doi: 10.1161/CIRCULATIONAHA.109.865907
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2009;119:2127-2130.)
© 2009 American Heart Association, Inc.
Editorial |
Clopidogrel and the Concept of High-Risk Pharmacokinetics
From the Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Dan M. Roden, MD, Professor of Medicine and Pharmacology, Director, Oates Institute for Experimental Therapeutics, Assistant Vice-Chancellor for Personalized Medicine, Vanderbilt University School of Medicine, 1285 Medical Research Bldg IV, Nashville, TN 37232-0575. E-mail dan.roden{at}vanderbilt.edu
Key Words: Editorials • clopidogrel • pharmacokinetics • pharmacogenetics
 |
Introduction |
|---|
 Top Introduction Anticipating This Result: The...ImplicationsWhat Now?References |
|---|
Four large trials, reported in the last several weeks, have identified loss-of-function alleles in the gene encoding cytochrome P450 2C19 (CYP2C19) as important risk factors predicting apparent failure of clopidogrel efficacy.1–4 Previous studies have shown that clopidogrel is a prodrug that requires bioactivation,5 mediated in part by CYP2C19, to achieve its antiplatelet efficacy.6 All 4 trials built on this knowledge and studied the effects of CYP2C19 variants on coronary events (including death, myocardial infarction, and in-stent thrombosis) in patients receiving clopidogrel. Hazard ratios for a single CYP2C19 variant allele ranged from 1.5 to 4, depending on the end point and the specific population. We describe here how this apparently surprising outcome could be anticipated from first principles in clinical pharmacology. We then discuss how considering this result within the context of a contemporary understanding of clinical pharmacokinetics and pharmacogenetics raises new hypotheses that require further testing.
|
Anticipating This Result: The Concept of High-Risk Pharmacokinetics |
|---|
|
TopIntroductionAnticipating This Result: The...ImplicationsWhat Now?References |
|---|
In an era of increasing attention on multiple genetic variants as mediators of variability in drug action (pharmacogenomics), it is a bit of a surprise to see such a spectacular effect of a single set of variants on clinically important outcomes for a very widely used drug. However, the new findings with clopidogrel are entirely consistent with a set of clinical pharmacokinetic findings that now extend back decades and define the concept of high-risk pharmacokinetics,7,8 a risk of serious drug toxicity when drug concentrations depend on variable activity of a single metabolic pathway.
The processes of absorption, distribution, metabolism, and excretion rely on specific proteins that metabolize drugs and move them into and out of cells. Although the activities of these processes vary among individuals, we now understand that genetic variation can result in near-complete absence of enzymatic activity in some individuals. It follows that drugs with a bioactivation that relies on a single pathway will display highly variable clinical effects if that pathway is inhibited or absent on a genetic basis. This is the issue with clopidogrel and a number of other drugs described here.
Variable Bioactivation of Other Prodrugs
Approximately 7% of the European American and African American populations lack functional alleles for another P450, CYP2D6.9 Codeine is bioactivated to its active metabolite (morphine) by this enzyme, and CYP2D6-poor metabolizers display decreased analgesic opioid effects of the drug.10 Tamoxifen is bioactivated by a number of pathways, including CYP2D6,11 and preliminary analyses of outcomes during tamoxifen therapy as a function of CYP2D6 genotype support the idea that poor metabolizers have an increased incidence of recurrent breast cancer during tamoxifen therapy.12–14
High-Risk Pharmacokinetics and Drug Elimination
A second high-risk situation is the administration of a drug that has the potential to cause serious toxicity at high concentrations and whose elimination depends on a single pathway. In this case, perturbation of that pathway, by genetic factors or by interactions, can lead to marked increases in drug concentrations (because alternate pathways for drug elimination are not present) and thus drug toxicity (see the Figure).
