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Dumontier::BIOL4301:Personalized Medicine
Personalized
Medicine
Michel Dumontier, Ph.D.
Associate Professor of Bioinformat...
Dumontier::BIOL4301:Personalized Medicine
“If it were not for the great
variability among individuals,
medicine might as w...
Dumontier::BIOL4301:Personalized Medicine
SNPs – a major source of variation
• Single Nucleotide Polymorphisms
(SNPs)
– Si...
Dumontier::BIOL4301:Personalized Medicine
Human Variation
• In human beings, 99.9 percent bases are same.
• Remaining 0.1 ...
Dumontier::BIOL4301:Personalized Medicine
Dumontier::BIOL4301:Personalized Medicine
Dumontier::BIOL4301:Personalized Medicine
Dumontier::BIOL4301:Personalized Medicine
Personalized Medicine
The ability to offer
• The Right Drug
• To The Right Patie...
Dumontier::BIOL4301:Personalized Medicine
Benefits of Personalized Medicine
• Better matching patients to drugs instead of...
Dumontier::BIOL4301:Personalized Medicine
Personalized Medicine : BiDil
• Combination pill containing two medications for
...
Dumontier::BIOL4301:Personalized Medicine
PGx
• Pharmacokinetics
– What the body does to the drug
– dose, dosage regimen, ...
Dumontier::BIOL4301:Personalized Medicine
Dumontier::BIOL4301:Personalized Medicine
PGx + genetics/genomics
• Pharmacogenetics
– The effect of genetic variation on ...
Dumontier::BIOL4301:Personalized Medicine
Cytochrome P450 Enzymes
In bacteria, fungi, insects, plants, fish, mammals
Catal...
Dumontier::BIOL4301:Personalized Medicine
Drug-Metabolizing Enzymes
Pharmacogenomics: Translating Functional Genomics into...
Dumontier::BIOL4301:Personalized Medicine
CYP enzymes are involved in the metabolism of
clinically important drugs
CYP Enz...
Dumontier::BIOL4301:Personalized Medicine
S. Rendic Drug Metab Rev 34: 83-448, 2002
Red indicates enzymes important in dru...
Dumontier::BIOL4301:Personalized MedicineWeinshilboum, R. N Engl J Med 2003;348:529-537
Nortriptyline (anti-depressant)
Ph...
Dumontier::BIOL4301:Personalized MedicineWeinshilboum, R. N Engl J Med 2003;348:529-537
Use of probe drugs to determine me...
Dumontier::BIOL4301:Personalized Medicine
CYP3A4
• Abundant in liver and intestines
and accounts for nearly 50% of
CYP450 ...
Dumontier::BIOL4301:Personalized Medicine
Dumontier::BIOL4301:Personalized Medicine
Quantitative Structure-Activity
Relationship (QSAR)
• find consistent relationsh...
Dumontier::BIOL4301:Personalized Medicine
3D QSAR for CYP3A4
Dumontier::BIOL4301:Personalized Medicine
3D QSAR for CYP3A4 with known
substrates
Dumontier::BIOL4301:Personalized Medicine
Dumontier::BIOL4301:Personalized Medicine
Wilson. PXR, CAR, and drug metabolism. Nat Rev Drug Disc 2002
CYP3A4 mediated Dr...
Dumontier::BIOL4301:Personalized Medicine
Dumontier::BIOL4301:Personalized Medicine
Codeine
Metabolism
Gasche Y et al. Codeine intoxication associated with ultrarap...
Dumontier::BIOL4301:Personalized Medicine
Diagnostics
AmpliChip CYP450: Range
of drug metabolism
phenotypes is observed fo...
Dumontier::BIOL4301:Personalized Medicine
Dumontier::BIOL4301:Personalized Medicine
Known side effects
Unavoidable Avoidable
Medication
errors
Product quality
defec...
Dumontier::BIOL4301:Personalized Medicine
LIPITOR:
Known Side Effects
• Lipitor blocks the
production of
cholesterol in th...
