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Pharmacogenetics & Pharmacogenomics Personalized Medicine

Pharmacogenetics & Pharmacogenomics Personalized Medicine. Drugs and Genes. Pharmacogenetics : Study of the genetic factors that influence an organism's reaction to a drug Pharmacogenomics: Development of drug therapies to compensate for genetic differences in patients. Review of Genes.

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Pharmacogenetics & Pharmacogenomics Personalized Medicine

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  1. Pharmacogenetics&PharmacogenomicsPersonalized Medicine

  2. Drugs and Genes • Pharmacogenetics: • Study of the genetic factors that influence an organism's reaction to a drug • Pharmacogenomics: • Development of drug therapies to compensate for genetic differences in patients

  3. Review of Genes • Genotype: • The genetic makeup of an organism • Phenotype: • An organisms’ observable traits

  4. Human Genome is Variable

  5. Human Genome is Variable • Contains 3x109 base pairs of DNA • 3 billion! • Between 2 people (except identical twins) the rate of genetic variation (individuality) is about 0.1% [0.1% of 3 billion = 3 million base pair differences]

  6. Single Nucleotide Polymorphism Polymorphism “Poly” Many “Morphe” Form • The most common cause of genetic variation • SNPs occur on average every 1000 bases • Understanding SNPs has shown promise for improving disease detection and treatments General Population 94% Single Nucleotide Polymorphism 6%

  7. Examples of SNPs and Disease SNPs in Beta-globin Sickle Cell Anemia SNPs in BRCA1 Predisposed for breast cancer

  8. Single Nucleotide Polymorphisms Regulatory Sequence Coding Region Linked SNPs Causative SNPs Outside gene Non-coding SNP: Coding SNP: changes amount of protein changes amino acid sequence (function) Protein

  9. Pharmacokinetic: changes in drug metabolism Pharmacodynamic: changes in drug targets enzymes, receptors, or transporters SNPs Can Change Drug Response Genetic Polymorphisms Pharmacokinetic Pharmacodynamic Absorption Distribution Metabolism Excretion Receptors Ion Channels Enzymes Immune System

  10. SNPs and CYPs • Cytochrome P450 enzymes are commonly found with SNPs

  11. Drug Metabolism PolymorphismSubstrate CYP2B6 doxorubicin, nicotine CYP2C9warfarin, doxorubicin CYP2C19 diazepam, proton pump inhibitors CYP2D6 beta-blockers, anti-depressants, codeine, tamoxifen CYP3A4 erythromycin, HIV protease inhibitors

  12. Effects of SNP in CYP2D6 Extensive Metabolizer 1: Normal enzyme activity Plasma Level of Drug Poor Metabolizer 2: Decreased enzyme activity Time

  13. Pharmacokinetics of Tamoxifen

  14. Mutations Impact Treatment Outcome No Polymorphisms on CYP2D6 Extensive n=115 Relapse-free Survival (%) Decreased n=65 Polymorphisms on CYP2D6 P=0.007 ClinPharmacolTher. 2008 January; 83(1): 160–166.

  15. Metabolism of Alcohol… 2 Steps

  16. Genetic Polymorphisms and Differences in Alcohol Metabolism

  17. Genetic Polymorphisms and Differences in Alcohol Metabolism

  18. 23andMe

  19. Better Drug Discovery with Pharmacogenetics & Pharmacogenomics • Increase drug efficacy • Eliminate adverse drug reactions • Ensure success for drug approval in clinical trials • Increase efficiency of clinical trials

  20. Drug Treatment No response Drug 1 Drug 2 Adverse side effect Available Drugs Drug 3 Weak response Drug 4 Strong response Currently best treatment determined by trial and error. Future genomics may enable us to pick the right drug the first time.

  21. Yesterday’s Medicine

  22. Tomorrow’s Medicine

  23. Personalized Medicine The right dose of the right drug for the right indication for the right patient at the right time.

  24. Personalized Medicine: Cancer Many factors contribute to tumor formation.

  25. Breast Cancer is a Perfect Model

  26. Pharmacogenomics: Gene Candidate to Drug Treatment Human epidermal growth factor receptor-2 (HER2) in breast cancer cells

  27. Herceptin in Clinical Trials

  28. Cancer Results from a Combination of Genomic Changes

  29. Drug Discovery

  30. The Clinical Trial Process Safe in humans? Does the treatment work? Better than current treatment? More info on the approved treatment File IND File NDA

  31. In a study of 14 clinical trials, 20-75% of subjects got no benefit Less than 1 in 10 Drugs in Clinical Trials Obtain a NDA

  32. Streamlining of Clinical Trials is the Future

  33. Pharmacogenetics and Pharmacogenomics Summary • SNPs in coding and non-coding regions can alter the function or expression of an enzyme that metabolizes drugs • Pharmacogenetics impacts the kinetics and dynamics of drugs. • Personalized medicine will help treat patients according to their genetic profile, increase drug efficacy, and reduce side effects • Designing clinical trials based on SNP profiles can reduce FDA approval time for drugs

  34. Concept Map Pharmacogenomics Pharmacodynamics Pharmacokinetics Gene SNPs Haplotype Phenotype Genotype CYPs Drug

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