|
Warfarin is bioinactivated by CYP2C9-mediated metabolism. Common variants in this enzyme lead to a reduction of function (CYP2C9*2) or near-complete reduction of function (CYP2C9*3). Rare individuals who are homozygous for the loss-of-function allele (*3/*3, 
1% of a white population) display striking reductions in warfarin dose requirement and may be at increased risk for complications during therapy.15,16 It is now apparent that warfarin dose requirements reflect variation in both CYP2C9 and VKORC1, which encodes a protein in the vitamin K receptor complex that is the target of the warfarin drug action. Because there is such a narrow margin between the dosages required for efficacy and those producing toxicity for this drug, adjustment of dose in the broad population exposed to the drug according to genotype, not simply identifying *3/*3 homozygotes, may be a preferred approach.17 Large trials testing this idea are now in the planning phase.18
Some drugs are markedly affected by genetic variation in metabolism, but because a wide range of concentrations is well tolerated, the clinical consequences are minor. Metoprolol and timolol undergo CYP2D6-mediated bioinactivation. Toxicity is not a problem in poor metabolizers, however, because marked increases in β-blocker concentrations do not result in severe adverse effects; some data suggest that metoprolol cardioselectivity may be lost in poor metabolizers.19
|
Implications |
|---|
|
TopIntroductionAnticipating This Result: The...ImplicationsWhat Now?References |
|---|
Drug Interactions
An obvious possibility raised by the clopidogrel findings is that coadministration of CYP2C19-inhibiting drugs might similarly reduce clopidogrel efficacy. One of the most potent CYP2C19 inhibitors in clinical use is the proton pump inhibitor (PPI) omeprazole; indeed, coadministration of omeprazole with clopidogrel has been reported to reduce platelet aggregation among patients with coronary disease.20,21 Furthermore, omeprazole is both a substrate22 and an inhibitor23 of CYP2C19; therefore, those individuals with CYP2C19-poor metabolizing alleles will have not only impaired formation of the clopidogrel active metabolite but also the highest concentrations of omeprazole, a potential double hit. This interaction has tremendous potential clinical importance because current guidelines from cardiology and gastroenterology societies strongly recommend the use of PPIs for gastroprotection in patients receiving clopidogrel plus aspirin.24 Two abstracts presented at the American Heart Association Scientific Sessions in late 2008 addressed the issue of clopidogrel-PPI interactions by examining the incidence of coronary events in large populations exposed to the 2 drugs. One study, a review of the experience of the large pharmacy benefit supplier Medco, strongly suggested an interaction.25 However, the second study, a reanalysis of the Clopidogrel for Reduction of Events During Observation (CREDO) data, pointed out that although patients receiving clopidogrel plus PPIs had a higher incidence of coronary events, this increase in event frequency also occurred among patients receiving placebo plus PPIs26; ie, the data suggested that sicker patients (those at higher cardiovascular risk) were the ones most likely to receive PPIs. A Canadian study that examined the incidence of coronary events in a cohort of patients receiving clopidogrel and PPIs suggests a higher risk for coronary events among patients receiving omeprazole compared with those receiving pantoprazole, a much less potent CYP2C19 inhibitor.23,27 Thus, interrogation of this database supports the idea of an interaction between clopidogrel and CYP2C19 inhibitors. A retrospective examination of outcomes in 8205 patients discharged on clopidogrel from 127 Veteran’s Administration Hospitals in 2003 to 2006 similarly found a higher event rate among those on PPIs, although specific agents of the class were not examined.28 However, database studies are not randomized controlled studies, and the problem of residual confounding resulting from baseline differences in patients receiving omeprazole can be difficult to exclude. Notably, the Clopidogrel and the Optimization of Gastrointestinal Events (COGENT-1) trial evaluating a clopidogrel-omeprazole combination product was terminated by the sponsor in early 2009.
Further retrospective analyses to weigh the risks and benefits of the combination are likely required because prospective randomized clinical trials to assess the effect this interaction on cardiovascular and gastrointestinal events are not available or planned. At this point, it seems clear that this potential interaction should be evaluated on a PPI-specific basis and that it is unlikely to represent an effect shared by all drugs in the class.
Other Drug Interactions Linked to High-Risk Pharmacokinetics
The concern about a clopidogrel-omeprazole interaction is the latest in a long line of serious adverse drug reactions based on the principles of high-risk pharmacokinetics.
