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Clopidogrel (Plavix) By Oksana Ekkert. Objectives At the end of this presentation, participants should be able to: 1. Describe CYP2C19 enzyme function.

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Presentation on theme: "Clopidogrel (Plavix) By Oksana Ekkert. Objectives At the end of this presentation, participants should be able to: 1. Describe CYP2C19 enzyme function."— Presentation transcript:

1 Clopidogrel (Plavix) By Oksana Ekkert

2 Objectives At the end of this presentation, participants should be able to: 1. Describe CYP2C19 enzyme function and its variant alleles. 2. Describe how CYP2C19 polymorphism affects the metabolism of the drugs. 3. Understand the mechanism of action and metabolism of clopidogrel. 4. Identify multiple factors involved in clopidogrel response variability. 5. Understand the importance and the nature of clopidogrel-PPI drug interaction.

3 The routes of elimination for the 200 drugs sold by prescription in the United States according to the RxList data listed in April

4 CYP2C19 CYP2C19 is primarily present in hepatic tissue, but a significant amount is also found in the gut wall, particularly the duodenum. Protein of 490 amino acids. Located in a densely packed region on chromosome 10 along with CYP2C8, 2C9, and 2C18 genes.

5 Variant alleles in CYP2C19 genotype. CYP2C19Nucleotide change EffectEuropeansBlacksAsians *1Wild type85%82%65% *2681GATruncated protein 13-19%10-25%20-30% *3636GATruncated protein <1%0-2%5-13% *17-806CT -3402CT Increased translation 18% 4%

6 Variant Alleles Extensive metabolism: CYP2C19*1/*1 Intermediate metabolism: CYP2C19*1/*2 or *1/*3 Poor metabolism: CYP2C19*2/*2, *2/*3 or *3/*3 (also *4,*5) Ultrarapid: CYP2C19*17 /*17

7 Comparison of pro-drugs and active drugs and clinical consequences Drug type Metabolizer Phenotype Effect on drug metabolism Potential consequence Prodrug Needs metabolism to work (clopidogrel) Poor to intermediate SlowPoor drug efficacy, patient at risk of therapeutic failure due levels of active drug. Accumulation of prodrug, patient at increased risk of drug-induced side effects. UltrarapidFastGood drug efficacy, rapid effect. Possible accumulation of active drug potential of adverse effects. Active drug Metabolized to inactive drug (omeprazole) Poor to intermediate SlowAccumulation of active drug, patient is at increased risk of drug-induced side effects. Patient requires lower dosage. UltrarapidFastPoor drug efficacy, patient is at risk of therapeutic failure. Patient likely will require higher dosage.

8 Anti-platelet agent In 2005, worlds 2nd highest selling drug--U.S. sales $5.9 billion Effective (with aspirin) for secondary prevention of MI and stroke, and thrombosis prevention after percutaneous coronary interventions (e.g., stent placement, angioplasty) Despite a short half-life ~2hrs, the irreversible binding of clopidogrel s active metabolite to the platelet receptor leads to a prolonged pharmacodynamic effect. Clopidogrel

9 P2X 1 P2Y 12 ATP Shape change Angiolillo DJ et al JACC 2007 P2Y 1 GqGq Initiation of Platelet Aggregation IP3 PKC GP IIb/IIIa receptor activation G 12 DAG + Shape change Granule secretion Stabilization of Platelet Aggregation βγβγ GP IIb/IIIa receptor activation Rap1b PKB/Akt αiαi AC cAMP VASP VASP-P cAMP GiGi PI3K Clopidogrel 15% active metabolite HOOC * HS N O Cl OCH 3 N S O Cl O CH 3 C 85% inactive metabolites (Esterases in blood) Gastro-intestinal absorption ADP Ca 2+ flux Ca 2+ mobilization PLCβ MLCK-P Rho Hepatic CYP Biotransformation AC GsGs GP IIb/IIIa receptor activation PGE 1 PIP2

10 T.E. KleinT.E. Klein, J.T. Chang, M.K. Cho, K.L. Easton, R. Fergerson, M. Hewett, Z. Lin, Y. Liu, S. Liu, D.E. Oliver, D.L. Rubin, F. Shafa, J.M. Stuart and R.B. Altman, "Integrating Genotype and Phenotype Information: An Overview of the PharmGKB Project" (220k PDF), The Pharmacogenomics Journal (2001) 1, R.B. AltmanIntegrating Genotype and Phenotype Information: An Overview of the PharmGKB Project220k PDF

11 First oxidative step: conversion of clopidogrel to 2- oxo-clopidogrel CYP1A2 (responsible for 36% of conversion): genetic polymorphisms: 16 identified SNPs CYP2B6 (responsible for 19% of conversion): genetic polymorphisms: 29 identified SNPs CYP2C19 (responsible for 45% of conversion): genetic polymorphisms: 25 identified SNPs Second oxidative step: conversion of 2-oxo- clopidogrel to the active metabolite CYP2B6: responsible for 33% of conversion CYP2C9 (responsible for 7% of conversion): genetic polymorphisms: 34 identified SNPs CYP2C19: responsible for 20% of conversion CYP3A4 (responsible for 40% of conversion): genetic polymorphisms: 20 identified SNPs

