Pharmacogenomics Flashcards
Define pharmacogenetics and describe how it
can be used to enhance patient care.
The study of genetic factors that underlie the variation in drug responses.
Understand how genetic differences influence the DRUG RESPONSE
- Identify patients that will respond to drug treatment
- Maximize drug efficacy
- Optimize drug dosing
- Minimize drug toxicity
- Aid in new drug developmen
List the main factors that can affect the genetic variability of the drug response.
Pharmacokinetics (what body does to drug)
- drug metabolizing enzymes
- drug transporters
(Polymorphisms in genes result in diff in how effective drug is, and how the enzymes/transporters work)
Pharmacodynamics (what drug does to body)
- drug therapeutic targets
- drug toxic targets
Leads to dosing, efficacy and adverse effects
What is the most common factor responsible for pharmacogentic differences in drug response?
Differences between individuals in the enzymes of drug metabolism
Many of the enzymes involved in drug metabolism are polymorphic
Describe how genetic polymorphisms in drug metabolizing enzymes can affect the metabolism of drugs and the effects that
this has on serum drug concentration, drug
efficacy and the risk of toxicity.
- existence of different alleles of a single gene within the population
- different alleles exhibit different degrees of metabolic activity
- The CYP450 family of drug metabolizing enzymes are highly polymorphic especially CYP2D6, 2C9 and 2C19
- increased/decreased/unchanged/absent/null enzyme activity
Describe how polymorphisms in drug transporter proteins can contribute towards the variability in drug responses.
Drug transporters mediate the influx or efflux of drugs in to or out of cells
Play an important role in determining plasma and tissue levels of a drug
Genetic polymorphisms in drug transporters can dramatically alter drug disposition and drug responses
Describe how polymorphisms in drug target proteins can contribute towards the
variability in drug responses.
Genetic variations in drug targets or downstream signaling proteins can also influence the drug response
- Zileuton decreases airway inflammation in asthma by inhibiting 5-lipoxygenase (ALOX5)
- Variations in the promoter of the ALOX5 gene influence the response to Zileuton
- Most common allele contains 5 copies of binding site for the SP1 transcription factor
- Common variants contain 4 or 3 copies (express less ALOX5 than common allele)
- Presence of the common allele or variant does not influence disease severity
- But does influence the response to Zileuton
so those with two variant alleles will not respond to Zileuton bc they are producing significantly less 5 lipoxygenase (the enzyme on which Zileuton acts)
Describe how polymorphisms in CYP2C9 and VKORC1 each contribute towards the variability in the response to warfarin.
Pharmacokinetics-
2C9*2 and 3 - reduced function variants
2C915 and *25 – null variants
patients w *2 or *3
- decreased metabolic inactivation of S-warfarin
- increased concentration of active warfarin with standard dose
- prone to experiencing bleeding events
- patients require lower warfarin dosing
Pharmacodynamics
- VKORC1 is the direct target of warfarin
- Common polymorphism found in the VKORC1 promoter region: -1639G to A
- G is associated with higher VKORC1 expression and a higher warfarin dose
- A is associated with lower VKORC1 expression and a lower warfarin dose needed
- 37% whites, 14% Africans & 90% Asians carry the A-allele
-Rare mutations in the VKORC1 coding region are associated with warfarin resistance (reduced affinity) that require v. high doses of warfarin to achieve anticoagulation
Discuss the different mechanisms by which genetic polymorphisms can contribute towards drug-induced adverse effects.
Can result from interaction of drug with its true target or a different target protein
Idiosyncratic drug reactions/hypersensitivity reactions- unrelated to PK or PD effects
- result from unanticipated interaction between drug and unique patient physiology
Pharmacokinetic based adverse reactions:
- polymorphisms in drug metabolizing enzymes causing elevated drug levels
- polymorphisms in drug transporters causing elevated drug levels
Pharmacodynamic-based adverse reactions
-polymorphisms in drug targets affect drug responsiveness (e.g. warfarin and VKORC1)
Drug-induced hepatotoxicity
Drug-induced hypersensitivity reactions (Allergic-like reactions, often life threatening)
List some of the current barriers to the full implementation of pharmacogenetics into
clinical practice.
Physician education and understanding of pharmacogenetics
Absence of data demonstrating clinical utility
Lack of evidence for added value to existing prescribing method
Availability of alternative medications where genetic variability is not an issue
Cost effectiveness
Timeliness of turnaround for genetic testing
Lack of reimbursement for tests/Insurance coverage
Lack of clear clinical guidelines
Define targeted therapy and explain how pharmacogenetic data
is used in the therapeutic
decision making process.
Therapy that is targeted towards a molecular target based upon unique mutations or genetics
Typically, used in the treatment of specific cancers
Treatment is based upon specific somatic mutations in key oncogenic drivers unique to the patient’s cancer
- Drug is only given to those patients with the specific mutation
Trastuzumab (Herceptin), an anti-Her2/ErbB2 monoclonal antibody used to treat breast cancer in patients whose tumor overexpresses the Her2/ErbB2 receptor
Which of the following, when variant, is least likely to cause significant difference in enzymatic activity between individuals?
CYP2C9
CYP3A4
CYP2D6
CYP2C19
ALL polymorphic; however, CYP3A4 alleles are v rare, little difference in enzymatic activity between individuals, redundancy with CYP3A5, polymorphisms are unlikely to be clinically significant
What accounts for differences in drug responses between ethnic groups?
CYP450 alleles are differentially distributed amongst racial and ethnic groups
A patient presents with severe broken leg and is in extreme pain; you prescribe x amount of codeine but thirty minutes later is still writhing in pain; you double check the dose and that it was administered but there were no errors. What might explain this?
drug isn’t working
-codeine is a Prodrug
-patient has variant form of 2D6 - could lead to poor metabolize and consequently decreased efficacy and lack of sedative effect
What ethnic population is most likely to carry a VKORC1 variant allele? What are the implications of this?
90 percent of Asians carry A-allele
A is associated with lower VKORC1 expression and a lower warfarin dose needed
What will decreased activity in an influx pump result in?
Discuss efficacy.
What if its expressed in liver?
Toxicity?
- Reduced cellular uptake
- Decreased efficacy
- If expressed in liver can affect drug metabolism and elimination
- Potential for increased “off target” toxicity