Terfenadine is a very potent QT-prolonging agent but, in the vast majority of individuals, undergoes near-complete presystemic metabolism by a single enzyme, CYP3A. Although individuals absolutely lacking CYP3A activity have not been described, patients receiving potent CYP3A inhibitors such as certain azole antifungals or macrolide antibiotics displayed inhibited presystemic metabolism, accumulation of terfenadine in plasma, marked QT prolongation, and torsades de pointes and sudden death.29 Cyclosporine is also eliminated by CYP3A-mediated metabolism, and coadministration of the CYP3A inhibitor ketoconazole can increase cyclosporin concentrations and lead to toxicity unless the dosage is lowered.30
CYP2D6 activity can be inhibited by a number of agents, including quinidine, some tricyclic antidepressants, and some (but not all) selective serotonin reuptake inhibitors, notably fluoxetine and paroxetine. It is common to coprescribe selective serotonin reuptake inhibitors and tamoxifen to prevent flushing, a frequent side effect. The parallels to clopidogrel-omeprazole are striking; although this therapy may alleviate adverse effects, it may also increase the likelihood of failure of drug efficacy.11 Studies are underway to examine the role of concomitant therapy with CYP2D6-inhibiting selective serotonin reuptake inhibitors on the outcome of tamoxifen therapy.
Digoxin is eliminated not by metabolism but by biliary and renal excretion mediated by a specific drug transport molecule, P-glycoprotein, encoded by the MDR1 (also known as ABCB1) gene. A range of commonly used drugs such as amiodarone, verapamil, quinidine, and itraconazole inhibit P-glycoprotein, and they reproducibly and reliably produce digoxin toxicity by eliminating the major route of drug excretion.31
Ethnicity
The distribution of loss-of-function alleles in CYP2C19 and many of the other genes involved in drug disposition described here varies across ethnicities. Loss-of-function CYP2C19 alleles are especially common in Asian populations, whereas CYP2D6 loss-of-function alleles are more common among European and African subjects, and the CYP2C9*3 allele is seen almost exclusively in European populations.17 Interestingly, omeprazole is a CYP2C19 substrate, and ulcer-healing efficacy was higher among Japanese subjects with loss-of-function alleles.22 An interesting question is the extent to which cardiovascular events in Asian subjects receiving clopidogrel reflect the prevalence of CYP2C19 variant alleles.
|
What Now? |
|---|
|
TopIntroductionAnticipating This Result: The...ImplicationsWhat Now?References |
|---|
It is almost inconceivable that clopidogrel represents the end of a long line of drugs with the potential to produce severe toxicity or suffer failure of efficacy as a result of high-risk pharmacokinetics. Furthermore, although the examples cited here focus on single variants producing important clinical effects, there is now little doubt that variation across many genes accounts for variability in response to widely used drugs such as warfarin and clopidogrel. An ongoing challenge is identification of these gene and pathways, validation of any findings, and ultimately translation to the bedside.
The idea of preprescription genotyping to identify patients at high risk for adverse effects has some appeal. However, it is important to establish that any change in drug therapy based on such results be evidence based. In the case of warfarin, algorithms to predict dosage requirements17 based on clinical features and CYP2C9 and VKORC1 genotypes are a key step to randomized trials. The situation is murkier for patients with variant CYP2C19 alleles in whom clopidogrel therapy is started because there is currently no basis for dose adjustment. One logical answer may be uniform tests of platelet aggregation during drug therapy.
Another approach is to prescribe alternative therapies for those at risk because of variant alleles. For both warfarin and clopidogrel, such alternative therapies, factor X inhibitors and prasugrel, are in late development. One strategy, which would require prospective evaluation, is to prescribe newer (and presumably more expensive and less well-studied) therapies in those subjects at risk of adverse drug effects because of DNA variants compared with treatment with older, cheaper drugs in those without the risk alleles. In the case of clopidogrel versus prasugrel, an informed decision requires consideration of the relative frequencies of adverse events with the 2 agents, the extent of gastroprotection conferred by PPIs, the extent of cardiovascular protection conferred by drug regimens that do or do not include PPIs, whether PPIs are clinically interchangeable in gastroprotection and in cardiovascular events, and the cost implications of a preprescription genotyping strategy. Clinical trials and further analyses of extant data sets may firm up some of the preliminary answers we are now getting.
|
Acknowledgments |
|---|
Disclosures
None.
|
Footnotes |
|---|
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
|
TopIntroductionAnticipating This Result: The...ImplicationsWhat Now?References |
|---|
1. Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009; 373: 309–317.[CrossRef][Medline] [Order article via Infotrieve]
2. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009; 360: 354–362.
3. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009; 360: 363–375.
4. Sibbing D, Stegherr J, Latz W, Koch W, Mehilli J, Dorrler K, Morath T, Schomig A, Kastrati A, Von Beckerath N. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J. February 4, 2009. DOI: 10.1093/eurheartj/ehp041. Available at: http://eurheartj.oxfordjournals.org.
