Ticagrelor

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Ticagrelor
Ticagrelor.svg
Ticagrelor ball-and-stick animation.gif
Clinical data
Trade names Brilinta, Brilique, others
Other namesAZD-6140
AHFS/Drugs.com Monograph
MedlinePlus a611050
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 36%
Protein binding >99.7%
Metabolism Liver (CYP3A4)
Elimination half-life 7 hrs (ticagrelor), 8.5 hrs (active metabolite AR-C124910XX)
Excretion Bile duct
Identifiers
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino]-5-(propylthio)- 3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.114.746 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H28F2N6O4S
Molar mass 522.57 g·mol−1
3D model (JSmol)
  • CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
  • InChI=1S/C23H28F2N6O4S/c1-2-7-36-23-27-21(26-15-9-12(15)11-3-4-13(24)14(25)8-11)18-22(28-23)31(30-29-18)16-10-17(35-6-5-32)20(34)19(16)33/h3-4,8,12,15-17,19-20,32-34H,2,5-7,9-10H2,1H3,(H,26,27,28)/t12-,15+,16+,17-,19-,20+/m0/s1 X mark.svgN
  • Key:OEKWJQXRCDYSHL-FNOIDJSQSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Ticagrelor, sold under the brand name Brilinta among others, is a medication used for the prevention of stroke, heart attack and other events in people with acute coronary syndrome, meaning problems with blood supply in the coronary arteries. It acts as a platelet aggregation inhibitor by antagonising the P2Y12 receptor. [7] The drug is produced by AstraZeneca.

Contents

90 mg tablet of Brilinta Brilinta.png
90 mg tablet of Brilinta

The most common side effects include dyspnea (difficulty breathing), bleeding and raised uric acid level in the blood. [6]

It was approved for medical use in the European Union in December 2010, [6] [8] [9] and in the United States in July 2011. [5] [10] [11] In 2020, it was the 247th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [12] [13]

Medical uses

In the US, ticagrelor is indicated to reduce the risk of stroke in people with acute ischemic stroke or high-risk transient ischemic attack. [5]

In the EU, ticagrelor, co-administered with acetylsalicylic acid (aspirin), is indicated for the prevention of atherothrombotic events in adults with acute coronary syndromes or a history of myocardial infarction and a high risk of developing an atherothrombotic event; and for the prevention of atherothrombotic events in adults with a history of myocardial infarction and a high risk of developing an atherothrombotic event. [6]

Contraindications

Contraindications to ticagrelor are active bleeding, increased risk of bradycardia, concomitant therapy of ticagrelor and strong cytochrome P-450 3A (CYP3A4) inhibitors and moderate or severe hepatic impairment due to the risk of increased exposure to ticagrelor. [14] [15]

Adverse effects

The common adverse effects are increased risk of bleeding (which may be severe) [16] and shortness of breath (dyspnoea). [17] Dyspnoea is usually transient and mild-to-moderate in severity, with a higher risk at < 1 month, 1–6 months and >6 months of follow up compared to clopidogrel. [17] [18] [19] [20] Discontinuation of therapy is rare, although some people do not persist or switch therapies. [17] [18] [19] People who develop tolerable dyspnoea as a side effect of ticagrelor should be reassured to continue therapy, as it does not impact on the drug's cardiovascular benefit and bleeding risk in acute coronary syndrome (ACS). [17] Furthermore, two small subgroup analyses found no associations between ticagrelor and adverse changes in heart and lung function that may induce dyspnoea in stable coronary artery disease (CAD) and people with ACS without heart failure or significant lung disease. [18] [21]

Ventricular pauses ≥3 seconds may occur in people with ACS the first week of treatment, but are likely to be mostly asymptomatic and transient, without causing increased clinical bradycardic adverse events. [22] Caution is recommended when using ticagrelor in people with advanced sinoatrial node disease. [23] Allergic skin reactions such as rash and itching have been observed in less than 1% of people taking ticagrelor. [24]

Interactions

Inhibitors of the liver enzyme CYP3A4, such as ketoconazole and possibly grapefruit juice, increase blood plasma levels of ticagrelor and consequently can lead to bleeding and other adverse effects. Ticagrelor is a weak CYP3A4 inhibitor and can increase the plasma concentration of CYP3A4 substrates [25] Current evidence suggests that use of ticagrelor with statins can increase the risk of adverse effects like myopathy and rhabdomyolysis. However, this evidence is weak, and more research is needed. [25] [26] While it appears that the risk is low for most people, caution should be used when the medications are combined. [25] [26] This is especially important in elderly patients, and some evidence suggests that extra caution should be used with renally impaired patients as well. [26] [25] CYP3A4 inducers, for example rifampicin and possibly St. John's wort, can reduce the effectiveness of ticagrelor. There is no evidence for interactions via CYP2C9.

