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withdrawn from the market due to ADRs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
true
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
