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Same Medicine, Different Result Pharmacogenetics: Where Are We Now?. Dr Richard FitzGerald Molecular & Clinical Pharmacology Institute of Translational Medicine University of Liverpool Richard.Fitzgerald@liverpool.ac.uk. The drugs don’t work. ....... they just make it worse.

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Same medicine different result pharmacogenetics where are we now

Same Medicine, Different ResultPharmacogenetics: Where Are We Now?

Dr Richard FitzGerald

Molecular & Clinical Pharmacology

Institute of Translational Medicine

University of Liverpool

Richard.Fitzgerald@liverpool.ac.uk




The problem variability

‘If it were not for the great variability among individuals, medicine might as well be a science and not an art.’

Sir William Osler, 1892

The problem: variability


Pythagoras 6 th century b c
Pythagoras (6 individuals, medicine might as well be a science and not an art.’th Century B.C.)

  • “…..be far from fava beans

    consumptions”

  • Met death in Ancient Italy

    because he refused to cross a

    field of beans

  • Many theories:

    • Contained souls

    • Looked like testicles

    • flatulence

    • Medical reason

FAVISM

RBC

haemolysis

Fava beans


Chemical individuality

First suggested by Sir Archibald individuals, medicine might as well be a science and not an art.’Garrod that genetics may affect chemical transformations

He used the example of alkaptonuria (1902)

‘Chemical Individuality’

‘One gene, one enzyme’


Modern pharmacogenetics
Modern pharmacogenetics individuals, medicine might as well be a science and not an art.’


Types of genetic variation
Types of Genetic Variation individuals, medicine might as well be a science and not an art.’


Drug response a complex trait
Drug Response: a complex trait? individuals, medicine might as well be a science and not an art.’


The early years one gene one disease
The early years: one gene, one disease individuals, medicine might as well be a science and not an art.’

  • Robert Smith investigated debrisoquine (a commercially available anti-hypertensive)

  • He took the tablet, along with most of his laboratory staff

  • He collapsed and became markedly hypotensive. Nobody else did.


Cyp2d6 major alleles
CYP2D6 Major Alleles individuals, medicine might as well be a science and not an art.’


Nortriptyline pharmacogenetics
Nortriptyline pharmacogenetics individuals, medicine might as well be a science and not an art.’


Codeine phosphate
Codeine phosphate individuals, medicine might as well be a science and not an art.’


Drug metabolising enzymes
Drug metabolising enzymes individuals, medicine might as well be a science and not an art.’

Most DME have clinically relevant polymorphisms

Those with changes in drug effects are separated from pie.


Same medicine different result pharmacogenetics where are we now

Azathioprine individuals, medicine might as well be a science and not an art.’

Xanthine

oxidase

TPMT

Thiouric

acid

6-Mercaptopurine

6-Me MP

HGPRT

6-thioinosine nucleotide

IMPDH

6-thioguanine

nucleotides

Immunosupression

Clinical benefit


Same medicine different result pharmacogenetics where are we now

TPMT (Thiopurine methyltransferase) individuals, medicine might as well be a science and not an art.’

Allelic polymorphism

High

TPMT

89%

Low

TPMT

1/300

Intermediate

TPMT

11%

?very high

TPMT

Severe Bone

Marrow

Suppression

High risk

of marrow

suppression

Low risk

Low risk

? poor

responders

-

+

clinical response


Pgx current applications
PGx: current applications individuals, medicine might as well be a science and not an art.’


Abacavir hypersensitivity
Abacavir Hypersensitivity individuals, medicine might as well be a science and not an art.’

  • Nucleoside analogue

  • Reverse transcriptase inhibitor

  • Hypersensitivity 5%

  • Fever, skin rash, gastro-intestinal symptoms, eosinophilia within 6 weeks

  • Re-challenge results in a more serious reaction


Abacavir hypersensitivity1

Association with individuals, medicine might as well be a science and not an art.’

HLA-B*5701

Clinical phenotype

Causal chemical

Clinical genotype

Abacavir Hypersensitivity


Pgx effects on drug usage
PGx: effects on drug usage individuals, medicine might as well be a science and not an art.’

Data from RLBUHT courtesy of Prof SayeKhoo


Same medicine different result pharmacogenetics where are we now

PREDICT-1 individuals, medicine might as well be a science and not an art.’


Abacavir genetics why so rapidly implemented
Abacavir Genetics: Why so Rapidly Implemented? individuals, medicine might as well be a science and not an art.’

  • Implemented even before RCT evidence

    • In some cases, observational study designs may provide adequate evidence

  • Successful implementation was because of several factors:

    • Good and replicated evidence of a large genetic effect size

    • Clinician community amenable to rapid change in clinical practice

    • Vocal and knowledgeable patient lobby


Carbamazepine induced hypersensitivity reactions
Carbamazepine-induced hypersensitivity reactions individuals, medicine might as well be a science and not an art.’

