The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response

Ankie M. Harmsze; Karen Robijns; Jochem W. van Werkum; Nicoline J. Breet; Christian M. Hackeng; Jurrien M. ten Berg; Hendrik J. T. Ruven; Olaf H. Klungel; Anthonius de Boer; Vera H. M. Deneer

doi:10.1160/TH09-08-0516

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 103(05): 920-925
DOI: 10.1160/TH09-08-0516

Theme Issue Article

Schattauer GmbH

The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response

Authors

Ankie M. Harmsze

¹Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands

²Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
Karen Robijns

¹Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Jochem W. van Werkum

³Department of Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands
Nicoline J. Breet

³Department of Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands
Christian M. Hackeng

⁴Department of Clinical Chemistry, St. Antonius Hospital, Nieuwegein, The Netherlands
Jurrien M. ten Berg

³Department of Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands
Hendrik J. T. Ruven

⁴Department of Clinical Chemistry, St. Antonius Hospital, Nieuwegein, The Netherlands
Olaf H. Klungel

²Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
Anthonius de Boer

²Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
Vera H. M. Deneer

¹Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands

Abstract

Summary

Clopidogrel is a prodrug that has to be converted in vivo to its active metabolite by cytochrome (CYP)P450 iso-enzymes. As calcium channel blockers (CCBs) are inhibitors of CYP3A4, concomitant use of these drugs might play a role in the wide inter-individual variability in the response to clopidogrel. However, some CCBs also have strong inhibitory effects on the drug transporter P-glycoprotein (Pgp), which mediates clopidogrel‘s intestinal absorption. It was the aim of this study to evaluate the effect of co-administration of Pgp-inhibiting and non-Pgp-inhibiting CCBs on on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective percutaneous coronary intervention (PCI). In a total of 623 consecutive patients undergoing elective PCI treated with clopidogrel and aspirin, platelet reactivity to 5 and 20 μM adenosine diphospate (ADP) and clopidogrel poor-response (defined as > 70% platelet aggregation to 20 μM ADP) were evaluated by light transmittance aggregometry. A total of 222 patients (35.6%) were on CCB treatment, of which 98 used Pgp-inhibiting CCBs (verapamil, nifedipine, diltiazem, barnidipine) and 124 patients used the non-Pgp-inhibiting CCB amlodipine. Adjusted mean ADP-induced on-clopidogrel platelet reactivity was significantly higher in both users of Pgp-inhibiting CCBs and amlodipine as compared to CCB non-users (all p<0.05). However, only the use of amlodipine was significantly associated with a 2.3-fold increased risk of clopidogrel poor-response. This study demonstrates that concomitant use of Pgp-inhibiting CCBs and amlodipine increases on-clopidogrel platelet reactivity. Only amlodi-pine was associated with clopidogrel poor-response. The drug-drug interaction between clopidogrel and amlodipine might be more clinically relevant as compared to P-glycoprotein-inhibiting CCBs.

Keywords

Clopidogrel - drug-drug interaction - percutaneous coronary intervention - platelet reactivity - calcium channel blockers - P-glycoprotein - CYP3A4

Full Text

References

References
1 Mehta SR, Yusuf S, Peters RJ. et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
2 Taubert D, von Beckerath N, Grimberg G. et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80: 486-501.
3 Mega JL, Close SL, Wiviott SD. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
4 Pereillo JM, Maftouh M, Andrieu A. et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos 2002; 30: 1288-1295.
5 Savi P, Pereillo JM, Uzabiaga MF. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-896.
6 Serebruany VL, Steinhubl SR, Berger PB. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246-251.
7 Hulot JS, Bura A, Villard E. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-2247.
8 Trenk D, Hochholzer W, Fromm MF. et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008; 51: 1925-1934.
9 Simon T, Verstuyft C, Mary-Krause M. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-375.
10 Sibbing D, Stegherr J, Latz W. et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009; 30: 916-922.
11 Collet JP, Hulot JS, Pena A. et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373: 309-317.
12 Giusti B, Gori AM, Marcucci R. et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol 2009; 103: 806-811.
13 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol 2006; 26: 1895-1900.
14 Suh JW, Koo BK, Zhang SY. et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. Cmaj 2006; 174: 1715-1722.
15 Brandt JT, Close SL, Iturria SJ. et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 05: 2429-2436.
16 Harmsze A, van Werkum JW, Bouman HJ. et al. Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation. Pharmacogenet Genomics 2010; 20: 18-25.
17 Katoh M, Nakajima M, Yamazaki H. et al. Inhibitory potencies of 1,4-dihydropyridine calcium antagonists to P-glycoprotein-mediated transport: comparison with the effects on CYP3A4. Pharm Res 2000; 17: 1189-1197.
18 Siller-Matula JM, Lang I, Christ G. et al. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008; 52: 1557-1563.
19 Gremmel T, Steiner S, Seidinger D. et al. Calcium-channel blockers decrease clopidogrel-mediated platelet inhibition. Heart 2010; 96: 186-189.
20 Zhou SF, Xue CC, Yu XQ. et al. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit 2007; 29: 687-710.
21 von Beckerath N, Pogatsa-Murray G, Wieczorek A. et al. Correlation of a new point-of-care test with conventional optical aggregometry for the assessment of clopidogrel responsiveness. Thromb Haemost 2006; 95: 910-911.
22 van Werkum JW, van der Stelt CA, Seesing TH. et al. A head-to-head comparison between the VerifyNow P2Y₁₂ assay and light transmittance aggregometry for monitoring the individual platelet response to clopidogrel in patients undergoing elective percutaneous coronary intervention. J Thromb Haemost 2006; 04: 2516-2518.
23 van Werkum JW, Harmsze AM, Elsenberg EH. et al. The use of the VerifyNow system to monitor antiplatelet therapy: a review of the current evidence. Platelets 2008; 19: 479-488.
24 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-2425.
25 Price MJ, Endemann S, Gollapudi RR. et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000.
26 Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13: 129-134.
27 Mahgoub AA, El-Medany AH, Abdulatif AS. A comparison between the effects of diltiazem and isosorbide dinitrate on digoxin pharmacodynamics and kinetics in the treatment of patients with chronic ischemic heart failure. Saudi Med J 2002; 23: 725-731.
28 Kirch W, Hutt HJ, Dylewicz P. et al. Dose-dependence of the nifedipine-digoxin interaction?. Clin Pharmacol Ther 1986; 39: 35-39.
29 Rodin SM, Johnson BF, Wilson J. et al. Comparative effects of verapamil and isradipine on steady-state digoxin kinetics. Clin Pharmacol Ther 1988; 43: 668-672.