Abstract 3201: Greater P2Y12 Inhibition With Prasugrel Compared With Clopidogrel in Aspirin-Treated Patients Based on Higher Plasma Concentration of the Active Metabolite.
Purpose: We compared pharmacokinetic/pharmacodynamic relationships of prasugrel (P) vs. Clopidogrel (C) in aspirin-treated pts with stable CAD.
Methods: 110 subjects were randomized to either C 600 mg loading dose (LD) followed by 75 mg o.d. or P 60 mg LD followed by 10 mg o.d. maintenance dose (MD) for 28 d. Whole blood flow cytometric analysis of platelet VASP-phosphorylation was evaluated by the “platelet reactivity index” (PRI, %), at pre-dose, 2 and 24h post-LD, and pre-dose at days 14 and 29. Plasma conc of the P and C active metabolites were measured at 0.5, 1, 2, 4 and 6 h post-LD and 0.5, 1, 2 and 4 h post-MD on days 14 and 29. To assess mechanisms of low response, 10 μM C active metabolite was added to plasma samples ex vivo.
Results: Mean area under the curve (AUC; μM*h) was higher with P vs. C post-LD [1.11 (90%CI 1.02–1.19) vs. 0.24(022– 0.26)] and post-MD [0.16(0.15–0.17) vs. 0.062 (0.057– 0.067)]. Post-LD P had lower and less variable PRI suggesting maximal effect (Emax) with saturation of the P2Y12 receptor. Post-MD, the relationship between log AUC and PRI was similar for P and C [r=0.81 (p<0.001)]. Ex vivo addition of the C active metabolite further reduced PRI if not already at Emax.
Conclusion: Inhibition of P2Y12-induced platelet reactivity is closely related to the exposure of active metabolites of P and C up to saturation levels of the P2Y12 receptor which, are only reached after LD with 60 mg P but not with 600 mg C. During MD there was good log-linear correlation between platelet inhibition and the exposure to C and P active metabolite. At all times P provides greater platelet inhibition than C based on higher levels of the AM. Poor response to C is caused by low levels of the AM.