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Clopidogrel (Plavix) By Oksana Ekkert. Objectives . At the end of this presentation, participants should be able to: Describe CYP2C19 enzyme function and its variant alleles. Describe how CYP2C19 polymorphism affects the metabolism of the drugs.

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objectives
Objectives

At the end of this presentation, participants should be able to:

  • Describe CYP2C19 enzyme function and its variant alleles.
  • Describe how CYP2C19 polymorphism affects the metabolism of the drugs.
  • Understand the mechanism of action and metabolism of clopidogrel.
  • Identify multiple factors involved in clopidogrel response variability.
  • Understand the importance and the nature of clopidogrel-PPI drug interaction.
slide3

The routes of elimination for the 200 drugs sold by prescription in the United States according to the RxList data listed in April 2008 1

cyp2c19
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.
variant alleles
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
clopidogrel
Clopidogrel
  • Anti-platelet agent
  • In 2005, world’s 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.
slide9

OCH3

CH3

O

O

O

C

N

HOOC

N

* HS

Cl

S

15% active metabolite

Cl

Gi

Gs

AC

Clopidogrel

ATP

ADP

P2X1

P2Y1

Gastro-intestinal absorption

Gq

G12

“Rho”

Ca2+ flux

Shape change

PIP2

P2Y12

PLCβ

Shape change

+

DAG

IP3

Hepatic CYP Biotransformation

PKC

αi

βγ

Ca2+

mobilization

MLCK-P

AC

PI3K

85% inactive metabolites

(Esterases in blood)

GP IIb/IIIa

receptor activation

Granule secretion

PKB/Akt

Rap1b

GP IIb/IIIa receptor activation

Initiation of Platelet Aggregation

cAMP

Stabilization of Platelet Aggregation

VASP

VASP-P

PGE1

cAMP

GP IIb/IIIa receptor activation

Angiolillo DJ et al JACC 2007

slide10

T.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, 167-170.

slide11

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
not only cyp2c19 genetics but
Not only CYP2C19 genetics, but--
  • Genetics of CYP2C9*3 and ABCB1 have been shown to be important
clopidogrel response variability 20 do not have adequate response
Clopidogrel Response Variability20% do not have adequate response

Intestinal Absorption

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

Hepatic Metabolism

Cytochrome P450 pathway

Active Metabolite

P2Y12 Receptor

(irreversible inhibition)

GP IIb/IIIa receptor expression

O’Donoghue M, Wiviott SD. Circulation. 2006;114:e600-e606

Simon T et al.NEJM. 2009;363-75

Feher G et al. Clin Genetics. 2009; 75:1-18.

mechanisms of clopidogrel response variability
Mechanisms of Clopidogrel Response Variability

Limited absorption capacity with ceiling effect at 600mg loading dose7

Esterases85%

ClopidogrelBisulfate

Inactive Carboxylic Acid Metabolite

Intestinal Absorption

?

P-glycoprotein

(MDR1 3435T genotype)2

15%

CYP3A4

CYP3A5

CYP2C19

CYP2C9

CYP3A4 inducers: rifampin

CYP3A4 inhibitors: erythromycin

Hepatic P450

Cytochromes

2C19 Genetic polymorphisms 2C19 inhibitors

2C9*3 Genetic polymorphisms

CYP1A2

CYP2B6, 2C19

Smoking (induction)

Multistep Conversion

Active Thiol Metabolite

P2Y12 Receptor

Inhibition of Platelet Aggregation (Wide Response Variability)1

1. Gurbel PA et al. Thromb Res. 2007;120:311-21. 2. Taubert et al. Clin Pharmacol. 2006;80:486-501. 3. von Beckerth et al. Eur Heart J.2007;28:1814-9.

why do we need ppi s with clopidogrel
Why do we need PPI’s with clopidogrel?

Deepak LB, et al. Circulation 2008; 118:1894-1909

k i m values of ppi s for cyp2c19 enzyme
Ki (μM) values of PPI’s for CYP2C19 enzyme

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. 2004 August 1;32(8):821-7.

risk of all cause mortality and recurrent acs in patients taking clopidogrel and ppi
Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI

Neither clopidogrel nor PPI

PPI without clopidogrel

Clopidogrel + PPI

Clopidogrel without PPI

0.70

0.60

0.50

0.40

0.30

0.20

0.10

0

Proportion of

Deaths or Recurrent ACS

90

180

270

360

450

540

630

720

810

900

990

1080

0

Days Since Discharge

Ho PM, Maddox TM, Wang L, et al. JAMA. 2009;301(9):937-944.

considerations for healthcare providers
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 H2 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 clopidogrel’s antiplatelet activity.
  • Rifampin has been shown to increase the concentrations of active metabolite through CYP3A4 induction.
  • At high concentrations in vitro, clopidogrel inhibits P450 (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.
in conclusion
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.

references
References
  • Wienkers LC, Heath TG (2005) Nat Rev Drug Discov 4:825–833 (top 200)
  • S. R. Steinhubl. Genotyping, Clopidogrel Metabolism, and the Search for the Therapeutic Window of Thienopyridines Circulation February 2, 2010 121:481-483
  • Plavix prescribing information. http://products.sanofi-aventis.us/plavix/plavix.html. Accessed February 20, 2010.
  • 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;38:92–99.
  • 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;121:512–518.
  • Klotz U, Schwab M, Treiber G. CYP2C19 polymorphism and proton pump inhibitors. Basic Clin Pharmacol Toxicol 2004; 95: 2–8.
  • 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;112:2946-50
  • 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. 2004 August 1;32(8):821-7.