Medicines Optimisation Through Precision

Munir PirmohamedDavid Weatherall Chair of Medicine

Department of Molecular and Clinical PharmacologyInstitute of Translational Medicine

University of Liverpool

ensuring that the right patients get the right choice of medicine, at the right time.

the goal is to help patients to: improve their outcomes; take their medicines

correctly; avoid taking unnecessary

medicines; reduce wastage of

medicines; and improve medicines safety.

Medicines optimisation

Current Paradigm

Efficacy • One drug fits all

Safety • One dose fits all

Case History

70 year old man Attended for hypertension – was on 7 antihypertensives In total was on 17 drugs Assured me he was fully adherent Was on beta-blocker but HR 92/min Assured me he was fully adherent

Urinary drugScreen by LCMS

CAFFEINE

WARFARIN

GWAS Warfarin Mean Weekly Dose (UK Prospective Cohort; n=714)

CYP2C9

VKORC1

Total = 57.9%

Age: 11.2%Height 3.56%Weight: 5.98%Interacting meds: 0.98%Sum of interacting meds: 2.2%VKORC1: 25.61%CYP2C9: 16.65%CYP4F2: 0.49%

Time in Therapeutic Range

7%

VK

*3

*2

ParaDNA: Point of Care Device

1. Take sample

2. Use device to transfer and seal sample into four wells pre-loaded with single or multiplex test chemicals

3. Four separate independent analyses possible

4. Analysis is complete in 45 minutes.

8Courtesy of LGC, Commercial in Confidence

Sample Dispense

Three genotyping tests (VKORC1, CYP2C9*2, *3)

Paul Downie, 56, of Grappenhall in Warrington was referred to the anticoagulation clinic following treatment for an irregular heart rate. He said: “The old way of prescribing warfarin is more hit and miss; this is bespoke medication, calculated on my gene type. “My mum went on warfarin eight months ago and she was back and forward to the clinic at least four times on a weekly basis before they got the dose right. I went back once, which meant I could go back to work quicker, feeling well enough to go back to normal life. I think this a win-win, for me and for the health service.”

NIHR Collaboration for Leadership inApplied Health Research and CareNorth West Coast

University of Liverpool

Clinics in Chester, Warrington and Liverpool

6.5% of all admissions to hospital are due to ADRs 2nd commonest cause was due to diuretic-induced acute renal

impairment

No clear guidance for renal function monitoring in the literature NICE guidance suggests once every 6 months – but not based on

robust data Practice likely to vary throughout UK

BMJ, 2004

Big Data Approach to Personalised Renal Function Monitoring: Phase I

Big Data

Anonymised electronic health recordsCardiac failureDiuretic doses

Machine learning

Development of robust algorithmsPatient acceptabilityGP acceptability

Aims

Personalised renal function monitoring guidanceAssess clinical effectiveness and cost effectiveness

Point of care renal function monitoring Use of sensor for non-invasive monitoring

Results sent via mobile phone technology to secure cloud based server

Personalised renal function monitoring algorithm – to be continually refined Personalised messaging to GP about review of patient to assess diuretic dosage

Personalised renal function monitoring would optimise diuretic dosing, prevent renal impairment, and prevent hospital admission in keeping with 5-year forward view

Cost effectiveness would need to be assessed

Big Data Approach to Personalised Renal Function Monitoring: Phase II

Changing Demographics

• Multiple diseases• Multiple organ systems affected• Deterioration in:

• Renal function• Liver function• Respiratory function• Cognitive function• Mobility

• Polypharmacy

• Over 50 years• Polypharmacy patients• Small trial n=57 vs 53• Pharmacogenetic profiling• Clinical outcome measures

• We already have kidney and liver tests before we prescribe.

• What if we also had genetic profiling?

• €15 million, H2020, 10 EU countries

• Implement pre-emptive PGx testing in a real world clinical setting across 7 EU sites

• Evaluate patient outcome and cost effectiveness using solid scientific methodology

• Start 1-1-2016, 5 years

• Consortium members:• H-J Guchelaar (Coordinator), • JJ Swen, M Kriek, LUMC• M Pirmohamed, R Turner, UOL• J Stingl, FDMD• M Ingelman-Sundberg, KI• M Karlsson, S Jonsson, PBUU• M Schwab, E Schaeffeler, IKP• VHM Deneer STZHM • M Samwald, G Sunder-Plassmann, MUWV

• M van Rhenen, KC Cheung, KNMP• C Mitropoulou, GHXF • D Steinberger, BIOL• CL Davila Fajardo, SAS• G Patrinos, UPAT• V Dolzan, ULMF• A Cambon-Thomsen, UPS• G Toffoli, E Cecchin, CROA

N=8,000

Project Outline

The Only Thing That Is Constant Is Change

Heraclitus (535BC - 475BC)