Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile.

Prasugrel (CS-747, LY640315) is a novel member of the thienopyridine class of oral antiplatelet agents that includes ticlopidine and clopidogrel. Like other thienopyridines, prasugrel is a prodrug that is inactive in vitro. Prasugrel's distinct chemical structure permits efficient conversion to its active metabolite with a less rigorous dependence on specific cytochrome P-450 enzymes.

Greater inhibition of platelet aggregation and reduced response variability with prasugrel versus clopidogrel: an integrated analysis.

Multiple studies report response variability to a 300-mg clopidogrel loading dose (LD). Pooled platelet aggregometry data compared responses (change in maximal platelet aggregation [DeltaMPA] or inhibition of platelet aggregation [IPA]) to clopidogrel 300-mg (n = 131) or prasugrel 60-mg (n = 109) LDs. Poor responder rates were determined using empiric criteria (IPA < 10% and DeltaMPA < 10% for 20 microM and 5 microM adenosine diphosphate [ADP]) and Bayesian model-based criteria (IPA < 20% and DeltaMPA < 15% for 20 microM ADP; IPA < 25% and DeltaMPA < 20% for 5 microM ADP).

Clopidogrel poor responders: an objective definition based on Bayesian classification.

Existing definitions of poor response to the antiplatelet effect of clopidogrel are empiric. Bayesian classification theory is widely used to classify subjects into non-overlapping groups based on observed responses. The purpose of this analysis is to objectively define pharmacodynamic poor responders to clopidogrel using Bayesian classification methodology.

Comparison of speed of onset of platelet inhibition after loading doses of clopidogrel versus prasugrel in healthy volunteers and correlation with responder status.

Failure to achieve an adequate level of platelet inhibition during percutaneous coronary intervention is associated with an increased risk for periprocedural myocardial injury. This study was conducted to compare the initial rate of platelet inhibition after a loading dose (LD) of prasugrel or clopidogrel and determine the association between the initial rate of inhibition and pharmacodynamic responder status. Data were pooled from 3 studies in which healthy subjects received LDs of prasugrel (60 mg; n = 76) or clopidogrel (300 mg; n = 87).

Dose-dependent inhibition of human platelet aggregation by prasugrel and its interaction with aspirin in healthy subjects.

The aims of this open-label, randomized, dose-escalation pharmacodynamic study of prasugrel, an orally active antiplatelet agent, were to assess its interaction with aspirin (ASA, 325 mg) in healthy subjects after a loading dose (LD) and subsequent 5 days of once-daily maintenance doses (MD) of prasugrel or the active comparator, clopidogrel. We measured platelet aggregation induced by ADP, collagen, and TRAP and compared effects on maximal and residual platelet aggregation responses. On a background of ASA, subjects were randomly assigned to 1 of 4 prasugrel treatment groups (LD/MD in mg: 20/5, 30/7.

A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation.

Background: The aim of this study was to compare rate of onset, magnitude, and consistency of platelet inhibition after administration of prasugrel or clopidogrel and to relate platelet inhibition to systemic exposure to each active metabolite. Thienopyridines are prodrugs, metabolized in vivo to active metabolites that inhibit the platelet P2Y12 adenosine diphosphate (ADP) receptor.

Methods: This was an open-label, 2-way, crossover study that randomized healthy subjects (n = 68) to an oral loading dose (LD) of prasugrel 60 mg or clopidogrel 300 mg.

A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans.

Aims: This double-blind, placebo-controlled trial was designed to evaluate the pharmacodynamics, pharmacokinetics, safety, and tolerability of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y(12) ADP receptor antagonist compared with clopidogrel, during multiple oral dosing in healthy subjects.

Methods: Thirty subjects received placebo, prasugrel 5 mg, 10 mg, or 20 mg, or clopidogrel 75 mg orally, daily for 10 days. Platelet aggregation, bleeding time, and prasugrel metabolites were measured and adverse events were recorded.

Population pharmacokinetic analysis of panipenem/betamipron in patients with various degrees of renal function.