Dumontier::BIOL4301:Personalized Medicine
FDA: Center for Drug Evaluation and Research
2005 - Report to the Nation
Drug re...
Dumontier::BIOL4301:Personalized Medicine
Many reasons for drug recalls
Reported Drug Quality Defects
Other, 9%
Contaminat...
Dumontier::BIOL4301:Personalized Medicine
Treatment for Acute Pain
increased risk of heart attack and stroke
(after 18 mon...
Dumontier::BIOL4301:Personalized Medicine
Vioxx targets prostaglandin
biosynthesis
• Prostaglandins, derivatives of C20
fa...
Dumontier::BIOL4301:Personalized Medicine
• 3 isoforms: COX-1, COX-2, COX-3.
• COX-1 constitutively expressed
• COX-2 only...
Dumontier::BIOL4301:Personalized Medicine
in silico Drug Discovery
• Need 3D structure
• Scan a virtual library of small m...
Dumontier::BIOL4301:Personalized Medicine
Successful drug discovery strategies involve
computational and experimental appr...
Dumontier::BIOL4301:Personalized Medicine
synthesis
of compound
↓
manipulation of
structure to get
better drug
(greater ef...
Dumontier::BIOL4301:Personalized Medicine
Dumontier::BIOL4301:Personalized Medicine
"When you're studying human genetics, you're studying the information that
goes ...
Dumontier::BIOL4301:Personalized Medicine
deCODE Genetics
For example, deCODE has used the Icelandic family tree to look a...
Dumontier::BIOL4301:Personalized Medicine
Dumontier::BIOL4301:Personalized Medicine
Things to Consider
• Does my doctor know enough about
genomic medicine to be adv...
Dumontier::BIOL4301:Personalized Medicine
How much will this cost?
• More drugs may succeed in clinical trials due to
posi...
Dumontier::BIOL4301:Personalized Medicine
There is still lots to figure out…
• Science still early. Limited data in public...
Dumontier::BIOL4301:Personalized Medicine
Personalized Medicine:
What’s your take?
Dumontier::BIOL4301:Personalized Medicine
dumontierlab.com
michel_dumontier@carleton.ca
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Personalized medicine

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A presentation on personalized medicine to a 4th year biotechnology class at Carleton University.

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Personalized medicine

  1. 1. Dumontier::BIOL4301:Personalized Medicine Personalized Medicine Michel Dumontier, Ph.D. Associate 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 Nov 18, 2010
  2. 2. Dumontier::BIOL4301:Personalized Medicine “If it were not for the great variability among individuals, medicine might as well be a science and not an art” Sir William Osler, 1892
  3. 3. Dumontier::BIOL4301:Personalized Medicine SNPs – a major source of variation • Single Nucleotide Polymorphisms (SNPs) – Single base change in DNA AAGCCTA AAGCTTA – SNPs arise as a consequence of mistakes during normal DNA replication – Average frequency 1/1000bp • Other sources of variation – Insertions, deletions, translocation, duplications, repeats – copy number variation is a major element SNP Deletion Translocation Insertion Most Common
  4. 4. Dumontier::BIOL4301:Personalized Medicine Human Variation • In human beings, 99.9 percent bases are same. • Remaining 0.1 percent (~3M bases) makes a person unique. – Different attributes / characteristics / traits • how a person looks, • diseases he or she develops. • These variations can be: – Harmless (change in phenotype) – Harmful (diabetes, cancer, heart disease, Huntington's disease, and hemophilia ) – Latent (variations found in coding and regulatory regions, are not harmful on their own, and the change in each gene only becomes apparent under certain conditions e.g. susceptibility to lung cancer)
  5. 5. Dumontier::BIOL4301:Personalized Medicine
  6. 6. Dumontier::BIOL4301:Personalized Medicine
  7. 7. Dumontier::BIOL4301:Personalized Medicine
  8. 8. Dumontier::BIOL4301:Personalized Medicine Personalized Medicine The ability to offer • The Right Drug • To The Right Patient • For The Right Disease • At The Right Time • With The Right Dosage Genetic and metabolic data will allow drugs to be tailored to patient subgroups
  9. 9. Dumontier::BIOL4301:Personalized Medicine Benefits of Personalized Medicine • Better matching patients to drugs instead of “trial and error • Customized pharmaceuticals may eliminate life- threatening adverse reactions • Reduce costs of clinical trials by – Quickly identifying total failures – Favourable responses for particular backgrounds • Improved efficacy of drugs
  10. 10. Dumontier::BIOL4301:Personalized Medicine Personalized Medicine : BiDil • Combination pill containing two medications for heart failure, cardiovascular disease, and/or diabetes. • Clinical trials did not show overall benefit across entire population. • Subgroup of patients showed best overall benefit – BiDil approved solely for use in African-descent patients. Controversial!
