Pharmacogenomics

Hailey M. Stoker, PharmD

PGY1 Pharmacy Resident Franciscan
Health Lafayette East
 DISCLOSURES

• The speaker has no actual or potential conflicts of interest

in relation to this presentation

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 Interior title
Learning goes here
Objectives

1. Describe pharmacogenomics and its role in safe and

effective medication therapies.
2. Recognize patients who may benefit from genetic testing.
3. Recognize medications which are known to have altered
activity related to genetic variants.
4. Locate resources for new pharmacogenomic
information.

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 What is Pharmacogenomics?1,2
•The "field of research that studies how a person’s genes
affect how he or she responds to medications.”1
•Precision medicine
•Long-term goal:
• Help patients be prescribed drugs and doses best suited
for them
•People are affected by drugs differently, some can be
predicted by genetic testing

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 Why Precision Medicine?2
Decreased
One-size-fits- patient
all approach satisfaction

Possible side
effects
"(A) person who needs a blood transfusion is not given blood
from a randomly selected donor; instead, the donor’s blood
type is matched to the recipient to reduce the risk of
complications."2

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 Pharmacogenomic Resources3,4,5
• PharmGKB: pharmgkb.org
• NIH-funded resource which collects, curates, and
disseminates information pertaining to pharmacogenomics
• Clinical Pharmacogenetic Implementation Consortium (CPIC):
cpicpgx.org
• International association which produces guidelines for
clinical genetic testing results
• Food and Drug Administration (FDA): fda.gov/medical-
devices/precision-medicine/table-pharmacogenetic-association
• Guidance relating to genetic testing results and clinical
decision making

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 Differences in Pharmacogenomic Resources6
• No uniform approach
• Different dosing recommendations
• Different/Additional gene-drug associations

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 Pharmacogenomic Collaborations7,8
•PharmCAT - Pharmacogenomic Clinical Annotation Tool
•STRIPE – Standarizing Laboratory Practices in
Pharmacogenomics

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 Gene-Drug Association3
•PharmGKB
•747 annotated drugs
•396 FDA label annotations
•189 annotated clinical guidelines

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 Pharmacogenomic Testing4
• Guidelines suggests genotyping will become widespread
• Cost-effective

Increased
adherence

Decreased Improved
ADRs & patient
hospitalizations outcomes

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 Interior title
Definitions 9,10goes here

• Pharmacogenetics vs Pharmacogenomics
• Pharmacogenetics: genetic causes of individual
variations in drug response
• Pharmacogenomics: impact of multiple variants in the
genome that may determine response to drug therapy
• Gene vs Allele
• Gene: DNA that carries a trait
• Allele: Gene variant
• Genotype vs Phenotype
• Genotype: Unique set of DNA, two inherited alleles
• Phenotype: Expression of the gene

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 Interior title
Definitions 9,11goes here

• Pharmacogenetics vs Pharmacogenomics

Roden DM, Altman RB, Benowitz NL, et al. Pharmacogenomics: challenges and opportunities. Ann Intern Med.
2006;145(10):749-757. doi:10.7326/0003-4819-145-10-200611210-00007

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 Interior title
Definitions 4,12goes here

• Variant
• Alteration in the most common DNA nucleotide
sequence
• Affected subgroups
• Specific genetic variant
• Phenotypes: classification of metabolism
Poor Intermediate Normal Rapid Ultrarapid
PM IM NM RM UM
• Cytochrome P450
• "CYP" enzymes which work to synthesize and metabolize
drugs

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 Interior
CPIC title goes here
Recommendations 4

CPIC Clinical Context Strength of Recommendation

Level
A Genetic information should be used to change At least one or more
affected drug. moderate or strong action
recommended
B Genetic information COULD be used to change At least one optional action is
prescribing of the affected drug. recommended
C There are published studies at varying levels of No prescribing actions are
evidence, but no prescribing actions are recommended
recommended.
D There are few published studies, clinical No prescribing actions are
actions are unclear, little mechanistic basis, recommended.
mostly weak evidence, or substantial
conflicting data.

