Ticagrelor
Encyclopedia
Ticagrelor is a platelet aggregation inhibitor produced by AstraZeneca
. The drug was approved for use in the European Union
by the European Commission
on December 3, 2010. The drug was approved by the US Food and Drug Administration
on July 20, 2011.
or heart attack) in patients with acute coronary syndrome
or myocardial infarction with ST elevation
. The drug is combined with acetylsalicylic acid unless the latter is contraindicated. Treatment of acute coronary syndrome with ticagrelor as compared with clopidogrel
significantly reduces the rate of death.
function and combination with drugs that strongly influence activity of the liver enzyme CYP3A4
, because the drug is metabolized via CYP3A4 and excreted via the liver.
, nosebleed
, gastrointestinal, subcutaneous or dermal bleeding. Allergic skin reactions such as rash
and itching have been observed in less than 1% of patients.
analogue with low solubility and low permeability under the Biopharmaceutics Classification System
.
and feces
.
Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly patients, women, patients of Asian ethnicity, and patients with mild hepatic impairment. They are decreased in patients that described themselves as 'coloured' and such with severe renal impairment. These differences are considered clinically irrelevant. In Japanese people
, concentrations are 40% higher than in Caucasians
, or 20% after body weight correction. The drug has not been tested in patients with severe hepatic impairment.
s prasugrel
, clopidogrel
and ticlopidine
, ticagrelor blocks 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. Moreover, the drug does not need hepatic activation, which might work better for patients with genetic variants regarding the enzyme CYP2C19
(although it is not certain whether clopidogrel is significantly influenced by such variants).
, funded by AstraZeneca, in mid-2009 found that ticagrelor had better mortality rate
s than clopidogrel (9.8% vs. 11.7%, p
<0.001) in treating patients with acute coronary syndrome
. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had greater chances of non-lethal bleeding (16.1% vs. 14.6%, p=0.0084).
Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel. 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.
and possibly grapefruit juice
, increase blood plasma
levels and consequently can lead to bleeding and other adverse effects. Conversely, drugs that are metabolized by CYP3A4, for example simvastatin
, show increased plasma levels and more side effects if combined with ticagrelor. CYP3A4 inductors, 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. Ticagrelor and AR-C124910XX levels are not significantly influenced by P-gp inhibitors.
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
. The drug was approved for use in the European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
by the European Commission
European Commission
The European Commission is the executive body of the European Union. The body is responsible for proposing legislation, implementing decisions, upholding the Union's treaties and the general day-to-day running of the Union....
on December 3, 2010. The drug was approved by the US Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
on July 20, 2011.
Indications
Ticagrelor is indicated for the prevention of thrombotic events (for example strokeStroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
or heart attack) in patients with acute coronary syndrome
Acute coronary syndrome
Acute coronary syndrome is usually one of three diseases involving the coronary arteries: ST elevation myocardial infarction , non ST elevation myocardial infarction , or unstable angina ....
or myocardial infarction with ST elevation
ST elevation
ST elevations refers to a finding on an electrocardiogram, wherein the trace in the ST segment is abnormally high above the isoelectric line.-Measurement:...
. The drug is combined with acetylsalicylic acid unless the latter is contraindicated. Treatment of acute coronary syndrome with ticagrelor as compared with clopidogrel
Clopidogrel
Clopidogrel 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-Aventis under the trade name Plavix. The drug works by irreversibly...
significantly reduces the rate of death.
Contraindications
Contraindications for ticagrelor are: active pathological bleeding and a history of intracranial bleeding, as well as reduced liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
function and combination with drugs that strongly influence activity of the liver enzyme CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
, because the drug is metabolized via CYP3A4 and excreted via the liver.
Adverse effects
The most common side effects are shortness of breath (dyspnea) and various types of bleeding, such as hematomaHematoma
A hematoma, or haematoma, is a localized collection of blood outside the blood vessels, usually in liquid form within the tissue. This distinguishes it from an ecchymosis, which is the spread of blood under the skin in a thin layer, commonly called a bruise...
, nosebleed
Nosebleed
Epistaxis or a nosebleed is the relatively common occurrence of hemorrhage from the nose, usually noticed when the blood drains out through the nostrils...
, gastrointestinal, subcutaneous or dermal bleeding. Allergic skin reactions such as rash
Rash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
and itching have been observed in less than 1% of patients.
Physical and chemical properties
Ticagrelor is a nucleosideNucleoside
Nucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
analogue with low solubility and low permeability under the Biopharmaceutics Classification System
Biopharmaceutics Classification System
The Biopharmaceutics Classification System is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration . The fundamental basis for the BCS was established by Dr...
.