  11. 11. Dumontier::BIOL4301:Personalized Medicine PGx • Pharmacokinetics – What the body does to the drug – dose, dosage regimen, delivery form – Drug fate: Absorption, distribution, metabolism, and elimination of drugs (ADME) • Pharmacodynamics – What the drug does to the body – Biochemical and physiological effects of drugs – mechanism of drug action – relationship between drug concentration and effect • Pharmacokinetics and pharmacodynamics are essential to assess the drug efficacy.
  12. 12. Dumontier::BIOL4301:Personalized Medicine
  13. 13. Dumontier::BIOL4301:Personalized Medicine PGx + genetics/genomics • Pharmacogenetics – The effect of genetic variation on drug response. • Pharmacogenomics – The application of genomics to the study of human variability in drug response. • Pharmacogenetics and pharmacogenomics are expected to play an important role in the development of better medicines for populations and targeted therapies with improved benefit/risk ratios for individuals
  14. 14. Dumontier::BIOL4301:Personalized Medicine Cytochrome P450 Enzymes In bacteria, fungi, insects, plants, fish, mammals Catalyze monooxygenation reaction: RH + 2H+ +O2 + NADPH  ROH + H2O + NADP+ Act on: – Endogenous substrates (cholesterol, steroids, fatty acids) – Exogenous (drugs, food additives, environmental toxins) Involved in – Production of steroids – Metabolism of fatty acids, prostaglandins, leukotrienes, retinoids – Activation or inactivation of therapeutic agents – Enzyme activation/inhibition resulting in drug-drug interactions, adverse events
  15. 15. Dumontier::BIOL4301:Personalized Medicine Drug-Metabolizing Enzymes Pharmacogenomics: Translating Functional Genomics into Rational 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
  16. 16. Dumontier::BIOL4301:Personalized Medicine CYP enzymes are involved in the metabolism of clinically important drugs CYP Enzyme Examples of substrates 1A1 Caffeine, Testosterone, R-Warfarin 1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin 2A6 17β-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 S. Rendic Drug Metab Rev 34: 83-448, 2002
  17. 17. Dumontier::BIOL4301:Personalized Medicine S. Rendic Drug Metab Rev 34: 83-448, 2002 Red indicates enzymes important in drug metabolism Factors Influencing Activity and Level of CYP Enzymes Nutrition 1A1;1A2; 1B1, 2A6, 2B6, 2C8,9,19; 2D6, 3A4,5 Smoking 1A1;1A2, 2E1 Alcohol 2E1 Drugs 1A1,1A2; 2A6; 2B6; 2C; 2D6; 3A3, 3A4,5 Environment 1A1,1A2; 2A6; 1B; 2E1; 3A3, 3A4,5 Genetic Polymorphism 2A6; 2C9,19; 2D6;
  18. 18. Dumontier::BIOL4301:Personalized MedicineWeinshilboum, R. N Engl J Med 2003;348:529-537 Nortriptyline (anti-depressant) Pharmacogenetics
  19. 19. Dumontier::BIOL4301:Personalized MedicineWeinshilboum, 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
  20. 20. Dumontier::BIOL4301:Personalized Medicine CYP3A4 • Abundant in liver and intestines and accounts for nearly 50% of CYP450 enzymes. • Activity can vary markedly among members of a population – Constitutive variability is ~5-fold but can increase to 400-fold through induction and inhibition • Activity affected by other drugs: – Grapefruit juice is an inhibitor Felodipine is a calcium channel blocker (calcium antagonist), a drug used to control hypertension (high blood pressure) 5mg tablet with juice
  21. 21. Dumontier::BIOL4301:Personalized Medicine
