L15: Personalized Medicine Flashcards
what is personalized medicine? and why is it a thing
Personalized medicine is the tailoring of medical treatment to the individual characteristics, needs, and preferences of the patient
Clinicians past/present observed that:
- Patients with similar symptoms may have different illnesses
- Medical interventions may work well in some patients with a disease, but not in others with apparently the same disease (i.e. non- responders)
- thats why personalized medicine exists
what are SNPs? How similar and different are humans genetically? what can the variations in genes coding for drug target proteins result in?
- Single nucleotide polymorphisms (SNPs) are the most common form of genetic variability
- Recall that SNPs are single base changes in the DNA: ex. instead of T its A
- Humans are 99.9% genetically identical; the remaining 0.1% is what makes us different from one another
–> Different physical attributes
–> Different predispositions to health conditions - Variation in genes coding for drug target proteins may result in differences in drug efficacy and side effects for different people
what is pharmacogenomics: also Pharmacodynamics and Pharmacokinetics
Pharmacogenomics is study of drug response based on genetic makeup and variability
Pharmacodynamics - What does the drug do to the body?
- Involve biochemical pathway and physiological effects
Affect drug efficacy, toxicity (e.g. side effects), and choice of treatment
Pharmacokinetics - What does the body do to the drug?
- Involve ADME
- Affect dose, delivery, and dosage regimen
what are the various sources that correspond with variations in drug responses
genetic and environmental factors effect the way the drug is processed after taken to yield a response.
they effect the absorption, distribution, metabolism, and excretion of the drug (ADME)
what are the pharmacological and toxicological consequences of drug metabolism
Inactivation: active drug to inactive product
Activation: inactive pro-drug to active product
- Maintenance/no change of activity
- Increased chemical reactivity – ex. protein, lipid, DNA binding
what do hepatic enzymes do
they act on drugs to help eliminate them
Part of evolutionary system to eliminate foreign compounds
Usually, the enzymatic reaction results in a more water-soluble product so it can be secreted
what are two examples of enzymatic reactions that result in a more water soluble product?
inactive –> active
active –> inactive
metabolic reactions
inactive/partially active drug (ex. codiene (pro-drug))
–> Drug-metabolizing enzyme (CYP2D6)
–> Active metabolite (e.g. morphine) ANALGESIA
or for ex.
Active drug (e.g. nicotine) PSYCHOSTIMULANT EFFECTS
–> Drug-metabolizing enzyme (CYP2A6)
–> Inactive/partially active drug (e.g. cotinine)
what can variability in drug metabolizing enzymes do?
Variability in drug-metabolizing enzymes can alter metabolite (small molecules that are intermediates or end products of metabolic processes) concentration levels, which can assist physicians in prescribing the right treatment dosage
for ex. if an enzyme creates little metabolites, we can increase the concentration of the enzyme to create more products.
What are three examples of perscribing different dosages of metabolizers (enzymes) and their ratio of starting material to product
use ex. of codiene, enzyme, product
Variability in drug-metabolizing enzymes can alter metabolite levels, which can assist physicians in prescribing the right treatment dosage
ex. with CYP2D6 enzymes
there can be….
- poor (slow) metabolizers
–> lots of initial codiene, little morphine
extensive (normal) metabolizers
–> little codeine, same amount of morphine
ulta-rapid metabolizers
–> little codeine, more morphine
therefore enzyme potency is positively correlated with product formation
what is a case study of morphine poisoning in a breast-fed infant and CYP2D6 metabolism
- In April 2005, a full-term healthy male infant: intermittent periods of difficulty in breathing and lethargy starting on day 7
- Regaining weight, by day 11, he had grey skin and lower milk consumption. He was found dead by day 13
- His blood concentration of morphine was 70 ng/mL
- The mother had been prescribed a combination preparation of codeine and paracetamol after birth for episiotomy pain
- After genotyping analysis of CYP2D6, they found that the mother was an ultra-rapid metabolizer (made a lot of morphine product) and was breast feeding the child
what are Diagnostic Tests & Personalized Therapeutics
can they be codeveloped
yes.
