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A/Prof Les Sheffield - Consultant Clinical Geneticist - Genome Sequencing in Predicting Drug...
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Transcript of A/Prof Les Sheffield - Consultant Clinical Geneticist - Genome Sequencing in Predicting Drug...
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Genome Sequencing in Predicting Drug
Response
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All drugs are not created equal, neither are the patients
who use them” (JAPHA 2011)
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© GenesFX
Pharmacogenomics – The First Application of Personalised Medicine
• Pharmacogenomics = study of genetic variations that
influence drug response
– correlate genetic change such as single-nucleotide polymorphisms
(SNPs) with a drug’s efficacy or toxicity
– Up till now do single genes and
• Specific mutations.
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© GenesFX
Who can drink coffee before bed?
• Caffeine is converted to xanthenes (theobromine,
aminophylline)
• Converted by an enzyme called Cytochrome P450 1A2
(CYP1A2)
• 50% of people are fast metabolisers of CYP1A2
• Some drugs won’t work for those people
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© GenesFX
Individual differences in response to medications
• Inter-individual differences in response was first described by
Pythagoras in 510 BC. He noted that some individuals
developed anaemia in response to fava bean ingestion.
(G6PD)
• Cytochrome P450s developed to protect the body from
poisons and now involved in drug metabolism
• About 40% of drug metabolism is mainly carried out by the
enzymes CYP2C9, CYP2C19 and CYP2D6
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© GenesFX
1. Non-genetic
Factors
Intrinsic
• Age
• Gender
• Pregnancy
• Disease
Extrinsic
• Diet
• Smoking
• Medications
• Medical
Interventions
• Haemodialysis
• Organ
transplant
Variability in Drug Response
2. Genetic
Factors
• Drug metabolising
enzymes
• Drug transporters
• Drug receptors
• Channel proteins
• HLA- immune
factors
http://www.healthplexus.net/files/images/2008/CGS/prescribingfig1.jpg
“Matching”
in RCT
3. Cancer cell
genetic changes
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Genotype then prescribe
The practice of psychopharmacology is gradually becoming more evidence
based, and clinicians can accurately predict how individual patients will
respond to specific medications Mrazek (2006), “Psychiatric pharmacogenomics”
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Case study
A 16 year old girl presented with
depression and anxiety
She was prescribed sertraline (Zoloft) and
diazepam (Valium)
Became suicidal , agitated, tachycardia
(serotonin syndrome), made several suicide
attempts and was hospitalised.
Gradually taken of the drug and made
complete recovery
The RIGHT DRUG - Depression
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CYP2C19 enzyme is the main enzyme responsible for metabolising both
sertraline and diazepam
Results: CYP2C19 *2/*2 Poor Metaboliser
Personalised treatment of Depression
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What Happened?
CYP2C19Sertraline Desmethylsertraline
(negligible action)
NordiazepamCYP2C19
Diazepam
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Narrow therapeutic index
Active Drug
CYP450 Enzyme
• Inactive Metabolite
No effect
Toxicity
Effect of non function of CYP450
CYP 2D6, CYP2C9,CYP3A4,CYP2B6
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© GenesFX
SLOW REDUCED NORMAL FAST
Metabolic Speed
Dru
g C
on
cen
trati
on
Optimal
Drug Effect
No efficacy
TOXICITY
The effect of metabolism on the level of the drug
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© GenesFX
CYP450 Allele Nomenclature
Family
(>40%)
Isoform
CYP 2 D 6
Cytochrome P450
SuperfamilySubfamily
(>55%)
*4
ALLELE
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© GenesFX
DNAdose – the right medication at the right dose
based on your DNA
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Presented at HGM2012 (March
GenesFX in-house data on genotype diversity in
Australian population (n=1619)
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Study many genes -
• Web tool genesfx.com and dnadose.com
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© GenesFX
Adverse Drug Reactions- Australia
• GP’s report 10% of patients experience ADR’s, of which
45% rated as moderate to severe. 7.6% resulted in
hospitalisation. (30% over 80years)
(MJA 2006;184(7):321).
• Therapeutic Goods Administration
– 140,000 patients admitted to hospital with an ADR
each year
– The cost is $14,000 extra per admission (Deloitte
report)
Second National Report on Patient Safety from the Australian Council for Safety and Quality in Health Care (2002)
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© GenesFX
ADVERSE DRUG REACTIONS-US
• Over 2 million ADRs/year in the US.
