Pharmacogenomics: Pharmacogenomics: advancing personalized advancing personalized

medicinemedicine

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 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.

Beta AgonistsBeta Agonists

Beta 2-adrenergic receptor (2-AR) gene

Leukotriene ModifiersLeukotriene Modifiers

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.

StatinsStatins

Subjects with the apoE*2 allele had greater

lipid reductions with statin treatment

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

“therapy with the right drug at the right dose in the right

patient”