PHARMACOKINETIC DRUG INTERACTION BETWEEN CLOPIDOGREL AND ESOMEPRAZOLE IN ADULT HEALTHY MALE VOLUNTEERS

  • Bhargav K Department of Pharmacy Practice, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.
  • Venkata Subbareddy B Department of Pharmacy Practice, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.
  • Venkata Sivakrishna K Department of Pharmacy Practice, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.
  • Himaja G Department of Pharmacy Practice, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.
  • Samuel Gideon Georgep Department of Pharmacy Practice, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.
  • Bhaskar Reddy K Department of Pharmaceutics, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.

Abstract

Objective: Proton pump inhibitors (PPIs) are known to impair cytochrome P2C19 mediated activation of clopidogrel, the antiplatelet agent used for cardiovascular risk prevention. Esomeprazole is an optical isomer of omeprazole with better efficacy and tolerability than conventional PPIs. Esomeprazole is often co-administered with clopidogrel considering the risk of associated gastrointestinal bleeding. This study was designed to determine the effect of esomeprazole on the mean pharmacokinetic profile clopidogrel.

Methods: A total of 14 adult healthy male participants who volunteered participation were enrolled, randomized equally into two cross-over sequences, dosed with clopidogrel and clopidogrel + esomeprazole in respective periods. Blood samples were collected through antecubital or forearm vein indwelling catheter. Concentration of clopidogrel parent prodrug in isolated plasma was determined using validated sensitive liquid chromatography – mass spectrometry. Pharmacokinetic modeling was carried out using PKSOLVER add-in for Microsoft Excel.

Results: The pharmacokinetic profile of clopidogrel was non-significantly altered by esomeprazole. Statistically significant difference in peak plasma concentration, apparent volume of distribution, and clearance of clopidogrel was observed only during period II in participants co-dosed with esomeprazole (p=0.0483, 0.0011, and 0.0015, respectively). All other primary and secondary pharmacokinetic parameters displayed minor alterations during either period (p>0.05).

Conclusion: The non-significant alteration of clopidogrel pharmacokinetics by esomeprazole can be potentiated by underlying predisposing factors such as the presence of CYP2C19 allelic variants and increasing the risk of cardiovascular events. Hence, co-administration of clopidogrel and esomeprazole should be under clinical monitoring and is not recommended in poor responders of antiplatelet therapy with clopidogrel.

Keywords: Clopidogrel, CYP2C19, Esomeprazole, Enzyme inhibition, Pharmacokinetics.

Author Biographies

Bhargav K, Department of Pharmacy Practice, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.
Student, Pharm D V year
Venkata Subbareddy B, Department of Pharmacy Practice, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.
Student, Pharm D V year
Venkata Sivakrishna K, Department of Pharmacy Practice, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.
Student, Pharm D V year
Himaja G, Department of Pharmacy Practice, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.
Student, PharmD V year
Samuel Gideon Georgep, Department of Pharmacy Practice, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.
Assistant Professor, Department of Pharmacy Practice
Bhaskar Reddy K, Department of Pharmaceutics, Sri Venkateshwara College of Pharmacy, Chittoor - 517 127, Andhra Pradesh, India.
Professor & Principal, Sri Venkateswara College of Pharmacy