• Over 100,000 deaths annually (6th leading cause of death in the U.S.*)
• Drug-related injuries occur in ~ 6.7% of
hospitalized patients
• Annual Hospital cost US$1.6 to 4 billion*Lazarou et al: Incidence of adverse drug reactions in hospitalized patients: a meta
analysis of 39 prospective studies. JAMA 1998; 279:1200-1205.
Gurwitz JH. Am J Med. 2000 Aug 1;109(2):87-94
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Macro economic benefits-Deloitte report 2008
• Potential economic $2.1 billion - $5.5 billion
over 5 yr
– 0.5%-1% all admissions
• Avoided wastage: $360 million - $720 million
over 5 years
• Improved quality: reduced strokes and breast
cancer / equivalent to more than $1 billion -
$6billion
• Total Savings 12 Billion over 5 years in
Australia
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© GenesFX
Standard dose/drug hope for the best
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Preliminary work with Garvan Institute using whole gene sequencing
• Started with genes of DNA dose
• Send the outputs and read the genotypes
• Incorporate into pharmacogenomic reports
SnpTool(Genotype Calculator)
CYP2C19 *1/*2
Report writing/decision support software
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XXConstruct
LibraryXX Sequence
Analyse Data
Genotype Drug Report
Genotype
Genotype
• *4/*4Drug
Pharmacogenomic Whole Genome Sequence Pipeline
C,G,A,T
Report
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© GenesFX
Current testing of 4 genes beneficial- much improved
benefit from WGS?
• DNAdose is a multi-gene test that covers ~ 50% of commonly prescribed
medications- (4 Genes)
• Test 4 genes and separate common mutations
• Eg CYP2D6 15 mutations
• CYP2C19 -3
• Multi-gene test
• CYP2D6• CYP2C19• CYP2C9• VKORC1
• 1300 Support line for doctors
• Online support tool at www.genesfx.com
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Narrow therapeutic index
Sertraline
CYP450 Enzyme
• Inactive Metabolite
No effect
Toxicity
Which CYP450?- All known mutations?
CYP 2D6, CYP2C9,CYP3A4,CYP2B6
as well CYP2C19 all mutations
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The literature and WGS
• 2013 Potential and difficulties
• JAMA March 2014- Tested Genes in DNAdose and regarded as significant findings recommended by PharmGKB CPIC. 11/12 had a >=1 with associated recommendation. Each individual had 1-3 changes. 3-10 additional changes per individual with PharmGKB evidence level 1B or higher.
• 2014(March) Huser et al 6 CPIC guidelines. 69 patients-Statin recommendation in 16%
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Francis Collins and Pharmacogenomics
• Head of USA National Genome Research Institute Group(2003).
• “pharmacogenomics was expected to be one of the first benefits of the genome sequencing knowledge”
• In December 2013 , as the Director of NIH, and the 10 year anniversary of the sequencing he said that Pharmacogenomics was a major area of opportunity which is yet to be fully exploited.
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Why not widely used in hospitals?
• Not realised because individual tests have to be ordered. If the whole genome results were in the EMR which allow a much faster use of the information to “get the right drug in the right dose for each patient”
• However our experience says this information is useless unless you have a whole a proper report matching the genetic findings with the drugs.
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Implementing a pharmacogenomic testing and a pharmacogenomic decision support software system in a public hospital
Pharmacogenomics Decision Support System:
Market Validation Program (MVP)
A Major Teaching Hospital in Melbourne
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• Accurate, fast and relatively cheap sequencing
• Methods of storing this and making it readily available
• For pharmacogenomics you need a system to be
knowledgeable about how the PGx genotypes interact with
specific drugs and drug combinations (extra steps in the
pipeline)
• You need a decision support system to help make this
information usable.
To make the most of WGS and Pharmacogenomics we
need
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The right drug in the right dose OR?
Favourite Drug A or B?
And/Or what shall I eat for lunch ?
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© GenesFX
CPIC Guidelines for CYP2D6 and CYP2C19 Genotypes and
Dosing of TCAs - 2013
Adapted from: Hicks JK et al. Clinical Pharmacogenomics Implementation Consortium Guidelines for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants. Clinical Pharmacology & Therapeutics. 2013 May;93(5):402-408.
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Some items in case presented recently published in
growing body of evidence
Swen et al (2011)