Author + information
- Received July 12, 2011
- Revision received December 5, 2011
- Accepted December 19, 2011
- Published online April 3, 2012.
- Andrew L. Frelinger III, PhD⁎,⁎ (, )
- Ronald D. Lee, PhD†,
- Darcy J. Mulford, PhD†,
- Jingtao Wu, PhD†,
- Sai Nudurupati, PhD†,
- Anu Nigam, MS⁎,
- Julie K. Brooks, MS⁎,
- Deepak L. Bhatt, MD, MPH‡ and
- Alan D. Michelson, MD⁎
- ↵⁎Reprint requests and correspondence:
Dr. Andrew L. Frelinger III, Children's Hospital Boston, Division of Hematology/Oncology, Karp 07212, 300 Longwood Avenue, Boston, Massachusetts 02115-5737
Objectives The aim of this study was to assess the effects of different proton pump inhibitors (PPIs) on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel.
Background Metabolism of clopidogrel requires cytochrome P450s (CYPs), including CYP2C19. However, PPIs may inhibit CYP2C19, potentially reducing the effectiveness of clopidogrel.
Methods A randomized, open-label, 2-period, crossover study of healthy subjects (n = 160, age 18 to 55 years, homozygous for CYP2C19 extensive metabolizer genotype, confined, standardized diet) was conducted. Clopidogrel 75 mg with or without a PPI (dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or, as a positive control to maximize potential interaction and demonstrate assay sensitivity, omeprazole 80 mg) was given daily for 9 days. Pharmacokinetics and pharmacodynamics were assessed on days 9 and 10. Pharmacodynamic end-points were vasodilator-stimulated phosphoprotein P2Y12 platelet reactivity index, maximal platelet aggregation to 5 and 20 μmol/l adenosine diphosphate, and VerifyNow P2Y12 platelet response units.
Results Pharmacokinetic and pharmacodynamic responses with omeprazole demonstrated assay sensitivity. The area under the curve for clopidogrel active metabolite decreased significantly with esomeprazole but not with dexlansoprazole or lansoprazole. Similarly, esomeprazole but not dexlansoprazole or lansoprazole significantly reduced the effect of clopidogrel on vasodilator-stimulated phosphoprotein platelet reactivity index. All PPIs decreased the peak plasma concentration of clopidogrel active metabolite (omeprazole > esomeprazole > lansoprazole > dexlansoprazole) and showed a corresponding order of potency for effects on maximal platelet aggregation and platelet response units.
Conclusions Generation of clopidogrel active metabolite and inhibition of platelet function were reduced less by the coadministration of dexlansoprazole or lansoprazole with clopidogrel than by the coadministration of esomeprazole or omeprazole. These results suggest that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of dexlansoprazole or lansoprazole rather than esomeprazole or omeprazole. (A Study of the Effects of Multiple Doses of Dexlansoprazole, Lansoprazole, Omeprazole or Esomeprazole on the Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Participants; NCT00942175)
This study was sponsored by Takeda Global Research & Development Center, Inc. In addition, this study was funded in part by a research grant from Takeda Global Research & Development Center to Children's Hospital Boston (Alan D. Michelson, principal investigator). Drs. Frelinger and Michelson have been principal investigators or co-investigators on research grants to the University of Massachusetts Medical School, Children's Hospital Boston, or both from Arena Pharmaceuticals, GLSynthesis, Eli Lilly/Daiichi Sankyo, and Sanofi Aventis/Bristol-Myers Squibb; and have been consultants to Eli Lilly/Daiichi Sankyo and PLx Pharma. Drs. Lee, Mulford, Wu, and Nudurupati are employees of Takeda Global Research & Development Center, Inc. Dr. Bhatt has received honoraria from WebMD; research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, and The Medicines Company; and is a research collaborator with PLx Pharma and Takeda and served as the Chair of the COGENT trial. Dr. Michelson has been a member of the data safety monitoring boards of clinical trials sponsored by Eli Lilly/Daiichi Sankyo and Sanofi Aventis/Bristol-Myers Squibb. All other authors have reported that they have no relationship relevant to the contents of this paper to disclose.
- Received July 12, 2011.
- Revision received December 5, 2011.
- Accepted December 19, 2011.
- American College of Cardiology Foundation