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

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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

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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