A Hands on Pharmacogenomics! An Introduction

Pharm 503
4th November 2019
Dalia A. Hamdy
BSc.(Pharm), MSc., PhD, RPh., MBA, MRSC
Founder and Manager of AbEx Health Services LTD.
Clinical Assistant Professor, FoPPS, University of Alberta
dhamdi@ualberta.ca
2-142K Katz

i. Getting introduced to the basics of
pharmacogenomics and its effect on drug
metabolism/pharmacokinetics (PK) and/or
pharmacodynamics (PK-PD).
ii. Apply Pharmacogenomics in precision medicine
iii. Having a Hands-on experience on the online
resources used to help you find dosing guidelines
(CPIC & PharmGKb)
iv. Integrating pharmacogenenomics into your clinical
assessment and decision in resolving drug therapy
problems and optimizing pharmacotherapy outcomes
Dr. Dalia A. Hamdy (FS 19/20AY) 2

1. Langman L, Dasgupta A. Pharmacogenomics in Clinical Therapeutics.;
Wiley-Blackwell 2012.
2. CPIC Guidelines for Simvastatin and SLCO1B1
https://www.pharmgkb.org/chemical/PA451363/guidelineAnnotation/
PA166105005
3. Roden D. Case Studies in personalized medicine. Vanderbilt University.
Online course through coursera.
https://www.coursera.org/lecture/personalizedmed/variability-in-drug-
therapy-spi4r
4. CPIC Guidelines for codeine and CYP2D6
https://www.pharmgkb.org/guidelineAnnotation/PA166104996
5. CPIC Guidelines for clopidogrel and CYP2C19
https://www.pharmgkb.org/guidelineAnnotation/PA166104948
6. CPIC Guidelines for voriconazole and CYP2C19
https://www.pharmgkb.org/chemical/PA10233/guidelineAnnotation/P
A166161537
7. Klein D. et al. PharmGKB summary: tamoxifen pathway,
pharmacokinetics. Pharmacogenet Genomics. 2013; 23(11): 643–647.
3Dr. Dalia A. Hamdy (FS 19/20AY)

1. SLCO1B1 is a (transporter/enzyme/receptor) that is
found in the hepatocytes also known as
(OATP1B1/OAT1B1/OCT1B1). The following Allelle(s)
(*1a/*5/*14/*2) has normal function whereas
(*1a/*5/*14/*2) has decreased function and
(*1a/*5/*14/*2) has increased function.
2. A patient shows up in your pharmacy with a genotype of
(*1a/*1a) what would be the recommended dose? Can we
give 80 mg qd for this patient? Why? What is your
reference?
3. A patient carrying a genotype of (*1a/*5) came across
your pharmacy and his cholesterol levels were not
adjusted using the 20 mg /day dose of statin? What would
be your recommendation?

“is the tailoring of medical treatment to the
individual characteristics of each patient”
The Age of Personalized Medicine
“The science of individualized prevention and
therapy”
National Institute of Health

11
One Size fits all
medicine
Vs.
Personalized
medicine
Dr. Dalia A. Hamdy (FS 19/20AY)

Pharmacogenetics:
The study of the effect of variations in DNA
sequence (genetic differences) on drug
response in terms of both the
metabolism/clearance (PK) and action (PD) of
the drug delivered

1. What is DNA?
DNA (deoxyribonucleic acid),
 the cell’s hereditary material.
 DNA is a polymer of nucleotides
(sugar, phosphate and one of four
nitrogenous bases (A,T,G,C)

Human genome consists of
about 3.2 billion base pair (bp)
Every person has two copies of
each gene, one inherited from
each parent (6.4 billion bp)
DNA molecule is packaged into
thread-like structures called
chromosomes.
23 pairs of Chromosomes
 Sex chromosome XX or XY
 22 pairs autosomes

2. What is the gene function?
DNA
• 99-98% Non-coding : its job is to actually regulate the
process whereby genes are translated into proteins.
• 1-2% coding : acts like the blueprint that encodes
proteins (enzymes, structural elements, signaling
molecules)

3. Types of polymorphism
-SNPs (Single-Nucleotide Polymorphisms)
–Indels(Insertions & Deletions)
–VNTR (Variable Number Tandem Repeats)
–CNV (Copy Number Variants)
–Haplotypes (combination of alleles or to a set
of single nucleotide polymorphisms (SNPs) found
on the same chromosome

 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)
19
SNP = SNV
which occur in
at least 1-2% of
the population

3. Types of genetic variants
SNP can be in the coding or non-coding regions
of the DNA resulting in
different proteins that could be functional or
non functional

• 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

Genes Alleles
CYP1A2 *1C, *1C, *1E,*1F, *1J, *1K, *1L, *1V, *1W, *6, *7, *8, *15
CYP2B6 *2, *4, *5, *6, *7, *8, *9, *13, *16, *18, *22, *34
CYP2C19 *2, *3, *4, *4B, *6, *8, *10, *17
CYP2C9 *2, *3, *4, *5, *6, *8, *9, *11, *12, *18, *27
CYP2D6 *2, *2A, *3, *4, *5, *6, *7, *9, *10, *14, *14A, *17, *29, *4N, *4M, *5, *6, *6C,
*7, *8, *9, *10, *11, *12, *13, *14A, *14B, *15, *17, *18, *19, *29, *31, *34, *35,
*36, *39,*41, *42, *63, *64, *68, *69, *70, *91, *109
CYP3A4 *1B, *3, *6, *11, *12, *16, *17, *18, *19, *22
CYP3A5 *2, *3A, *3B, *6, *7
COMT VAL158MET
DPYD *2A, *4, *5, *6, *9A, *13, rs7376798A
DRD2 PROMOTER VARIANT -241A>G
F2 20210G>A
F5 ARG534GLN (LEIDEN, 1691G>A)
GRIK4 NON-CODING (INTRONIC) T>C VARIANT
HTR2A INTRON 2, T>C VARIANT
HTR2C PROMOTER VARIANT -759C>T
IFNL3 rs1297860 C/T
IL28B (IFNL4) NON-CODING (INTRONIC) C>T VARIANT
NUDT15 ARG139CYS
OPRM1 ASN40ASP, A118G
SLC6A4 C,-1810A>G; -1791_-1749DEL43
SLCO1B1 *1B, *5, *9, *15, *31
TPMT *2, *3A, *3B, *3C, *4, *8
UGT1A1 *6, *27, *38, *60, *80
VKORC1 c.-1639G>T, A and G variants
25
Commercially available
pharmacogenomic testing
available in the Canadian
market

