Personalized medicine

Dumontier::BIOL4301:Personalized Medicine

Personalized Medicine

Michel Dumontier, Ph.D.

Associate Professor of BioinformaticsDepartment of Biology, Institute of Biochemistry, School of Computer Science

Carleton University

Ottawa Institute for Systems BiologyOttawa-Carleton Institute for Biomedical Engineering

Nov 18, 2010


“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


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


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)





Personalized MedicineThe 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


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


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!


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.



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


Cytochrome P450 EnzymesIn bacteria, fungi, insects, plants, fish, mammalsCatalyze 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


Drug-Metabolizing Enzymes

Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics. Evans and Relling Science 1999

Most DME have clinically relevant polymorphismsThose with changes in drug effects are separated from pie.

Phase I: modification of functional groups Phase II: conjugation with endogenous substitutents


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 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

S. Rendic Drug Metab Rev 34: 83-448, 2002

Dumontier::BIOL4301:Personalized MedicineS. 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;

Dumontier::BIOL4301:Personalized MedicineWeinshilboum, R. N Engl J Med 2003;348:529-537

Nortriptyline (anti-depressant) Pharmacogenetics

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


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



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


3D QSAR for CYP3A4


3D QSAR for CYP3A4 with known substrates



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



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


Diagnostics

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



Known side effects

Unavoidable Avoidable

Medicationerrors

Product qualitydefects

Preventableadverseevents

Injuryor death

Remaininguncertainties

• 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


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



Drug recalls are surprisingly common

Drug Recalls

191226 248

352 354

254215

40160

53 34

88

72 156 83

88

71

101

248316

176

72

0

300

600

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Fiscal year

Nu

mb

er

Prescription Over-the-counter


Many reasons for drug recallsReported 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



Treatment for Acute Pain

increased risk of heart attack and stroke(after 18 months)

VIOXX: Unknown Side Effects


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.


• 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


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


Successful drug discovery strategies involve computational and experimental approaches

oral bioavailabitybinding

Less pain

Fewer side effects

repeat…


synthesisof compound

↓

manipulation of structure to get

better drug(greater efficacy, fewer side effects)Aspirin



"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


deCODE GeneticsFor 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."



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?


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?


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


Personalized Medicine:What’s your take?


[email protected]

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Personalized medicine