pharmacogenetics, pharmacogenomics and personalised medicine Flashcards
What is personalised medicine
Tailoring healthcare to an individuals genetic makeup rather than “one-size fits all” approach
“The right dose of the right drug to the right person”
What are Pharmacogenetics and Pharmacogenomics
Pharmacogenetics: Studying an individual’s genetic make up in order to predict responses to a drug
Pharmacogenomics: Analysing entire genomes, across groups of individuals, to identify the genetic factors influencing responses to a drug
Pharmacogenetics often deals with single genes/small number of genes (Large single variant effect)
Whilst pharmacogenomics deals with whole complex biological pathways/ whole genome (smaller effect, multiple variants)
Factors contributing to variability in drug response/compliance with drug prescription
Environmental: Climate Parasites Pollutants Smoking Alcohol Drugs
Cultural factors
Attitudes
Beliefs
Family influence
Biological factors Age Gender Weight Disease GENES--PHARMACOGENETICS/ PHARMACOGENOMICS
Cardiovascular drugs and racial/ethnic origin
ACE inhibitors: More effective in Caucasians than in African Americans
Beta blockers: More effective in Caucasians than in African Americans
Alpha blockers: More effective in Caucasians that in African Americans
Thiazide: More effective in African Americans than in Caucasians
BiDil in African-Americans with congestive heart failure
Isosorbide/hydralazine combination (NitroMed)
BiDil is the first drug approved for use only in African-Americans
Stevens Johnson syndrome
Rare, serious disorder of skin and mucous membranes
Reaction to medication or an infection
Anti-gout medications Pain relievers such as acetaminophen, ibuprofen Penicillin Anticonvulsants and antipsychotics Radiation therapy
Toxic epidermal necrolysis in a teenager
Rare allergic reaction to paracetamol and virus
The genetic approach to drug therapy
Identification of genes responsible for drug metabolism and action
Advance understanding of variability in drug response
Optimised drug response according to genetic background
Sources of pharmacogenetic variation
Pharmacokinetic
Variability in concentration of drug at site of drug effect
Pharmacodynamic
Variability of drug in affecting target
Underlying disease mechanisms
Variability in disease being treated
Medication is absorbed into the GI/liver
Into the central compartment (this is the part pharmacokinetics control)
Distribution into peripheral tissues or metabolized and excreted (pharmacodynamics)
Categories of major cardiovascular variants
Eg in major cardiovascular pharmacogenetic variants
Genetic variants in pharmacodynamic genes influence the drugs ability to affection the action of its target eg VKORC1 and warfarin
Genetic variants in pharmacokinetic genes influence the concentration of drug at the site of its target eg CYP2D6 and metoprolol
Genetic variants in underlying process genes affect a drug target’s ability to modify the disease process
E.g. PEAR 1 and aspirin
Genetic polymorphisms and drug response
Genetic polymorphisms
(single nucleotide polymorphisms, SNP
Pharmacokinetics
Transporters
Plasma protein binding
Metabolism
Pharmacodynamics Receptors Ion channels Enzymes Immune molecules
Underlying disease mechanisms
Often downstream of drug target
Potential consequences of genetic variability in drug metabolism
Metabolism may influence plasma drug levels
Fast metabolisers vs slow metabolisers
Efficacy of drug
Toxic vs non-toxic responses (Safety)
striking the balance between toxicity, efficacy and ineffective drugs
Beta blockers and hypertension
Beta-adrenoreceptor antagonists (Beta-blockers) are widely used agents in the treatment of hypertension
Marked variability in response to beta-blockers
30-60% of patients fail to achieve adequate blood pressure lowering with beta-blockers
Common beta-blockers used in hypertension include:
Metoprolol
Atenolol
Examples of genetic variants and drug response
Pharmacokinetics Warfarin: CYP2C9 Clopidogrel: CYP2C19 Simvastatin: SLCO1B1 Metoprolol: CYP2D6
Pharmacodynamics
Clopidogrel: P2RY12
Simvastatin: HMGCR
Metoprolol: ADRB1
Underlying disease mechanisms
Hydrochlorothiazide: ADD1
Simvastatin: APOE
Genetic variation and effects on Pharmacokinetics
The cytochrome P-450 mono-oxygenase system is largely responsible for catalysing phase 1 reactions
Complex supergene family ( > 40 enzymes expressed in human tissues)
Enzymes located on smooth endoplasmic reticulum
CYP1A2, 3A4, 2C9, 2C19, 2D6, 2E1 exert a major role in drug metabolism
Phase 1 reactions add or expose a functional group through oxidative reactions
N-dealkylation O-dealkylation Hydroxylation N-oxidation S-oxidation Deamidation
Many CYP450 Enzymes Are Polymorphic
Responsible for metabolism of 40% of all Rx drugs
metaprolol balance
If metoprolol is metabolised too quickly, it may decrease the drug’s efficacy (e.g. when multiple copies of CYP2D6 expressed)
Reduced function variants e.g. CYP2D6*4 results in absence of CYP2D6 activity
Carriers have higher systemic exposure to metoprolol
Greater reduction in HR and BP
Slow metabolism may also result in toxicity
Inherited Activity of CYP2D6 and drug dosing
Genetic variation can influence blood levels of the drug
Dose may need to be adjusted according to genetic background
Common variant of CYP2D6
is CYP2D6*4 associated with
absence of activity of CYP2D6
(reduced function variant)
2) Genetic variation and effects on Pharmacodynamics/Drug Targets
Pharmacodynamics Receptors Ion channels Enzymes Immune molecules
Pharmacodynamics Clopidogrel: P2RY12 Simvastatin: HMGCR B2 agonists: ADRB2 Metoprolol/Propranolol: ADRB1
ADRB1 allele frequency and functional consequences
Gly389 variants have decreased response to metoprolol
Arg389 variants have increased response to metoprolol
Targeted treatment of non small cell lung carcinoma
Targeted treatments based on mutational analysis
EGFR antagonists (TKIs and mAbs) ALK inhibitors (TKI e.g. crizotinib)
FDA Approves First Personalized Medicine for EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer in the United States
On May 14, 2013, the FDA approved Tarceva® (erlotinib) tablets for the initial (first-line) treatment of people with metastatic non-small cell lung cancer (NSCLC) whose tumours have been identified to have certain epidermal growth factor receptor (EGFR) mutations by an FDA-approved test
The FDA also approved the cobas® EGFR Mutation Test, validated in the pivotal EURTAC study
Genetic variation and effects on underlying disease mechanisms
platelet endothelial aggregation receptor-1 (PEAR1) expressed on platelets and endothelial cells
Signalling receptor secondary to platelet activation
Genetic variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes with aspirin
The future for pharmacogenetics/ pharmacogenomics
Moving Pharmacogenetics/ Pharmacogenomics to Clinical Practice
The importance of single variants is well recognised for several drug treatment protocols
Use of Tarceva, Herceptin, Gleevec and Erbitux for cancer based on genomic information
Genetic information is increasing on Drug prescribing information labels
Further progress and translation into clinical practice will require
Documenting the superiority of using pharmacogenomic
information versus the conventional treatment approach for both clinical practice and drug development
Overcoming barriers: cost, time, lack of understanding, patent expiry