  22. 22. Dumontier::BIOL4301:Personalized Medicine Quantitative Structure-Activity Relationship (QSAR) • find consistent relationship between biological activity and molecular properties, so that these “rules” can be used to evaluate the activity of new compounds. • extract features (hydrophobicity, pK, van der Waals radii, hydrogen bonding energy, conformation) • build mathematical relationship f(activity|features) • automatically assesses the contribution of each feature • can be used to make predictions on a new molecule
  23. 23. Dumontier::BIOL4301:Personalized Medicine 3D QSAR for CYP3A4
  24. 24. Dumontier::BIOL4301:Personalized Medicine 3D QSAR for CYP3A4 with known substrates
  25. 25. Dumontier::BIOL4301:Personalized Medicine
  26. 26. Dumontier::BIOL4301:Personalized Medicine Wilson. PXR, CAR, and drug metabolism. Nat Rev Drug Disc 2002 CYP3A4 mediated Drug-Drug Interaction PXR: pregnane X receptor; RXR: retinoid X receptor • Protect against xenobiotics • Diverse drugs activate through heterodimer complex • Cause drug-drug interactions
  27. 27. Dumontier::BIOL4301:Personalized Medicine
  28. 28. Dumontier::BIOL4301:Personalized Medicine Codeine Metabolism Gasche Y et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. NEJM 2004 • 80% codeine normally converted to glucuronide, eliminated by kidney. • 5-10% codeine is metabolized into morphine by CYP2D6 • inhibition of CYP3A4 or rapid metabolic variants of CYP2D6 during renal failure would show toxicity – 7% of caucasians have a nonfunctional CYP2D6 variant – <2% are CYP2D6 ultrarapid metabolizers which may suffer from opioid intoxication
  29. 29. Dumontier::BIOL4301:Personalized Medicine Diagnostics AmpliChip CYP450: Range of drug metabolism phenotypes is observed for individuals based upon the cytochrome P-450 genes
  30. 30. Dumontier::BIOL4301:Personalized Medicine
  31. 31. Dumontier::BIOL4301:Personalized Medicine Known side effects Unavoidable Avoidable Medication errors Product quality defects Preventable adverse events Injury or death Remaining uncertainties • Unexpected side effects • Unstudied uses • Unstudied populations Sources of risk from drug products FDA: Center for Drug Evaluation and Research 2005 - Report to the Nation
  32. 32. Dumontier::BIOL4301:Personalized Medicine LIPITOR: Known Side Effects • Lipitor blocks the production of cholesterol in the body. • May reduce risk of hardening of the arteries, which can lead to heart attacks, stroke, and peripheral vascular disease
  33. 33. Dumontier::BIOL4301:Personalized Medicine FDA: Center for Drug Evaluation and Research 2005 - Report to the Nation Drug recalls are surprisingly common Drug Recalls 191 226 248 352 354 254 215 401 60 53 34 88 72 156 83 88 71 101 248 316 176 72 0 300 600 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Fiscal year Number Prescription Over-the-counter
  34. 34. Dumontier::BIOL4301:Personalized Medicine Many reasons for drug recalls Reported Drug Quality Defects Other, 9% Contamination/ sterility, 3% Fill problem, 4% Packaging, 6% Delivery system, 10% Product defect, 14% Formulation/ substitution, 22% Adverse drug reports, 18% Labeling, 14% Fiscal year 2005 FDA: Center for Drug Evaluation and Research 2005 - Report to the Nation
  35. 35. Dumontier::BIOL4301:Personalized Medicine Treatment for Acute Pain increased risk of heart attack and stroke (after 18 months) VIOXX: Unknown Side Effects
  36. 36. Dumontier::BIOL4301:Personalized Medicine Vioxx targets prostaglandin biosynthesis • Prostaglandins, derivatives of C20 fatty acids, often trigger pain, fever, and inflammation. • Aspirin, Ibuprofen, acetominaphen are non-steroidal anti-inflammatory drugs (NSAIDS) that inhibit prostaglandin H2 synthase (A.K.A. COX) – no pain.
