1. Pharmacogenomics: The Promise of Personalized Medicine Christina Aquilante, Pharm.D. Assistant Professor Department of Pharmaceutical Sciences School of Pharmacy University of Colorado at Denver and Health Sciences Center

5. “ We wish to suggest a structure for the salt of [DNA]. This structure has novel features which are of considerable biological interest.”

7. Newsweek June 25, 2001 “… pharmacogenetics promises to target treatment to a patient’s genetic profile…”

9. Current Concept of Pharmacogenomics Roden DM et al. Ann Intern Med 2006; 145:749-57

10. Potential of Pharmacogenomics All patients with same diagnosis 1 2 Responders and patients not predisposed to toxicity Non-responders and toxic responders Treat with alternative drug or dose Treat with conventional drug or dose

21. Pharmacogenomics DRUG TARGETS DRUG METABOLIZING ENZYMES DRUG TRANSPORTERS PHARMACOKINETICS PHARMACODYNAMICS Variability in Efficacy/Toxicity Johnson JA. Trends in Genetics 2003: 660-666

23. Drug Metabolizing Enzymes

24. Examples of Drug Metabolism Pharmacogenomics NEJM 2003; 348: 529-537

25. Examples of Drug Metabolism Pharmacogenomics NEJM 2003; 348: 529-537

31. CYP2D6 Phenotypes NEJM 2003; 348:529 Roden DM et al. Ann Intern Med 2006; 145:749-57

36. Roche AmpliChip: FDA-Approved

39. Variability in TPMT Activity

40. Genotype-Guided 6-MP Dosing Pharmacogenomics 2002;3(1):89-98.

44. Drug Target Pharmacogenomics

46. Complexity of Drug Effect

49. Examples of Drug Target Pharmacogenomics Evans WE. NEJM 2003; 348:538-48

50. Examples of Disease or Treatment Modifying Pharmacogenomics Evans WE. NEJM 2003; 348:538-48

52. Beta-1 Adrenergic Receptor Podlowski, et al. J Mol Med 2000;78:90. Codon 49 Ser  Gly Codon 389 Arg  Gly

53. Beta-1 Receptor Polymorphisms and Response to Metoprolol Johnson JA et al. Clin Pharmacol Ther 2003; 74:44-52

57. VKORC1 Genotype and Warfarin Dose Requirements 33 mg/wk 46 mg/wk 21 mg/wk G/G G/A A/A

63. Disease Risk Polymorphisms Polymorphisms can predispose individuals to a disease or increase the risk for disease If a drug with a known adverse effect is given to a person with a genetic susceptibility to that adverse effect, there is an increased likelihood for that adverse effect

65. Oral Contraceptive Pills and Blood Clots Martinelli I. Pharmacogenetics 2003; 13:589-594 Patients on OCP who are homozygous for Factor V Leiden have 50 to100-fold increased risk of VTE Heterozygotes

77. Pharmacogenomic Paradigm in the Drug Development Process Current Options Options with Pharmacogenomics Proportion of patients showing poor or no response Low High Continue clinical trials to market Abandon drug before market Optimize clinical trials, making them smaller and shorter Continue trials safely by excluding at-risk pts

79. Pharmacogenomic Paradigm in the Pharmaceutical Industry Rare side effect prediction Efficacy prediction Market expansion Common side effect prediction

81. Pharmacogenomics Information in the Published Literature Zineh I et al. Ann Pharmacother. 2006; 40: 639-44

82. Pharmacogenomics Information in FDA-Approved Prescribing Information Zineh I et al. Pharmacogenomics J; 2004: 1-5

83. Moving Pharmacogenomics to Clinical Practice Identify sequence variability in candidate genes In vitro functional studies Proof-of-concept clinical studies Studies that mimic clinical practice Documenting sufficient variability to predict clinical utility Document Pgx superiority: Pgx-guided versus usual care Johnson JA. Trends in Genetics 2003; 19: 660-66

85. "Here's my sequence..." The New Yorker

86. “ Personalized medicine: elusive dream or imminent reality ? In summary: it is both.” Larry Lesko, Director of the FDA Office of Clinical Pharmacology and Biopharmaceutics Clin Pharmacol Ther; 2007: 807-816