Adverse Drug Reactions & Pharmacogenomics Flashcards
Therapeutic tx’s:
Revolutionized medicine
Accompanied w/:
- Adverse drug rxns
- Non-response
Adverse Drug Reactions (ADRs):
- Negative / undesirable effects of drug treatment
- Can influence different systems
- Severely debilitating and potentially fatal
- Growing elderly population
- Strain on resource-constrained healthcare systems
Type A:
Pharmacological effect; predictable; dose dependent
Type B:
Caused by immune-mediation & nonimmune-mediation; non-predictable; dose independent
Why is this clinically important?
Drug safety and effectiveness
Affects both drug efficacy and toxicity
Clinical trials (average) vs real world (what is seen in clinic, subgroups)
Can occur via different mechanisms:
◦ Pharmacokinetic:
Different concentrations at sites of drug action
◦ Pharmacodynamic:
Different responses to the same drug concentration
Pharmacogenomics
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
What is Precision medicine?
Precision medicine takes both genetic and non-genetic factors into account
◦ Drug dosing algorithms
◦ Previously termed personalized medicine
Precision Medicine Initiative describes it as:
an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.”
Simple genetic traits i.e., one gene contributes towards trait
CAVEAT
Not all traits/diseases involve one gene/genetic variant
How does genetic variation in a gene eventually lead to altered activity?
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
What is Expression Quantitative Trait Loci (eQTLs)?
Examine the association
◦Between genetic variants and gene expression levels
◦Example: CYP2C19*17 allele and clopidogrel
Alleles:
Version of the same gene that have different DNA spelling changes compared to each other.
Genotype:
The genetic state of both copies of a genetic variant.
Haplotype:
A combination of multiple spelling changes within a
particular gene.
Phenotype:
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.
Star allele:
A method of labeling haplotypes in genes (e.g., *2, *3, etc.).
How pharmacogenomics can improve treatment?
- Improving efficacy
- Predicting drug dose
- Preventing adverse drug rxns
- Enabling drug discovery/development
- Developing targeted drugs for cancer therapy
- Predicting the activation of prodrugs
Important clinical considerations for pharmacogenomic biomarkers and clinical implementation:
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
Clinical Practice Guidelines:
Facilitate genotype guided therapy
Clinical Pharmacogenetics Implementation Consortium (CPIC)
◦Standardized, peer-reviewed
◦International consortium, formed in 2009
◦Systematic grading of evidence and clinical recommendations
FDA testing required:
req’s testing before getting a drug
The value if pharmacogenomics in clinical practice:
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%!
Pharmacogene example: CYP2D6:
CYP2D6 is an important drug metabolizing enzyme
Polymorphic (PGx applications)
Currently: 16 drugs with clinical guidelines for CYP2D6 PGx
More than 100 genetic variants changing the function of ______
CYP2D6
In addition to single nucleotide variants, CYP2D6 has large scale rearrangements in some patients
Examples of CYP2D6 alleles:
> 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
Codeine/CYP2D6 clinical implications example:
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
Breast cancer treatment:
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
Which enzymes metabolize tamoxifen?
CYP2D6 is a major metabolizing enzyme
CYP2D6
- Major drug metabolizing enzyme of tamoxifen
CYP2D6 metabolizer status
- Correlates with endoxifen levels
CYP2D6 inhibitors
- Correlate with endoxifen levels
CYP2D6 genetic variants
- Associated with tamoxifen survival outcomes
Do you think ER positive breast cancer patients that are CYP2D6 poor metabolizers are:
Less likely to respond to tamoxifen treatment
Summarized CYP2D6 / tamoxifen CPIC Recommendations
> 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)
Severe cutaneous adverse reaction pharmacogenomics (SCAR):
Numerous medications cause severe cutaneous adverse reactions (SCARs) in a subset of patients
SCAR ranges in severity and prevalence:
◦ MPE: Maculopapular exanthema
◦ HSS: Drug-induced hypersensitivity syndrome
◦ SJS: Stevens-Johnson syndrome!!
◦ TEN: Toxic epidermal necrolysis!!
Genomic studies:
Variation in the human leukocyte antigen (HLA) system found to be associated with a proportion of the liability towards these SCAR
Human leukocyte antigen (HLA) system
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
Anti-epileptics and SCAR:
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)
___________ can help reduce the rate of ADRs
Pharmacogenomic based prescribing
Phenytoin SCAR PGx:
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
