Prasugrel
Encyclopedia
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 syndrome
s planned for percutaneous coronary intervention
(PCI). Prasugrel was approved for use in Europe in February 2009, and is currently available in the UK. On July 10, 2009, the US Food and Drug Administration approved the use of prasugrel for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with PCI
.Baker WL, White CM. Role of Prasugrel, a Novel P2Y12 Receptor Antagonist, in the Management of Acute Coronary Syndromes. American Journal of Cardiovascular Drugs Aug 1, 2009; 9 (4): 213-229. Link text
class of ADP receptor inhibitors, like ticlopidine
(trade name Ticlid) and clopidogrel
(trade name Plavix). These agents reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12
receptors. Compared to clopidogrel, prasugrel inhibits adenosine diphosphate–induced platelet aggregation more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel in healthy volunteers and in patients with coronary artery disease, including those undergoing PCI". Clopidogrel, unlike prasugrel, was issued a black box warning
from the FDA on March 12, 2010, as the estimated 2-14% of the US population that have low levels of the CYP 2C19 liver enzyme needed to activate clopidogrel may not get the full effect. Tests are available to predict if a patient would be susceptible to this problem or not.
Prasugrel has not been shown to carry those same limitations.
Platelet aggregation gradually returns to baseline values over 5–9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and initiating prasugrel 10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not greater than that typically produced by a 10 mg maintenance dose of prasugrel alone. It should also be noted that increasing platelet inhibition could increase bleeding risk. The relationship between inhibition of platelet aggregation and clinical activity has not been established. http://pi.lilly.com/us/effient.pdf
and is rapidly metabolized to a pharmacologically active metabolite
and inactive metabolites. The active metabolite has an elimination half-life of about 7 hours (range 2–15 hours). Healthy subjects, patients with stable atherosclerosis
, and patients undergoing PCI show similar pharmacokinetics.
, both in combination with aspirin, and found that, as a more potent anti-platelet agent, prasugrel reduced the combined rate of death from cardiovascular causes, nonfatal myocardial infarction
, or nonfatal stroke
(12.1% for clopidogrel vs. 9.9% for prasugrel). This difference in the primary endpoint was mainly driven by the reduction of non-fatal myocardial infarctions. However, an increased rate of serious bleedings (1.4%, vs. 0.9% in the clopidogrel group) and fatal bleedings (0.4% vs. 0.1%) was also observed. Overall mortality did not differ between the two treatment groups.
From the editorial in the NEJM, "In TRITON–TIMI 38, for each death from cardiovascular causes prevented by the use of prasugrel as compared with clopidogrel, approximately one additional episode of fatal bleeding was caused by prasugrel".
In patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention
(PCI), prasugrel was associated with a significantly lower incidence of ischemic events than clopidogrel, and was particularly effective in specific subgroups of patients, such as those with diabetes mellitus. In this sub-group there is a 30% relative risk reduction
(4.2% ARR for unstable angina
/NSTEMI and 5% AAR
for STEMI) compared to the clopidogrel group without significant increased risk for major bleeding(2.2% vs. 2.3%). However, the efficacy of prasugrel was offset by a higher risk of bleeding than clopidogrel, with patients aged ≥75 years, those weighing <60 kg and those with a history of stroke or transient ischemic attack at the greatest risk. A lower dose of prasugrel in patients aged ≥75 years and those weighing <60 kg may help to minimize the bleeding risk, although more data are needed to establish this; prasugrel is contraindicated in patients with a history of stroke or transient ischemic attack. The estimated number of patients needed to be treated with prasugrel at the dosage studied, as compared with standard-dose clopidogrel, to prevent one primary efficacy end point during a 15-month period was 46. The number of patients who would have to be treated to result in an excess non–CABG-related TIMI major hemorrhage was 167.
Furthermore, data from a pharmacodynamic study suggests that acute coronary syndrome (ACS) patients can be safely switched from clopidogrel to prasugrel and that doing so results in a further reduction in platelet function after one week. When patients receive a loading dose of prasugrel prior to switching from clopidogrel, the reduction in platelet function occurs within two hours.
