MODULE 6- Pharmacogenomics I Flashcards
Variation among patients in their responses to
medication is noted
Due to:
o Environmental factors – Drug-drug interactions – Co-morbid disease – Age, sex, diet o Genetic factors
The Goal of Pharmacogenomics
• To identify genetic differences among patients that influence treatment response • This is essential in 3 main areas: – 1. Efficacy – 2. Safety – 3. Optimum dose
- efficacy
• Drug resistance or non-response is a serious
clinical issue
– E.g. 30% of patients with epilepsy and 30-50% of
patients with schizophrenia do not respond to any
currently available drug treatment
• Studies that elucidate the genetic basis of
treatment failure facilitate the development of new
compounds
- safety
• Drug treatment is frequently associated with adverse
drug reactions (ADRs)
– mild to fatal
• Estimated 5-13% of hospital admissions are due to
ADRs (first world)
• Many medications fail clinical trials or need to be
withdrawn from the market due to ADRs
• E.g. severe ADR has led to the withdrawal of drugs including
astemizole (allergy medication), grepafloxacin (an antibiotic), sertindole
(an antipsychotic)
- dose
• Many drugs have a narrow therapeutic range
– too high → toxicity and dose-related ADR
– too low, → not effective
– e.g. warfarin
• Different patients can require dramatically
different doses
– e.g. epileptic, cancer, and psychiatric drugs
– dose titration can take months
Pharmacogenomics aims to
– develop rational means to optimize drug therapy, with respect
to the patients’ genotype
– ensure maximum efficacy with minimal adverse effects
So: two people with the same diagnosis might receive
different therapies or drug dosages
pharmacogenomics
The study of the interaction of an individual’s genetic
makeup and response to a drug
studying the effect many
variants across the genome
pharmacogenetics
studying the effect of one
a variant in one gene
What is the genetic study approach?
- take a group of patients, non-responders,responders, toxic responders
- Look at genotype of each group
- Which gene variants are specific to each group?
- Associated variants can be used as a diagnostic tool to
predict a person’s drug response
Drug response is polygenic and is influenced
by environmental factors
drug response is a multifactorial trait
what is haplotype
• In genetic studies, groups of variants are often found to be associated with a particular trait – Haploid – cell having one set of chromosomes – Genotype – genetic make-up • ‘Haplotype’: describes a group or cluster of variants inherited together from one parent on one chromosome – inherited together because they are physically close to each other on the same chromosome
ADME genes
A – Absorption • D – Distribution • M – Metabolism • E – Excretion • Genes that are associated with drug metabolism – metabolism enzymes – transporters
ADME genes currently described
• 32 core genes plus 340 extended genes
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A higher diversity has been observed in some functionally important ADME genes in African
Americans as compared to Europeans (Li et al 2014)
– “drug response heterogeneity between populations”
– significant genetic differences in the ADME genes between different populations could
lead to therapeutic failure, or adverse drug responses
Inconsistent patient responses to
drug therapies
Poor metabolisers: – build up of drug in liver • can be toxic – lack of efficacy →give less drug
• Ultra-rapid metabolisers: – drug cleared too quickly in liver – lack of efficacy →give more drug
Genetics explains inconsistent
response phenotypes
Poor metaboliser: – two non-functional alleles • Intermediate metaboliser: – one functional allele and one non-functional allele – OR two partially functional alleles • Extensive metaboliser: – two functional alleles • Ultra-rapid metaboliser: – more than one increased functional allele
Drug Metabolising Enzymes
• > 30 families
• e.g. cytochrome P450 (CYP450) superfamily
– Metabolise approx 60% of prescribed drugs
– Expressed primarily in liver
– 57 genes known to date
– 3 families: CYP1, CYP2, CYP3
Drug Metabolising Enzymes – CYP2
• Most polymorphic of all CYP450 enzymes
• 20 to 30% of all drugs metabolised
• subfamilies A – E
• genes are described e.g. CYP2D6, CYP2C8
• Variants (alleles) are described e.g. CYP2C91,
CYP2C92, CYP2C9*3
Types of genetic variants
Metabolic pathways are affected by a wide
range of types of DNA variants including
– single nucleotide polymorphisms (SNPs)
– mutations in the regulatory elements of genes
– variable number of tandem repeats (VNTRs)
– variations in gene copy number (gene deletions or
duplications)
examples
refer to the document
The aim of studying pharmacogenomics
To inform:
Personalised Medicine /
Precision Medicine
Definition of Precision Medicine
Medical care designed to optimize efficiency or therapeutic
benefit for particular individual / groups of patients, especially
by using genetic or molecular profiling
Serious considerations
Availability of technology
- Cost
Precision Public Health
vs Precision Personalised Medicine
New concept of ‘Precision Public Health’
• Health decisions based on populations and
communities as opposed to individuals
• More cost-effective approach for developing countries
In Botswana, efavirenz is no longer a first line ARV and changes
are being considered for recommended first line treatments in
Zimbabwe and South Africa
Different African ethnicities each need to evaluate the
frequencies (even complete absence?) of various
polymorphisms involved in the pharmacogenomics of a
particular drug
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Practical hurdles to implementing
pharmacogenomic testing at present
• Complexity of finding gene variations that affect drug
response
• Some polymorphisms do not show associations in
different ethnic groups
• Limited drug alternatives
• Disincentives for drug companies to make multiple
pharmacogenomic products
Educating healthcare providers
take-home message
• Necessary to set boundaries in the expectations of the applications of
pharmacogenomics to clinical medicine
• Health-care professionals need to become educated in the interpretation
of genetic data (what genetic testing can and cannot tell you..)
• Clear differences exist between African, Asian and Caucasian population
structure demonstrating the need for population-specific preclinical and
clinical studies and trials
• Precision health (as opposed to precision medicine) is important to
consider for a health care system in a developing country
