An Introduction to Pharmacogenomics, Pharmacogenetics and Personalised Medicine REVIEW LECTURE NOTES Flashcards Preview

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Flashcards in An Introduction to Pharmacogenomics, Pharmacogenetics and Personalised Medicine REVIEW LECTURE NOTES Deck (22):

What is pharmacogenomics?

Pharmacogenomics can be thought of as the whole genome application of pharmacogenetics, which examines the single gene interactions with drugs
Terms gene, genes or genome are often used interchangeably


What is genomics?

The study of a person's entire genome
Genome: an organisms hereditary information, encoded by DNA
Human genome project to map the entire genome
Potential to understand relationships between genes, peptides, proteins and disease


What are polymorphisms?

Variations in DNA sequences that occur in at least 1% of the population
Single nucleotide polymorphisms (SNPs) are single base differences in DNA sequence
SNP profiles (haplotypes) can alter clinical phenotypes
Some of these may be responsible for changes in enzymes, transporters and receptors


What is expression profiling?

Synthesise a range of drugs for a particular target
Expose cells in culture to the drug
Investigate response of groups of genes
To indicate toxicity, efficacy or specificity
Select the drug used for good responders


What is disease stratification?

Understand molecular mechanisms of disease
Detect altered gene expression patterns by pharmacogenomics testing
Develop targeted therapies
e.g. Gilvec for chronic myeloid leukaemia, identify chromosomal abnormality- Philadelphia chromosome produces mutant, overactive protein (kinase) resulting in excessive proliferation


Decisions for pre-clinical testing

Exclude/include patient groups?
OR ensure inclusive patient groups?


Rescue in late stage trial

Later stages of trials
Retrospective rescue of drugs with serious ADRs if genetically identified
4% withdrawn due to ADRs
Drug developed for sub-populations


The identification of good responders

Test prospective drugs in patient sub-groups or retrospective rescue in later trials
Marginal patient benefit within a population
Identify the group of patients who respond well to treatment
Licensed in a specific genomic group


Pharmacogenetics and personalised medicine

Individual response (PKs and PDs) to treatment
Genetic factors account for ~15-30% of inter-individual differences
Can account for 95%
May be due to mutations of a single gene


Which individual responses are relevant to practice?

Relevance is determined by:
Allele frequency
Clinical outcome
Therapeutic window of a drug


Metabolic status (PK) affecting pharmacogenomics

Monogenic traits affecting metabolism
Best recognised and understood examples
Single gene defects that may enhance or reduce metabolism


CYP 450 enzymes

Genetic polymorphisms in CYP450 can be associated with disease e.g. hypertension and cancer
Genetic polymorphisms associated with drug metabolism
Multiple families of the enzyme with different levels of activity for different drugs


CYP 2D6 alleles

More than 51 recognised 2D6 alleles
~20-25% of drugs in use are metabolised at least in part by this enzyme
Western Europe ~7% are poor metabolisers
Varies geographically
Poor metabolisers- increased accumulation of drug and potential side effects
Rapid metabolisers- poor therapeutic response


CYP 2D6 and pro drugs

Codeine is a pro drug of morphine
Therefore the reverse effect to antidepressants
Poor metabolisers get less morphine, fast metabolisers get more


Warfarin algorithms

CYP2C9 *2 and *3 genotypes reduce metabolism by 30 and 80% respectively
Variant genotypes therefore need lower dose than wild type (1*)
Consider homo/heterozygous
Carriers of certain polymorphism need higher warfarin maintenance dose


Extending drugs restricted by ADRs

Restricted use of marketed drugs due to severe side effects
Limits clinical usefulness
Identify sub group at most risk of ADR to expand therapy


Stratification through PG

PGx can determine interaction with receptor targets and ADME
Principle: right drug to the right individual at the optimal dose


Is there a clinical need for testing?

Other biomarkers
Magnitude of effect
Avoid by selecting alternative drug
Disease severity- mild, chronic, severe
Side effects- severity
Therapeutic window- chemotherapy
Complex medical situations- clozapine


Is the test reliable and valid?

PGx dependent on testing
Test development is complex and time consuming
Difference between populations e.g. TPMT testing
Invasive conditions
Easy to perform, reliable, inexpensive, interpretable


Genetic inequalities

Disease susceptibility
Racial grouping
Patient consent
Health insurance



HIV/AIDS drug severe hypersensitivity reaction (5%)
Close monitoring required
Identify sub-group at most risk of ADR to expand therapy


Thiopurine S-methyl-transferase (TPMT)

Developed in 1950s
Genetic testing, identify TPMT deficient patients, reduce drug dose 5-10% of conventional dose
Enzyme detection, myelosuppression, higher cost, applicability across populations, ADRs