Pharmacogenetics, Pharmacogenomics & Precision Medicine Flashcards
What is the definition of pharmacogenetics
The study of how people respond differently to medicines due to their genetic inheritance
What is the definition of pharmacogenomics
The science of increasing the effectiveness of drugs and minimising their side effects by matching drugs to people according to their genetic make up
What is the definition of precision medicine
An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person
What are the 2 main sources of evidence for pharmacogenetics
- Twin studies: monozygotic vs non-monozygotic
- Large pharmacokinetic studies
- Hardy-Weinberg equation
What are the different CYP enzymes involved in drug metabolism (9)
CYP3A4 and CYP3A5
CYP2D6
CYP2C9
CYP2C19
CYP1A2
CYP2E1
CYP2A6
CYP2B6
What does CYP2D6 do and what pharmacogenetic variation does it have
Metabolizes antidepressants (e.g., fluoxetine), opioids (e.g., codeine), and beta-blockers (e.g., metoprolol).
Pharmacogenetic Variation:
- Highly polymorphic with phenotypes ranging from
- poor metabolizers (e.g., CYP2D64/4): adverse reactions to psychotherapy drugs
- ultra-rapid metabolizers (e.g., multiple CYP2D6 gene copies): very high doses of antidepressants required
This variability can affect drug efficacy and toxicity, such as insufficient analgesia from codeine in poor metabolizers.
What does CYP2C9 do and what pharmacogenetic variation does it have
Metabolises S-warfarin, phenytoin, THC
Induced by rifampicin and other induces
Inhibitors include the sulphonamides
Pharmacogenetic variation:
- CYP2C92 and CYP2C93 reduce enzyme activity: requiring dose adjustments for drugs like warfarin to prevent bleeding complications.
What does CYP2C19 do and what pharmacogenetic variation does it have
Metabolizes proton pump inhibitors (e.g., omeprazole), antiplatelet drugs (e.g., clopidogrel), and some antidepressants.
Pharmacogenetic Variation:
- CYP2C192 (loss-of-function) and CYP2C1917 (gain-of-function) influence clopidogrel activation (pro-drug): impacting its efficacy in preventing cardiovascular events.
How is TPMT used as a predictor for ADRs
Thiopurine methyltransferase (TPMT) is used as a predictor for adverse drug reactions (ADRs) with thiopurine drugs (e.g., azathioprine, mercaptopurine, thioguanine).
TPMT metabolizes these drugs into inactive forms, reducing toxic metabolites that can damage bone marrow.
Patients with low TPMT activity (due to genetic polymorphisms like TPMT2, TPMT3A, or TPMT*3C) cannot inactivate thiopurines effectively,
- leading to excessive toxic metabolites and a high risk of severe myelosuppression.
Pre-treatment TPMT testing helps identify such patients, enabling dose adjustments or alternative therapies to prevent ADRs.
How is Abacavir used with pharmacogenomic biomarkers to screen for hypersensitivity reactions
Abacavir is an antiretroviral drug used to treat HIV, and its safety is influenced by the pharmacogenomic biomarker HLA-B*57:01.
HLA-B*57:01 Biomarker: Patients with this genetic variant are at a significantly increased risk of developing a potentially life-threatening hypersensitivity reaction (HSR) to abacavir.
Genetic testing for HLA-B*57:01 is recommended before initiating abacavir therapy.
How is carbamazepine used with pharmacogenomic biomarkers to screen for hypersensitivity reactions
The pharmacogenomic biomarker HLA-B*15:02 is associated with an increased risk of severe skin reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
HLA-B*15:02 Biomarker: This variant is most common in individuals of Asian ancestry, particularly in Han Chinese, Thai, and Indian populations.
Genetic testing for HLA-B*15:02 is recommended before initiating carbamazepine in high-risk populations
How is phenytoin used with pharmacogenomic biomarkers to screen for hypersensitivity reactions
HLA-B*15:02:
- Linked to an increased risk of severe skin reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
- Common in individuals of Asian ancestry.
- Screening: Recommended for populations at high risk before starting phenytoin. If positive, alternative therapies are considered.
CYP2C9:
- Phenytoin is metabolized by CYP2C9, and genetic variants (e.g., CYP2C92, CYP2C93) result in reduced enzyme activity.
- Patients with these variants metabolize phenytoin more slowly, leading to higher plasma concentrations and an increased risk of dose-dependent toxicity such as neurological side effects (e.g., ataxia, nystagmus).
What are the benefits of precision medicine
Earlier more accurate diagnosis, supporting earlier intervention and better targeted treatments
Better infection prevention and control strategies and more effective management of infectious diseases
Capture the potential of genomic data to R&D
Enrichment of clinical trials
Strong framework to support collaboration with Industry, including the presicion medicines catapult
What are the types of biomarkers used in personalised medicine
Risk biomarkers
Prognostic biomarkers
Predictive biomarker
What is the role of a risk biomarker
Identify predisposition to a particular disease
What is the role of a prognostic biomarker
Associated with a disease outcome without treatment or with standard (non-targeted) treatment
What is the role of a predictive biomarker
Prospectively identifies favourable clinical outcomes from using a targeted treatment
What are examples of risk biomarkers
BRCA1 and BRCA2
What are some examples of prognostic biomarkers
ER, HER2, PR and EGFR
What are some examples of predictive biomarkers
HER2 and trastuzumab
What is the meaning of practical enrichment in clinical trials
Reducing variability of measurement and heterogeneity (by avoiding enrolment of patients with other diseases and individuals in whom the disease disappears spontaneously)
What is the meaning od prognostic enrichment in clinical trials
Finding patients who are likely to have event of interest when enrolling for risk-reduction studies
What is the meaning of predictive enrichment in clinical trials
Selecting individuals who are more likely to respond
