Lecture 2 Flashcards
How many motivations are there for personalised medicine?
What does each entail?
2
- Cost of Adverse Drug Reactions- Adverse Drug Reactions (ADRs) account for 3% - 18% of all UK hospitalizations, with an annual cost to the NHS of £1 - £2 billion.
- Cost of lack of efficacy - E.g. treatment of epilepsy
Start on low dose of Drug A
Gradually increase dose until effective treatment or negative result. If the latter start on low dose of Drug B … Keep continuing until effective treatment attained
What is the hope if personalised medicine can be improved?
Better outcomes
Less time-consuming
More cost-effective
Using better ways of measuring the individual to both predict and monitor the patient’s response to treatment
Pharmacogenetics in 2020 include 21 drugs (non-cancer) have testing required by US FDA
True or false
False
31
What type of biomarkers are mostly FDA approved in oncology?
Somatic
What is a major drug metabolising enzyme that controls how fast the body utilises drug and thus how long that drug remains effective?
CYP2D6
What is Azathioprine?
A thiopurine drug which induces T-cell apoptosis (cell death)
What is Azathioprine widely used as?
An immunosuppressant agent in transplantation and inflammatory bowel disease
What enzyme is associated with the challenges of Azathioprine use?
And why?
TPMT
TPMT enzyme is required to catalyze azathioprine and deficient enzyme levels can lead to bone marrow depression with azathioprine
TPMT enzyme activity is controlled by genetic polymorphisms in TPMT gene, and one in 300 subjects have very low enzyme activity – therefore not safe to prescribe this to such individuals
Is Pharmacogenetic testing for Azathioprine performed by measuring enzyme activity or genotyping?
Measuring enzyme levels
Pharmacogenetic testing for Azathioprine is recommended where?
The US
About half of the UK patients are tested for what prior to treatment with azathioprine?
TMPT
TMPT testing predicts other adverse events
True or false
False
Does not predict other adverse events
Frequency of TMPT variants vary across population groups.
True or false
What is the implication of this in relation to Azathioprine?
True
Implication:
TPMT~0: Avoid or very low dose. High risk of fatal toxicity.
Intermediate TPMT:
Use a 50% dosing
strategy.
Normal TPMT:
Usual dosing strategy
What is Warfarin used for?
To prevent blood clotting in patients atrial fibrillation, strokes, deep vein thrombosis, pulmonary embolism
Therapeutic dose varies from patients to patient 20-fold difference in effective dose among Caucasian patients
True or false
True
What can warfarin trigger?
- Fatal haemorrhaging if dose too high
- Stroke if dose too low
How is warfarin dosage in effectiveness measured?
Monitored via regular INR (International Normalised Ratio) measurements of blood clotting time
What two key polymorphisms influence optimal dose of warfarin?
VKORC1 (drug action)
CYP2C9 (drug metabolism)
Since 2007, the FDA have recommended using genetic information in administrating warfarin if it is available.
True or false
True
US warfarin/ Coumadin label has a table of suggested starting dose depending on genetic test results
True or false
True
Why is warfarin therapy so difficult?
- Narrow therapeutic window
- INR too high: risk of intracranial hemorrhage
- INR too low: risk of stroke - Wide inter-individual variability in dose requirement
- Age, body surface area, and genetic account for 50% of variation in daily dose required - Many drug and food interactions
- Warfarin use is increasing
Can genetics help solve improve warfarin treatment according to an EU: Randomized Trial of Genotype-Guided Dosing of Warfarin (EU-PACT)?
Why?
Yes
Trial arms:
Genotype-guided group: warfarin doses with pharmacogenetic-based algorithms
Control group: treatment as usual
Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range.
Median time to reach a therapeutic INR was 21 days in the genotype-guided group, compared to 29 days in the control group (P<0.001).
What is a point of care test?
Results for patients available immediately
Can genetics help solve improve warfarin treatment according to a USA: Randomized Trial of Genotype-Guided Dosing of Warfarin (COAG)?
Why?
No
Trial arms:
Genotype-guided group: warfarin doses with pharmacogenetic-based algorithms
Control group: treatment as usual
No difference in %age of time in therapeutic range. 45.2% in genotype-guided group. 45.4% in clinically guided group. No significant difference
Why are the warfarin clinical trial results so different?