12 Not only CYP2C19 genetics, but-- Genetics of CYP2C9*3 and ABCB1 have been shown to be important

13 Clopidogrel Response Variability 20% do not have adequate response GP IIb/IIIa receptor expression Hepatic Metabolism Cytochrome P450 pathway Poor compliance Inadequate administration Variable absorption Genetic polymorphisms CYP2C19PMs, CYP2C9*3, ABCB1 Drug-drug interactions Genetic polymorphisms P2Y12 receptor Alternate pathways of platelet activation Genetic polymorphisms ODonoghue M, Wiviott SD. Circulation. 2006;114:e600-e606 Simon T et al.NEJM. 2009; Feher G et al. Clin Genetics. 2009; 75:1-18. Intestinal Absorption P2Y 12 Receptor (irreversible inhibition) Active Metabolite

14 Inhibition of Platelet Aggregation (Wide Response Variability) 1 Mechanisms of Clopidogrel Response Variability Clopidogrel Bisulfate Intestinal Absorption Inactive Carboxylic Acid Metabolite CYP3A4 CYP3A5 CYP2C19 CYP2C9 Active Thiol Metabolite P2Y 12 Receptor Limited absorption capacity with ceiling effect at 600mg loading dose 7 Hepatic P450 Cytochromes CYP3A4 inducers: rifampin CYP3A4 inhibitors: erythromycin 2C19 Genetic polymorphisms 2C19 inhibitors Multistep Conversion 15% Esterases 85% 1. Gurbel PA et al. Thromb Res. 2007;120: Taubert et al. Clin Pharmacol. 2006;80: von Beckerth et al. Eur Heart J. 2007;28: P-glycoprotein (MDR1 3435T genotype) 2 ? Smoking (induction) CYP1A2 CYP2B6, 2C19 2C9*3 Genetic polymorphisms

15 Why do we need PPIs with clopidogrel? Deepak LB, et al. Circulation 2008; 118:

16 K i (μM) values of PPIs for CYP2C19 enzyme Brand Generic Ki (μM)Model Inhibitor HLM a rCYP2C19 b Ticlopidine HLM 0.31±0.05 rCYP2C ±0.04 Prilosecomeprazole6.2±0.82.4±0.05 Aciphexrabeprazole21.3±2.8 (2.4±0.1) c 18.8±1.3 (2.8± 0.1) d Nexiumesomeprazole8.6±1.07.9±0.5 Prevacidlansoprazole0.45± ±0.09 Protonixpantoprazole69.4± ±1.1 a,b marker reaction used was S-Mephenytoin 4-Hydroxylation c,d rabeprazole thioether; HLM=human liver microsomes Li X, 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 August 1;32(8):821-7.

17 Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI Ho PM, Maddox TM, Wang L, et al. JAMA. 2009;301(9): Days Since Discharge Proportion of Deaths or Recurrent ACS Neither clopidogrel nor PPI PPI without clopidogrel Clopidogrel + PPI Clopidogrel without PPI

18 Considerations for Healthcare Providers Patients receiving clopidogrel for MI or stroke may not receive the expected antiplatelet activity if omeprazole is used concurrently. Separating the time of administration of clopidogrel and omeprazole does not reduce the chance of the interaction. The FDA does not have sufficient drug interaction information to provide recommendations for concurrent use of other PPIs. There is no evidence that H 2 antagonists (other than cimetidine) interfere with antiplatelet activity of clopidogrel. Both cimetidine and omeprazole are available in nonprescription (OTC) forms and patients should be educated to avoid these drugs if receiving clopidogrel. Concurrent use of cimetidine, esomeprazole, etravirine, erythromycin, felbamate, fluconazole, fluvoxamine, fluoxetine, ketoconazole, voriconazole and ticlopidine should also be avoided because they may also reduce clopidogrels antiplatelet activity. Rifampin has been shown to increase the concentrations of active metabolite through CYP3A4 induction. At high concentrations in vitro, clopidogrel inhibits P 450 (2C9). Accordingly, clopidogrel may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is coadministered with clopidogrel.

19 In Conclusion The totality of all of the CYP2C19 polymorphism data suggests that it would be appropriate to begin genotyping all potential patients and thus identify those patients who would be at increased risk for thrombosis or bleeding if treated with clopidogrel.

20 References 1. Wienkers LC, Heath TG (2005) Nat Rev Drug Discov 4:825–833 (top 200) 2. S. R. Steinhubl. Genotyping, Clopidogrel Metabolism, and the Search for the Therapeutic Window of Thienopyridines Circulation February 2, : Plavix prescribing information. Accessed February 20, Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38:92– Sibbing D, Koch W, Gebhardt D, Schuster T, Braun S, Stegherr J, Morath T, Schomig A, Kastrati A. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010;121:512– Klotz U, Schwab M, Treiber G. CYP2C19 polymorphism and proton pump inhibitors. Basic Clin Pharmacol Toxicol 2004; 95: 2–8. 7. Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE Trial. Circulation 2005;112: Li X, 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 August 1;32(8):821-7.

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