1. Pharmacogenetics and New Drug Discovery

2. Outlines Pharmacogenetics Pharmacogenomics
Impact of genomic and genetic medicine
Drug development

3. Pharmacogenetics Pharmacogenomics
Application of genetic information on pharmacological therapy
Pharmacogenomics
Application of genomic information on pharmacological therapy

5. Human Genome Project Human genome draft Functional genomics
Functional genomics
Human variations

6. DNA polymorphism Variations in genetic substances Markers
Genetic studies
Forensic medicine
Evolutions studies
Genome map
Others

7. Types of polymorphism Blood group Electrophoretic mbility variants
~20,
Electrophoretic mbility variants
~30,
HLA typing
Chms 6, 1970-
RFLP
>100,000, 1975
Tandem repeats
>100,000, 1985
SNP: 1998
>1,000,000, 1998

8. STRP Short tandem repeat polymorphism
Di- or tri- nucleotide repeat (up to 6)
Approximately 100,000 in human genome
Highly informative

9. Example

13. SNP
Single nucleotide polymorphism
One in 1000 bp
PCR based detection

15. Impact on Drug Therapy Differences in drug response
Differences in adverse effects
Differences in dosing
New target for therapy

16. CML and Philadelphia chromosome
Fusion protein of BCR and ABL
Imatinib: targeting the ABL tyrosine kinase

18. Imatinib blocks the ATP binding site

19. Predicting efficacy of gefitinib: epidermal growth factor receptor blocker

20. Gefitinib is an EGFR blocker

21. Gefitinib:EGFR blocker

22. Ezetimibe:
Drug for CHO
Bind to NPC1L1

23. NPC1L1 genotypes

24. Predicting dosing of warfarin

25. Warfarin dose vs VKORC1 genotypes

27. Predictive toxicology: Stevens-Johnson’s syndrome due to allopurinol

28. Genome-wide SNP screening

29. Impact on drug development
New target of drug action
Large scale screening of compounds
Productivity
Post-marketing survey

32. New Drug Discovery

33. New targets for drug action
Focus on 500 targets
New targets: 3000 to 10000

34. Clinical Trial: productivity

35. Post-marketing withdrawal
Cerivastatin
Troglitazone
Roficoxib
Could these be saved or prevented?

36. New Drug Application Testing of drug response before marketing
FDA requirement for drug approval
Optional
mandatory
Drug cost

37. Obstacles and problems
Technical problems
Financial problems
Current structure
Scientific uncertainty

38. Commercialized kit Roche: cytochrome p450 kit Costly? Accuracy?
Real benefit?

39. Conclusions and take home message
Definition of pharmacogenetics
Examples of application
Impact on current drug development
Future directions

40. Thank you for your attention!