1. A patient appears with a T4 prescription in your pharmacy.
While discussing with him the use and checking his history you
realize that he has been on T3 and the pain is not manageable
and the dr. moved him to T4. In few days, he appears again
with a higher dose of codeine and still his pain is not in control.
-would you recommend a pharmacogenetic testing for this patient?
Why?
-If his PGX results came like that
CYP2D6 *4/*7, CYP2C19*1/*17, CYP2C9*1/*1, VKORC1 AA
What would you recommend and why?
2. What if the patient carried CYP2D6 *4/*9?
3. Knowing the mechanism of action of codeine, What other
information could be missing?

1. CYP 2D6

1. CYP 2D6
This had been determined using genotyping and
phenotyping. In phenotyping, a CYP2D6 speciﬁc probe
drug such as dextromethorphan is administered
the relative ratio between the concentration of probe
drug (dextromethorphan: DM) and its CYP2D6 speciﬁc
metabolite (dextorphan:DX)is obtained.
DM:DX ratios poor metabolizers.
DM:DX ratios extensive metabolizers

1. CYP 2D6

1. CYP 2D6
What is the effect of 2D6 on codeine?
Codeine
• Opiate analgesic
• Prodrug of morphine - is found naturally but
at low concentrations so usually synthesized
from morphine

1. CYP 2D6

33
1. Codeine is bioactivated to morphine, a strong opioid
agonist, by the hepatic cytochrome P450 2D6
2. The efficacy and safety of codeine are governed by
CYP2D6 activity.
3. Polymorphisms are a major cause of CYP2D6
variability.

Dr. Dalia A. Hamdy (SS18/19AY) 34

35
Similarly What about CYP2D6 and Tamoxifen?
Tamoxifen:
• a selective estrogen receptor modulator
• Used for the treatment and prevention of
estrogen receptor (ER)-positive breast cancer
• The drug is extensively metabolized by
CYP2D6 and other enzymes.

37
Similarly What about CYP2D6 and Tamoxifen?
• 4-hydroxytamoxifen and endoxifen, are more
potent and considered the primary active
forms of the drug.

38
Phenotype Genotype Therapeutic
recommendation for
tamoxifen
Ultrarapid metabolizer More than two copies of
functional alleles
None
Intermediate metabolizer One active allele and one
inactive allele, or two
decreased activity alleles,
or one decreased activity
allele and one inactive
allele
Increased risk for relapse of
breast cancer. Avoid
concomitant use of CYP2D6
inhibitors. Consider
aromatase inhibitor for
postmenopausal women
Poor metabolizer Two inactive alleles Increased risk for relapse of
breast cancer. Consider
aromatase inhibitor for
postmenopausal women

45
PCI:Percutaneous coronary intervention
ACS: Acute coronary syndromeDr. Dalia A. Hamdy (FS 19/20AY)

48
1. What is expected to happen when I have
a. PM or IM CYP2C19?
b. UM or RM CYP2C19?
2. If we know that voriconazole is used for ttt
of invasive fungal infections in cancer patients.
Also that trough concentrations <2 mcg/ml is
associated with worse clinical outcomes? What
are the CPIC guidelines for a pt. with CYP2C19
*1/*17 or *2/*3?

52
Using the CPIC guidelines how would you consider
carbamazepine therapy in the following pts.
1. A patient was using CBZ for 4 months and stopped
for problems with insurance coverage and
hospitalization periods. The dr. wants to restart him
again on CBZ. The dr. phones you and asks that he
heard about an available pharmacogenomic test
that is needed for this pt.? Would you strongly
recommend doing the test ? For what gene?
Why/why not?
2. The patient did the test and those were the results
CYP2D6 *4/*7, CYP2C19*1/*17, CYP2C9*1/*1, VKORC1
AA, HLA-B*15:02 negative
What would you suggest the dr. to do?

53
Using the CPIC guidelines how would you
consider carbamazepine therapy in the
following pts.
3. A naïve pt. patient wants to start CBZ
therapy and his genetic testing shows HLA-
A*31:01 genotype
What would you suggest the dr. to do?

54
Discussion point

Pharmacists are expected to
1. Be the point of testing for the patients
2. Receive the patients reports and interpret
them in a meeting in lay language
3. Keep the results, consent and data in the
patient profile
4. Release the results or give results access to
patient
5. Communicate the results with other
healthcare professionals that the patient
chooses.

 Pharmacists are encouraged to communicate
with local physicians and introduce them to
report samples
 Physicians are expected to act positively if
they are aware and familiar with the shape
or the results.
 Pharmacists should encourage the patients to
contact their physicians if the results
warrants any change in therapy

 A pharmacist must prepare the dr. to the
referral . Surprises are not recommended!

A Hands on Pharmacogenomics! An Introduction

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