Pharmacokinetics and pharmacodynamics of prasugrel, a thienopyridine P2Y12 inhibitor

Research output: Contribution to journalReview article

53 Citations (Scopus)

Abstract

The platelet P2Y12 receptor has proved an effective target for therapeutic inhibition of arterial thrombosis, as demonstrated by the significant reductions in cardiovascular events in patients receiving the thienopyridine agents ticlopidine and clopidogrel. However, limitations of these drugs have led to the development of alternative antiplatelet agents including prasugrel (CS-747), an oral thienopyridine with a rapid onset of action, consistent antiplatelet activity, and prolonged duration of effect. Prasugrel is a prodrug that is metabolized to one active metabolite (R-138727) and numerous inactive metabolites. Absorption is complete and rapid, with mean time to peak plasma concentration of approximately 30 minutes for R-138727. The pharmacokinetics of prasugrel metabolites were linear and dose proportional in healthy volunteers. Median plasma half-life of the active metabolite is approximately 4 hours, and excretion is mainly urinary. Plasma clearance data suggest that prasugrel metabolism does not vary significantly among individuals. Pharmacodynamic studies have shown potent and selective P2Y12 blockade and dose-dependent inhibition of platelet aggregation with prasugrel (or R-138727). Onset of antiplatelet action is within 30 minutes, and steady state is reached in 3 days. Inhibition of platelet aggregation by prasugrel has been shown to be more rapid, more potent (on a mg/bodyweight basis), and more consistent than that with clopidogrel. Prasugrel does not appear to interact to any clinically relevant extent with other drugs, including those also metabolized by the hepatic cytochrome P450 isoenzymes CYP3A4, CYP2C9, CYP2C19, and CYP2B6, which are responsible for prasugrel metabolism. Thus, prasugrel has a pharmacokinetic and pharmacodynamic profile that compares favorably with those of existing antiplatelet agents.

Original languageEnglish (US)
Pages (from-to)1089-1102
Number of pages14
JournalPharmacotherapy
Volume29
Issue number9
DOIs
StatePublished - Sep 1 2009

Fingerprint

Pharmacokinetics
clopidogrel
Platelet Aggregation Inhibitors
Platelet Aggregation
thienopyridine
Prasugrel Hydrochloride
Ticlopidine
Cytochrome P-450 CYP3A
Prodrugs
Pharmaceutical Preparations
Cytochrome P-450 Enzyme System
Isoenzymes
Half-Life
Healthy Volunteers
Thrombosis
Blood Platelets
Liver

Keywords

  • Antiplatelet therapy
  • Cardiology
  • Coronary artery disease
  • Drug interactions
  • Pharmacodynamics
  • Pharmacokinetics
  • Pharmacology
  • Prasugrel

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Pharmacokinetics and pharmacodynamics of prasugrel, a thienopyridine P2Y12 inhibitor. / Dobesh, Paul P.

In: Pharmacotherapy, Vol. 29, No. 9, 01.09.2009, p. 1089-1102.

Research output: Contribution to journalReview article

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abstract = "The platelet P2Y12 receptor has proved an effective target for therapeutic inhibition of arterial thrombosis, as demonstrated by the significant reductions in cardiovascular events in patients receiving the thienopyridine agents ticlopidine and clopidogrel. However, limitations of these drugs have led to the development of alternative antiplatelet agents including prasugrel (CS-747), an oral thienopyridine with a rapid onset of action, consistent antiplatelet activity, and prolonged duration of effect. Prasugrel is a prodrug that is metabolized to one active metabolite (R-138727) and numerous inactive metabolites. Absorption is complete and rapid, with mean time to peak plasma concentration of approximately 30 minutes for R-138727. The pharmacokinetics of prasugrel metabolites were linear and dose proportional in healthy volunteers. Median plasma half-life of the active metabolite is approximately 4 hours, and excretion is mainly urinary. Plasma clearance data suggest that prasugrel metabolism does not vary significantly among individuals. Pharmacodynamic studies have shown potent and selective P2Y12 blockade and dose-dependent inhibition of platelet aggregation with prasugrel (or R-138727). Onset of antiplatelet action is within 30 minutes, and steady state is reached in 3 days. Inhibition of platelet aggregation by prasugrel has been shown to be more rapid, more potent (on a mg/bodyweight basis), and more consistent than that with clopidogrel. Prasugrel does not appear to interact to any clinically relevant extent with other drugs, including those also metabolized by the hepatic cytochrome P450 isoenzymes CYP3A4, CYP2C9, CYP2C19, and CYP2B6, which are responsible for prasugrel metabolism. Thus, prasugrel has a pharmacokinetic and pharmacodynamic profile that compares favorably with those of existing antiplatelet agents.",
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