Adverse Drug Reactions & Pharmacogenomics

Question 1

Therapeutic tx’s:

Answer 1

Revolutionized medicine

Accompanied w/:
- Adverse drug rxns
- Non-response

Question 2

Adverse Drug Reactions (ADRs):

Answer 2

• Negative / undesirable effects of drug treatment
• Can influence different systems
• Severely debilitating and potentially fatal
• Growing elderly population
• Strain on resource-constrained healthcare systems

Question 3

Type A:

Answer 3

Pharmacological effect; predictable; dose dependent

Question 4

Type B:

Answer 4

Caused by immune-mediation & nonimmune-mediation; non-predictable; dose independent

Question 5

Why is this clinically important?

Answer 5

Drug safety and effectiveness

Affects both drug efficacy and toxicity

Clinical trials (average) vs real world (what is seen in clinic, subgroups)

Question 6

Can occur via different mechanisms:

Answer 6

◦ Pharmacokinetic:
Different concentrations at sites of drug action
◦ Pharmacodynamic:
Different responses to the same drug concentration

Question 7

Pharmacogenomics

Answer 7

Individual genetics
◦ Inherited variation (DNA)
◦ Human genomes are >99.9% alike, however:
~3 million variants / individual human genome
◦ General traits (e.g., height)
◦ Disease (rare and complex)
◦ Key determinant of response to medication

Pharmacogenomics (sometimes referred to as PGx)
◦ How genetic variants can impact treatment response
◦ Predict, understand & prevent non-optimal treatments
◦ Cheaper genotyping
◦ Barriers to clinical implementation is a key area of current focus

Question 8

What is Precision medicine?

Answer 8

Precision medicine takes both genetic and non-genetic factors into account
◦ Drug dosing algorithms
◦ Previously termed personalized medicine

Question 9

Precision Medicine Initiative describes it as:

Answer 9

an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.”

Question 10

Simple genetic traits i.e., one gene contributes towards trait

Answer 10

CAVEAT
Not all traits/diseases involve one gene/genetic variant

Question 11

How does genetic variation in a gene eventually lead to altered activity?

Answer 11

Regulatory variation
- Increased expression
- Decreased expression

Coding variation
- Missense
- Start/stop lost
- Inframe insertion/deletion
- Stop gained
- Frameshift

Splice-site variation
- Create/abolish acceptor site
- Create/abolish donor site

Question 12

What is Expression Quantitative Trait Loci (eQTLs)?

Answer 12

Examine the association
◦Between genetic variants and gene expression levels
◦Example: CYP2C19*17 allele and clopidogrel

Question 13

Alleles:

Answer 13

Version of the same gene that have different DNA spelling changes compared to each other.

Question 14

Genotype:

Answer 14

The genetic state of both copies of a genetic variant.

Question 15

Haplotype:

Answer 15

A combination of multiple spelling changes within a
particular gene.

Question 16

Phenotype:

Answer 16

A physical characteristic which is determined by genetic variants in your genome. Examples of phenotypes include eye color, hair color and how quickly you metabolize medications.

Question 17

Star allele:

Answer 17

A method of labeling haplotypes in genes (e.g., *2, *3, etc.).

Question 18

How pharmacogenomics can improve treatment?

Answer 18

• Improving efficacy
• Predicting drug dose
• Preventing adverse drug rxns
• Enabling drug discovery/development
• Developing targeted drugs for cancer therapy
• Predicting the activation of prodrugs

Question 19

Important clinical considerations for pharmacogenomic biomarkers and clinical implementation:

Answer 19

Associations between genetic variants and adverse drug reactions should be reliably REPLICATED

Robust ADR PHENOTYPING is essential
◦ e.g., Common Terminology Criteria for Adverse Events

Risk conferred by variants should be CLINICALLY RELEVANT

Implementation is assisted by CLINICAL PRACTICE GUIDELINES

Question 20

Clinical Practice Guidelines:

Answer 20

Facilitate genotype guided therapy

Clinical Pharmacogenetics Implementation Consortium (CPIC)
◦Standardized, peer-reviewed
◦International consortium, formed in 2009
◦Systematic grading of evidence and clinical recommendations

Question 21

FDA testing required:

Answer 21

req’s testing before getting a drug

Question 22

The value if pharmacogenomics in clinical practice:

Answer 22

Multi-country randomized controlled trial
Swen et al. (2023) Lancet
◦ Hospitals, community centers and pharmacies
◦ Seven European countries ◦ Pre-emptive genotyping
A 12-gene pharmacogenomic panel (50 variants) reduced ADR frequency by 30%!