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 Interior title
PharmGKB goes here
Recommendations 3

PharmGKB Description Scoring Level of

Level Range Evidence
1A Variant-specific prescribing guidance available. ≥80 High
Supportive publication available.

1B No variant-specific combinations with high level 25-79.9 High

of evidence.
2A Implies causation of drug phenotype is more 8-24.9 Moderate
likely.
2B Implies association, however some cohorts 8-24.9 Moderate
contain conflicting evidence.
3 Conflicting studies or single study available. 0-7.9 Low

4 No evidence for an association. <0 Unsupported

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 CARDIOLOGY

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 Anticoagulant4,13

Drug Gene Affected Description of Gene-Drug

subgroups Interaction
Warfarin CYP2C9 IM/PM (A, 1A) Altered systemic
concentrations.
Warfarin CYP4F2 V433M variant (A, 1A) May affect dosage
requirements.
Warfarin VKORC1 -1693G>A (A, 1A) Altered dosage
variant requirements.
See recommendations on following slide

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 CPIC
Guidelines4

Package
Insert
Algorithm13

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 Anticoagulant3
• Warfarin:
CYP2C9

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 Anticoagulant3
• Warfarin:
VKORC1
CYP4F2

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 Antiplatelet4,14

Drug Gene Affected Description of Gene-Drug

subgroups Interaction
Clopidogrel CYP2C19 IM/PM (A, 1A) Lower systemic active
metabolite. Lower antiplatelet
response, increased
cardiovascular risk. Another
P2Y12 inhibitor may be used.
Most common in Asian populations

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 Antiplatelet recommendations4,13

Clopidogrel recommendations:

CYP2C19 altered metabolism

• IM/PM

Recommend alternative treatment

• Ticagrelor
• Prasugrel

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 Antiplatelet3
• Clopidogrel

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 Antilipemic4

Drug GeneAffected Description of Gene-Drug

subgroups Interaction
Simvastatin SLCO1B1 521 TC or (A, 1A) Higher systemic
Rosuvastatin 521 CC concentrations. Higher risk of
adverse effects. Monitor for
side effects and adjust to
desired effect.
Most common in Asian populations

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 Antilipemic3

• Simvastatin
• Rosuvastatin

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 CHEMOTHERAPY

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 Chemotherapy4

Drug Gene Affected Description of Gene-Drug

subgroups Interaction
5-FU DPYD IM/PM (A, 1A) Higher risk of adverse
Capecitabine reactions. Discontinue or withhold
in the presence of severe
reactions.
Azathioprine TPMT IM/PM (A, 1A) Higher risk of adverse
6-MP NUDT15 reactions. Reduce dose or
Thioguanine* considered alternative therapies.
5-FU: Fluorouracil, 6-MP: Mercaptopurine
DPYD variations: Most often seen in White or Black populations
TPMT variations: Most often seen in White or Black populations
NUDT15 variations: Most often seen in Asian or Hispanic
populations
*(A, 3)
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 Chemotherapy Recommendations4

Fluoropyrimidines
• 5-FU, Capecitabine
• Discontinue or withhold in the presence of severe
reactions

Thiopurines
• Azathioprine, 6-MP, Thioguanine
• Reduce dose or consider alternative therapies

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 Chemotherapy3
• Fluoropyrimidines

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 Chemotherapy3

• Thiopurines

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 NEUROLOGY

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 Antipsychotics4

Drug Gene
Affected Description of Gene-Drug
subgroups Interaction
Aripiprazole CYP2D6 PM Increase in systemic
Brexpiprazole concentrations. Suggest
Clozapine starting at a lower dose.
Iloperidone

Aripiprazole (B, 1A)

Brexpiprazole (B/C, --)
Clozapine (B/C, --)
Iloperidone (B/C, 3)