  37. 37. Dumontier::BIOL4301:Personalized Medicine • 3 isoforms: COX-1, COX-2, COX-3. • COX-1 constitutively expressed • COX-2 only expressed in response to inflammation • Drugs were designed to fit into COX-2 active site channel, but not COX-1 (20% smaller channel) • Vioxx & Celebrex lack non-specific side effects of NSAIDS, but Vioxx caused cardiac side effects & was withdrawn in 2004
  38. 38. Dumontier::BIOL4301:Personalized Medicine in silico Drug Discovery • Need 3D structure • Scan a virtual library of small molecules and “dock” them to a site of interest on a protein structure • Predict binding energy • Filters thousands of compounds relatively quickly • Top hits can be used for more rigorous computational/experimental characterization and optimization
  39. 39. Dumontier::BIOL4301:Personalized Medicine Successful drug discovery strategies involve computational and experimental approaches oral bioavailabity binding Less pain Fewer side effects repeat…
  40. 40. Dumontier::BIOL4301:Personalized Medicine synthesis of compound ↓ manipulation of structure to get better drug (greater efficacy, fewer side effects)Aspirin
  41. 41. Dumontier::BIOL4301:Personalized Medicine
  42. 42. Dumontier::BIOL4301:Personalized Medicine "When you're studying human genetics, you're studying the information that goes into the making of man and how that information flows from one generation to the next. To be able to do that well, you have to know the population structure. We can basically take the list that includes everyone in the country or 2,000 people with schizophrenia. We can know within minutes exactly how everyone is related to everyone else, which is key for being able to study the genetics of anything in a sensible manner." deCODE Genetics in Reykjavik, Iceland. Country-wide genotyping and family tree reconstruction
  43. 43. Dumontier::BIOL4301:Personalized Medicine deCODE Genetics For example, deCODE has used the Icelandic family tree to look at people who are taking statins. Approximately 10,000 people in Iceland take statins, but about 2,000 of those don't respond. The list of patients who don't respond can be run through the genealogy database. "I can tell you that they are related to each other, and we can get families that have a structure that allows us to map a gene that indicates a lack of response to statins."
  44. 44. Dumontier::BIOL4301:Personalized Medicine
  45. 45. Dumontier::BIOL4301:Personalized Medicine Things to Consider • Does my doctor know enough about genomic medicine to be advising me? – Are there genetic counselors available? • Will the test only be for this condition? – What if I am susceptible to another disease? • Who will know about this? – Doctors… insurance companies? • How exactly will the results be kept secure and in confidence?
  46. 46. Dumontier::BIOL4301:Personalized Medicine How much will this cost? • More drugs may succeed in clinical trials due to positive outcome for smaller subset – Will pharma attempt to recoup costs with a pricier drug? • Will public health cover the costs of genetic testing? – Reduce overall health cost due to fewer ADRs – Should we determine clinically validated genes or should we sequence the genome? • How will insurance premiums be affected?
  47. 47. Dumontier::BIOL4301:Personalized Medicine There is still lots to figure out… • Science still early. Limited data in public domain. • Many variations not clinically significant • Expensive to test for genotype (currently) • Ethical issues in testing individual genotype • Unclear how to deliver information to the practitioner
  48. 48. Dumontier::BIOL4301:Personalized Medicine Personalized Medicine: What’s your take?
  49. 49. Dumontier::BIOL4301:Personalized Medicine dumontierlab.com michel_dumontier@carleton.ca

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