The drug also inhibits P-glycoprotein (P-gp), leading to increased plasma levels of digoxin, ciclosporin and other P-gp substrates. Levels of ticagrelor and AR-C124910XX (the active metabolite of ticagrelor formed by O-deethylation [27] ) are not significantly influenced by P-gp inhibitors. [24]

It is generally recommended to use low-dose aspirin (75-100 mg per day) with ticagrelor when dual antiplatelet therapy (DAPT) is indicated. It has been observed that the use of 325 mg daily aspirin in DAPT increases the risk of bleeding events, without lowering the rate of a major adverse cardiovascular event (MACE) such as cardiovascular death, heart attack, stroke or unplanned revascularisation (restoration of blood flow). [28]

Pharmacology

Mechanism of action

Like the thienopyridines prasugrel, clopidogrel and ticlopidine, ticagrelor blocks adenosine diphosphate (ADP) receptors of subtype P2Y12. In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible. [29] Moreover, the drug does not need hepatic activation, which might work better for people with genetic variants regarding the enzyme CYP2C19 (although it is not certain whether clopidogrel is significantly influenced by such variants). [30] [31] [32] Ticagrelor was found to result in a lower risk of stroke at 90 days than clopidogrel, which requires metabolic conversion, among Han Chinese CYP2C19 loss-of-function carriers with minor ischemic stroke or TIA. [33]

Pharmacokinetics

Ticagrelor is absorbed quickly from the gut, the bioavailability being 36%, and reaches its peak concentration after about 1.5 hours. The main metabolite, AR-C124910XX, is formed quickly via CYP3A4 by de-hydroxyethylation at position 5 of the cyclopentane ring. [27]

Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly people, women, people of Asian ethnicity, and people with mild hepatic impairment. They are decreased in people that self-identified as 'black' and those with severe renal impairment. These differences are not considered clinically relevant. In Japanese people, concentrations are 40% higher than in Caucasians, or 20% after body weight correction. The drug has not been tested in people with severe hepatic impairment. [24] [34]

Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel. [35] This means it has to be taken twice instead of once a day which is a disadvantage in respect of compliance, but its effects are more quickly reversible which can be useful before surgery or if side effects occur. [24] [36]

Chemistry

Ticagrelor is a nucleoside analogue: the cyclopentane ring is similar to the sugar ribose, and the nitrogen rich aromatic ring system resembles the nucleobase purine, giving the molecule an overall similarity to adenosine. The substance has low solubility and low permeability under the Biopharmaceutics Classification System. [8]

Ticagrelor as a nucleoside analogue Ticagrelor.svg
Ticagrelor as a nucleoside analogue
The nucleoside adenosine for comparison Adenosin.svg
The nucleoside adenosine for comparison

Research

With clopidogrel

The PLATO trial concluded superiority of ticagrelor compared to clopidogrel in reducing the rate of death from vascular causes, MI, and stroke in people presenting with acute coronary syndromes. [14] A post-hoc subgroup analysis of the PLATO trial suggested a reduction in total mortality with ticagrelor compared to clopidogrel in people with non-ST elevation acute coronary syndrome. [37] However, this finding should only be considered exploratory as it was not a primary endpoint of the PLATO trial. [14] Ticagrelor, as monotherapy, dual antiplatelet therapy (DAPT), and in comparison to clopidogrel, is associated with decreased all-cause mortality. When in comparison to clopidogrel, there is evidence for increased risk of bleeding. [38]

The PLATO trial [39] found that ticagrelor use, in conjunction with low-dose aspirin (where tolerated), had better all-cause mortality rates than the same treatment plan with clopidogrel (4.5% vs. 5.9%) in treating people with acute coronary syndrome. People given ticagrelor were less likely to die from vascular causes, heart attack, or stroke, regardless of whether the treatment plan was invasive.