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 Antidepressants4

Drug Gene Affected Description of Gene-Drug

subgroups Interaction
Citalopram CYP2C19 PM (A, 1A) Higher systemic
Escitalopram concentrations. Higher risk of
adverse reactions. May decrease
starting dose or consider an
alternative agent.
Paroxetine CYP2D6 UM/PM (A, 1A) Altered systemic
concentrations. UM may consider an
alternative agent due to decreased
efficacy. PM may decrease starting
dose or consider an alternative
agent due to side effects.
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 Antidepressants Cont.4

Drug Gene Affected Description of Gene-Drug Interaction

subgroups
Amitriptyline CYP2C19 UM/IM/PM (A, 1A) Altered systemic concentrations.
UM may consider using alternative
agent. IM/PM may consider starting at
lower doses.
Amitriptyline CYP2D6 UM/IM/PM (A, 1A) Altered systemic concentrations.
Nortriptyline UM may consider using an alternative
agent. IM/PM may consider starting at
lower doses.
Venlafaxine CYP2D6 PM (A/B, 1A) Altered systemic
concentrations. Consider dosage
reduction.

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 Antidepressants Recommendations3
• Many uses for each antidepressant
• Prescriber discretion

Are any of these

What other
What is the medications
medications can be
medication being metabolized through
used to treat the
used for? an alternative
ailment?
pathway?

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 Antidepressants3
• Citalopram
• Escitalopram

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 Antidepressants3
• Paroxetine

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 Antidepressants4
Amitriptyline vs. Nortriptyline

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 Antidepressants3
• Venlafaxine

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 Anticonvulsants4

Drug Gene Affected Description of Gene-Drug

subgroups Interaction
Carbamazepine HLA-B *15:02 allele (A, 1A) Increased risk of SJS/TEN.
Oxcarbazepine
Fosphenytoin* CYP2C9 IM/PM (A, 1A) Higher systemic active
Phenytoin metabolite. Higher risk of adverse
reactions. May decrease starting
dose or consider alternative agent.
Fosphenytoin* HLA-B *15:02 allele (A, 1A) Increased risk of SJS/TEN.
Phenytoin
SJS/TEN: Stevens Johnson Syndrome/Toxic Epidermal Necrolysis
HLA-B variant: Most common in Asian populations
*(A, --)
See recommendations for HLA-B*15:02 on following slide
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 Anticonvulsant Recommendations4

HLA-B*15:02 0-3 months of use:

• Avoid carbamazepine, oxcarbazepine, phenytoin and fosphenytoin
• Alternative options may be eslicarbazepine, lamotrigine,
phenobarbital, or levetiracetam

HLA-B*15:02 ≥ 3 months of use:

• Can continue use of medication
• Low risk

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 Anticonvulsants3
• Fosphenytoin
• Phenytoin

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 ANALGESICS

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 Analgesics4

Drug Gene Affected Description of Gene-Drug Interaction

subgroups
Celecoxib CYP2C9 PM (A, 1A) Increase in systemic
Meloxicam concentrations. Suggest starting at a
lower dose.
Codeine CYP2D6 UM (A, 1A) Higher systemic active
Tramadol metabolite. Higher risk of adverse
reactions. May consider alternative
agent.
Codeine CYP2D6 PM (A, 1A) Lower systemic activation.
Tramadol Reduced efficacy may occur. May
consider alternative agent.

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 Codeine and Tramadol in Breastfeeding
Recommendations15,16

•Should not be given

• Active morphine
metabolite passed
from UM

https://www.scarymommy.com/how-hold-baby

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 Analgesics3

• Celecoxib
• Meloxicam

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 Analgesics4
• Tramadol
• Codeine

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 Miscellaneous
Medications

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 Miscellaneous4

Drug Gene Affected Description of Gene-Drug Interaction

subgroups
Abacavir HLA-B *57:01 (A, 1A) Increased risk of hypersensitivity
reactions. Do not use.
Allopurinol HLA-B *58:01 (A, 1A) Increased rate of severe skin
reactions. Contraindicated.
Atomoxetine CYP2D6 PM (A, 1A) Higher systemic active metabolite.
Higher risk of adverse reactions. Adjust to
effect and monitor for side effects.
Omeprazole CYP2C19 PM (A, 1A) Lower systemic activation.
Pantoprazole Reduced efficacy may occur. May consider
increased dose.

