Clinical Pharmacogenomics: Implications of New Developments for
the NHS
Munir PirmohamedNHS Chair of Pharmacogenetics
Department of Molecular and Clinical PharmacologyInstitute 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 ComputerScientist
Definitions
The study of the genetic basis for the difference between individuals in response to drugs
Pharmacogenetics(after Vogel, 1957)
1. Use of population genetic information for drug research, design and development
2. Clinical management of drug therapy (drug dosing and drug choice)
Pharmacogenomics(after Marshall, 1997)
Evolution of Clinical Pharmacogenomics
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
Technology-Based Reduction in the Burden of ADRs: The Case of Abacavir Hypersensitivity
Clinical phenotype
Association with HLA-B*5701
Clinical genotype
CH2OH
H2N
N
NN
N
NH
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
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
JanFebM
arAprM
ayJunJulAugSepO
ctN
ovD
ecJanFebM
arAprM
ayJunJulAugSepO
ctN
ovD
ecJanFebM
arAprM
ayJunJulAugSepO
ctN
ovD
ecJanFebM
arAprM
ayJunJulAugSepO
ctN
ovD
ecJanFebM
arAprM
ayJunJul
2005 2006 2007 2008 2009
Patie
nt d
ays
of tr
eatm
ent
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
Cum
ulati
ve n
umbe
r of H
LA te
sts
Combivir Kivexa Truvada Trizivir Atripla HLA tests
Evolution of Clinical Pharmacogenomics
Evolution of Clinical Pharmacogenomics
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
European Union Pharmacogenetics of AntiCoagulant Therapy
HLA Genotyping to Prevent Serious Adverse Drug Reactions
Since 2001, 22 new alleles associated with serious immune-mediated 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.”
“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
Poste, Nature, 2011
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
AcknowledgementsDept of PharmacologyAna 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, iSAECFunders• Department of Health (NHS Chair
of Pharmacogenetics), NIHR programme, MRC, EU-FP7, Wellcome Trust