There is some conjecture in the safety and efficacy of ticagrelor within the Asian population, despite significant thrombotic benefits. [37] A meta-analysis of observational studies in several Asian countries proposed that ticagrelor did not increase the risk of considerable bleeding events in Asian individuals. [40] There is evidence to suggest that East Asian individuals are at a higher risk of bleeding events when using ticagrelor. [41] [42] [43] The guidelines recommend that people of East Asian origin exercise caution and that treatment continuation after six months be based on net-clinical benefit. [44]

With prasugrel

In 2019, the ISAR-REACT 5 trial comparing ticagrelor and prasugrel in participants with acute coronary syndrome showed that people with acute coronary disease receiving prasugrel had lower incidence of death, myocardial infarction, or stroke compared to those who received ticagrelor. [45]

A 2019 study showed antibacterial activity against antibiotic-resistant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus. [46] This study used concentrations of ticagrelor for bactericidal activity that far exceeded those achieved by standard post acute coronary syndrome doses. [46] Research indicates that ticagrelor may help reduce the risk of infections, such as pneumonia and sepsis. [47] [48]

Related Research Articles

<span class="mw-page-title-main">Aspirin</span> Medication

Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever.

<span class="mw-page-title-main">Coronary artery disease</span> Reduction of blood flow to the heart

Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the cardiac muscle due to build-up of atherosclerotic plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. Types include stable angina, unstable angina, and myocardial infarction.

<span class="mw-page-title-main">Angioplasty</span> Procedure to widen narrow arteries or veins

Angioplasty, also known as balloon angioplasty and percutaneous transluminal angioplasty (PTA), is a minimally invasive endovascular procedure used to widen narrowed or obstructed arteries or veins, typically to treat arterial atherosclerosis.

An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation where classical Vitamin K antagonist anticoagulants have minimal effect.

<span class="mw-page-title-main">Clopidogrel</span> Antiplatelet medication

Clopidogrel, sold under the brand name Plavix among others, is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. It is also used together with aspirin in heart attacks and following the placement of a coronary artery stent. It is taken by mouth. Its effect starts about two hours after intake and lasts for five days.

<span class="mw-page-title-main">Ticlopidine</span> Chemical compound

Ticlopidine, sold under the brand name Ticlid, is a medication used to reduce the risk of thrombotic strokes. It is an antiplatelet drug in the thienopyridine family which is an adenosine diphosphate (ADP) receptor inhibitor. Research initially showed that it was useful for preventing strokes and coronary stent occlusions. However, because of its rare but serious side effects of neutropenia and thrombotic microangiopathy it was primarily used in patients in whom aspirin was not tolerated, or in whom dual antiplatelet therapy was desirable. With the advent of newer and safer antiplatelet drugs such as clopidogrel and ticagrelor, its use remained limited.

<span class="mw-page-title-main">Prasugrel</span> Medication used to prevent formation of blood clots

Prasugrel, sold under the brand name Effient in the US, Australia and India, and Efient in the EU) is a medication used to prevent formation of blood clots. It is a platelet inhibitor and an irreversible antagonist of P2Y12 ADP receptors and is of the thienopyridine drug class. It was developed by Daiichi Sankyo Co. and produced by Ube and marketed in the United States in cooperation with Eli Lilly and Company.

<span class="mw-page-title-main">Acute coronary syndrome</span> Medical condition

Acute coronary syndrome (ACS) is a syndrome due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies. The most common symptom is centrally located pressure-like chest pain, often radiating to the left shoulder or angle of the jaw, and associated with nausea and sweating. Many people with acute coronary syndromes present with symptoms other than chest pain, particularly women, older people, and people with diabetes mellitus.

<span class="mw-page-title-main">Eptifibatide</span> Antiplatelet drug

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P2Y<sub>12</sub> Protein-coding gene in the species Homo sapiens

P2Y12 is a chemoreceptor for adenosine diphosphate (ADP) that belongs to the Gi class of a group of G protein-coupled (GPCR) purinergic receptors. This P2Y receptor family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. The P2Y12 receptor is involved in platelet aggregation and is thus a biological target for the treatment of thromboembolisms and other clotting disorders. Two transcript variants encoding the same isoform have been identified for this gene.

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<span class="mw-page-title-main">Coronary stent</span> Medical stent implanted into coronary arteries

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<span class="mw-page-title-main">Thienopyridine</span> Class of chemical compounds

Thienopyridines are a class of selective, irreversible ADP receptor/P2Y12 inhibitors used for their anti-platelet activity. They have a significant role in the management of cardiovascular disease.