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 Miscellaneous Cont.4

Drug Gene Affected Description of Gene-Drug Interaction

subgroups
Succinylcholine BCHE* IM/PM (B/C, 3) Higher systemic concentrations.
Higher risk of adverse reactions.
Tacrolimus CYP3A5 IM/NM (A, 1A) Lower systemic concentrations.
Higher risk of rejection. Consider
increased dosing.
Tamoxifen CYP2D6 IM/PM (A, 1A) Lower systemic active
metabolite. Consider an alternative agent
or increased dosing.
Voriconazole CYP2C19 IM/PM (A, 1A) Higher systemic concentrations.
Higher risk of adverse events. Consider
alternative agent.
*CACNA1S, RYR1
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 Gene-Drug Association3

•PharmGKB
•747 annotated drugs
•396 FDA label annotations
•189 annotated clinical guidelines

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 EMR Example

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 Known gene-drug interactions3

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References

1. Pharmacogenomics. National Institute of General Medical Sciences.

https://nigms.nih.gov/education/fact-sheets/Pages/pharmacogenomics.aspx. Accessed
September 10, 2022.
2. What is precision medicine?: Medlineplus Genetics. MedlinePlus.
https://medlineplus.gov/genetics/understanding/precisionmedicine/definition/. Accessed
September 10, 2022.
3. PharmGKB. https://pharmgkb.org/. Accessed September 12, 2022.
4. CPIC. https://cpicpgx.org/guidelines/ . Accessed September 12, 2022.
5. Table of Pharmacogenetic Association. FDA. https://www.fda.gov/medical-devices/precision-
medicine/table-pharmacogenetic-associations. Accessed September 12, 2022.
6. Pritchard D, Patel JN, Stephens LE, McLeod HL. Comparison of FDA Table of
Pharmacogenetic Associations and Clinical Pharmacogenetics Implementation Consortium
Guidelines. Am J Health-Syst Pharm. 2022;79(12):993-1005.
Doi:https://doi.org/10.1093/ajhp/zxac064
7. Pharmacogenomics Clinical Annotation Tool. PharmCAT. https://pharmcat.org. Accessed
September 12, 2022.
8. STRIPE Collaborative Community. American Society of Pharmacovigilance.
https://www.stopadr.org/stripe. Accessed September 12, 2022.

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References

9. Dere WH, Suto TS. The role of pharmacogenetics and pharmacogenomics in improving
translation medicine. Clin Cases Miner Bone Metab. 2009 Jan-Apr; 6(1): 13–16.
10. Allele vs. Gene. Diffen. https://www.diffen.com/difference/Allele_vs_Gene#:~:text=A%20gen
e%20is%20a%20stretch,an%20allele%20for%20brown%20eyes. Accessed September 15,
2022
11. Roden DM, Altman RB, Benowitz NL, et al. Pharmacogenomics: challenges and
opportunities. Ann Intern Med. 2006;145(10):749-757. doi:10.7326/0003-4819-145-10-
200611210-00007
12. Variant. NIH: National Cancer Institute.
https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/variant.
Accessed September 20, 2022.
13. Warfarin. Package insert. Camber Pharmaceuticals Inc; 2012.
14. Clopidogrel. Package insert. ACI Healthcare USA Inc; 2020.
15. Dean L, Kane M. Codeine therapy and CYP2D6 genotype. Medical Genetic
Summaries. 2012.
16. Pharmacogenomics – Codeine and breastfeeding. Gecko.
https://geneticseducation.ca/educational-resources/gec-ko-on-the-run/codeine-and-
breastfeeding-pharmacogenomics/. Accessed September 20, 2022.

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Questions?

Hailey M. Stoker, PharmD

Hailey.Stoker@franciscanalliance.org

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