Central nervous system: Headache (6%), dizziness (4%), fatigue (4%), fever (3%), extremity pain (3%)
Dermatologic: Rash (3%)
Endocrine & metabolic: Hypercholesterolemia/hyperlipidemia (7%)
Gastrointestinal: Nausea (5%), diarrhea (2%), gastrointestinal hemorrhage (2%)
Hematologic: Leukopenia (3%), anemia (2%)
Neuromuscular & skeletal: Back pain (5%)
Respiratory: Epistaxis (6%), dyspnea (5%), cough (4%)
Daiichi Sankyo Co.
is a global pharmaceutical company and the second largest pharmaceutical company in Japan. It achieved JPY 970 billion in revenue in 2010 and is currently ranked number 17 in world sales. Its headquarter is based in Tokyo. The company also owns the American biotechnology company Plexxikon, the...
and produced by Ube
Ube Industries
is a Japanese chemical company.-Chemicals and plastics:*Caprolactam*Polyamide*Synthetic rubber*Ammonia*Acrylonitrile butadiene styrene*Polyethylene-Speciality chemicals and products:*Liquid electrolyte*Diol*dimethyl carbonate*Polyimide...
and currently marketed in the United States in cooperation with Eli Lilly and Company
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
for 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 ....
s planned for percutaneous coronary intervention
Percutaneous coronary intervention
Percutaneous coronary intervention , commonly known as coronary angioplasty or simply angioplasty, is one therapeutic procedure used to treat the stenotic coronary arteries of the heart found in coronary heart disease. These stenotic segments are due to the build up of cholesterol-laden plaques...
(PCI). Prasugrel was approved for use in Europe in February 2009, and is currently available in the UK. On July 10, 2009, the US Food and Drug Administration approved the use of prasugrel for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with PCI
Percutaneous coronary intervention
Percutaneous coronary intervention , commonly known as coronary angioplasty or simply angioplasty, is one therapeutic procedure used to treat the stenotic coronary arteries of the heart found in coronary heart disease. These stenotic segments are due to the build up of cholesterol-laden plaques...
.Baker WL, White CM. Role of Prasugrel, a Novel P2Y12 Receptor Antagonist, in the Management of Acute Coronary Syndromes. American Journal of Cardiovascular Drugs Aug 1, 2009; 9 (4): 213-229. Link text
Pharmacology
Prasugrel is a member of the thienopyridineThienopyridine
Thienopyridines are a class of ADP receptor/P2Y12 inhibitors used for their anti-platelet activity.-Examples:These drugs include:Prasugrel ,Ticlopidine ,Clopidogrel ....
class of ADP receptor inhibitors, like 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...
(trade name Ticlid) and 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...
(trade name Plavix). These agents reduce the aggregation ("clumping") of platelets by irreversibly binding to 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....
receptors. Compared to clopidogrel, prasugrel inhibits adenosine diphosphate–induced platelet aggregation more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel in healthy volunteers and in patients with coronary artery disease, including those undergoing PCI". Clopidogrel, unlike prasugrel, was issued a black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
from the FDA on March 12, 2010, as the estimated 2-14% of the US population that have low levels of the CYP 2C19 liver enzyme needed to activate clopidogrel may not get the full effect. Tests are available to predict if a patient would be susceptible to this problem or not.
Prasugrel has not been shown to carry those same limitations.
Pharmacodynamics
Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry. Following a 60-mg loading dose of Effient, approximately 90% of patients had at least 50% inhibition of platelet aggregation by 1 hour. Maximum platelet inhibition was about 80% (Figure 2). Mean steady-state inhibition of platelet aggregation was about 70% following 3 to 5 days of dosing at 10 mg daily after a 60-mg loading dose of Effient.Platelet aggregation gradually returns to baseline values over 5–9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and initiating prasugrel 10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not greater than that typically produced by a 10 mg maintenance dose of prasugrel alone. It should also be noted that increasing platelet inhibition could increase bleeding risk. The relationship between inhibition of platelet aggregation and clinical activity has not been established. http://pi.lilly.com/us/effient.pdf
Pharmacokinetics
Prasugrel is a prodrugProdrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
and is rapidly metabolized to a pharmacologically active metabolite
Active metabolite
- Prodrugs :Sometimes drugs are formulated deliberately so they will break down inside the body to form the active drug, these are called prodrugs. The reason for this may be because the drug is more stable during manufacture and storage as the prodrug form, or because the prodrug is better...
and inactive metabolites. The active metabolite has an elimination half-life of about 7 hours (range 2–15 hours). Healthy subjects, patients with stable atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, and patients undergoing PCI show similar pharmacokinetics.
TRITON-TIMI 38 study
As published in the New England Journal of Medicines online edition, the TRITON-TIMI 38 study of 13,608 patients with acute coronary syndromes compared prasugrel against clopidogrelClopidogrel
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...
