Effect of rifampin on the pharmacokinetics and pharmacodynamics of prasugrel in healthy male subjects

ABSTRACT

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 P2Y₁₂ 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.

Key words: :

• Cytochrome P450
• Induction
• Metabolites
• Pharmacodynamics
• Pharmacokinetics
• Platelets
• Prasugrel
• Rifampin

Transparency

Declaration of funding

This work was supported by Daiichi Sankyo Company, Limited and Eli Lilly and Company and is related to study protocol H7T-EW-TAAS.

Declaration of financial/other relationships

N.A.F. is a shareholder and retiree of Lilly. D.E.S. is an employee and shareholder of Daiichi Sankyo. J.A.J., C.D.P., Y.G.L., Y.J., C.S.E., K.J.W., J.T.B. and D.S.S. are employees and shareholders of Lilly.

All peer reviewers received honoraria for peer reviewing for CMRO; they disclosed no significant relationships with this study or the study sponsor nor any significant competing financial interests or relationships with other commercial entities relevant to the reviewed manuscript's content.

Acknowledgment

The authors express their appreciation to Jeffrey Gates, DHSc (MedScriptus LLC), Mary Pat Knadler, PhD, and Christopher Konkoy, PhD, for assistance with the development of the manuscript, and to Mrs. Yvonne Kreutz laboratory assistance with the post hoc studies.