- Greater heterogeneity of patients in the COAG trial
- Different algorithmic strategies used in the two trials
- National differences in the quality of anticoagulant care
- Age differences: EU-PACT trial older, more atrial afibrilation
- Differences in when genotype results available: Point of care (EU) v 3 days after test (US)
Case for genetic testing to improve warfarin treatment is strong enough.
True or false
False
It is not strong enough
New drugs (e.g. Dabigatran) offer same therapeutic effect in relation to warfarin without need for genetic testing, but are more expensive.
True or false
True
Why is drug response a simpler complex trait?
- Much known about drug pathways
- Obvious candidate genes often carry gene variants that influence drug response.Obvious candidate genes because drug biochemistry usually well understood (or small number of alternate pathways)
- Some causal variants are common with large effect size. Common variants because selection has not acted in same way here (drugs are modern inventions)
-Direct clinical relevance: change dose
select appropriate drug
What did a drug response GWAS for Statin ADR (muscular myopathy) find?
UK statin therapy trial of 80 mg simvastatin in 12k participants
GWAS performed for muscular myopathy with simvastatin
85 participants with myopathy and 90 matched controls
GWAS showed strong association of myopathy with rs4363657 inSLCO1B1
SLCO1B1 encodes the organic anion–transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins.
The prevalence of the rs4149056 C allele in the European population is 15%.
Risk of myopathy (compared to baseline TT)
- increased in CT genotypes
- highest in CC genotypes
What did a drug response GWAS for Statin ADR (muscular myopathy) confirm?
Large effect sizes
N was very small
What are three clinical tests performed for specific variants prior to drug prescription?
- Abacavir / HLA-B*57:01
- Azathioprine / TPMT variants
- Carbamazepine / HLA-B*15:02
What is one strategy that can be used instead of clinical tests performed prior to drug prescription?
Pre-emptive genetic testing - Testing for panel of pharmacogenetic variants
Genetic data then forms part of Electronic Health Record
Prior to any drug prescription, genetic information is checked for potential ADE or efficacy
Personalised medicine!
Why are there so few pharmacogenetic tests in clinical practice?
Clinical practice lags behind academic findings
Much still not known
-Difficult to attain good sample sizes (ADRs are rare)
-Little research in populations of non-European ancestry
Time delay in waiting for genetic test results
If ADR not severe and easily monitored, gradual adjustment of dose may be more cost-effective
“Less complicated” clinical procedure less likely to go wrong
Biomarkers may be better than genotypes at predicting ADR
Economics: proving cost effectiveness is difficult
What effect did screening for HLA-B*15:02 have on: carbamazepine prescribing SJS/TEN incidence ?
Carbamazepine prescriptions declined from 16% to 3% (of all anti-epileptic drugs prescribed). Clinicians avoided this drug.
Prescription of other anti-epileptic drugs increased proportionately
Carbamazepine-induced SJS/TEN incidence decreased from 0.24% to 0%
However Phenytoin induced SJS/TEN incidence increased from 0.15% to 0.26%
Phenytoin carried risk of SJS/TEN, but pharmacogenetic test not mandated
Test-prescription policy was adhered to in only 26% of relevant patients
What is HLA-B*15:02 is associated with?
How many asian individuals carry the HLA-B*15:02 allele?
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) induced by carbamazepine
Up to 15%
In 2008, Hong Kong introduced mandatory screening for HLA0B*15:02 prior to carbamazepine prescription
True or false
True
What did the Chen et al. 2014 study investigate?
Anti-epileptic drug prescribing for new prescriptions from 2005 – 2011 (Chen, Liew, Kwan, Neurology, 2014)
Are there any pharmacogenic tests used in clinical practise?
No
Warfarin is an example of what?
Warfarin is an example in a different category. Not required in either country, but recommended in the US
Testing company is not informing clinician exactly how to treat patient, rather they are providing information based on genetics of patient. Clinician can then use this information in corroboration with other patient info for an informed decision
True or false
True
The antidepressant Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of what enzyme?
Cytochrome P450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established.
The antidepressant Escitalopram encodes what enzyme?
Cytochrome P4502C19 (CYP2C19)