Diagnostic Test
- Medical test performed to aid in the diagnosis of a disease
personalized therapeutic
- A treatment, therapy or drug that is personalized
- Moving towards developing (and FDA-approving) both test and drug therapy in combination
Case study: Testing for HER2 overexpression in patients with breast cancer to improve treatment success
explain the case study
- what percent of breast cancers are HER2-positive
- what do normal breast cells and HER2 positive breast cancer cells look like in terms of the HER2 receptors in them?
- how does herceptin (medication used in the treatment of certain types of breast cancer) interact with HER2 receptors
- About 20% of breast cancers are HER2-positive
- Drug can slow or stop the growth of the breast cancer
in normal breast cells
- HER2 receptors send signals telling cells to grow and divide
in HER2 Positive breast cancer cells
- there are too many HER2 receptors, which may make the cancer cells grow and divide faster
- Herceptin works by attaching itself to the HER2 receptors and blocking them from receiving growth signals (antagonist)
what are benefits of personalized medicine (6)
- Better tailoring of medication to the patient instead of trial and error
- Shift emphasis in medicine from reaction to prevention
–> Enhanced patient adherence to treatment
–> Safer drug profile (i.e. minimize the occurrence of adverse events) - Reductions in costs of trials
–> Identifying those populations that are responsive to treatment - improves health outcomes (like for heart, leukemia, and colorectal cancer patients)
- make the health system more efficient (strokes are prevented, chemotherapy use goes down, so does costs for colorectal cancer)
Smoking cessation treatments exist with different efficacy.
how many people does tobacco kill yearly and what are three FDA approved smoking cessation treatments?
Tobacco use kills around >8 million individuals yearly worldwide
Three FDA-approved smoking cessation treatments exist:
- Varenicline (Champix)
- Nicotine replacement therapy
- Bupropion (Welbutrin)
How can you optimize smoking cessation treatments based on a smokers nicotine metabolism: a case study
- how is NMR calculated
- how is the liver enzyme CYP2A6 related to the NMR number
Nicotine Metabolite Ratio (NMR) = assess how efficiently ones body metabolizes nicotine. Calculated by dividing the concentration of a nicotine metabolite called 3’-hydroxycotinine (3’-HC) by the concentration of another nicotine metabolite called cotinine (COT) in a person’s urine or blood sample.
- Activity level of liver enzyme CYP2A6 (enzyme which metabolizes nicotine) reflects the NMR value.
- A higher NMR indicates faster metabolism of nicotine (makes more faster ‘3-HC), while a lower NMR indicates slower metabolism (makes less slowly ‘3-HC).
How can you optimize smoking cessation treatments based on a smokers nicotine metabolism: a case study
what did the clinical trial look like for the treatment of a nicotine patch vs varenicline?
- what is the quantifying technique, an odds ratio
- what were the odds ratio for slow and fast NMR groups
- which treatment was better for each group?
- Conducted a clinical trial to determine which treatment (nicotine patch vs. varenicline) is most optimal based on nicotine metabolizer group.
- Relative treatment efficacy was quantified using an odds ratio
–> Odds ratio = proportion of an event (i.e. quitting smoking) taking place in one group (i.e. varenicline) relative to another group (i.e. nicotine patch)
results:
- for slow NMR (<0.31): odds ratio was 1.16 meaning the quit rate using either treatment was around the same (30%)
- for fast NMR (≥0.31): odds ratio was 2.54 where the quit rate for patches was around 25% but for varenicline it was around 45%
conclusion:
- for higher NMR values Varenicline is better drug, for same NMR values, either patch or varenicline works the same.
what are combinatorial pharmacogenetics and how are they predictive
using Pharmacodynamics and Pharmacokinetics principles, and integrating that with psychiatric pharmacology to predict antidepressants responses and report classification for certain drugs (how cautious do you have to be to use the drug?)
