1. NHS Chair of Pharmacogenetics
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

2. Prediction is very difficult, especially about the future
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

3. Definitions Pharmacogenetics Pharmacogenomics (after Vogel, 1957)
The study of the genetic
basis for the difference
between individuals in
response to drugs
Pharmacogenetics
(after Vogel, 1957)
Use of population genetic information for drug research, design and development
Clinical management of drug therapy (drug dosing and drug choice)
Pharmacogenomics
(after Marshall, 1997)

4. Evolution of Clinical Pharmacogenomics
Phenotype
Probe drug
Metabolite: parent drug ratio
Individual genes
PCR-based
Current Standard
GWAS
Increasing use
Robust findings
Sequencing
Future?
Implementation

5. 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

6. Evolution of Clinical Pharmacogenomics
Phenotype
Probe drug
Metabolite: parent drug ratio
Individual genes
PCR-based
Current Standard
GWAS
Increasing use
Robust findings
Sequencing
Future?
Implementation

7. Incidence before and after testing for HLA-B*5701
Technology-Based Reduction in the Burden of ADRs: The Case of Abacavir Hypersensitivity
Association with
HLA-B*5701
Clinical genotype
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

8. Effect of Pharmacogenetics on Drug Usage

9. Evolution of Clinical Pharmacogenomics
Phenotype
Probe drug
Metabolite: parent drug ratio
Individual genes
PCR-based
Current Standard
GWAS
Increasing use
Robust findings
Sequencing
Future?
Implementation

11. Evolution of Clinical Pharmacogenomics
Phenotype
Probe drug
Metabolite: parent drug ratio
Individual genes
PCR-based
Current Standard
GWAS
Increasing use
Robust findings
Sequencing
Future?
Implementation

12. Malignant Melanoma and BRAF Inhibitor: Baseline and 2 Weeks After

13. Evidence What type of evidence is required
for demonstration of clinical utility?

14. Warfarin Pharmacogenetics: Controversy Regarding Genotyping
Change in warfarin
label (2007) and dosing tables (2010)
We genotyped 201 warfarin-treated patients for five common polymorphisms in and around VKORC1, and all covaried significantly with warfarin dose. VKORC1 has a larger impact on warfarin dose than CYP2C9, which affects dosing through polymorphic metabolism of warfarin.

15. Pharmacogenetic-Based Dosing: Warfarin Randomised Controlled Trial
FP7 sponsored EU trials
3 trials: warfarin, phenprocoumon, acenocoumarol
patients in each
%TIR as primary outcome measure
Point of Care test for genotyping
European Union Pharmacogenetics of AntiCoagulant Therapy

16. 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?

17. “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.”

18. Evidence standards differ between non-genetic and genetic tests
3 examples given:
Drug exposure
Prevention of adverse drug reactions
Health technology assessment

19. 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

20. 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

21. 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?

22. Patient Empowerment

23. 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

24. Acknowledgements 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
Dept of Pharmacology
Ana Alfirevic, Dean Naisbitt, Andrea Jorgensen, Dan Carr, Mas Chaponda, Fabio Miyajima, Kevin Park plus many others