Clopidogrel Clopidogrel (Plavix)(Plavix)

By Oksana EkkertBy Oksana Ekkert

ObjectivesObjectives 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.

The routes of elimination for the 200 drugs sold The routes of elimination for the 200 drugs sold by prescription in the United States according to by prescription in the United States according to the RxList data listed in April 2008 the RxList data listed in April 2008 11

CYP2C19CYP2C19

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 in CYP2C19 genotype.Variant alleles in CYP2C19 genotype.

CYP2C19 Nucleotide change

Effect Europeans Blacks Asians

*1 Wild type 85% 82% 65%

*2 681G→A Truncated protein

13-19% 10-25% 20-30%

*3 636G→A Truncated protein

<1% 0-2% 5-13%

*17 -806C→T-3402C→T

Increased translation

18% 18% 4%

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

Comparison of pro-drugs and Comparison of pro-drugs and active drugs and clinical active drugs and clinical

consequencesconsequencesDrug type

Metabolizer Phenotype

Effect on drug

metabolismPotential consequence

Prodrug

Needs metabolism to work (clopidogrel)

Poor to intermediate

Slow Poor 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.

Ultrarapid Fast Good drug efficacy, rapid effect. Possible accumulation of active drug → potential of adverse effects.

Active drug

Metabolized to inactive drug (omeprazole)

Poor to intermediate

Slow Accumulation of active drug, patient is at increased risk of drug-induced side effects. Patient requires lower dosage .

Ultrarapid Fast Poor drug efficacy, patient is at risk of therapeutic failure. Patient likely will require higher dosage.

• 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.

ClopidogrelClopidogrel

P2X1

P2Y12

ATPATP

Shape change

Angiolillo DJ et al JACC 2007

P2Y1

Gq

Initiation of Platelet AggregationInitiation of Platelet Aggregation

IP3

PKC

GP IIb/IIIa receptor activation

G12

DAG+

Shape change

Granule secretion

Stabilization of Platelet AggregationStabilization of Platelet Aggregation

βγ

GP IIb/IIIa receptor activation

Rap1bPKB/Akt

αi

AC

cAMP

VASPVASP VASP-PVASP-P

cAMP

Gi

PI3K

ClopidogrelClopidogrel

15% active metabolite

HOOC

* HS

N

O

Cl

OCH3

N

S

O

Cl

O CH3

C

85% inactive metabolites (Esterases in blood)

Gastro-intestinal absorption

ADPADP

Ca2+ flux

Ca2+

mobilization

PLCβ

MLCK-P

“Rho”

Hepatic CYP Biotransformation

AC

Gs

GP IIb/IIIa receptor activation

PGE1PGE1

PIP2

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.

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--

Genetics of CYP2C9*3 and ABCB1 have been shown to be important

Clopidogrel Response VariabilityClopidogrel Response Variability20% do not have adequate 20% do not have adequate responseresponse

GP IIb/IIIa receptor expression

Hepatic MetabolismCytochrome P450 pathway

Poor complianceInadequate administration

Variable absorption

Genetic polymorphisms CYP2C19PMs, CYP2C9*3, ABCB1 Drug-drug interactions

Genetic polymorphisms P2Y12 receptorAlternate pathways of platelet activation

Genetic polymorphisms

O’Donoghue M, Wiviott SD. Circulation. 2006;114:e600-e606Simon T et al.NEJM. 2009;363-75Feher G et al. Clin Genetics. 2009; 75:1-18.

Intestinal Absorption

P2Y12 Receptor(irreversible inhibition)

Active Metabolite

Inhibition of Platelet Aggregation (Wide Response Variability)1

Mechanisms of Clopidogrel Mechanisms of Clopidogrel Response VariabilityResponse Variability

ClopidogrelBisulfate

Intestinal Absorption

Inactive Carboxylic Acid Metabolite

CYP3A4

CYP3A5

CYP2C19

CYP2C9

Active Thiol Metabolite

P2Y12 Receptor

Limited absorption capacity with ceiling effect at 600mg loading dose7

Hepatic P450Cytochromes

CYP3A4 inducers: rifampinCYP3A4 inhibitors: erythromycin

2C19 Genetic polymorphisms 2C19 inhibitors

Multistep Conversion

15%

Esterases

85%

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.

P-glycoprotein(MDR1 3435T genotype)2

?

Smoking (induction)CYP1A2

CYP2B6, 2C19

2C9*3 Genetic polymorphisms

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

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

KKii ( (μμM) values of PPI’s for M) values of PPI’s for

CYP2C19 enzymeCYP2C19 enzyme

Brand

Generic

Ki (μM) Model Inhibitor

HLMa rCYP2C19b

TiclopidineHLM 0.31±0.05

rCYP2C19 0.68±0.04

Prilosec omeprazole 6.2±0.8 2.4±0.05 Aciphex rabeprazole 21.3±2.8

(2.4±0.1)c 18.8±1.3(2.8± 0.1)d

Nexium esomeprazole 8.6±1.0 7.9±0.5 Prevacid lansoprazole 0.45±0.07 0.74±0.09 Protonix pantoprazole 69.4±9.2 15.3±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. 2004 August 1;32(8):821-7.

Risk of All-Cause Mortality and Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Recurrent ACS in Patients Taking Clopidogrel and PPI Clopidogrel and PPI

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

0.70

0.60

0.50

0.40

0.30

0.20

0.10

00 90 180 270 360 450 540 630 720 810 900 990 1080

Days Since Discharge

Pro

port

ion

of

Death

s o

r R

ecu

rren

t A

CS

Neither clopidogrel nor PPIPPI without clopidogrelClopidogrel + PPIClopidogrel without PPI

Considerations for Healthcare Considerations for Healthcare ProvidersProviders 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 ConclusionIn 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.

ReferencesReferences1. 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, 2010 121:481-483

3. Plavix prescribing information. http://products.sanofi-aventis.us/plavix/plavix.html. Accessed February 20, 2010.

4. 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.

5. 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.

6. 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;112:2946-50

8. 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.