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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
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
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 Genetic variants in drug metabolismmetabolism
Thiopurine methyltransferase “null variants”– incidence of about 1 in 300– Pts. Cannot metabolize chemo
drugs used to treat leukemia(6-mercaptopurine, 6-thioguanine & 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 = coumadinWarfarin = 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.
WarfarinWarfarin
• 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: Trends in Warfarin Use: 1.5-fold Increase (45%)1.5-fold Increase (45%)
Prescriptions Dispensed in the U.S. for Warfarin Tablets and Vials
10
15
20
25
30
1998 1999 2000 2001 2002 2003 2004 YTD9/2005
Year
Dis
pe
ns
ed
Rx
(m
illio
ns
)
Source: IMS Health National Prescription Audit PlusTM Data Extracted 11/2005
Safety of Safety of WarfarinWarfarin
•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%
DosingDosing of Warfarin is of Warfarin is ComplexComplex
• 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 Warfarin MetabolismMetabolism
• 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 VariantsVKORC1 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 SensitivityWarfarin 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 Mechanistic Basis of Dosing ProblemDosing Problem
Large interindividual variability related to S-warfarin metabolism by CYP2C9 (genetics)– *1 (wild type), *2 and *3 (variant alleles)GenotypeGenotype
(N = 188)(N = 188)PrevalencPrevalenc
ee% Enzyme % Enzyme
ActivityActivity
S/R S/R WarfarinWarfarin(mg/L)(mg/L)
Weekly Weekly DosesDoses(mg)(mg)
ClearanceClearance/LBW/LBW
(ml/min/(ml/min/kgkg))
2C9 *1/*12C9 *1/*1 63%63% 100%100% 0.45 0.45 (0.11)(0.11)
34.134.1(19.5)(19.5)
0.065 0.065 (0.025)(0.025)
2C9 *1/*X2C9 *1/*X 31%31% 50-70%50-70% 0.690.69(0.28)(0.28)
19.019.0(10.8)(10.8)
0.041 0.041 (0.021)(0.021)
2C9 *X/*X 2C9 *X/*X 6%6% 10%10% 1.431.43(0.63)(0.63)
11.511.5(7.2)(7.2)
0.020 0.020 (0.011)(0.011)
Herman et al, The Pharmacogenomics J 4:1-10. 2005
Dosing Adjustments Based on Dosing Adjustments Based on Genotype-Specific S-Warfarin Genotype-Specific S-Warfarin
ClearanceClearance
0%
20%
40%
60%
80%
100%
PDR
Reco
mm
ende
d Do
se,
%Wild Type *1/*2 *1/*3 *2/*2 *3/*3
Equivalent Warfarin Doses in Common Genotypes
Stefanovic and Samardzija, Clin Chem & Lab Med, 42(1) 2004
PharmacogenPharmacogenomics and omics and
asthmaasthma• 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.
Inhaled Inhaled CorticosteroidsCorticosteroids
• Polymorphisms of TBX21• the gene coding for transcription
factor T-bet (T-box expressed in T cells),
• associated with significant improvement in methacholine responsiveness in children with asthma.
ACE inhibitorsACE 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 SNPs = Single Nucleotide PolymorphismsPolymorphisms
Occur throughout the genome
Occur about every 1,000 bases
May be “linked” to differences
in drug response
Under intense study bypharmaceutical 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
SNPsSNPs
Characterization of SNPs may help in identifying subsets of individuals at risk for specific diseases
SNPs may predict drug responses/adverse reactions