Personalised Medicine Flashcards
Define pharmacokinetics
Relationship between drug administration and exposure to drug
Define pharmacodynamics
Relationship between exposure to drug and effect:
• “dose(concentration) -response
relationship”
• duration of exposure
What is the traditional approach to drugs?
Diagnosis of disease leads to the recommended drug
Clinical trials are undertaken of a heterogeneous population of patients
What is the personalised approach to drugs?
Diagnosis of the disease leads to the molecular characterisation of factors that affect the drug in individual patients leading to a recommended drug
Clinical trial data from patients with the actual disease and various molecular characteristics
What are the types of markers and what do they do?
Diagnostic markers
– eg tumour subclasses – eg different lymphoma subtypes
Prognostic markers
– eg predict whether additional chemotherapy likely to be beneficial (“treat versus no-treat decision”)
Predictive markers
– predict response to drug – patient selection
– “pharmacogenomics”
Pharmacodynamic markers
– measure response to drug
What can be used as biomarkers?
DNA – “genomics”
– whole genome: sequencing
– individual gene polymorphisms: eg genome
hybridization, SNPs
mRNA “transcriptomics” (and microRNA ?)
– whole transcriptome: expression arrays
– individual gene: eg PCR
protein expression “proteomics”
– whole proteome: protein arrays, 2 D gels
– Individual proteins: eg proteins eg ELISA,
immunohistochemistry, mass spectroscopy
metabolomics
What are synonymous SNPs?
Both alleles of a gene encode the same polypeptide
What are non-synonymous SNPs?
The alleles encode a different polypeptide
How does Illumina work?
Chain termination – similar concept to Sanger method
Terminating nucleotide is fluorescently labelled
Fluorescence identified which nucleotide added
Termination can be reversed
How does Hercrptin work?
It inhibits Her2 receptors but it only affects Her2 positive tumours
What is cetuximab and how dies it work?
Cetuximab – monoclonal antibody inhibiting EGF-R
Cetuximab recommended for treatment of colorectal cancer
Only for patients with wild-type ras
Patients with mutated (activated) ras don’t respond to cetuximab
What is gefitinib and how does it work?
Gefitinib – inhibitor of EGF-R kinase
EGF-R is mutated in a subset of NSCLC patients
mutation activates the receptor
Gefitinib licensed for NSCLC patients with positive EGF-R mutation status
What is maraviroc and how does it work?
HIV entry into T cells requires CD4 and either CCR5 or CXCR4 co-receptors
Maraviroc inhibits HIV binding to CCR5 co-receptor but not to CXCR4
Not used for patients with HIV strains that bind CXCR4
What issues are associated with personalised medicine?
•Scientific & technical
– Appropriate biomarkers needed for each drug & clinical data to confirm their success
– $1000 genome
• Regulatory
– approval of these data for decision making
• Logistical - how to implement personalized medicine?
– Longer time diagnosis→ prescribe
– more physician (GP, specialist etc) visits?
• Financial issues
– Cost of diagnostics added to cost of drug
– Smaller markets for each drug = increased cost of drug
• Although markets may not be smaller –we don’t know yet
• Eg could we use herceptin for all HER2 positive cancer not just breast cancer ?
– But savings by reducing “wasted therapy” & better outcomes?
• Legal
– privacy issues pertaining to genetic data
What may happen if elimination is slow?
Exposure to the drug may lead to toxicity
What may happen if elimination is fast?
The drug may not have the desired effect
What does phase 1 metabolism achieve?
Conversion to more reactive form to allow conjugation
What does phase 2 metabolism achieve?
Conjugation with another biomolecule to increase solubility to allow excretion
What are the causes of patients with reduced 2D6 P450 activity?
Allele encodes enzyme with compromised catalytic activity
Deletion of gene
What are the characteristics of a patient with reduced 2D6 activity?
Increased response to drugs that are metabolically inactivated by 2D6 (eg nortryptyline)
Decrease response to pro-drugs that are activated by 2D6 (eg codeine, tamoxifen) –2D6 genotype can influence survival of breast cancer patients receiving tamoxifen.
What are the characteristics of a patient with increased 2D6 activity?
multiple copies of 2D6
“ultrarapid metabolizers”
What are the characteristics of Butyrylcholine esterase encoded by G209?
More rapid degradation of suxamethonium so less effective muscle relaxant
What are the characteristics of Butyrylcholine esterase encoded by A209?
Slow degradation of suxamethonium so potential prolonged paralysis
What is Isoniazid used to treat? What is it’s major ADR?
Used to treat Tuberculosis
Major ADR is peripheral neuropathy
What is Isoniazid metabolised by?
N-acetyl Transferase
What are the characteristics of fast and slow acetylators?
Fast: Patients efficiently metabolise Isoniazid
Slow: Patients slowly metabolise Isoniazid and are at increased risk of peripheral nerve damage
What are the characteristics of 6-mercaptopurine?
It is used as cytotoxic chemotherapy for leukaemia by inhibiting the synthesis of purine nucleotides
It has a narrow therapuetic window
Its major ADR is myelosuppression
It is metabolised by TPMT
What are the two variants that substantially reduce Cyp
enzyme activity with warfarin?
Arg144Cys
Ile358Leu
What is VKORC and what does it do?
Vitamin k epoxide reductase
Target of warfarin
Different alleles encode variants of enzyme with different sensitivities to warfarin
What is Warfarin metabolised by?
CYP 2C9
What is the mode of action of cisplatin, carboplatin and oxaliplatin?
Platinum based compounds used as chemotherapy for
cancer which platinate DNA and prevent replication
How are cisplatin, carboplatin and oxaliplatin cleared?
Conjugation to glutathione
What are the significant polymorphisms of Glutathione S transferase?
There are >8 isoforms of GST
The genes encoding these may have no, one or both allele deleted
Each allele may have several SNPs
How are genome wide studies carried out?
- Clinial trial subjects receive the drugs and patients are split into responder and non-responders
- Genome wide comparison is carried out of the DNA of responder and non-responders
- Key genetic differences that are associated with the response are identified
- These factors are confirmed in a second cohort
- This identifies a clinical useful biomarker
What are the characteristics of the OATP1B1 T521C SNP with statins?
C at 521 impairs uptake into hepatocytes (site of action of statin)
Greater AUC
Greater accumulation of drug in muscle tissue
Both alleles need to be affected (i.e. C)for significant myopathy
