Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel.
OBJECTIVE
Clopidogrel is an oral thienopyridine antiplatelet agent indicated for the treatment of atherothrombotic events in patients with acute coronary syndrome (ACS). Prasugrel, a novel oral thienopyridine, is under investigation for the reduction of atherothrombotic events in patients with ACS undergoing percutaneous coronary intervention. Prasugrel's solubility decreases with increasing pH, suggesting that concomitantly-administered medications that increase gastric pH may lower the rate and/or extent of prasugrel absorption. This study evaluated the influence of ranitidine coadministration on the pharmacokinetics and pharmacodynamics of the respective active metabolite of prasugrel and clopidogrel.


METHODS
In this open-label, two-period, two-treatment, crossover study, 47 healthy male subjects were randomized to one of two study arms, receiving either prasugrel (60-mg loading dose [LD], 10-mg maintenance dose [MD] for 7 days; n = 23) or clopidogrel (600-mg LD, 75-mg MD for 7 days; n = 24). In one treatment period, subjects received prasugrel or clopidogrel alone, and in the alternate period received the same thienopyridine with ranitidine (150 mg twice daily, starting 1 day before the LD). Pharmacokinetic parameter estimates (AUC(0-t last), C(max), and t(max)) and inhibition of platelet aggregation (IPA) by light transmission aggregometry were assessed at multiple time points after the LD and final MD.


RESULTS
Ranitidine had no clinically significant effect on the area under the plasma-concentration-time curve (AUC) and did not affect the time to C(max) (t(max)) for active metabolites of either prasugrel or clopidogrel. It reduced the geometric mean maximum concentrations of active metabolite (C(max)) after a prasugrel and clopidogrel LD by 14% and 10%, respectively, but these differences were not statistically significant. When coadministered with a 60-mg prasugrel LD, ranitidine did not affect the time to, or magnitude of, peak IPA, but did result in a modest reduction at 0.5 h from 67.4 to 55.1% (p < 0.001). Ranitidine did not affect prasugrel IPA during MD. For clopidogrel, IPA was not affected by ranitidine. Prasugrel and clopidogrel were both well-tolerated, with/without ranitidine.


CONCLUSIONS
Results from this study suggest that there is no significant drug-drug interaction between oral ranitidine therapy and concomitantly-administered prasugrel or clopidogrel.
Small
David S
DS
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. dsmall@lilly.com
Farid
Nagy A
NA
Li
Ying G
YG
Ernest
C Steven
CS
Payne
Christopher D
CD
Salazar
Daniel E
DE
Winters
Kenneth J
KJ
D000328:Adult; D002853:Chromatography, Liquid; D000077144:Clopidogrel; D018592:Cross-Over Studies; D004347:Drug Interactions; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010879:Piperazines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride; D011899:Ranitidine / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013876:Thiophenes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
D006635:Histamine H2 Antagonists; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; D011899:Ranitidine; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine