Pharmacogenetics of Cardiovascular
Antithrombotic Therapy
O
C
CH3
O
Clopidogrel
N
S
(oral ingestion of pro-drug)
Cl
Intestinal absorption
Genetic targets
MDR-1
CYP Enzyme System
Two sequential steps:
One step: CYP3A4, CYP3A5, CYP2C9, CYP1A2
Both steps: CYP2B6, CYP2C19
Platelet Membrane Receptors
P2Y12, GPIIb/IIIa, GPIa
CYP = cytochrome P450. GP = glycoprotein. MDR = multidrug resistance protein.
Marín F, et al. J Am Coll Cardiol. 2009;54:1041-1057.
HOOC
HS
Hepatic generation
of active metabolite
O
C
O
CH3
N
Cl
Platelet inhibition
Clopidogrel ─ Pharmacogenetic Information
WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS
The effectiveness of clopidogrel is dependent on its activation to an active
metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
Clopidogrel at recommended doses forms less of that metabolite and has a
smaller effect on platelet function in patients who are CYP2C19 poor
metabolizers. Poor metabolizers with ACS or who are undergoing PCI treated
with clopidogrel at recommended doses exhibit higher cardiovascular event
rates than patients with normal CYP2C19 function. Tests are available to
identify a patient's CYP2C19 genotype; these tests can be used as an aid in
determining therapeutic strategy. Consider alternative treatment or treatment
strategies in patients identified as CYP2C19 poor metabolizers.
ACS = acute coronary syndrome. PCI = percutaneous coronary intervention.
Plavix® (clopidogrel bisulfate) tablets [package insert]. Bridgewater, NJ: Bristol-Myers Squibb Company/sanofi-aventis Partnership; 2009.
2009 Updated Labeling for Clopidogrel – PPI
Interaction
FDA-required label changes1,2:
• Warning: Co-administration of clopidogrel with omeprazole, a PPI that is an inhibitor of
CYP2C19, reduces the pharmacological activity of clopidogrel if given concomitantly or
if given 12 hours apart.
• Drug-drug interactions: Avoid concomitant use of drugs that inhibit CYP2C19, including
omeprazole, esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole,
etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine.
• Based on PK/PD studies showing that concomitant omeprazole reduced clopidogrel
active metabolite and effect on platelets.1
– Did not include COGENT study data2
• EMEA warning extends to discourage concomitant use of all PPIs.3
– Concomitant use of drugs that inhibit CYP2C19 discouraged; concomitant use of any PPI
should be avoided unless absolutely necessary.4
EMEA = European Medicines Agency. PD = pharmacodynamic. PK = pharmacokinetic. PPI = proton pump inhibitor.
1. FDA. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafety InformationforHeathcareProfessionals/ucm190787.htm.
Accessed September 22, 2012. 2. Plavix® (clopidogrel bisulfate) tablets [package insert]. Bridgewater, NJ: Bristol-Myers Squibb Company/sanofi-aventis Partnership; 2009. 3. Wathion N.
Available at: http://www.emea.europa.eu/humandocs/PDFs/EPAR/Plavix/32895609en.pdf. Accessed September 22, 2012. 4. Plavix® (clopidogrel bisulfate) tablets [summary of product
5
characteristics]. Paris, France: Bristol-Myers Squibb Company/sanofi-aventis Partnership; 2009.
ACC/AHA/SCAI Guideline Recommendations Regarding Genetic
Testing and Concurrent Use of PPI and Antiplatelet Therapy
Genetic Testing:
• Genetic testing might be considered to identify whether a patient at high risk for poor clinical
outcomes is predisposed to inadequate platelet inhibition with clopidogrel – Class IIb - Level C
evidence
• When a patient predisposed to inadequate platelet inhibition with clopidogrel is identified by genetic
testing, treatment with an alternate P2Y12 inhibitor (eg, prasugrel or ticagrelor) might be considered
– Class IIb - Level C evidence
• Routine clinical use of genetic testing to screen patients treated with clopidogrel who are
undergoing PCI is not recommended – Class III (no benefit) - Level C evidence
PPI Use:
• PPIs should be used in patients with a history of prior GI bleeding who require dual antiplatelet
therapy – Class I - Level C evidence
• PPI use is reasonable in patients with increased risk of gastrointestinal bleeding (advanced age,
concomitant use of warfarin, steroids, NSAIDs, H. pylori infection, etc.) who require dual antiplatelet
therapy – Class IIa - Level C evidence
• Routine use of a PPI is not recommended for patients at low risk of GI bleeding who have much
less potential to benefit from prophylactic therapy – Class III (no benefit) - Level C evidence
GI = gastrointestinal. NSAIDs = nonsteroidal anti-inflammatory drugs.
Levine GN, et al. J Am Coll Cardiol. 2011;58:e44-e122.