of platelets, 0.2% severe cases as compared to 0.1% under aspirin)

Clopidogrel 3D.png
Systematic (IUPAC) name
(+)-(S)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate
Clinical data
Trade namesPlavix
AHFS/Drugs.commonograph
MedlinePlusa601040
Licence dataUS FDA:link
Pregnancy cat.B1 (AU) B (US)
Legal statusPrescription Only (S4) (AU)POM (UK) ℞-only (US)
RoutesOral
Pharmacokinetic data
Bioavailability>50%
Protein binding94–98%
MetabolismHepatic
Half-life7–8 hours (inactive metabolite)
Excretion50% renal
46% biliary
Identifiers
CAS number113665-84-2 Yes
ATC codeB01AC04
PubChemCID 60606
DrugBankDB00758
ChemSpider54632 Yes
UNIIA74586SNO7 Yes
KEGGD07729 Yes
ChEBICHEBI:37941 Yes
ChEMBLCHEMBL1771 Yes
Chemical data
FormulaC16H16ClNO2S 
Mol. mass321.82 g/mol

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,[19][20] butpantoprazole appears to be safe.[21] 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.[22]

Pharmacology

Clopidogrel is a prodrug, which requires CYP2C19 for its activation.[23] It acts on the ADP receptor on platelet cell membranes. The drug specifically and irreversibly inhibits theP2Y12 subtype of ADP receptor, which is important in activation of platelets and eventual cross-linking by the protein fibrin.[24] 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.[25]

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) hasZ configuration at the double bond C3–C16 and possiblyR configuration at the newly asymmetric C4.[26]
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.[citation needed]
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,[26] 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.[citation needed]
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.[27][28][29]
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.[30][31]

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.[30] 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.[32]

Marketing and litigation


A box of Plavix
Plavix is marketed worldwide in nearly 110 countries, with sales of US$6.6 billion in 2009.[33] It had been the second-top-selling drug in the world for a few years as of 2007[34] and was still growing by over 20% in 2007. U.S. sales were US$3.8 billion in 2008.[35]
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.[36] The court ruled that Bristol-Myers Squibb's patent was valid and provided protection until November 2011.[37] The FDA extended the patent protection of clopidogrel by six months, giving exclusivity that would expire on May 17, 2012.[38] The FDA approved generic versions of Plavix on May 17, 2012.[39]
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.[40]
Generic clopidogrel is produced by several pharmaceutical companies in India and elsewhere, and often sold under its INN. It is marketed by Cipla under the trade name Clopivas, by Sun Pharmaceuticals as Clopilet, by Ranbaxy Laboratories as Ceruvin, as Clavix by Intas Pharmaceuticals, and as Deplatt by Torrent Pharmaceuticals. In India, it is sold as Clopivas AP by Cipla, Clopigrel A by USV, and Clopitab A by Lupin(mixed with aspirin).[citation needed]
Generic clopidogrel is produced in Slovenia (European Union) under the trade names Zyllt, Kardogrel and Clopidogrel Krka by Krka d.d., Novo Mesto.[41]
Another generic clopidogrel is produced for Julphar brand (Gulf Pharmaceutical Industries) UAE (GCC) as Lavigard, and by EGIS Pharmaceuticals PLC, Budapest, Hungary, as Clopidogrel.

Dosage forms




Clopidogrel is marketed as clopidogrel bisulfate (clopidogrel hydrogen sulfate), most commonly under the trade name Plavix, as 75- and 300-mg oral tablets.[42]

Use in cat

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.[43]

Racemic Synthesis 1


Preparation of Clopidogrel 1: U.S. Patent 5,036,156 Michel Bouisset, Joel Radisson; Sanofi (1991).

Racemic Synthesis 2


Preparation of Clopidogrel 2: U.S. Patent 5,132,435 Andre Bousquet, Serge Calet, Alain Heymes; Sanofi (1992).

Asymmetric Synthesis 1


Asymmetric Preparation of Clopidogrel 1: U.S. Patent 5,204,469 (1993).

Asymmetric Synthesis 2



    Asymmetric Preparation of Clopidogrel 2: US 0225320 (2007); US 0191609 (2007).


    References

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    External links


    Racemic Synthesis 1


    Preparation of Clopidogrel 1: U.S. Patent 5,036,156 Michel Bouisset, Joel Radisson; Sanofi (1991).

    Racemic Synthesis 2


    Preparation of Clopidogrel 2: U.S. Patent 5,132,435 Andre Bousquet, Serge Calet, Alain Heymes; Sanofi (1992).

    Asymmetric Synthesis 1


    Asymmetric Preparation of Clopidogrel 1: U.S. Patent 5,204,469 (1993).

    Asymmetric Synthesis 2


    Asymmetric Preparation of Clopidogrel 2: US 0225320 (2007); US 0191609 (2007).

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