5% of patients on carbamazepine (CBZ) develop hypersensitivity reactions

10% in prospective SANAD study (UK)

Clinical manifestations

  • Maculopapular exanthema

    usually mild

  • Hypersensitivity reaction (HSS)

    1/1000 patients

    Fever, hepatitis, eosinophilia

  • Stevens-Johnson syndrome

    Toxic epidermal necrolysis

    5-30% fatality rate


Fda warning
FDA warning individuals, medicine might as well be a science and not an art.’

  • PATIENTS WITH ASIAN ANCESTRY SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH Carbamazepine.


Same medicine different result pharmacogenetics where are we now

HLA-B*1502 testing → 0 incidence of SJS/TEN


Same medicine different result pharmacogenetics where are we now

  • University of Liverpool individuals, medicine might as well be a science and not an art.’(SANAD, EUDRAGENE, Swiss, WT Sanger, Harvard)

  • EPIGEN Consortium (Ireland, Duke University, UCL, Belgium)

  • Faculty of 1000 -top 2% of published articles in biology and medicine

  • American Academy of Neurology meeting- voted as one of the top articles in neurology this year


Same medicine different result pharmacogenetics where are we now

HLA-A*3101 individuals, medicine might as well be a science and not an art.’

HLA-A*3101

22 patients with HSS 43 patients with MPE

2691 healthy control subjects 1296 healthy control subjects

McCormack et al. NEJM 2011


Same medicine different result pharmacogenetics where are we now

Pooled analysis of case-control studies individuals, medicine might as well be a science and not an art.’

P=0.03

P=8 x10-7

P=8 x10-5

P=1x10-7

P=

McCormack et al. NEJM 2011


Same medicine different result pharmacogenetics where are we now
GWAS identifies individuals, medicine might as well be a science and not an art.’HLA-A*3101 allele as a genetic risk factor for CBZ-induced cutaneous adverse drug reactions in Japanese population

HLA-A*3101

Ozeki et al. Hum Mol Genet 2011


Conclusions
Conclusions individuals, medicine might as well be a science and not an art.’

  • HLA-A*3101 - a prospective marker for CBZ hypersensitivity

  • Associated with several phenotypes

  • Further work needed to enable clinical use

  • Need for consortia

  • Possibility of rare variants and CNVs

    (exome-sequencing/WGS)

  • Mechanistic studies to follow genetics


Flucloxacillin induced cholestatic hepatitis whole genome scan
Flucloxacillin-Induced Cholestatic Hepatitis: Whole Genome Scan

  • Illumina 1 million SNP array

  • Strong (P=10-30) association with SNP in LD with HLA-B*5701

  • Weaker association with novel marker on chromosome 3 (p < 1.4 x 10-8 )

  • Weak association with copy number polymorphism

Daly at al, 2009

Performed in collaboration with the Serious Adverse Event Consortium


Same medicine different result pharmacogenetics where are we now

Implicated SNP is in the SLCO1B1 gene (transporter) Scan

Shown with simvastatin 40mg and 80mg

C variant may account for 60% of the cases of myopathy





Conclusions1
Conclusions Scan

  • Clear adverse effect of the CYP2C19*2 polymorphism on clinical and pharmacodynamic outcomes

    • PD Meta-analysis limited by multiple outcome measures

  • Potential utility in CYP2C19*2 as marker of clopidogrel non-response and risk of adverse outcome

  • Translation into clinical practice

    • Increase dose of clopidogrel from 75mg/day to 150mg/day

      • Evidence from CURRENT-OASIS 7 trial

      • Bleeding risk

    • Use of alternative anti-platelet drugs (Prasugrel, Ticagrelor)

      • Better platelet inhibition

      • Higher rates of bleeding (+ other adverse effects)

      • Benefit may be only seen in those with the CYP2C19*2 allele

      • Cost


Warfarin a more complex variation
Warfarin: a more complex variation Scan

  • Widely used drug

  • A variety of acute/chronic indications

  • Large numbers of patients

  • 6% of all patients over 80 years of age

  • Narrow therapeutic index

  • Drug interactions and alcohol

  • Efficacy


Same medicine different result pharmacogenetics where are we now

  • 10% of all ADR-related hospital admissions


  • The clinical phenotype
    The clinical phenotype Scan

    • 10-50 fold variability in dose requirements

    • Increased age; decreased requirements

      • 8% decrease in warfarin dose per decade

      • Enhanced responsiveness (PD)

      • Reduced clearance (PK)


