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PR4152 Multi-Morbidity > IC4 Pharmacogenomics > Flashcards

IC4 Pharmacogenomics Flashcards

1
Q

What is pharmacogenomics?

A

study of how genetic differences influence the variability in patient’s response to drugs

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2
Q

Can both PK and PD be affected by the presence of PG variation? Give general examples of what will be affected.

A

Yes
Genetic Variations e.g. Single nucleotide polymorphism (SNP), insertion/deletion of nucleotide
→ Pharmacokinetic (PK) changes
Enzyme activity, e.g. enzyme metabolising activity becomes less effective
E.g. CYP2C19
→ Pharmacodynamic (PD) changes
Receptor activity or transporter / Drug target
E.g. SLC6A4
→→ Increased Toxicity
→→ Lack of Efficacy

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3
Q

About what percentage of people carry >= 1 clincially actionable PGX variant (but may or may not be taking medications that are affected)?

A

91-99% of the population

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4
Q

What is the percentage of patients who have been prescribed a drug for which they are predicted to have an atypical response (based on PGx test results)?

A

~24%

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5
Q

Which of the following statements is/ are correct?
A) Drug response is only affected by genetic variations
B) 91-99% of the population have been prescribed a drug for which they are predicted to have an atypical response based on genomics results
C) Genetic variations may alter drug response via pharmacokinetic but not pharmacodynamic changes
D) Clinicians may optimize drug response through changing dose or drug choices based on pharmacogenomics test results

A

Ans: D
A→ other genetic factors, there are a lot of other clinical factors that affect drug response e.g. organ function, age weight
B → 25% that is on a drug that will be affected by pgx factors
But 91-99% carry the variation but may not be on the drug
C → pharmacogenetic changes can change both PK and PD

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6
Q

What are the types of pharmacogenomic variations?

A

SNP - Single Nucleotide polymorphism – single base pair substitution

Structural variation - e.g. insertion/ deletion, inversion, Copy number variation (CNV)

  • Tandem duplication e.g. UGT1A1, repeat the same region many times e.g. normal people have that part repeated 6x but those with genetic variations have that part repeated about 7x
  • Copy number variation (CNV) important when we talk about genes like CYP2D6, have a lot of the same gene copied so e.g. have a lot of enzyme activity
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7
Q

What is the difference between tandem duplication and copy number variation (CNV)?

A

Tandem duplicates are usually very short 1-10 or sometimes up to a 100 and they are usually not within coding regions; but CNV is usually larger in size

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8
Q

What is a haplotype?

A
  • set of DNA variations inherited together on the same allele
  • Look at entire stretch e.g. AGCCTTA haplotype rather than just 1 allele
  • This term is used rarely

A haplotype (a contraction of the term ‘haploid genotype’) is a combination of alleles at multiple loci that are transmitted together on the same chromosome.

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9
Q

What is a genotype?

A

Combination of 2 alleles (a pair) at a specific location in DNA
E.g. GT genotype

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10
Q

What is a phenotype?

A

Observable traits (predicted based on the genotype testing)
E.g. Normal metabolizer, poor metabolizer, ultra-rapid metabolizer

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11
Q

How is HLA results usually represented?

A
  • Either positive or negative
  • As long as u carry 1 you’re at risk already
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12
Q

If HLA is positive what does it mean?

A

Most are predicted to have hypersensitivity risk

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13
Q

There are 2 ways to represent the phenotype for metabolizers, what are they?
State out all the different phenotypes for the 2 ways.

A

URM/RM/NM/IM/PM vs AS (Activity score)

  • AS is similar to the description of metabolisers but it is a more granular way of looking at the activity of the enzyme/metaboliser, so help us to see where the enzyme activity exactly is
  • Normal metabolizer is 2.0 instead of 1.0, becos 1 point from mom 1 from dad so add together is 2
  • PM = 0
  • IM = 1
  • NM = 2
  • RM = 2.5
  • URM = 3
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14
Q

What does *1 means?

A

wild type allele/ absence of variants included in the test, there could be other variants not covered by the assay

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15
Q

Is genotyping or sequencing preferred?

A

Genotyping

  • The orange arrows are the variants, so if have variation at at particular arrow, the assay will detect it
  • But if the variation is at the yellow circle, then the assay will not be able to detect it
  • So we try to build genotype assay such that the orange arrows cover everything that is more than 0.1% in the populations, so most patients should be covered by the orange arrows
  • Genotyping is much cheaper than sequencing
  • Thus for now still prefer genotyping
    Important to ask what your test include, if the test does not include e.g. *9 or *10, it will report as *1. Can we actually conclude that the person is *1 for that particular gene?