Background: Although plasma concentrations of panipenem were elevated and the risk of adverse events would increase in patients with renal impairment, a precise dosage regimen for patients with renal impairment has not been established.

Methods: Population pharmacokinetic analyses were performed with plasma concentrations from 26 healthy volunteers and 41 patients. Optimal dosage regimens for patients with renal impairment were determined based on the bacteriostatic index of C(20%T)>(MIC), the concentration corresponding to the time above MIC of 20% of the dosing interval.

Prediction of pharmacokinetics of antibiotics in patients with end-stage renal disease.

A novel and convenient method to predict the pharmacokinetics of several kinds of antibiotic agents in patients with end-stage renal disease (ESRD) was examined based on the in vitro extraction ratios and pharmacokinetic parameters in healthy volunteers. The dializability of 17 antibiotic agents in 4% human serum albumin solution were determined using a high-performance hemodialytic membrane for clinical use. We assumed that the off-hemodialysis clearance approximated the non-renal clearance, while the on-hemodialysis clearance was considered to be sum of the off-hemodialysis clearance and the hemodialytic clearance.

Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a multiple-dose study in healthy humans.

This double-blind, placebo-controlled trial evaluated the safety, pharmacodynamics, and pharmacokinetics of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 ADP receptor antagonist, during multiple oral dosing in healthy subjects. Eighteen subjects received placebo, or prasugrel 2.5 or 10 mg, orally, daily for 10 days.

Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a single ascending dose study in healthy humans.

We assessed the tolerability, pharmacodynamics as measured by inhibition of platelet aggregation (IPA), and pharmacokinetics of prasugrel (CS-747, LY640315), a novel thienopyridine antiplatelet agent in healthy volunteers. Twenty-four subjects were randomized into four groups of six in a double-blind, placebo-controlled trial. One subject in each group received placebo and five subjects received prasugrel orally at single doses of 2.

The platelet inhibitory effects and pharmacokinetics of prasugrel after administration of loading and maintenance doses in healthy subjects.

Prasugrel (CS-747, LY640315), a novel thienopyridine, is a potent and orally active antiplatelet agent in vivo. The aims of this double-blind, double-dummy, placebo-controlled, randomized, parallel group phase 1 study were to investigate the antiplatelet effects of prasugrel after oral administration of a loading dose (LD) and subsequent 20 days of once-daily maintenance dosing (MD), to characterize the pharmacokinetics of prasugrel metabolites with an LD/MD regimen, and to assess the safety and tolerability of prasugrel in healthy subjects. Subjects were randomly assigned in a 1:1:1 ratio to prasugrel 40 mg LD/7.

Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease.

Aims: This study was designed to compare the degree of inhibition of platelet aggregation (IPA) of prasugrel with that of clopidogrel in stable aspirin-treated patients with coronary artery disease (CAD).

Methods And Results: Subjects (n=101) were randomly assigned to the following loading dose (LD) (day 1)/maintenance dose (MD) (days 2-28) combinations: prasugrel, 40 mg/5 mg; 40 mg/7.5 mg; 60 mg/10 mg; 60 mg/15 mg; or clopidogrel, 300 mg/75 mg.

Quantitative evaluation of effect of renal failure on the pharmacokinetics of panipenem in rats.

The pharmacokinetics of panipenem in experimental renal failure animal models was investigated in order to identify the appropriate covariates affecting the pharmacokinetic behavior. Panipenem and betamipron were administered intravenously to rats with a variety of renal failures, such as nephritis induced by glycerol, gentamicin, uranium and antiserum against glomerular basement membrane as well as 5/6 subtotal nephrectomy. Panipenem in plasma and urine was determined and pharmacokinetic analysis was performed using a one-compartment open model.

Brain insulin impairs amyloid-beta(1-40) clearance from the brain.

Cerebral amyloid-beta peptide (Abeta) clearance plays a key role in determining the brain level of Abeta; however, its mechanism remains unclear. In this study, we investigated cerebral Abeta clearance across the blood-brain barrier (BBB) by using the Brain Efflux Index method. [125I]Abeta(1-40) was eliminated from rat brain to circulating blood with a half-life of 48.