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