Sequencing: Read the whole DNA strand 1 by 1, so it will pick up the yellow patch

  • Generate too much data (letter by letter), which is bulky and expensive
  • Sometimes get the yellow patch but we might not know what to do with it, e.g. is it reduce function or loss of function allele
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16
Q

What can alter the phenotype?

A

environmental factors e.g.

  • DDI,
  • CYP inhibitor/ inducer,
  • liver impairment,
  • nutrition
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17
Q

If a person is a CYP2C19 intermediate metabolizer and is given omeprazole, what is the following therapeutic recommendation?

A

No action required. Initiate therapy with recommended starting dose.

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18
Q

How does PGx optimize pharmacotherapy?
A) Helps with the choice of drug
B) Helps with dosing
C) Both A and B

A

C

19
Q

Which of the following is not considered a type of genetic variation?
A) Single nucleotide polymorphism
B) Copy number variation
C) Phenoconversion
D) Insertion

A

Ans: C

  • SNP is the most common genetic variation that we see in PGx
  • Insertion is worst, since SNP u only affect one amino acid but insertion/deletion, even though only 1 nucleotide is added or remove, it causes a frame shift → 3 nucleotides encodes 1 amino acid, so that it changes the interpretation of the entire DNA
20
Q

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

A

Ans: D

  • HSA mandated test, it is the standard of care to check HLA-B*15:02 before starting carbamazepine
  • Always wait for the test results before starting on the drug
  • Rapid metaboliser is a phenotype
  • HLA just positive or negatives
  • The *alleles are reported with the CYP enzymes
  • A/A is for the warfarin, VKORC gene
  • C/C genotype means high warfarin sensitivity
21
Q

Which part should I focus on when interpreting a PGx report?
A) Genotype
B) Phenotype

A

B

22
Q

Which of the following is NOT a resource for translating genotype/phenotype to therapeutic recommendation?
A) CPIC
B) PharmVar
C) DPWG
D) PharmGKB

A

Ans: B

PharmVar is for scientist of pharmacogeneticists that wants to look at a particular variant to see if have been reported before, e.g. do sequencing assay, and have a yellow patch, then dont know what to do with the results. So go onto PharmVar to see if it’s a pathogenetic variant or not. If first one to discover then report there, but it doesn’t give you therapeutic recommendations

23
Q

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

A

B

24
Q

Which of the following could cause phenoconversion e.g. mismatch between genotype and predicted phenotype?
A) Organ failure
B) Diet
C) DDI
D) All of the above

A

Ans: D

Hint: in exam, if see all of the above, it is usually all of the above:”)

25
Q

What is the recommendation for starting Abacavir in a patient tested positive for HLA-B*57:01?
A) Higher risk of hypersensitivity; avoid
B) Higher risk of therapeutic failure; avoid
C) Higher risk of ischemic heart attack, reduce dose
D) Follow standard prescribing

A

A

  • HLA-B usually predicts risk for hypersensitivity, except for flucloxacillin which predicts for risk of liver failure (odd one out)
  • Sometimes clinicians run out of choices, so might just persist with abacavir if the rash is mild and they feel that they can manage the rash on top of the others issues
  • HLA-B*57:01 is known to have a very strong positive predictive value of about 50% (meaning that if 10 people are tested positive, about 5 people are truly positive)
  • For HLA-B*15:02, the positive predictive value is about 1-5%, out of 100 patients tested positive, 5% are truly positive and will get SJS if given carbamazepine
  • Seems low but then since SJS can kill, u might not want to risk anyone getting it
26
Q

What is the recommendation for starting azathioprine in a patient who is a NUDT15 intermediate metabolizer and TPMT normal metabolizer?
A) Avoid azathioprine and mercaptopurine
B) Change to mercaptopurine
C) Start with 1mg/kg/day
D) Follow standard prescribing

