Dumontier::BIOL4301:Towards Personalized Medicine:Nov 25, 2008 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
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.
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
• Discovery: – Identify the molecular target– Design an assay for regulation of activity– Identify hits with chemical screening– Determine mechanism of action– Identify a lead compound with strong binding
affinity, KD < 1μM
– Demonstrate therapeutic value with in vivo proof of concept in animals/cell cultures
The development phase evaluates drug effectiveness
• Drugs must overcome numerous challenges– chemically stable in stomach (pH 1)– not digested by gastrointestinal enzymes– absorbed into the bloodstream
• pass through series of cell membranes
– not bind tightly to other substances– survive xenobiotic detoxification by liver enzymes– avoid excretion by kidneys– brain: cross blood-brain barrier (blocks polar substances)– intracellular receptor: pass through cell membrane
• Unexpected side effects• Unstudied uses• Unstudied populations
Adverse Drug Reactions
• ADR is one of the leading causes of hospitalization and death • 6.7% of hospitalized patients have serious ADRs• 0.3% of hospitalized patients have fatal ADRs
• Global Alliance for Tuberculosis Drug Development– www.tballiance.org – "The Economics of TB Drug Development"
• Costs to discover and develop a new anti-TB drug range from $115 million to $240 million.– $40 million to $125 million for discovery– $76 million to $115 million for preclinical
The Hatch-Waxman Act (1984)• Drug Price Competition and Patent Term
Restoration Act• Open the market to generics immediately after patent
expiry, but new tactics to protect– Easier for generics to obtain FDA marketing approval
• Drug Company– 30-month stay against generic manufactures that challenge
their patents. – Additional period (< 5 yrs) of marketing exclusivity in addition
to 20 year patent exclusivity– Easy patents for drug variants
• keep generics off the market by protecting their drugs with extra patents of poor quality, filing lawsuits to protect the patents even when the lawsuit will be lost, but getting the extra market exclusivity anyway.
• Matrix Metallo Proteinase Inhibitors (MMPI) are a class of cancer therapeutics– MMP levels are increased in areas surrounding tumor– Degrade extracellular matrix proteins and can lead to
spread of cancer– Inhibitors
• can prevent metastasis • may also play role in blocking tumor growth
Melissa Passino. Structural Bioinformatics in Drug Discovery.
• Provides a framework for understanding general macromolecular features– Automatic identification of binding
pockets.– Measurement size of surface binding
pockets.
• Speeds up key steps in drug discovery– Understand molecular basis for disease – Determine potential interactors– Identify potential targets which bind small
Genetics as the basis for variability in drug response
• 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
Pharmacokinetics and pharmacodynamics are essential to assess the drug efficacy.
• 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
• 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
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.
• 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