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Unlike clopidogrel, prasugrel is effective in most individuals, although there have been several case reports of decreased responsiveness to prasugrel. <ref>{{cite journal | author=Silvano M, et al. | title=A case of resistance to clopidogrel and prasugrel after percutaneous coronary angioplasty. | journal=J Thromb Thrombolysis | year=2011 | volume=31(2) | page =233-4 | PMID=21088983}}</ref>
Prasugrel has not been shown to carry those same limitations.


==Pharmacodynamics==
==Pharmacodynamics==

Revision as of 20:31, 27 January 2012

Prasugrel
Clinical data
Trade namesEffient, Efient
AHFS/Drugs.comMonograph
MedlinePlusa609027
License data
Pregnancy
category
  • B
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability≥79%
Protein bindingActive metabolite: ~98%
MetabolismRapid intestinal and serum metabolism via esterase-mediated hydrolysis to a thiolactone (inactive), which is then converted, via CYP450-mediated (primarily CYP3A4 and CYP2B6) oxidation, to an active metabolite (R-138727)
Elimination half-life~7 hours (range 2-15 hours)
ExcretionUrine (~68% inactive metabolites); feces (27% inactive metabolites)
Identifiers
  • (RS)-5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-
    tetrahydrothieno[3,2-c]pyridin-2-yl acetate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.228.719 Edit this at Wikidata
Chemical and physical data
FormulaC20H20FNO3S
Molar mass373.442 g/mol g·mol−1
3D model (JSmol)
  • CC(=O)Oc1cc2c(s1)CCN(C2)C(c3ccccc3F)C(=O)C4CC4
  • InChI=1S/C20H20FNO3S/c1-12(23)25-18-10-14-11-22(9-8-17(14)26-18)19(20(24)13-6-7-13)15-4-2-3-5-16(15)21/h2-5,10,13,19H,6-9,11H2,1H3 checkY
  • Key:DTGLZDAWLRGWQN-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Prasugrel (marketing name Effient in the US, Efient in the EU and Prasita in India) is a 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 (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.[1]

Pharmacology

The reaction of prasugrel (top left) to its active metabolite (top right). Unlike the related drug clopidogrel, prasugrel activation does not involve oxidation by the enzyme CYP2C19, as the relevant oxygen (at the thiophene ring) is already present in the prodrug. Instead, both the first and last steps are hydrolyses. The two structures at the bottom are tautomers of each other.

Prasugrel is a member of the thienopyridine 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".[2] 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 CYP2C19 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.[3][4] Unlike clopidogrel, prasugrel is effective in most individuals, although there have been several case reports of decreased responsiveness to prasugrel. [5]

Pharmacodynamics

Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry.[6] 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.[7]

Pharmacokinetics

Prasugrel is a prodrug 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.

TRITON-TIMI 38 study

As published in the New England Journal of Medicine's online edition, the TRITON-TIMI 38 study of 13,608 patients with acute coronary syndromes compared prasugrel against clopidogrel, 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.[2] 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".[8]

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.[9] 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.[2]

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.[10]

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 and metabolic: Hypercholesterolemia/hyperlipidemia (7%)
  • Gastrointestinal: Nausea (5%), diarrhea (2%), gastrointestinal hemorrhage (2%)
  • Hematologic: Leukopenia (3%), anemia (2%)
  • Neuromuscular and skeletal: Back pain (5%)
  • Respiratory: Epistaxis (6%), dyspnea (5%), cough (4%)

References

  1. ^ 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
  2. ^ a b c Wiviott SD; Braunwald E; McCabe CH; et al. (2007). "Prasugrel versus clopidogrel in patients with acute coronary syndromes". N Engl J Med. 357 (20): 2001–15. doi:10.1056/NEJMoa0706482. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  3. ^ "FDA Announces New Boxed Warning on Plavix: Alerts patients, health care professionals to potential for reduced effectiveness" (Press release). Food and Drug Administration (United States). March 12, 2010. Retrieved March 13, 2010.
  4. ^ "FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug". Drug Safety and Availability. Food and Drug Administration (United States). March 12, 2010. Retrieved March 13, 2010.
  5. ^ Silvano M; et al. (2011). "A case of resistance to clopidogrel and prasugrel after percutaneous coronary angioplasty". J Thromb Thrombolysis. 31(2): 233-4. PMID 21088983. {{cite journal}}: Explicit use of et al. in: |author= (help)
  6. ^ O'Riordan, Michael. "Switching from clopidogrel to prasugrel further reduces platelet function". http://www.theheart.org. Retrieved 1 April 2011. {{cite web}}: External link in |publisher= (help)
  7. ^ Efient: Highlights of prescribing information
  8. ^ Bhatt DL (2007). "Intensifying Platelet Inhibition — Navigating between Scylla and Charybdis". N Engl J Med. 357 (20): 2078–81. doi:10.1056/NEJMe0706859. PMID 17982183.
  9. ^ Duggan ST, Keating GM. Prasugrel: A Review of its Use in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention. Drugs Aug 20, 2009; 69 (12): 1707-26 Link text
  10. ^ O'Riordan, Michael. "Switching from clopidogrel to prasugrel further reduces platelet function". 1.Angiolillo DJ, Saucedo JF, DeRaad R, et al. Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes. J Am Coll Cardiol 2010; 56: 1017-23. http://www.theheart.org. Retrieved 1 April 2011. {{cite web}}: External link in |publisher= (help)
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