    Same medicine different result pharmacogenetics where are we now

    Warfarin and metabolism by CYP2C9 Scan

    CYP2C9*1 Wild Type Arg144 Ile359

    CYP2C9*2 Arg144Cys

    : interaction with cytochrome

    P450 reductase

    CYP2C9*3 Ile359Leu

    : substrate binding site

    : affects Km, Vmax

    Variant alleles have 5-12% of the activity of wild-type

    • Steward et al, Pharmacogenetics (1997), 7, 361-367


    Warfarin and pharmacokinetics

    CYP2C9 genotype Scan

    Number of patients

    Aggregate mean dose (mg)

    CYP2C9*1*1

    639

    5.5

    CYP2C9*1*2

    207

    4.5

    CYP2C9*1*3

    109

    3.4

    CYP2C9*2*2

    7

    3.6

    CYP2C9*2*3

    11

    2.7

    CYP2C9*3*3

    5

    1.6

    Warfarin and pharmacokinetics


    Warfarin and pharmacodynamics

    Polymorphisms in vitamin K Scanepoxide reductase (VKOR)C1

    Associated reductions in warfarin dose

    Accounts for greater variance in dose than CYP2C9

    Variation in genes encoding γ-glutamylcarboxylase and factors II, VII and X

    Warfarin and pharmacodynamics


    Genetic and environmental factors and dose requirements of warfarin

    55% Scan

    Age: p<0.0001, r2 = 0.10

    Body weight: p=0.0018, r2 = 0.05

    Genetic and Environmental Factors and Dose Requirements of Warfarin

    Independent effects of VKORC1 and CYP2C9:

    VKORC1: p<0.0001, r2 = 0.29

    CYP2C9: p=0.0003, r2 = 0.11

    Wadelius et al. 2005


    Warfarin multiple genes factors
    Warfarin: multiple genes/factors Scan

    GENETIC

    • Cytochrome P450 polymorphisms

    • Vitamin K epoxide reductase

    • Phase II metabolising genes

    • Drug transporters

    • Clotting factors

    • Disease genes

    ENVIRONMENTAL

    • Sex

    • Age

    • Smoking

    • Interacting drugs

    • Alcohol

    • Compliance

    • Diet





    Same medicine different result pharmacogenetics where are we now


    Two randomised controlled trials
    Two Randomised Controlled Trials or fixed dosing

    COAG

    EU-PACT

    EU FP7 sponsored EU trials

    3 trials: warfarin, phenprocoumon, acenocoumarol

    900 patients in each (2700 total)

    Final study design completed

    %TIR as primary outcome measure

    • NIH-sponsored US trial

    • 1200 patients

    • Genetic algorithm vs clinical algorithm

    • %TIR as primary outcome measure


    Closing the loop
    Closing The Loop or fixed dosing


    Same medicine different result pharmacogenetics where are we now

    New technologies: or fixed dosing

    Pharmacogenomics

    Proteomics

    Metabolomics

    Systems Biology

    Minimise risk and maximize benefit

    Uncertainty reduced but not abolished

    Pre-clinical

    Phases I, II, III

    Phase IV


    Advances in technologies

    14 billion bases/day or fixed dosing

    Advances in Technologies


    Pgx and prospective utility
    PGx and Prospective Utility or fixed dosing

    • Drug development process

    • Potential prospective use of PGx to enhance success

    • Increase confidence

    • US$1 billion to market a new drug

    • Target discovery

    • Proof of concept

    • Candidate gene/whole genome association


    Current status of genetic tests
    Current Status of Genetic Tests or fixed dosing

    “Today, there is no mechanism to ensure that genetic tests are supported by adequate evidence

    before they are marketed or that marketing claims for such tests are truthful and not misleading. Misleading claims about tests

    may lead health-care providers and patients to make inappropriate decisions about whether to test or how to interpret test results.”

    Science, 4 April 2008


    Personalised medicines the future
    Personalised Medicines: The Future? or fixed dosing

    • Many recent advances

    • Here to stay, and likely to be supported by increasing evidence

    • Evolutionary process, not revolutionary

    • Lot of cynicism about personalised medicine approaches

    • Evidence being required is much greater with other tests


    Personalised vs empirical paradigms
    Personalised vs. Empirical Paradigms or fixed dosing

    Empirical (intuitive) medicine

    Personalised (precision) medicine


    Terminology
    Terminology or fixed dosing

    Personalised Medicine

    not

    Personal Medicine

    • We cannot truly personalise medicines

    • No test or prediction rule will be 100% effective


    Same medicine different result pharmacogenetics where are we now

    “ What we know about the genome today is not enough for all the miracles many expect from this field. There’s a lot about what regulates the genes and how they interact that we still need to understand. We won’t have the answers by tomorrow.”

    Arno Motulsky

    29th April 2008