, both in combination with aspirin, and found that, as a more potent anti-platelet agent, prasugrel reduced the combined rate of death from cardiovascular causes, nonfatal myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, or nonfatal stroke
Stroke
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...
(12.1% for clopidogrel vs. 9.9% for prasugrel). This difference in the primary endpoint was mainly driven by the reduction of non-fatal myocardial infarctions. However, an increased rate of serious bleedings (1.4%, vs. 0.9% in the clopidogrel group) and fatal bleedings (0.4% vs. 0.1%) was also observed. Overall mortality did not differ between the two treatment groups.
From the editorial in the NEJM, "In TRITON–TIMI 38, for each death from cardiovascular causes prevented by the use of prasugrel as compared with clopidogrel, approximately one additional episode of fatal bleeding was caused by prasugrel".
In patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention
Percutaneous coronary intervention
Percutaneous coronary intervention , commonly known as coronary angioplasty or simply angioplasty, is one therapeutic procedure used to treat the stenotic coronary arteries of the heart found in coronary heart disease. These stenotic segments are due to the build up of cholesterol-laden plaques...
(PCI), prasugrel was associated with a significantly lower incidence of ischemic events than clopidogrel, and was particularly effective in specific subgroups of patients, such as those with diabetes mellitus. In this sub-group there is a 30% relative risk reduction
Relative risk reduction
In epidemiology, the relative risk reduction is a measure calculated by dividing the absolute risk reduction by the control event rate.The relative risk reduction can be more useful than the absolute risk reduction in determining an appropriate treatment plan, because it accounts not only for the...
(4.2% ARR for unstable angina
Unstable angina
Unstable angina is a type of angina pectoris that is irregular. It is a type of acute coronary syndrome.It can be difficult to distinguish from non–Q-wave myocardial infarction.-Definition:...
/NSTEMI and 5% AAR
AAR
-Aviation:*AAR Corporation, an American aviation engineering company*"Air-to-air refueling", also known as aerial refueling, the practice of transferring fuel from one aircraft to another during flight*AAR, IATA airport code for Aarhus Airport in Tirstrup, Denmark...
for STEMI) compared to the clopidogrel group without significant increased risk for major bleeding(2.2% vs. 2.3%). However, the efficacy of prasugrel was offset by a higher risk of bleeding than clopidogrel, with patients aged ≥75 years, those weighing <60 kg and those with a history of stroke or transient ischemic attack at the greatest risk. A lower dose of prasugrel in patients aged ≥75 years and those weighing <60 kg may help to minimize the bleeding risk, although more data are needed to establish this; prasugrel is contraindicated in patients with a history of stroke or transient ischemic attack. The estimated number of patients needed to be treated with prasugrel at the dosage studied, as compared with standard-dose clopidogrel, to prevent one primary efficacy end point during a 15-month period was 46. The number of patients who would have to be treated to result in an excess non–CABG-related TIMI major hemorrhage was 167.
Furthermore, data from a pharmacodynamic study suggests that acute coronary syndrome (ACS) patients can be safely switched from clopidogrel to prasugrel and that doing so results in a further reduction in platelet function after one week. When patients receive a loading dose of prasugrel prior to switching from clopidogrel, the reduction in platelet function occurs within two hours.
Adverse Effects
Cardiovascular: Hypertension (8%), hypotension (4%), atrial fibrillation (3%), bradycardia (3%), noncardiac chest pain (3%), peripheral edema (3%)Central nervous system: Headache (6%), dizziness (4%), fatigue (4%), fever (3%), extremity pain (3%)
Dermatologic: Rash (3%)
Endocrine & metabolic: Hypercholesterolemia/hyperlipidemia (7%)
Gastrointestinal: Nausea (5%), diarrhea (2%), gastrointestinal hemorrhage (2%)
Hematologic: Leukopenia (3%), anemia (2%)
Neuromuscular & skeletal: Back pain (5%)
Respiratory: Epistaxis (6%), dyspnea (5%), cough (4%)
External links
- Prasugrel information at Prous ScienceProus ScienceProus Science is an international health science publishing company, established in 1958 and headquartered in Barcelona, Spain.Its head offices are located in Barcelona and it has subsidiaries in Philadelphia , Buenos Aires and Tokyo...
- http://www.clevelandclinicmeded.com/online/webcasts/acute-coronary-syndrome/non-st-elevation/webcast.asp ; Use of prasugrel vs clopidogrel and other anti-aggregant drugs in ACS