Clinical Pharmacogenomics:
Implications of New Developments for
the NHS
Munir Pirmohamed
NHS Chair of Pharmacogenetics
Department of Molecular and Clinical Pharmacology
Institute of Translational Medicine
University of Liverpool
The Next 20 Years
Prediction is very difficult, especially
about the future
Niels Bohr, Danish Physicist
The best way to predict the future is
to invent it
Alan Kay, American Computer
Scientist
Definitions
Pharmacogenetics
(after Vogel, 1957)
The study of the genetic
basis for the difference
between individuals in
response to drugs
Pharmacogenomics
(after Marshall, 1997)
1. Use of population genetic information for drug research, design
and development
2. Clinical management of drug therapy (drug dosing and drug
choice)
Evolution of Clinical Pharmacogenomics
Phenotype
Individual
genes
GWAS
Sequencing
Probe drug
PCR-based
Increasing use
Future?
Metabolite:
parent drug
ratio
Current
Standard
Robust findings
Implementation
Thiopurine Methyl Transferase (TPMT): A
Phenotypic Test






Metabolises azathioprine and
6-mercaptopurine
Thioguanine accumulation
inversely related to TPMT
activity
Associated with severe
haemopoietic toxicity
Molecular basis defined
Phenotyping assays available
and still used
PATCHY UPTAKE and
dependent of specialty
Evolution of Clinical Pharmacogenomics
Phenotype
Individual
genes
GWAS
Sequencing
Probe drug
PCR-based
Increasing use
Future?
Metabolite:
parent drug
ratio
Current
Standard
Robust findings
Implementation
Technology-Based Reduction in the Burden of
ADRs: The Case of Abacavir Hypersensitivity
NH
N
H2N
Clinical genotype
N
N
Association with
HLA-B*5701
N
CH2OH
Clinical phenotype
Incidence before and after testing for HLA-B*5701
Country
Pre testing
Post testing
Reference
Australia
7%
<1%
Rauch et al, 2006
France
12%
0%
Zucman et al, 2007
UK (London)
7.8%
2%
Waters et al, 2007
Effect of Pharmacogenetics on Drug Usage
6000
Combivir
Kivexa
Truvada
Trizivir
Atripla
700
HLA tests
650
5500
600
550
4500
500
4000
450
3500
400
350
3000
300
2500
250
2000
200
1500
150
1000
100
500
50
0
0
Jul
Jun
May
Apr
Mar
Feb
Jan
Dec
Nov
Oct
Sep
Aug
Jul
Jun
May
Apr
Mar
Feb
Jan
Dec
Nov
Oct
Sep
Aug
Jul
Jun
May
Apr
Mar
Feb
Jan
Dec
Nov
Oct
Sep
Aug
Jul
Jun
May
Apr
Mar
Feb
Jan
Dec
Nov
Oct
Sep
Aug
Jul
Jun
May
Apr
Mar
Feb
Jan
2005
2006
2007
2008
2009
Cumulative number of HLA tests
Patient days of treatment
5000
Evolution of Clinical Pharmacogenomics
Phenotype
Individual
genes
GWAS
Sequencing
Probe drug
PCR-based
Increasing use
Future?
Metabolite:
parent drug
ratio
Current
Standard
Robust findings
Implementation
Evolution of Clinical Pharmacogenomics
Phenotype
Individual
genes
GWAS
Sequencing
Probe drug
PCR-based
Increasing use
Future?
Metabolite:
parent drug
ratio
Current
Standard
Robust findings
Implementation
Malignant Melanoma and BRAF Inhibitor:
Baseline and 2 Weeks After
Evidence
What type of evidence is required
for demonstration of clinical utility?
Warfarin Pharmacogenetics:
Controversy Regarding Genotyping
Change in warfarin
label (2007) and dosing
tables (2010)
Pharmacogenetic-Based Dosing: Warfarin
Randomised Controlled Trial
FP7 sponsored EU trials
 3 trials: warfarin,
phenprocoumon,
acenocoumarol
 400-450 patients in each
 %TIR as primary outcome
measure
 Point of Care test for
genotyping

European Union
Pharmacogenetics of
AntiCoagulant Therapy
HLA Genotyping to Prevent Serious
Adverse Drug Reactions
Since 2001, 22 new alleles associated with serious immunemediated adverse drug reactions have been identified
 Many of these have been based on genome wide association studies
with initial results being replicated
 Examples include:





Carbamazepine: HLA-B*1502 and Stevens-Johnson Syndrome
Carbamazepine: HL-A*3101 and hypersensitivity syndrome
Allopurinol: HLA-B*5801 and serious cutaneous adverse reactions
Flucloxacillin: HLA-B*5701 and cholestatic hepatitis
Are we going to require RCTs for all of these association?
 Can we afford it?

“Hierarchies of evidence should be replaced by accepting—indeed
embracing—a diversity of approaches.....
...It is a plea to investigators to continue to develop and improve
their methods; to decision makers to avoid adopting entrenched
positions about the nature of evidence; and for both to accept that
the interpretation of evidence requires judgment.”
Evidence standards differ between non-genetic and genetic tests
 3 examples given:

 Drug exposure
 Prevention of adverse drug reactions
 Health technology assessment
Drug Exposure: Differential
Evidential Standards

Example: Aztreonam SmPC
 “after an initial usual dose, the dosage of aztreonam should be halved
in patients with estimated creatinine clearances between 10 and 30
mL/min/1.73 m2”
Many different examples in hepatic and renal impairment with dose
instructions based on PK studies and occasionally PK-PD modelling
 No need for RCTs – in fact, would be impractical


However, a genetic polymorphism leading to same degree of change
in drug exposure is often ignored and/or RCT data are required for
implementation
Differential Evidence Standards





Unfamiliarity with
genetic tests
Lack of experience in
interpretation
Perceived cost of
genetic testing
Lack of availability of
tests
Poor turnaround time
recommendations on dosing evaluation in
patients with polymorphisms in known
metabolic pathways
The Future?
10 years
 A whole genome costs less
than £100
 Only needs to be done once
 Good visualisation software

Patient who requires a drug
metabolised by CYP2D6
 Absent in 8% of the population
 Are you going to ignore the
genetic data in the patient’s
medical record?

Patient Empowerment
Translation into Clinical Practice
Lost in Translation
•
•
•
•
Major on-ongoing advances
Identify evidence needs
Consistency in evidence standards
Streamlined processes for
adoption into NHS
• Innovation into practice a major
driver for the AHSN
Poste, Nature, 2011
Acknowledgements
Dept of Pharmacology
Ana Alfirevic, Dean Naisbitt, Andrea
Jorgensen, Dan Carr, Mas
Chaponda, Fabio Miyajima, Kevin
Park plus many others
Collaborators
• Wellcome Trust Sanger Institute
(Panos Deloukas, Stephane
Bourgeois, Trevor Lawley, Gordon
Dougan)
• University of Bangor (Dyfrig
Hughes)
• Epigen, DILIGEN, iSAEC
Funders
• Department of Health (NHS Chair
of Pharmacogenetics), NIHR
programme, MRC, EU-FP7,
Wellcome Trust