A

C: Start with 1mg/kg/day

  • Since NUDT15 is intermediate metabolizer, patient has lower ability to metabolise azathioprine and accumulates more azathioprine (myelosuppressive drug), thus may need lower dose to prevent from getting side effects
  • Start with 1mg/kg/day then gradually titrate up based on patients tolerance (don’t cap at 1mg/kg/day)
  • For IBD patients in NUH, patients start with 50mg which ends up with 1mg/kg/day anyways so doesn’t change their practice, but now knowing that they are NUDT15 intermediate metabolizer, they will titrate slowly before uping the dose to 2-3mg/kg/day
  • If poor metabolizer, then would want to avoid azathioprine and mercaptopurine which is the prodrugs of azathioprine
  • Changing to mercaptopurine is not useful becos when it goes into the body, the aza is changed in to mercap, so it’s the same thing
  • D is wrong, because the patient is at risk of myelosuppression so must be careful when starting azathioprine
27
Q

What is the recommendation for starting Ondansetron in a CYP2D6 intermediate metabolizer?
A) Avoid ondansetron
B) Reduce dose of ondansetron
C) Increase dose of ondansetron
D) Follow standard prescribing

A

D: Follow standard prescribing

  • Ondansetron is cleared by CYP2D6
  • Ondansetron helps with N&V, so if it’s an ultrarapid metabolizer, clearing the drug too fast will reduce its effectiveness
  • But evidence is not there for us to do anything different if intermediate or poor metabolizer, so just follow standard prescribing
  • But might worry about side effects, but most of the time ondansetron is a mellow drug and in general setting, use lower dose compared to oncology setting (higher dose), so don’t observed side effects in patients who are CYP2D6 intermediate metabolizer and on ondansetron
  • In asian populations, there are a lot of CYP2D6 intermediate metabolizer (see CPIC guidelines 1st page > frequency table > phenotype frequency)
    Central / south asian → indian
    East asian → chinese
    Malay is in between
28
Q

In a patient that carries HLA-B*58:01, which of the followings statement is correct?
A) Patient might develop liver failure when prescribed carbamazepine
B) Patient might develop hypersensitivity reaction when prescribed allopurinol
C) Patient might develop renal failure when prescribed allopurinol
D) Patient might develop seizure reaction when prescribed abacavir

A

Ans: B
C is a risk factor but not what it will result in
The rest are not relevant
Except for Flucloxacillin(HLA-B*57:01), HLA positive usually predicts hypersensitivity reactions
(Drug-induced liver injury (DILI w/ flucloxacillin)

29
Q

Which of the following genes affect the drug response to atorvastatin?
A) HLA-A*31:01
B) CYP2C19
C) ABCG2
D) SLCO1B1

A

Ans: D
No recommendations for the other options
SLCO1B1: transporter that brings → affects all statins especially rosuvastatin
ABCG2 to rosuva but not atorva
CYP2C19 does not affect atorva even though it is in the guidelines (guidelines refer to all statins)

30
Q

What is the recommendation with regard to escitalopram in patients who are poor metabolizer of CYP2C19?
A) Reduce dose of escitalopram
B) Avoid escitalopram
C) No action
D) Increase dose of escitalopram

A

Ans: A and B
Consider an alternative first, but if cant then reduce dose by 50%

31
Q

What is the recommendation with regard to clopidogrel in patients undergoing percutaneous coronary intervention who are ultrarapid metabolizer of CYP2C19?
A) Avoid clopidogrel
B) No action
C) Increase dose of clopidogrel
D) Reduce dose of clopidogrel

A

Ans: B
Drug response might be altered, so have a lot of active compound but not associated with higher bleeding in the clinical setting so follow standard dosing

32
Q

Which of the followings are information sources for pharmacogenomics recommendations?
A) PharmVar
B) Clinical Pharmacogenetics Implementation Consortium (CPIC)
C) Dutch Pharmacogenetics Working Group (DPWG)
D) PharmGKB

A

Ans: BCD
PharmVar: Adding data by pharmacogenomists
More on variants, does not really give recommendations on drug therapy

33
Q

Which of the following drug is metabolized by CYP2D6 into an active metabolite?
A) Amitriptyline
B) Tramadol
C) Fluvoxamine
D) Escitalopram

A

Ans: B (metabolised to 200x more active metabolite by CYP2D6)
A: amitriptyline converted to nortriptyline by CYP2C19, both deactivated by CYP2D6
C: fluvoxamine into inactive metabolite (cleared by CYP2D6)
D: escitalopram metabolised by CYP2C19
Refer to pharmGKB to see the pathways of metabolism

34
Q

Which of the following pharmacogenetic tests is mandated by Singapore Health Science Authority/ Ministry of Health prior to the initiation of carbamazepine?
A) HLA-A15:01
B) HLA-B15:02
C) HLA-B58:02
D) HLA-A31:01

A

HLA-B*15:02 (mandate and it is the standard of care)

Option A HLA-A15:01 does not exist.
CPIC: also has recommendations for if you have HLA-A31:01 results
Option d: sg population is very low and if a rash is present, it is very mild.

