Pharmacogenetics and New Drug Discovery

Outlines Pharmacogenetics Pharmacogenomics Impact of genomic and genetic medicine Drug development

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

Human Genome Project Human genome draft Functional genomics http://www.ensembl.org/Homo_sapiens/ Functional genomics Human variations

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

Types of polymorphism Blood group Electrophoretic mbility variants ~20, 1910-1960 Electrophoretic mbility variants ~30, 1960-1975 HLA typing Chms 6, 1970- RFLP >100,000, 1975 Tandem repeats >100,000, 1985 SNP: 1998 >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 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 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 Optional mandatory Drug cost

Obstacles and problems Technical problems Financial problems Current structure Scientific uncertainty

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

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

Thank you for your attention!