Clopidogrel (Plavix) By Oksana Ekkert

1
Clopidogrel (Plavix) By Oksana Ekkert
2
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.

3
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
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.
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
6
Variant Alleles

• Extensive metabolism CYP2C191/1 
• Intermediate metabolism
• CYP2C191/2 or 1/3
• Poor metabolism
• CYP2C192/2, 2/3 or 3/3 (also 4,5) 
• Ultrarapid CYP2C1917 /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 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.
8
Clopidogrel

• 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.

9
Clopidogrel
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
10
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.
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 CYP2C93 and ABCB1 have been shown to
  be important

13
Clopidogrel 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.
14
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
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.
15
Why do we need PPIs with clopidogrel?
Deepak LB, et al. Circulation 2008 1181894-1909
16
Ki (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.
17
Risk 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.
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 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.

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

• 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.
  http//products.sanofi-aventis.us/plavix/plavix.ht
  ml. 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. 2010389299.
• Sibbing D, Koch W, Gebhardt D, Schuster T, Braun
  S, Stegherr J, Morath T, Schomig A, Kastrati A.
  Cytochrome 2C1917 allelic variant, platelet
  aggregation, bleeding events, and stent
  thrombosis in clopidogrel-treated patients with
  coronary stent placement. Circulation.
  2010121512518.
• Klotz U, Schwab M, Treiber G. CYP2C19
  polymorphism and proton pump inhibitors. Basic
  Clin Pharmacol Toxicol 2004 95 28.
• 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 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.