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 and peaks after about 2.5 hours. Both ticagrelor and AR-C124910XX are bound to plasma proteins (>99.7%), and both are pharmacologically active. Blood plasma concentrations are linearly dependent on the dose up to 1260 mg (the sevenfold daily dose). The metabolite reaches 30–40% of ticagrelor's plasma concentrations. Drug and metabolite are mainly excreted via bileBile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
and feces
Feces
Feces, faeces, or fæces is a waste product from an animal's digestive tract expelled through the anus or cloaca during defecation.-Etymology:...
.
Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly patients, women, patients of Asian ethnicity, and patients with mild hepatic impairment. They are decreased in patients that described themselves as 'coloured' and such with severe renal impairment. These differences are considered clinically irrelevant. In Japanese people
Japanese people
The are an ethnic group originating in the Japanese archipelago and are the predominant ethnic group of Japan. Worldwide, approximately 130 million people are of Japanese descent; of these, approximately 127 million are residents of Japan. People of Japanese ancestry who live in other countries...
, concentrations are 40% higher than in Caucasians
Caucasian race
The term Caucasian race has been used to denote the general physical type of some or all of the populations of Europe, North Africa, the Horn of Africa, Western Asia , Central Asia and South Asia...
, or 20% after body weight correction. The drug has not been tested in patients with severe hepatic impairment.
Mechanism of action
Like the thienopyridineThienopyridine
Thienopyridines are a class of ADP receptor/P2Y12 inhibitors used for their anti-platelet activity.-Examples:These drugs include:Prasugrel ,Ticlopidine ,Clopidogrel ....
s prasugrel
Prasugrel
Prasugrel is a novel platelet inhibitor developed by Daiichi Sankyo Co. and produced by Ube and currently marketed in the United States in cooperation with Eli Lilly and Company for acute coronary syndromes planned for percutaneous coronary intervention...
, clopidogrel
Clopidogrel
Clopidogrel 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-Aventis under the trade name Plavix. The drug works by irreversibly...
and ticlopidine
Ticlopidine
Ticlopidine is an antiplatelet drug in the thienopyridine family. Like clopidogrel, it is an adenosine diphosphate receptor inhibitor. It is used in patients in whom aspirin is not tolerated, or in whom dual antiplatelet therapy is desirable...
, ticagrelor blocks ADP receptors of subtype P2Y12
P2Y12
In the field of molecular biology, the P2Y12 protein is found mainly but not only on the surface of blood platelet cells and is an important regulator in blood clotting....
. 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. Moreover, the drug does not need hepatic activation, which might work better for patients with genetic variants regarding the enzyme CYP2C19
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
(although it is not certain whether clopidogrel is significantly influenced by such variants).
Comparison with clopidogrel
The PLATO clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
, funded by AstraZeneca, in mid-2009 found that ticagrelor had better mortality rate
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...
s than clopidogrel (9.8% vs. 11.7%, p
P-value
In statistical significance testing, the p-value is the probability of obtaining a test statistic at least as extreme as the one that was actually observed, assuming that the null hypothesis is true. One often "rejects the null hypothesis" when the p-value is less than the significance level α ,...
<0.001) in treating patients with acute coronary syndrome
Acute coronary syndrome
Acute coronary syndrome is usually one of three diseases involving the coronary arteries: ST elevation myocardial infarction , non ST elevation myocardial infarction , or unstable angina ....
. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had greater chances of non-lethal bleeding (16.1% vs. 14.6%, p=0.0084).
Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel. This means it has to be taken twice instead of once a day which is a disadvantage in respect of compliance
Compliance (medicine)
In medicine, compliance describes the degree to which a patient correctly follows medical advice...
, but its effects are more quickly reversible which can be useful before surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
or if side effects occur.
Interactions
Inhibitors of the liver enzyme CYP3A4, such as ketoconazoleKetoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
and possibly grapefruit juice
Grapefruit juice
Grapefruit juice is the fruit juice from grapefruits. It is rich in Vitamin C and ranges from sweet-tart to very sour. It is considered by some cultures to be a mystical tonic which promotes health and vigor. Certain civilizations have had holy men who live on Grapefruit juice alone...
, increase blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
levels and consequently can lead to bleeding and other adverse effects. Conversely, drugs that are metabolized by CYP3A4, for example simvastatin
Simvastatin
Simvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...
, show increased plasma levels and more side effects if combined with ticagrelor. CYP3A4 inductors, for example rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
and possibly St. John's wort, can reduce the effectiveness of ticagrelor. There is no evidence for interactions via CYP2C9
CYP2C9
Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
.
The drug also inhibits P-glycoprotein
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
(P-gp), leading to increased plasma levels of digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
, ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
and other P-gp substrates. Ticagrelor and AR-C124910XX levels are not significantly influenced by P-gp inhibitors.