Key result
Rifampin coadministered with prasugrel decreases platelet inhibition by ~6-9 percentage points after the loading dose.
Why the study?
Does rifampin coadministration affect the pharmacokinetics and pharmacodynamics of prasugrel in healthy male subjects?
Does rifampin coadministration affect the pharmacokinetics and pharmacodynamics of prasugrel in healthy male subjects?
Effect estimate: 6-9 percentage point decrease
p-value: p=<0.01
Coadministration of prasugrel with the potent CYP inducer rifampin does not affect the formation of prasugrel's active metabolite, suggesting dose adjustment is unnecessary.
Rifampin may modestly reduce prasugrel antiplatelet effect despite unchanged metabolite exposure; leaves open clinical relevance in patients on CYP inducers.
OBJECTIVE: Prasugrel is a thienopyridine antiplatelet agent for the prevention of atherothrombotic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Since cytochrome P450 enzymes CYP3A4 and CYP2B6 play a major role in prasugrel's active metabolite formation, the effect of potent CYP induction by rifampin on the pharmacokinetics of prasugrel and on the pharmacodynamic response to prasugrel was evaluated in healthy male subjects. RESEARCH DESIGN AND METHODS: This was an open-label, two-period, fixed-sequence study conducted at a single clinical research center. In the first treatment period, subjects received prasugrel as an oral 60-mg loading dose (LD) on the first day followed by ten oral, 10-mg daily maintenance doses. After a 2-week washout period, subjects received oral rifampin alone (600 mg once daily) for 8 days, followed by coadministration of oral rifampin with prasugrel, given as a 60-mg LD on the first day followed by five daily 10-mg MDs. Blood collection for pharmacokinetic and pharmacodynamic analyses occurred after the LD and fifth MD of prasugrel in both periods. CLINICAL TRIAL SYNOPSIS: clinicalstudyresults.org ID #8976 RESULTS: Rifampin coadministration (600 mg daily) did not affect exposure to prasugrel's active metabolite (R-138727). However, at 2 and 4 h after the prasugrel loading dose (60 mg), rifampicin coadministration was associated with a 6-9 percentage point decrease (p < 0.01) in the magnitude of platelet inhibition; similarly, a 5-17 percentage point decrease (p < 0.05) was observed with rifampin coadministration during the prasugrel maintenance dose (10 mg) period. Post hoc in vitro experiments demonstrated a dose-dependent R-138727-rifampin interaction at the P2Y(12) level unrelated to enzyme induction. A limitation of this study is that while results of the in vitro post hoc study indicate a pharmacodynamic interaction with rifampin, the mechanism underlying this interaction has not been elucidated. CONCLUSIONS: Dose adjustment should not be necessary when prasugrel is administered with CYP inducers since formation of prasugrel's active metabolite is not affected by potent enzyme induction with rifampin.
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Farid et al. (2009) studied Healthy. Rifampin vs. Prasugrel alone was evaluated on Magnitude of platelet inhibition (6-9 percentage point decrease, p=<0.01). Rifampin coadministration with prasugrel did not affect active metabolite exposure but decreased platelet inhibition by 6-9 percentage points after the loading dose (p<0.01).