References

1. Florian K, Hae YS, Volker K. Antiplatelet drugs in cardiological practice: Established strategies and new developments. Vasc Health Risk Manag 2008;4(3):637-45.
2. Katrin S, Teri EK, Russ BA. Clopidogrel pathway. Pharmacogn Genomics 2010;20(7):463-5.
3. Thomas M, John O. Metabolic activation of clopidogrel: In vitro data provide conflicting evidence for the contributions of CYP2C19 and PON1. Ther Adv Drug Saf 2011;2(6):253-61.
4. Caitrin WM, Leslie AM, Braxton DM, Yan GP, Richard BH, Joshua PL, et al. CYP2C19 metabolizer status and clopidogrel efficacy in the secondary prevention of small subcortical strokes (SPS3) study. J Am Heart Assoc 2015;4(6):e001652.
5. Pare G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010;363(18):1704-14.
6. Johnson JA, Roden DM, Lesko LJ, Ashley E, Klein TE, Shuldiner AR. Clopidogrel: A case for indication-specific pharmacogenetics. Clin Pharmacol Ther 2012;91(5):774-6.
7. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: A review of the evidence. J Am Coll Cardiol 2005;45(8):1157-64.
8. Zhi YW, Meng C, Ling LZ, LuShan Y, Su Z, Mei X, et al. Pharmacokinetic drug interactions with clopidogrel: Updated review and risk management in combination therapy. Ther Clin Risk Manag 2015;11:449-67.
9. Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. J Am Coll Cardiol 2011;57(11):1251-63.
10. Carmelo S, Luigi G, Angelo Z, Corrado B. Effective and safe proton pump inhibitor therapy in acid-related diseases - A position paper addressing benefits and potential harms of acid suppression. BMC Med 2016;14:179-214.
11. Hiroshi Y, Yasumasa M, Yoshinori S, Sunichiro O, Shinya I, Masaki Y, et al. Treatment and prevention of gastrointestinal bleeding in patients receiving antiplatelet therapy. World J Crit Care Med 2015;4(1):40-6.
12. Meyer UA. Interaction of proton pump inhibitors with cytochromes P450: Consequences for drug interactions. Yale J Biol Med 1996;69(3):203-9.
13. Suresh DM, Hiren RT, Dinesh MP, Prashant SD, Chacko J. Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence. Indian J Pharmacol 2011;43(2):183-6.
14. Shah BS, Parmar SA, Mahajan S, Mehta AA. An insight into the interaction between clopidogrel and proton pump inhibitors. Curr Drug Metab 2012;13(2):225-35.
15. Lau WC, Gurbel PA. The drug-drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180(7):699-700.
16. Gralnek IM, Dulai GS, Fennerty MB, Spiegel BM. Esomeprazole versus other proton pump inhibitors in erosive esophagitis: A meta-analysis of randomized clinical trials. Clin Gastroenterol Hepatol 2006;4(12):1452-8.
17. Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 2004;32(8):821-7.
18. Kahrilas PJ, Falk GW, Johnson DA, Schmitt C, Collins DW, Whipple J, et al. Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: A randomized controlled trial. The Esomeprazole Study Investigators. Aliment Pharmacol Ther 2000;14(10):1249-58.
19. Karazniewicz-Lada M, Danielak D, Burchardt P, Kruszyna L, Komosa A, Lesiak M, et al. Clinical pharmacokinetics of clopidogrel and its metabolites in patients with cardiovascular diseases. Clin Pharmacokinet 2014;53(2):155-64.
20. Mo C, Sun G, Wang YZ, Lu ML, Yang YS. PPI versus histamine H2 receptor antagonists for prevention of upper gastrointestinal injury associated with low-dose aspirin: Systematic review and meta-analysis. PLoS One 2015;10(7):e0131558.
21. Cohen M. Expanding the recognition and assessment of bleeding events associated with antiplatelet therapy in primary care. Mayo Clin Proc 2009;84(2):149-60.
22. Gurbel PA, Bliden KP, Logan DK, Kereiakes DJ, Lasseter KC, White A, et al. The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: The PARADOX study. J Am Coll Cardiol 2013;62(6):505-12.
23. Deray G, Bagnis C, Brouard R, Necciari J, Leenhardt AF, Raymond F, et al. Clopidogrel activities in patients with renal function impairment. Clin Drug Investig 1998;16(4):319-28.
24. Small DS, Farid NA, Li YG, Ernest CS 2nd, Payne CD, Salazar DE, et al. Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. Curr Med Res Opin 2008;24(8):2251-7.
25. Beierle I, Meibohm B, Derendorf H. Gender differences in pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther 1999;37(11):529-47.
26. Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol 2001;2(6):349-51.
27. Rubinow DR, Moore M. Sex-dependent modulation of treatment response. Dialogues Clin Neurosci 2004;6(1):39-51.
28. Wagner H, Angiolillo DJ, Ten Berg JM, Bergmeijer TO, Jakubowski JA, Small DS, et al. Higher body weight patients on clopidogrel maintenance therapy have lower active metabolite concentrations, lower levels of platelet inhibition, and higher rates of poor responders than low body weight patients. J Thromb Thrombolysis 2014;38(2):127-36.
29. Balamuthusamy S, Arora R. Hematologic adverse effects of clopidogrel. Am J Ther 2007;14(1):106-12.
30. Ganesan S, Williams C, Maslen CL, Cherala G. Clopidogrel variability: Role of plasma protein binding alterations. Br J Clin Pharmacol 2013;75(6):1468-77.
31. Venkateswaramurthy N, Krishnaveni K, Mercy FR, Sambath KR. Assessment of potential drug-drug interaction in stroke patients. Int J Pharm Pharm Sci 2016;8(12):221-4.
32. Jian JZ, Shao LC, Jie T, Ling L, Ying YZ, Hai MX. Increased risk for developing major adverse cardiovascular events in stented Chinese patients treated with dual antiplatelet therapy after concomitant use of the proton pump inhibitor. PLoS One 2014;9(1):e84985.
33. Mukesh K, Vicky D, Shruti M, Dinesh S, Neha M, Mangla R. Cardiovascular disease prevalence and drug utilization patterns at a tertiary care hospital in North Eastern India. Int J Pharm Pharm Sci 2016;8(6):116-9.
34. Nirogi RV, Kandikere VN, Mudigonda K. Effect of food on bioavailability of a single oral dose of clopidogrel in healthy male subjects. Arzneimittelforschung 2006;56(11):735-9.
35. McEwen J, Strauch G, Perles P, Pritchard G, Moreland TE, Necciari J, et al. Clopidogrel bioavailability: Absence of influence of food or antacids. Semin Thromb Hemost 1999;25 Suppl 2:47-50.
36. Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009;302(8):849-57.
37. Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthélémy O, et al. 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.
Statistics
404 Views | 456 Downloads
Citatons
How to Cite
K, B., V. S. B, V. S. K, H. G, S. G. Georgep, and B. R. K. “PHARMACOKINETIC DRUG INTERACTION BETWEEN CLOPIDOGREL AND ESOMEPRAZOLE IN ADULT HEALTHY MALE VOLUNTEERS”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 10, no. 7, July 2017, pp. 336-41, doi:10.22159/ajpcr.2017.v10i7.18855.
Section
Original Article(s)