35
Q

Mr Ong BL has been prescribed clopidogrel after his NSTEMI 12 years ago. He was recently genotyped to be a CYP2C19 poor metabolizer and the doctor decided to switch his clopidogrel to aspirin. What do you think?
A) Agree. Clopidogrel may not be well transformed to active metabolites in CYP2C19 metabolizer.
B) Disagree. This is drug gene interaction does not require any action.
C) Agree. Aspirin is the first line antiplatelet for patients with NSTEMI.
D) Disagree. Patient has been stable on clopidogrel for the past 12 years without a cardiovascular event.

A

Ans: A

CV risk increases with age - unless undergo drastic lifestyle changes. CV events are usually hard to observe until you get the endpoint - the fact that the patient has not gotten an MI in the past 12 years does not mean he will not get one tomorrow.

Guidelines incl FDA labelling generally agree to avoid clopidogrel if poor metaboliser of CYP2C19

Why patient not on aspirin in the first place? Normally DAPT then continue aspirin lifelong. Probably the reason - is it PUD? Allergy?
If the patient has allergy, consider desensitisation
If the patient has PUD, consider adding PPI to aspirin

36
Q

The doctor is planning to start Madam Tan YP on allopurinol for gout prophylaxis and is pondering whether he should test for HLA-B*58:01 prior to initiation of therapy. Based on the advisory from Health Science Authority, the following factors will support the decision to test: https://www.hsa.gov.sg/announcements/safety-alert/allopurinol-induced-severe-cutaneous-adverse-reactions-and-the-role-of-hla-b-5801-genotyping-a-reminder
A) Renal impairment
B) Advanced age
C) Liver impairment
D) High positive predictive value for developing allopurinol hypersensitivity syndrome

A

Ans: AB

D: +ve predictive value is low in general population, about 2%. But it goes up to 18% for renal impairment.

37
Q

Madam Lee SY is suffering from depression and the psychiatrist is planning to start her on an antidepressant. The PGx testing showed that she is a CYP2D6 poor metabolizer and CYP2C19 normal metabolizer. Which of the following antidepressants is the most appropriate based on the genotyping results?
A) Vortioxetine
B) Venlafaxine
C) Paroxetine
D) Sertraline

A

Ans: D (Sertraline)

38
Q

Which anti-depressants are metabolised by CYP2D6?

A

(SSRI) Paroxetine (into inactive), vortioxetine (into inactive),
fluvoxamine (into inactive),
(SNRI) venlafaxine (prodrug)

39
Q

Which antidepressants are metabolized by CYP2C19?

A

(SSRI) Escitalopram, sertraline (both into inactive)

40
Q

How does CYP2C19 affect escitalopram and clopidogrel individually?

A
  • clopidogrel (prodrug)
  • escitalopram (into inactive metabolites)
41
Q

How does omeprazole affect CYP2C19?

A

It is a moderate inhibitor, thus reducing CYP2C19 metabolizing activity

42
Q

What to do when CYP2C19 is a poor metabolizer and patient is on clopidogrel and escitalopram?

A
  • Switch out Clopidogrel 75mg OM for Ticagrelor 90mg BD. to complete 21 days (for minor stroke)
  • Escitalopram 10mg OM should be considered switching for another clinically appropriate antidepressant. If not, consider a lower starting dose of 5mg OM and a slower titration schedule increments of 5 mg. Max is 20mg/day.
  • watch out for bleeding if on DAPT and SSRI

Escitalopram can cause bleeding, QTc prolongation and serotonin syndrome

43
Q

If patient is HLA-B*58:01 positive and is on allopurinol for 4 years without getting any SCAR, what do you do?

A
  • SCAR usually occur in the 1st 3 months of initiating allopurinol. Since have not had SCAR for 4 years, consider continuing allopurinol
  • but most ensure uric acid is <6mg/dL and close monitoring
  • OR could consider switching to Febuxostat 40mg OM (more expensive and black box warning for CVD)

PR4152 Multi-Morbidity (7 decks)

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