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Pharmacogenomics:
advancing personalized medicine
Pharmacogenomics
Will allow:
• individualized medication use
based on genetically determined
variation in effects and side
effects
• use of medications otherwise
rejected because of side effects
• More accurate methods of
determining appropriate dosage
Pharmacogenomics
Challenges to drug design
Drug responses are genetic!
• Drug metabolism/response can be
monogenic
– alteration of the key metabolizing enzyme can
alter drug’s effect
• Drug responses are polymorphic
– Drugs trigger downstream events that can vary
among patients
Drug response curve
Variation in drug response is hereditary
• Variations in absorption rates
• Variations in drug metabolism
• Variations in drug
inactivation/elimination
• Variation in target receptors
Genetic variants in drug metabolism
Thiopurine methyltransferase “null variants”
– incidence of about 1 in 300
– Pts. Cannot metabolize chemo drugs used to
treat leukemia(6-mercaptopurine, 6thioguanine & azathioprine) into their inactive
methylated forms
– Pts. Can be treated with 10-15 times less
chemo than commonly prescribed
– Genotyping or functional enzyme assay is now
the STANDARD PRACTICE in cancer centers
Warfarin = coumadin
Warfarin inhibits vitamin K
reductase, which is the
enzyme responsible for
recycling oxidated vitamin
K back into the system. For
this reason, drugs in this
class are also referred to as
vitamin K antagonists.
Warfarin
• Discovered 60 years ago and one
of the most widely prescribed drugs in the world
• Intended to prevent and treat thromboembolisms
– Afib, recurrent stroke, DVT, pulmonary embolism, heart
valve prosthesis
•
Multi-source anticoagulant
– 1, 2, 2.5, 3, 4, 5, 6, 7.5 and 10 mg tablet strengths
• Significant increase in Rx’s over past 10 years especially
in the elderly
Trends in Warfarin Use:
1.5-fold Increase (45%)
Prescriptions Dispensed in the U.S. for
Warfarin Tablets and Vials
Dispensed Rx
(millions)
30
25
20
15
10
1998
1999
2000
2001
2002
Year
2003
2004
YTD
9/2005
Source: IMS Health National Prescription Audit Plus TM Data Extracted 11/2005
Safety of Warfarin
•Major risk is bleeding: frequent and
severe
•1.2 – 7 major bleeding episodes per
100 patients
•Responsible for 1 in 10 hospital
admissions
•Relative risk of fatal extracranial
bleeds 0 - 4.8%
Dosing of Warfarin is Complex
• Narrow therapeutic index
– Small separation between dose-response
curves for preventing emboli and excess
coagulation
• Nonlinear dose-response (INR)
– Small changes in dose may cause large
changes in INR with a time lag
• Wide range (50x) of doses (2-112 mg/week)
to achieve target INR of 2-3
– Patient intrinsic and extrinsic factors
DNA testing for
Warfarin sensitivity
The FDA Clinical Pharmacology Subcommittee
of the Advisory Committee for Pharmaceutical
Sciences has recommended testing for variations
in the CYP2C9 and VKORC1 in patients
requiring warfarin therapy. The drug label will
reflect this recommendation soon.
Warfarin Metabolism
• Two polymorphic genes, CYP2C9 and VKORC1, affect
warfarin metabolism and response.
• Allelic frequencies of these two genes are usually
associated with ethnicity.
• Here are the concerns with prescribing warfarin to
patients with CYP2C9 or VKORC1 polymorphisms:
• Overdose can result in bleeding which can be fatal.
• Under dose can result in thrombosis which can be fatal
VKORC1 Variants
VKORC1 polymorphisms
may explain up to 25% of
patient variability in
response to warfarin.
Patients with VKORC1
polymorphisms are at risk
for exaggerated
anticoagulant response.
CYP2C9 variants take more time to achieve
stable dosing, and are associated with increased
risk of bleeding events. Low CYP2C9 activity
results in higher plasma levels of warfarin so the
patient is at risk for bleeding
Warfarin Sensitivity
The Warfarin Sensitivity DNA Test determines
the presence of specific variations in the
CYP2C9 and VKORC1 genes that confer
sensitivity to warfarin and thus significantly
reduce the required maintenance dose.
CYP2C9 is involved in warfarin metabolism
and VKORC1 influences warfarin's
anticoagulation effect through vitamin K.
Mechanistic Basis of Dosing
Problem
Large interindividual variability related to S-warfarin
metabolism by CYP2C9 (genetics)
– *1 (wild type), *2 and *3 (variant alleles)
Genotype
(N = 188)
Prevalence
% Enzyme
Activity
S/R Warfarin
(mg/L)
Weekly
Doses
(mg)
Clearance/LB
W
(ml/min/kg)
2C9 *1/*1
63%
100%
0.45
(0.11)
34.1
(19.5)
0.065 (0.025)
2C9 *1/*X
31%
50-70%
0.69
(0.28)
19.0
(10.8)
0.041 (0.021)
2C9 *X/*X
6%
10%
1.43
(0.63)
11.5
(7.2)
0.020 (0.011)
Herman et al, The Pharmacogenomics J 4:1-10. 2005
Dosing Adjustments Based on
Genotype-Specific S-Warfarin Clearance
PDR Recommended Dose,
%
Equivalent Warfarin Doses in Common Genotypes
100%
80%
60%
40%
20%
0%
Wild Type
*1/*2
Stefanovic and Samardzija, Clin Chem & Lab Med, 42(1) 2004
*1/*3
*2/*2
*3/*3
Pharmacogenomics
and asthma
• As many as two-thirds of patients with asthma
may not attain full control of their asthma.
• Up to one-third of patients treated with inhaled
corticosteroids (ICSs) may not achieve objective
improvements in airway function
• However, not simple because host factors such
as age, disease severity, concomitant drugs, and
disease etiology, can affect responses.
Beta Agonists
Beta 2-adrenergic receptor (2-AR) gene
Leukotriene Modifiers
Inhaled Corticosteroids
• Polymorphisms of TBX21
• the gene coding for transcription factor Tbet (T-box expressed in T cells),
• associated with significant improvement in
methacholine responsiveness in children with
asthma.
Statins
Subjects with the apoE*2 allele had greater
lipid reductions with statin treatment
ACE inhibitors
• widely used drugs for treatment of hypertension,
heart failure, and prevention of diabetic
nephropathy
• A polymorphism occurs in the ACE gene in which
the two alleles differ by the presence (insertion) or
absence (deletion) of a 287 basepair insertion.
• The insertion/deletion (I/D)polymorphism has
been noted to account for 47% of the variability in
serum ACE levels
• DD homozygotes have the highest serum ACE
levels.
SNPs = Single Nucleotide Polymorphisms
Occur throughout the genome
Occur about every 1,000 bases
May be “linked” to differences
in drug response
Under intense study by
pharmaceutical companies.
Pharmacogenomics will most likely use
“panels” of polymorphisms to calculate the
relative risk–benefit ratio of a particular
therapeutic course for an individual patient
SNPs
Characterization of SNPs
may help in identifying
subsets of individuals
at risk for specific
diseases
SNPs may predict drug
responses/adverse
reactions
“therapy with the right drug at
the right dose in the right
patient”