<span class="mw-page-title-main">Myocardial infarction</span> Interruption of cardiac blood supply

A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction to the heart muscle. The most common symptom is retrosternal chest pain or discomfort that classically radiates to the left shoulder, arm, or jaw. The pain may occasionally feel like heartburn.

<span class="mw-page-title-main">Cangrelor</span> Chemical compound

Cangrelor, sold under the brand name Kengreal among others, is a P2Y12 inhibitor FDA approved as of June 2015 as an antiplatelet drug for intravenous application. Some P2Y12 inhibitors are used clinically as effective inhibitors of adenosine diphosphate-mediated platelet activation and aggregation. Unlike clopidogrel (Plavix), which is a prodrug, cangrelor is an active drug not requiring metabolic conversion.

Adenosine diphosphate (ADP) receptor inhibitors are a drug class of antiplatelet agents, used in the treatment of acute coronary syndrome (ACS) or in preventive treatment for patients who are in risk of thromboembolism, myocardial infarction or a stroke. These drugs antagonize the P2Y12 platelet receptors and therefore prevent the binding of ADP to the P2Y12 receptor. This leads to a decrease in aggregation of platelets, prohibiting thrombus formation. The P2Y12 receptor is a surface bound protein found on blood platelets. They belong to G protein-coupled purinergic receptors (GPCR) and are chemoreceptors for ADP.

<span class="mw-page-title-main">Management of acute coronary syndrome</span>

Management of acute coronary syndrome is targeted against the effects of reduced blood flow to the affected area of the heart muscle, usually because of a blood clot in one of the coronary arteries, the vessels that supply oxygenated blood to the myocardium. This is achieved with urgent hospitalization and medical therapy, including drugs that relieve chest pain and reduce the size of the infarct, and drugs that inhibit clot formation; for a subset of patients invasive measures are also employed. Basic principles of management are the same for all types of acute coronary syndrome. However, some important aspects of treatment depend on the presence or absence of elevation of the ST segment on the electrocardiogram, which classifies cases upon presentation to either ST segment elevation myocardial infarction (STEMI) or non-ST elevation acute coronary syndrome (NST-ACS); the latter includes unstable angina and non-ST elevation myocardial infarction (NSTEMI). Treatment is generally more aggressive for STEMI patients, and reperfusion therapy is more often reserved for them. Long-term therapy is necessary for prevention of recurrent events and complications.

<span class="mw-page-title-main">Regrelor</span> Chemical compound

Regrelor is an experimental antiplatelet drug that was under investigation by Merck Sharp and Dohme in human clinical trials. Although it was initially found to be well tolerated in healthy subjects, safety concerns led to cessation of clinical trials.

Bentracimab is a monoclonal antibody medication which has been shown in phase one and two clinical trials to function as a reversal agent for the anti–blood clotting drug ticagrelor (which acts as a P2Y12 inhibitor and is sold under the brand name Brilinta among others). It is under investigation for use in major, life-threatening bleeding in patients being treated with ticagrelor. It is not commercially available.

References

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  2. ↑ "Ticalor; Blooms The Chemist Ticagrelor; Apo-Ticagrelor; Ticagrelor Arx (Accelagen Pty Ltd)". Therapeutic Goods Administration (TGA). 11 November 2022. Retrieved 9 April 2023.
  3. ↑ "Product monograph brand safety updates". Health Canada. February 2024. Retrieved 24 March 2024.
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  31. ↑ Owen RT, Serradell N, Bolos J (2007). "AZD6140". Drugs of the Future. 32 (10): 845–853. doi:10.1358/dof.2007.032.10.1133832.
  32. ↑ [ unreliable medical source? ]Tantry US, Bliden KP, Wei C, Storey RF, Armstrong M, Butler K, et al. (December 2010). "First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies". Circulation: Cardiovascular Genetics. 3 (6): 556–566. doi: 10.1161/CIRCGENETICS.110.958561 . PMID   21079055.
  33. ↑ Wang Y, Meng X, Wang A, Xie X, Pan Y, Johnston SC, et al. (December 2021). "Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA". The New England Journal of Medicine. 385 (27): 2520–2530. doi: 10.1056/NEJMoa2111749 . PMID   34708996. S2CID   240072625.
  34. ↑ "Brilique: EPAR – Product Information" (PDF). European Medicines Agency. 16 October 2019.
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