5. Savi P, Herbert JM, Pflieger AM, Dol F, Delebassee D, Combalbert J, Defreyn G, Maffrand JP. Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel. Biochem Pharmacol. 1992; 44: 527–532.[CrossRef][Medline] [Order article via Infotrieve]
6. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006; 108: 2244–2247.
7. Roden DM. Cardiovascular pharmacogenomics. Circulation. 2003; 108: 3071–3074.
8. Roden DM. Drug-induced prolongation of the QT Interval. N Engl J Med. 2004; 350: 1013–1022.
9. Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol. 2004; 369: 23–37.[CrossRef][Medline] [Order article via Infotrieve]
10. Caraco Y, Sheller J, Wood AJ. Impact of ethnic origin and quinidine coadministration on codeine’s disposition and pharmacodynamic effects. J Pharmacol Exp Ther. 1999; 290: 413–422.
11. Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, Flockhart DA. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003; 95: 1758–1764.
12. Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM, Desta Z, Nguyen A, Flockhart DA, Perez EA, Ingle JN. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat. 2007; 101: 113–121.[CrossRef][Medline] [Order article via Infotrieve]
13. Gaston C, Kolesar J. Clinical significance of CYP2D6 polymorphisms and tamoxifen in women with breast cancer. Clin Adv Hematol Oncol. 2008; 6: 825–833.[Medline] [Order article via Infotrieve]
14. Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, Simon W, Eichelbaum M, Brauch H. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007; 25: 5187–5193.
15. Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999; 353: 717–719.[CrossRef][Medline] [Order article via Infotrieve]
16. Ablin J, Cabili S, Eldor A, Lagziel A, Peretz H. Warfarin therapy is feasible in CYP2C9*3 homozygous patients. Eur J Intern Med. 2004; 15: 22–27.[CrossRef][Medline] [Order article via Infotrieve]
17. International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009; 360: 753–764.
18. Shurin SB, Nabel EG. Pharmacogenomics: ready for prime time? N Engl J Med. 2008; 358: 1061–1063.
19. Lennard MS, Silas JH, Freestone S, Ramsay LE, Tucker GT, Woods HF. Oxidation phenotype: a major determinant of metoprolol metabolism and response. N Engl J Med. 1982; 307: 1558–1560.[Medline] [Order article via Infotrieve]
20. Gilard M, Arnaud B, Cornily JC, Le GG, Lacut K, Le CG, Mansourati J, Mottier D, Abgrall JF, Boschat J. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole Clopidogrel Aspirin) study. J Am Coll Cardiol. 2008; 51: 256–260.
21. Gilard M, Arnaud B, Le GG, Abgrall JF, Boschat J. Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haemost. 2006; 4: 2508–2509.[CrossRef][Medline] [Order article via Infotrieve]
22. Furuta T, Ohashi K, Kamata T, Takashima M, Kosuge K, Kawasaki T, Hanai H, Kubota T, Ishizaki T, Kaneko E. Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer. Ann Intern Med. 1998; 129: 1027–1030.
23. 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: 821–827.
24. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FKL, Furberg CD, Johnson DA, Mahaffey KW, Quigley EM. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2008; 118: 1894–1909.
25. Aubert RE, Epstein RS, Teagarden JR, Xia F, Yao J, Desta Z, Skaar T, Flockhart DA. Proton pump inhibitors effect on clopidogrel effectiveness: the Clopidogrel Medco Outcomes Study. Abstract presented at: 2008 American Heart Association Scientific Sessions; November 8–12, 2008; New Orleans, La.
26. Dunn SP, Macaulay TE, Brennan DM, Campbell CL, Charnigo RJ, Smyth SS, Berger PB, Steinhubl SR, Topol EJ. Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO trial. Abstract presented at: 2008 American Heart Association Scientific Sessions; November 8–12, 2008; New Orleans, La.
27. Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009; 180: 713–718.
28. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009; 301: 937–944.
29. Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA. 1993; 269: 1532–1536.
30. Keogh A, Spratt P, McCosker C, Macdonald P, Mundy J, Kaan A. Ketoconazole to reduce the need for cyclosporine after cardiac transplantation. N Engl J Med. 1995; 333: 628–633.
31. Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM. Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine. Circulation. 1999; 99: 552–557.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||