Omeprazole, Pantoprazole, and CYP2C19 Effects on Clopidogrel Pharmacokinetic-pharmacodynamic Relationships in Stable Coronary Artery Disease Patients

Overview

Journal Eur J Clin Pharmacol

Specialty Pharmacology

Date 2015 Jun 14

PMID 26071277

Citations 6

Authors

Nicolas Simon

Jonathan Finzi

Guillaume Cayla

Gilles Montalescot

Jean-Philippe Collet

Jean-Sebastien Hulot

Affiliations

Soon will be listed here.

Abstract

Purpose: Proton-pump Inhibitors use and CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses and increased cardiovascular events.

Methods: Post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 41) or homozygous (*2/*2, n = 7) for the CYP2C19*2 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel loading dose. A PK/PD model was defined using the variation of the P2Y12 reaction unit relative to baseline.

Results: Carriage of CYP2C19*2 allele and the use of omeprazole/esomeprazole were associated with the inter-individual variability in the active metabolite clearance. The relationship between inhibition of platelet aggregation (IPA, %) and the active metabolite AUC (h*μg/L) was described by a sigmoid function (Emax 56 ± 5%; EAUC50 15.9 ± 0.8 h*μg/L) with a gamma exponent (7.04 ± 2.26).

Conclusion: This on/off shape explains that a small variation of exposure may have a clinical relevance.

Citing Articles

Genetic Testing for Oral P2Y12 Inhibitor Therapy: A Scientific Statement From the American Heart Association.

Pereira N, Cresci S, Angiolillo D, Batchelor W, Capers 4th Q, Cavallari L Circulation. 2024; 150(6):e129-e150.

PMID: 38899464 PMC: 11300169. DOI: 10.1161/CIR.0000000000001257.

Precision medication: An illustrative case series guiding the clinical application of multi-drug interactions and pharmacogenomics.

Bain K, McGain D, Cicali E, Knowlton C, Michaud V, Turgeon J Clin Case Rep. 2020; 8(2):305-312.

PMID: 32128178 PMC: 7044418. DOI: 10.1002/ccr3.2604.

Impact of genetic polymorphisms on platelet function and response to anti platelet drugs.

Strisciuglio T, Franco D, Di Gioia G, De Biase C, Morisco C, Trimarco B Cardiovasc Diagn Ther. 2018; 8(5):610-620.

PMID: 30498685 PMC: 6232354. DOI: 10.21037/cdt.2018.05.06.

Comparison of prophylactic effect of UGIB and effects on platelet function between PPIs and HRAs combined with DAPT: systematic review and meta-analysis.

Yi Z, Qiu T, Zhang Y, Liu Z, Zhai S Ther Clin Risk Manag. 2017; 13:367-377.

PMID: 28392699 PMC: 5373835. DOI: 10.2147/TCRM.S127292.

Concomitant Use of Proton-Pump Inhibitors and Clopidogrel Increases the Risk of Adverse Outcomes in Patients With Ischemic Stroke Carrying Reduced-Function CYP2C19*2.

Yi X, Han Z, Zhou Q, Cheng W, Lin J, Wang C Clin Appl Thromb Hemost. 2016; 24(1):55-62.

PMID: 27637911 PMC: 6714622. DOI: 10.1177/1076029616669787.

References

Angiolillo D . Variability in responsiveness to oral antiplatelet therapy. Am J Cardiol. 2009; 103(3 Suppl):27A-34A. DOI: 10.1016/j.amjcard.2008.11.020. View

Rassen J, Choudhry N, Avorn J, Schneeweiss S . Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation. 2009; 120(23):2322-9. PMC: 2818789. DOI: 10.1161/CIRCULATIONAHA.109.873497. View

Hagihara K, Kazui M, Kurihara A, Yoshiike M, Honda K, Okazaki O . A possible mechanism for the differences in efficiency and variability of active metabolite formation from thienopyridine antiplatelet agents, prasugrel and clopidogrel. Drug Metab Dispos. 2009; 37(11):2145-52. DOI: 10.1124/dmd.109.028498. View

Collet J, Hulot J, Pena A, Villard E, Esteve J, Silvain J . Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2008; 373(9660):309-17. DOI: 10.1016/S0140-6736(08)61845-0. View

Ray W, Murray K, Griffin M, Chung C, Smalley W, Hall K . Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med. 2010; 152(6):337-45. PMC: 3176584. DOI: 10.7326/0003-4819-152-6-201003160-00003. View

Hulot J, Wuerzner G, Bachelot-Loza C, Azizi M, Blanchard A, Peyrard S . Effect of an increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopidogrel in CYP2C19-genotyped healthy subjects. J Thromb Haemost. 2009; 8(3):610-3. DOI: 10.1111/j.1538-7836.2009.03729.x. View

Tuffal G, Roy S, Lavisse M, Brasseur D, Schofield J, Delesque Touchard N . An improved method for specific and quantitative determination of the clopidogrel active metabolite isomers in human plasma. Thromb Haemost. 2011; 105(4):696-705. DOI: 10.1160/TH10-09-0582. View

Cayla G, Hulot J, OConnor S, Pathak A, Scott S, Gruel Y . Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA. 2011; 306(16):1765-74. DOI: 10.1001/jama.2011.1529. View

Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M . Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost. 2009; 101(4):714-9. View

10.

Shuldiner A, OConnell J, Bliden K, Gandhi A, Ryan K, Horenstein R . Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009; 302(8):849-57. PMC: 3641569. DOI: 10.1001/jama.2009.1232. View

11.

Ho P, Maddox T, Wang L, Fihn S, Jesse R, Peterson E . Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009; 301(9):937-44. DOI: 10.1001/jama.2009.261. View

12.

Juurlink D, Gomes T, Ko D, Szmitko P, Austin P, Tu J . A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009; 180(7):713-8. PMC: 2659819. DOI: 10.1503/cmaj.082001. View

13.

Yun K, Rhee S, Park H, Yoo N, Kim N, Oh S . Effects of omeprazole on the antiplatelet activity of clopidogrel. Int Heart J. 2010; 51(1):13-6. DOI: 10.1536/ihj.51.13. View

14.

Hulot J, Collet J, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O . Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010; 56(2):134-43. DOI: 10.1016/j.jacc.2009.12.071. View

15.

Yusuf S, Zhao F, Mehta S, Chrolavicius S, Tognoni G, Fox K . Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345(7):494-502. DOI: 10.1056/NEJMoa010746. View

16.

Siller-Matula J, Spiel A, Lang I, Kreiner G, Christ G, Jilma B . Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J. 2008; 157(1):148.e1-5. DOI: 10.1016/j.ahj.2008.09.017. View

17.

Steinhubl S, Berger P, Mann 3rd J, Fry E, DeLago A, Wilmer C . Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 288(19):2411-20. DOI: 10.1001/jama.288.19.2411. View

18.

Cuisset T, Frere C, Quilici J, Poyet R, Gaborit B, Bali L . Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol. 2009; 54(13):1149-53. DOI: 10.1016/j.jacc.2009.05.050. View

19.

Mega J, Close S, Wiviott S, Shen L, Hockett R, Brandt J . Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2008; 360(4):354-62. DOI: 10.1056/NEJMoa0809171. View

20.

Brendel K, Comets E, Laffont C, Laveille C, Mentre F . Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharm Res. 2006; 23(9):2036-49. PMC: 2124466. DOI: 10.1007/s11095-006-9067-5. View