Personalized medicine involves the prescription of specific therapeutics best suited for an individual based on their genetic or proteomic profile. This talk discusses current approaches in drug discovery/development, the role of genetics in drug metabolism, and lawful/ethical issues surrounding the deployment of new health technology.

1. Towards Personalized Medicine Michel Dumontier, Ph.D. Assistant Professor of Bioinformatics Department of Biology, Institute of Biochemistry, School of Computer Science Carleton University Ottawa Institute for Systems Biology Ottawa-Carleton Institute for Biomedical Engineering

2. Drug Development Life Cycle Years 0 2 4 6 8 10 12 14 16 Discovery Preclinical Testing (Lab and Animal Testing) Phase I (20-30 Healthy Volunteers used to check for safety and dosage) Phase II (100-300 Patient Volunteers used to check for efficacy and side effects) Phase III (1000-5000 Patient Volunteers used to monitor reactions to long-term drug use) FDA Review & Approval Post-Marketing Testing

7. VIOXX: Unknown Side Effects Treatment for Acute Pain increased risk of heart attack and stroke (after 18 months)

8. FDA: Center for Drug Evaluation and Research 2003 - Report to the Nation

13. Most drugs approved are only slightly modified

14. Less innovative than you think

16. Profits as a Percentage of Assets, 2002 Top 7 of Fortune 500 Industries Source: Fortune Magazine, April 14, 2003

25. combinatorial synthesis of non-peptide drugs + 1) 2) RXN 1 RXN 2

28. Structural bioinformatics to design nonpeptidic hydroxylates oral bioavailabity binding anti-growth anti-metastasis repeat…

42. Drug-Metabolizing Enzymes Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics. Evans and Relling Science 1999 Most DME have clinically relevant polymorphisms Those with changes in drug effects are separated from pie. Phase I: modification of functional groups Phase II: conjugation with endogenous substitutents

44. Participation of the CYP Enzymes in Metabolism of Some Clinically Important Drugs S. Rendic Drug Metab Rev 34: 83-448, 2002 CYP Enzyme Examples of substrates 1A1 Caffeine , Testosterone , R-Warfarin 1A2 Acetaminophen , Caffeine , Phenacetin, R-Warfarin 2A6 17  -Estradiol, Testosterone 2B6 Cyclophosphamide, Erythromycin, Testosterone 2C-family Acetaminophen , Tolbutamide (2C9); Hexobarbital, S- Warfarin (2C9,19); Phenytoin, Testosterone , R- Warfarin , Zidovudine (2C8,9,19); 2E1 Acetaminophen , Caffeine , Chlorzoxazone, Halothane 2D6 Acetaminophen , Codeine, Debrisoquine 3A4 Acetaminophen , Caffeine , Carbamazepine, Codeine, Cortisol, Erythromycin, Cyclophosphamide, S- and R-Warfarin , Phenytoin, Testosterone , Halothane, Zidovudine

45. Factors Influencing Activity and Level of CYP Enzymes S. Rendic Drug Metab Rev 34: 83-448, 2002 Red indicates enzymes important in drug metabolism

51. Pharmacogenetics: number of genes affects drug potency Weinshilboum, R. N Engl J Med 2003;348:529-537 Nortryptyline: Anti-depressant

52. Weinshilboum, R. N Engl J Med 2003;348:529-537 Use of probe drugs to determine metabolic activity due to CYP2D6 variants Antihypertensive debrisoquin decreases blood pressure

54. Diagnostics AmpliChip CYP450: Range of drug metabolism phenotypes is observed for individuals based upon the cytochrome P-450 genes

61. 3D QSAR for CYP3A4

62. 3D QSAR for CYP3A4 with known substrates

63. Drug Metabolic Fate What are the potential by-products of a drug? Going beyond QSAR to de novo predictions Quantify differences in binding due to natural variation.

65. GTP binding site of S. cerevisiae Homolog 2. The ASP 137 ASN mutation has been shown to cause a decrease in the affinity for GDP (Jones, B et al . 2003). This mutation has been associated with Chylomicron retention disease.

66. Qualitative Functional Inference

67. Genomic Medicine: Predictive, personalized, and pre-emptive

72. Michel Dumontier [email_address] http://dumontierlab.com