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©2012 Mayo Foundation for Medical Education and Research. All rights reserved.
CYP2C19 and Response to Clopidogrel
CYP2C19 metabolizes clopidogrel to its active form Common CYP2C19 loss-of-function alleles
1
PGx Biomarkers in Drug Labels
Drug exposure and clinical response variability Risk for adverse events Genotype-specific dosing Mechanisms of drug action Polymorphic drug target and disposition genes
*2: Caucasians 15%; Blacks 15%; Asian 29%-35%; Mexican Americans 19% *3: Asian 1%-9%
Associated with lower levels of active metabolite of clopidogrel Associated with marked decrease in platelet responsiveness to clopidogrel (higher on-treatment platelet aggregation)
Due to many variables
Underdosing Interactions with CYP inhibitors and substrates
eg, lipophilic statins, calcium antagonists, PPIs
Genetics
Pharmacogenetics
Disclosures
None
Pharmacogenetics
©2012 Mayo Foundation for Medical Education and Research. All rights reserved.
Pharmacogenomics
A component of individualized medicine Focuses on how genetic factors influence individual responses to different medications
CYP2C19
CYP2D6
Psychiatry Cardiovascular Derm and Dental Analgesics
Citalopram, Fluoxetine, Paroxetine, Venlafaxine, (numerous) Carvedilol, Metoprolol, Propranolol, (others) Cevimeline Codeine
Pharmacogenetics
©2012 Mayo Foundation for Medical Education and Research. All rights reserved.
Mayo CYP2C19 Test
2C19S/60439 Cytochrome P450 2C19 Genotype by Sequence Analysis Sequencing of select CYP2C19 exons to determine presence of:
Clopidogrel (Plavix)
Commonly used antiplatelet agent given as a prodrug
Activated by CYP enzymes
Used to reduce atherosclerotic events (MI, stroke, vascular death) in patients with ACS and/or following PCI Often given as alternative to aspirin or in combination with aspirin (dual antiplatelet therapy) Highly variable response to clopidogrel
2
The FDA and PGx-related Drug Label Updates
March 2010 Clopidogrel response by CYP2C19 poor metabolizers
Pharmacogenetics
©2012 Mayo Foundation for Medical Education and Research. All rights reserved.
Efficacy, side-effects, adverse events
Clinical goals
Minimize adverse drug events (ADE) Maximize drug efficacy
Pharmacogenetics
©2012 Mayo Foundation for Medical Education and Research. All rights reserved.
HLA-B *1502 HLA-B *5701 UGT1A1
Neurology Antiretrovirals Oncology Pulmonary Hematology
Carbamazepine, Phenytoin Abacavir Irinotecan, Nilotinib Indacterol
Pharmacogenetics
©2012 Mayo Foundation for Medical Education and Research. All rights reserved.
3
CYP2C19 and Response to Clopidogrel (cont.) Associated with increased rate of subsequent cardiovascular events and death
FDA-approved Drugs with PGx-related Label Information
Biomarker CYP2C9 Therapeutic Area Analgesics Psychiatry Hematology Musculoskeletal Psychiatry Neurology Cardiovascular Gastroenterology Psychiatry Cardiovascular Derm and Dental Analgesics Neurology Antiretrovirals Oncology Pulmonary Hematology Drugs Celecoxib Fluvoxamine Warfarin Carisoprodol Citalopram, Diazepam, Fluvoxamine Clobazam Clopidogrel, Prasugrel Esomeprazole, Omeprazole, Pantoprazole Citalopram, Fluoxetine, Paroxetine, Venlafaxine, (numerous) Carvedilol, Metoprolol, Pranolol, (others) Cevimeline Codeine Carbamazepine, Phenytoin Abacavir Irinotecan, Nilotinib Indacterol
CYP2C19 PGx Testing for Clopidogrel
Clinically available Routine clinical use of CYP2C19 genotyping not recommended per 2011 guidelines by ACC/AHA/SCAI Test subgroups of patients, e.g. those undergoing coronary stenting Large, randomized, prospective trials are likely needed
VKORC1
ቤተ መጻሕፍቲ ባይዱ
Warfarin ©2012 Mayo Foundation for Medical Education and Research. All rights Source: www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm reserved.
CYP2C19
CYP2D6
HLA-B *1502 HLA-B *5701 UGT1A1
VKORC1
Warfarin ©2012 Mayo Foundation for Medical Education and Research. All rights Source: www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm reserved.
Pharmacogenetics
©2012 Mayo Foundation for Medical Education and Research. All rights reserved.
FDA-approved drugs with PGx-related label information
Biomarker CYP2C9 Therapeutic Area Analgesics Psychiatry Hematology Musculoskeletal Psychiatry Neurology Cardiovascular Gastroenterology Drugs Celecoxib Fluvoxamine Warfarin Carisoprodol Citalopram, Diazepam, Fluvoxamine Clobazam Clopidogrel, Prasugrel Esomeprazole, Omeprazole, Pantoprazole
The Use of Genetics in Guiding Therapy
Linnea M. Baudhuin, PhD Division of Clinical Biochemistry Mayo Clinic Rochester, Minnesota
©2012 Mayo Foundation for Medical Education and Research. All rights reserved.
Higher risks for heterozygote and homozygote *2 carriers
Pharmacogenetics
©2012 Mayo Foundation for Medical Education and Research. All rights reserved.
Mega et al, NEJM 2009;360:354-362 (TRITON-TIMI 38)
Relative 53% increased risk of death from CV causes, MI, or stroke 3-fold increased risk of stent thrombosis
*2, *3, *4, *6, *7, *8, *17, and any other rare variants that may occur in the regions sequenced
