PGX applications in CVD

Question 1

 Gene mutations
 Inherited from a parent
 Acquired during a person’s lifetime
▪ Mutations range in size from
▪ single base-pair mutation that occurs at a
specific site in the DNA sequence (SNV)
▪ to a large segment of a chromosome (CNV)

snp

Answer 1

SNP = SNV
which occur in
at least 1-2% of
the population

• Polymorphism in enzymes, receptors and
transporters proteins can affect the PK and PD
of several medications
• In fact, 50–75% of medications are substrates of
the cytochrome P450 (CYP) 3A4 enzyme, 2C9,
and/or 2D6 metabolizing enzymes
• 50% of CPIC drugs guidelines involves 2C19, and/or
2D6

Question 2

review types of metabolizers

Answer 2

slide 11

Question 3

role in CV tx

Answer 3

1. Anticoagulants - Warfarin and other Vit K antagonists
2. Antiplatelets- Clopidogrel
3. Statins -Atorvastatin, simvastatin
4. Beta-blockers
   metoprolol, carvedilol, and propranolol
   not enoguh guidelines
5. Hypertension???? ….future discovery
   ➢ PGx trials have not provided an evidence base to
   support genotype-guided HTN pharmacotherapy,
   ➢ therapeutic recommendations remain stratified
   by self-reported ethnicity,
   ➢ with ‘black’ Europeans and Americans
   recommended a different treatment regime
6. Antiarrhythmia ….future discovery
   ➢ Medications known to prolong the QT interval
   should be avoided in those known to harbour
   long-QT-associated genetic variants
   (Drug-Disease interaction, involving genetic
   makeup…..falls more under diagnostic rather than
   therapy management)
7. Chemotherapy-induced cardiomyopathy….HW!
   Doxorubicin and paclitaxel
   ➢ Are there any clinical guidelines for PGX testing?
   ➢ Why?
   ➢ What is the reference for that? Guideline body and
   the year if possible?
   ➢ What is the level of evidence?

Question 4

who is good candidate for genetic testing

Answer 4

1. CPIC and DWPG do not specify who are the better candidates
2. Challenges as cost, technology availability and ethical considerations
3. Professional decisions based on best evidence based data available

Ethnicity !
vs.
actual individual PGX testing data!
cant take ethnicity as there is chance the person does not have it

Question 5

1. Two PCI patients and one patient with deep vein
   thrombosis appeared with a clopidogrel prescription
   in your pharmacy.
   a. PCI, White Caucasian, 66 years old male,
   b. PCI, Black, 70 years old male
   c. Deep vein thrombosis, Asian, 62 years old female
   -would you recommend a pharmacogenetic testing for
   these patients? Which genes will you be testing? Why?
   -If his PGX results came like that
   a. CYP2C19 2/2, b. CYP2C191/17, c. CYP2C191/1
   What would you recommend and why?

Answer 5

navitage PharmGKB

prescribign info - start with CPIC

see slide 22-26

answer is pt a or b
c: Even if it has a she has a problem it won’t help me give her a clinical decision,

• 2/*2 –> poor metabolizer, strong evidence
  recommendation: avoid standard dose (75mg/day) if possible, use prasgrel or tic at standard dose if no contra

1/17 –> rapid met, strong evidence
use standard dose clopid

look at other pt aspects too

Question 6

Clinical annotation scores

Answer 6

Clinical annotation scores are only used to determine the level of evidence and is not intended to be
used to rank or compare clinical annotations within a given level of evidence.
Clinical annotations must have at least two supporting annotations from independent publications, one of
which must be a variant annotation, in order to be assigned levels 1 or 2.

Clinical annotations which have a high enough score to rise above level 3 but are only supported by a
single publication will remain at level 3 until independent support from another publication or a guideline or
drug label is curated and added to the annotation.

level 1, 2, 3, 4 (level 1 high support of evidence)

Question 7

questions to ask

Answer 7

1. is it a drug or prodrug
2. what type of allele, phenotype-genotype relationship (allele and functionality)
3. diplotypes -> poor metabolizer, rapid metabolizer
4. level of evidence
5. what is tx outcome, do I need to change tx
   (can use calculators on pharmKGB)

Question 8

clopidogrel

Answer 8

guidelines related to ACS and PCI pt
Asian lady has high possibility of carrying intermediate bt does not have PCI or ACS, not a good gandidate

UM, EM –> clopid at standard dose
IM, PM –> alternative antiplatelet (prasugrel or ticarelor)

PCI:Percutaneous coronary intervention
ACS: Acute coronary syndrome