Case study: what is the IMPACT study and how does it work
The IMPACT Study uses genetic testing to identify genetic
variants that influence response to psychiatric medications
how:
- Tests 8 genes
- via saliva sample
- Provides recommendations re: 33 antidepressant/
antipsychotic medications
- > 11,000 participants so far
Case study: Comparison of Outcomes at Week 8 in Patients who
entered on pharmacogenetically incompatible medications and were switched (to better ones for their need)
vs.
patients remaining on pharmacogenetically incompatible medications
what were the results for remission, response, and symptoms
remission: 15.3% improvement for switch
response: 71% improvement for switch
symptoms improved: 59% for switch
Challenges to Personalized Medicine - Logistical
How do we get genomic information into a patient’s (long-term)
electronic medical record?
General steps to sequencing:
- sample
- test sample
- graph and collect
- store on a database
Once the patient has been genotyped, the digital information can be centralized, and “checking the patient’s sequence” becomes an electronic event
- this can have some worries on how encrypted the electronic data is
Challenges to Personalized Medicine - Economical problem and a retalliation
Recall first step of drug discovery:
- sometimes you want to make a drug against a certain target that only a small subset of cancer patients have – this can be costly and is usually not prioritized
- However, it is noteworthy to mention that personalized medicines may cause public health costs to be reduced. A $400 personalized test could avoid the waste and harm of a $40,000 cancer drug - if for some reason it doesnt end up working
Challenges to Personalized Medicine – Language/
Communication
what are the different names for “personalized medicine” on a scale from most liked to least liked.
what you should say when you communicate about personalized medicine
ordered from like to dislike on the term used instead of “personalized medicine”:
- individualized medicine
- personalized medicine
- targeted therapies
- precision medicine
- stratified medicine
An example of how to communicate personalized medicine:
- explain the treatment
- how effective it is
- what exactly it biologically combats
- and how its sure you have the combating variable in your body
- prevalence of their disease
- odds of remission
- does it sometimes not work? if so are their alternatives
has the number of personalized medicines increased through the years?
yes
2008: 5
2012: 81
2016: 132
2020: 286
steady increase
do many drugs on the market have the potential to be personalized medicines?
yes.
42% of all drugs in development are personalized
73% of oncology drugs in development are personalized
why are biomarkers used in clinical trials? and have they increased in use
used to detect if the drug is working
they have increased in use over the years, especially in oncology personalized medicine development
what is hepatitis C and who does it impact more so.
what: a virus that affects the liver
who: anyone can get hepatitis C, but certain populations have been hit harder:
these include:
- people who inject drugs
- people with prison experience
- indigenous peoples
- gay bi and other men who have sex with men
- immigrants and other newcomers
how is hepatitis C diagnosed (and what percent of people are unaware of their diagnoses) and how is it treated (what percent of people are cured when they take treatment and what does the treatment look like)?
In canada
diagnosed:
- must get tested for diagnosis
- About 25% of people who have ever had hepatitis C are not aware of their current or past infection.
- A person can have hepatitis C for decades before they notice any symptoms.
treated:
- Hepatitis C can be cured!
- Most people will need treatment to be cured
- Treatment cures over 95% of all people with hepatitis C
and is simple to take.
- It involves taking one to three pills every day for eight or 12 weeks, with mild to no side effects.
how variable is the HepC viral genotypes across the globe? what are the genotype specific and general drugs for HepC in Canada
- very variable across the globe
genotype specific:
- Harvoni
- Zapatier
genotype general:
- Epclusa
- Mavriet
what is project gradient
Project GRADIENT = Genomic Research Approach for Diversity and Optimising Therapeutics
essentially using personalized medicine in researching and understanding genetic diversity
