Pharmacogenomics Flashcards
List 3 values of pharmacogenomics
1) Optimized dose
2) Optimized drug choice
3) Optimizing drug therapy -> right drug to the right patient
List 8 types of gene variants
1) Single Nucleotide polymorphism
2) Insertion
3) Deletion
4) Copy number variation
5) Tandem duplication
6) Interspersed duplication
7) Translocation
8) Inversion
What are same alleles also known as?
Homozygous
What are different alleles also known as?
Heterozygous
What is an allele?
Version of a gene
What is a haplotype?
A set of DNA variations inherited together on the same allele
What is a genotype?
A combination of different alleles at a specific location in DNA
What are phenotypes?
Observable traits
E.g. normal metabolizer, poor metabolizer, skin colour, hair colour
*1 alleles are usually known as?
Wild type/ absence of variant tested
How is the genotype for HLA usually presented?
Positive/negative- considered at risk even with 1 copy
HLA mostly predicts for?
Hypersensitivity risk
List 3 main enzymes where activity score is usually used to predict the phenotype for?
CYP2C9, CYP2D6, DPYD
Based on the activity score, what does the score 2.0 stand for?
Normal (Extensive) Metabolizer
Based on the activity score, what does the score 3.0 stand for?
Ultrarapid metabolizer
State whether the following is true or false: phenotype is predicted based on genotype
True
State whether the following is true or false: phenotype is affected by other clinical factors e.g. organ function, drug interaction
True
List 4 main resources for pharmacogenomics
1) CPIC- American Clinical guidelines
2) DPWG - dutch clinical guidelines
3) PharmGKB - one stop database that curates current PGx knowledge
4) Sequence2script
What does genotyping assay do? List down 1 disadvantage of genotyping assays
Tests for specific variants
Disadvantage: will miss variants that weren’t included in the test
What does sequencing assay do? List down 2 disadvantages of this assay
Identifies all variants within the regions tested
Disadvantages:
1) Expensive
2) Turn-around-time is typically longer
List down 2 caveats to the use of pharmacogenomics in practice
1) *1 represents the absence of variants covered by a genotyping panel
2) Behavioural, social and environmental factors may affect drug response and contribute phenoconversion
How does PGx optimise pharmacotherapy?
A) helps with choice of drug
B) helps with dosing
c) Both A & B
C) Both A & B
Which of the following is NOT considered a type of genetic variation?
A) Single nucleotide polymorphism
B) Copy number variation
C) Phenoconversion
D) Insertion
C) Phenoconversion
Which of the following is a potential genotype reported for HLA-B* 15:02?
A) Rapid metabolizer
B) 2/3
C) A/A
D) Positive
Positive
Which part should I focus on when interpreting a PGx report?
A) Genotype
B) Phenotype
B) Phenotype
Which of the following is NOT a resource for translating genotype/phenotype for therapeutic recommendations?
A) CPIC
B) PharmVar
C) DPWG
D) PharmGKB
B) PharmVar
Which of the following is a more accurate depiction of *1 in a genotyping assay?
A) wild type allele
B) Absence of variants covered by the assay
B) Absence of variants covered by the assay
Which of the following could cause phenoconversion i.e. mismatch between genotype and predicted phenotype?
A) Organ failure
B) Diet
C) Drug drug interactions
D) All of the above
D) all of the above
List the substrates of CYP2B6 (3)
1) Tramadol
2) Vortioxetine
3) Sertraline
List the substrates for CYP2C9 (3)
1) Clopidogrel
2) Vortioxetine
3) Sertraline
Which drug is an example of a weak inhibitor of CYP2B6
Clopidogrel
Which drug is a prodrug that is converted to an active metabolite by CYP2C19?
Clopidogrel
List the substrates for CYP2C19 (5)
1) Clopidogrel -> converted to active metabolite
2) Omeprazole
3) Escitalopram
4) Vortioxetine
5) Sertraline
Give an example of a drug that is a moderate inhibitor of CYP2C19
Omeprazole
Which drug is converted to an active metabolite with a much higher activity by CYP2D6?
Tramadol -> converted to active metabolite that has 200x more activity
List the substrates of CYP2D6 (8)
1) Tramadol -> active metabolite
2) Escitalopram
3) Venlafaxine (major)
4) Amitriptyline
5) Fluvoxamine
6) Paroxetine (major)
7) Vortioxetine (major)
8) Sertraline
List 3 examples of weak inhibitors of CYP2D6
1) Escitalopram
2) Venlafaxine
3) Sertraline
What is a drug that is a strong inhibitor of CYP2D6?
Paroxetine
List substrates for CYP3A4 (7)
1) Clopidogrel
2) Omeprazole
3) Tramadol
4) Escitalopram
5) Atorvastatin
6) Vortioxetine
7) Sertraline
Omeprazole is a weak inhibitor of which enzymes?
CYP3A4, CYP3A5
List the substrates for CYP3A5 (5)
1) Clopidogrel
2) Omeprazole
3) Tramadol
4) Escitalopram
5) Atorvastatin
Which gene affects the drug response of rosuvastatin?
ABCG2 gene
Which gene testing is mandated by HSA/MOH and for which drug?
HLA-B*15:02
For carbamazepine to avoid SJS/TENs
Which gene is also associated with hypersensitivity in carbamazepine that is not mandated in SG?
HLA-B*31:01;
more prevalent in European and Japanese population
What gene has been reported to be related to cause adverse liver reactions, and in which drug?
HLA-B*57:01
Flucloxacillin
FYI: associated with hypersensitivity in abacavir
Which gene is associated with SCAR in allopurinol?
HLA-B*58:01
Which gene is known to affect drug response to statins?
SLCO1B1;
Simvastatin (most affected), atorvastatin
If a patient is found to be a CYP2D6 ultra-rapid metabolizer, list 3 drugs that will be affected, and the respective recommended changes to be made for these drugs.
1) Paroxetine: consider alternative therapy
2) Venlafaxine: increase dose
3) Vortioxetine: consider alternative therapy/ increase dose
If a patient is found to be a CYP2D6 intermediate metabolizer, list 1 drugs that will be affected, and the respective recommended changes to be made for the drug.
1) Paroxetine: decrease dose/slower titration
If a patient is found to be a CYP2D6 poor metabolizer, list 4 drugs that will be affected, and the respective recommended changes to be made for these drugs.
1) Paroxetine: decrease dose/slower titration
2) Fluvoxamine: consider alternative OR decrease dose/slower titration
3) Venlafaxine: consider alternative OR decrease dose/slower titration
4) Vortioxetine: consider alternative OR decrease dose/slower titration
If a patient is found to be a CYP2C19 ultra-rapid metabolizer, list 1 drug that will be affected, and the respective recommended changes to be made for the drug
1) Escitalopram: consider alternative/ increase dose
If a patient is found to be a CYP2C19 rapid metabolizer, list 1 drug that will be affected, and the respective recommended changes to be made for the drug
1) Escitalopram: consider alternative/ increase dose
If a patient is found to be a CYP2C19 intermediate metabolizer, list 2 drugs that will be affected, and the respective recommended changes to be made for the drugs
1) Escitalopram: decrease dose/ slower titration
2) Sertraline: decrease dose/ slower titration
If a patient is found to be a CYP2C19 poor metabolizer, list 2 drugs that will be affected, and the respective recommended changes to be made for the drugs
1) Escitalopram: consider alternative OR decrease dose/slower titration
2) Sertraline: consider alternative OR decrease dose/slower titration
List 2 factors that supports the decision to conduct HLA-B*58:01 gene testing for allopurinol
1) Renal impairment
2) Old age