Question 23

Pharmacogene example: CYP2D6:

Answer 23

CYP2D6 is an important drug metabolizing enzyme

Polymorphic (PGx applications)

Currently: 16 drugs with clinical guidelines for CYP2D6 PGx

Question 24

More than 100 genetic variants changing the function of ______

Answer 24

CYP2D6

In addition to single nucleotide variants, CYP2D6 has large scale rearrangements in some patients

Question 25

Examples of CYP2D6 alleles:

Answer 25

> 140 CYP2D6 alleles described on PharmVar
Single nucleotide polymorphisms, duplications, deletions, hybrid genes

• CYP2D6*1 (reference allele): normal functional
• CYP2D61xN (full gene duplication): increased function * CYP2D63 (259frameshift): non-functional
• CYP2D6*4 (1847G>A splice defect): non-functional
• CYP2D6*5 (full gene deletion): non-functional
• CYP2D6*17 (missense T107I): decreased function

Question 26

Codeine/CYP2D6 clinical implications example:

Answer 26

Pharmacokinetics: codeine is converted to morphine by CYP2D6

Breast feeding cases
◦ Drug label changes

Ultra-rapid metabolizers should NOT be prescribed codeine due to toxicity risks
◦ Non-opioid alternatives
◦ Population differences

Question 27

Breast cancer treatment:

Answer 27

Tamoxifen
◦Estrogen-receptor positive breast cancer treatment
◦Decreases relapse rate by 40%
◦Mechanism of action complex
◦ Active metabolites bind to the estrogen receptor, blocks proliferation

Inter-individual variability in relapse rates
◦30-50% of patients relapse

Question 28

Which enzymes metabolize tamoxifen?

Answer 28

CYP2D6 is a major metabolizing enzyme

Question 29

CYP2D6

Answer 29

• Major drug metabolizing enzyme of tamoxifen

Question 30

CYP2D6 metabolizer status

Answer 30

• Correlates with endoxifen levels

Question 31

CYP2D6 inhibitors

Answer 31

• Correlate with endoxifen levels

Question 32

CYP2D6 genetic variants

Answer 32

• Associated with tamoxifen survival outcomes

Question 33

Do you think ER positive breast cancer patients that are CYP2D6 poor metabolizers are:

Answer 33

Less likely to respond to tamoxifen treatment

Question 34

Summarized CYP2D6 / tamoxifen CPIC Recommendations

Answer 34

> 2.0 - Recommend standard of care dosing (tamoxifen 20 mg/day)
1.5 - 2.0 - Recommend standard of care dosing (tamoxifen 20 mg/day)
1.0 - Consider higher dosing (tamoxifen 40 mg/day)
0.5 - Consider alternative (e.g., AI) OR if contraindicated, higher dosing (tamoxifen 40 mg/day)
0.0 - Recommend alternative (e.g., AI) OR if contraindicated, higher dosing (tamoxifen 40 mg/day)

Question 35

Severe cutaneous adverse reaction pharmacogenomics (SCAR):

Answer 35

Numerous medications cause severe cutaneous adverse reactions (SCARs) in a subset of patients

Question 36

SCAR ranges in severity and prevalence:

Answer 36

◦ MPE: Maculopapular exanthema
◦ HSS: Drug-induced hypersensitivity syndrome
◦ SJS: Stevens-Johnson syndrome!!
◦ TEN: Toxic epidermal necrolysis!!

Question 37

Genomic studies:

Answer 37

Variation in the human leukocyte antigen (HLA) system found to be associated with a proportion of the liability towards these SCAR

Question 38

Human leukocyte antigen (HLA) system

Answer 38

Major histocompatibility system of man
◦ Cell surface proteins involved in invoking immune response and self-recognition
↑ polymorphic region in the genome
Numerous genetic associations:
◦ Common disease risk
◦ Adverse drug reactions
Four-digit genotyping

Question 39

Anti-epileptics and SCAR:

Answer 39

Carbamazepine, phenytoin and lamotrigine are frequently prescribed anti-epileptics

Uses include the treatment of
◦ Epilepsy and other seizure disorders
◦ Certain psychiatric disorders

Cause rare, but often life-threatening, severe cutaneous adverse reactions (SCARs)

Question 40

___________ can help reduce the rate of ADRs

Answer 40

Pharmacogenomic based prescribing

Question 41

Phenytoin SCAR PGx:

Answer 41

Narrow therapeutic index

Hepatic CYP2C9
◦Genomics confirmed by in vitro
◦Activity score system (substrate dependent *2 AS=0.5 vs. *3 AS=0)

HLA also important
◦ HLA-B*15:02