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Pharmacogenetics
and
New Drug Discovery
Outlines
 Pharmacogenetics
 Pharmacogenomics
 Impact of genomic and genetic
medicine
 Drug development
Pharmacogenetics
 Application of genetic information on
pharmacological therapy
Pharmacogenomics
 Application of genomic information on
pharmacological therapy
Human Genome Project
 Human genome draft
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http://www.ensembl.org/Homo_sapiens/
 Functional genomics
 Human variations
DNA polymorphism
 Variations in genetic substances
 Markers
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Genetic studies
Forensic medicine
Evolutions studies
Genome map
Others
Types of polymorphism
 Blood group
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~20, 1910-1960
 Electrophoretic mbility variants
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~30, 1960-1975
 HLA typing
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Chms 6, 1970-
 RFLP
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>100,000, 1975
 Tandem repeats
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>100,000, 1985
 SNP: 1998
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>1,000,000, 1998
STRP
 Short tandem repeat polymorphism
 Di- or tri- nucleotide repeat (up to 6)
 Approximately 100,000 in human
genome
 Highly informative
Example
SNP
 Single nucleotide polymorphism
 One in 1000 bp
 PCR based detection
Impact on Drug Therapy
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Differences in drug response
Differences in adverse effects
Differences in dosing
New target for therapy
CML and Philadelphia chromosome
 Fusion protein of BCR and ABL
 Imatinib: targeting the ABL tyrosine kinase
Imatinib blocks the ATP binding site
Predicting efficacy of gefitinib:
epidermal growth factor receptor blocker
Gefitinib is an EGFR blocker
Gefitinib:EGFR blocker
Ezetimibe:
Drug for CHO
Bind to
NPC1L1
NPC1L1
genotypes
Predicting dosing of warfarin
Warfarin dose vs VKORC1
genotypes
Predictive toxicology:
Stevens-Johnson’s syndrome
due to allopurinol
Genome-wide SNP screening
Impact on drug development
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New target of drug action
Large scale screening of compounds
Productivity
Post-marketing survey
New Drug Discovery
New targets for drug action
 Focus on 500 targets
 New targets: 3000 to 10000
Clinical Trial:
productivity
Post-marketing withdrawal
 Cerivastatin
 Troglitazone
 Roficoxib
 Could these be saved or prevented?
New Drug Application
 Testing of drug response before
marketing
 FDA requirement for drug approval
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Optional
mandatory
 Drug cost
Obstacles and problems
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Technical problems
Financial problems
Current structure
Scientific uncertainty
Commercialized kit
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Roche: cytochrome p450 kit
Costly?
Accuracy?
Real benefit?
Conclusions and take home message
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Definition of pharmacogenetics
Examples of application
Impact on current drug development
Future directions
Thank you for your attention!