Title: Clopidogrel (Plavix) By Oksana Ekkert
1Clopidogrel (Plavix) By Oksana Ekkert
2Objectives
- 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.
3The routes of elimination for the 200 drugs sold
by prescription in the United States according to
the RxList data listed in April 2008 1
4CYP2C19
- 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.
5Variant 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 lt1 0-2 5-13
17 -806C?T-3402C?T Increased translation 18 18 4
6Variant Alleles
- Extensive metabolism CYP2C191/1Â
- Intermediate metabolism
- CYP2C191/2 or 1/3
- Poor metabolism
- CYP2C192/2, 2/3 or 3/3 (also 4,5)Â
- Ultrarapid CYP2C1917 /17
7Comparison 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 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.
Prodrug Needs metabolism to work (clopidogrel) 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 .
Active drug Metabolized to inactive drug (omeprazole) Ultrarapid Fast Poor drug efficacy, patient is at risk of therapeutic failure. Patient likely will require higher dosage.
8Clopidogrel
- 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.
9Clopidogrel
ATP
ADP
P2X1
P2Y1
Gastro-intestinal absorption
Gq
G12
Rho
Ca2 flux
Shape change
PIP2
P2Y12
PLCß
Shape change
DAG
IP3
Hepatic CYP Biotransformation
PKC
ß?
ai
Ca2 mobilization
MLCK-P
AC
PI3K
85 inactive metabolites (Esterases in blood)
GP IIb/IIIa receptor activation
Granule secretion
Rap1b
PKB/Akt
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
10T.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.
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
12Not only CYP2C19 genetics, but--
- Genetics of CYP2C93 and ABCB1 have been shown to
be important
13Clopidogrel Response Variability20 do not have
adequate response
Intestinal Absorption
Poor compliance Inadequate administration Variabl
e absorption Genetic polymorphisms
CYP2C19PMs, CYP2C93, 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
ODonoghue M, Wiviott SD. Circulation.
2006114e600-e606 Simon T et al.NEJM.
2009363-75 Feher G et al. Clin Genetics. 2009
751-18.
14Mechanisms 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
2C93 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. 2007120311-21.
2. Taubert et al. Clin Pharmacol.
200680486-501. 3. von Beckerth et al. Eur Heart
J.2007281814-9.
15Why do we need PPIs with clopidogrel?
Deepak LB, et al. Circulation 2008 1181894-1909
16Ki (µM) values of PPIs for CYP2C19 enzyme
Brand Generic Ki (µM) Ki (µM) Model Inhibitor
Brand Generic HLMa rCYP2C19b Ticlopidine HLM 0.310.05 rCYP2C19 0.680.04
Prilosec omeprazole 6.20.8 2.40.05 Ticlopidine HLM 0.310.05 rCYP2C19 0.680.04
Aciphex rabeprazole 21.32.8 (2.40.1)c 18.81.3 (2.8 0.1)d Ticlopidine HLM 0.310.05 rCYP2C19 0.680.04
Nexium esomeprazole 8.61.0 7.90.5 Ticlopidine HLM 0.310.05 rCYP2C19 0.680.04
Prevacid lansoprazole 0.450.07 0.740.09 Ticlopidine HLM 0.310.05 rCYP2C19 0.680.04
Protonix pantoprazole 69.49.2 15.31.1 Ticlopidine HLM 0.310.05 rCYP2C19 0.680.04
a,b marker reaction used was S-Mephenytoin 4-Hydroxylation c,d rabeprazole thioether HLMhuman liver microsomes a,b marker reaction used was S-Mephenytoin 4-Hydroxylation c,d rabeprazole thioether HLMhuman liver microsomes a,b marker reaction used was S-Mephenytoin 4-Hydroxylation c,d rabeprazole thioether HLMhuman liver microsomes a,b marker reaction used was S-Mephenytoin 4-Hydroxylation c,d rabeprazole thioether HLMhuman liver microsomes a,b marker reaction used was S-Mephenytoin 4-Hydroxylation c,d rabeprazole thioether HLMhuman 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 132(8)821-7.
17Risk of All-Cause Mortality and Recurrent ACS in
Patients Taking Clopidogrel and 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.
2009301(9)937-944.
18Considerations 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
clopidogrels 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.
19In 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.
20References
- Wienkers LC, Heath TG (2005) Nat Rev Drug Discov
4825833 (top 200) - S. R. Steinhubl. Genotyping, Clopidogrel
Metabolism, and the Search for the Therapeutic
Window of Thienopyridines Circulation February 2,
2010 121481-483 - Plavix prescribing information.
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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
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Cytochrome 2C1917 allelic variant, platelet
aggregation, bleeding events, and stent
thrombosis in clopidogrel-treated patients with
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Absorption, metabolization, and antiplatelet
effects of 300-, 600-, and 900-mg loading doses
of clopidogrel results of the ISAR-CHOICE Trial.
Circulation 20051122946-50 - 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 132(8)821-7.