Presentation on theme: "NHS Chair of Pharmacogenetics"— Presentation transcript:
1 NHS Chair of Pharmacogenetics Clinical Pharmacogenomics: Implications of New Developments for the NHSMunir PirmohamedNHS Chair of PharmacogeneticsDepartment of Molecular and Clinical PharmacologyInstitute of Translational MedicineUniversity of Liverpool
2 Prediction is very difficult, especially about the future The Next 20 YearsPrediction is very difficult, especially about the futureNiels Bohr, Danish PhysicistThe best way to predict the future is to invent itAlan Kay, American ComputerScientist
3 Definitions Pharmacogenetics Pharmacogenomics (after Vogel, 1957) The study of the geneticbasis for the differencebetween individuals inresponse to drugsPharmacogenetics(after Vogel, 1957)Use of population genetic information for drug research, design and developmentClinical management of drug therapy (drug dosing and drug choice)Pharmacogenomics(after Marshall, 1997)
4 Evolution of Clinical Pharmacogenomics PhenotypeProbe drugMetabolite: parent drug ratioIndividual genesPCR-basedCurrent StandardGWASIncreasing useRobust findingsSequencingFuture?Implementation
5 Thiopurine Methyl Transferase (TPMT): A Phenotypic Test Metabolises azathioprine and 6-mercaptopurineThioguanine accumulation inversely related to TPMT activityAssociated with severe haemopoietic toxicityMolecular basis definedPhenotyping assays available and still usedPATCHY UPTAKE and dependent of specialty
6 Evolution of Clinical Pharmacogenomics PhenotypeProbe drugMetabolite: parent drug ratioIndividual genesPCR-basedCurrent StandardGWASIncreasing useRobust findingsSequencingFuture?Implementation
7 Incidence before and after testing for HLA-B*5701 Technology-Based Reduction in the Burden of ADRs: The Case of Abacavir HypersensitivityAssociation withHLA-B*5701Clinical genotypeClinical phenotypeIncidence before and after testing for HLA-B*5701CountryPre testingPost testingReferenceAustralia7%<1%Rauch et al, 2006France12%0%Zucman et al, 2007UK (London)7.8%2%Waters et al, 2007
11 Evolution of Clinical Pharmacogenomics PhenotypeProbe drugMetabolite: parent drug ratioIndividual genesPCR-basedCurrent StandardGWASIncreasing useRobust findingsSequencingFuture?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 warfarinlabel (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 trials3 trials: warfarin, phenprocoumon, acenocoumarolpatients in each%TIR as primary outcome measurePoint of Care test for genotypingEuropean 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 identifiedMany of these have been based on genome wide association studies with initial results being replicatedExamples include:Carbamazepine: HLA-B*1502 and Stevens-Johnson SyndromeCarbamazepine: HL-A*3101 and hypersensitivity syndromeAllopurinol: HLA-B*5801 and serious cutaneous adverse reactionsFlucloxacillin: HLA-B*5701 and cholestatic hepatitisAre 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 exposurePrevention of adverse drug reactionsHealth 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 modellingNo need for RCTs – in fact, would be impracticalHowever, 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 testsLack of experience in interpretationPerceived cost of genetic testingLack of availability of testsPoor turnaround timerecommendations 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 onceGood visualisation softwarePatient who requires a drug metabolised by CYP2D6Absent in 8% of the populationAre you going to ignore the genetic data in the patient’s medical record?
23 Translation into Clinical Practice Lost in TranslationMajor on-ongoing advancesIdentify evidence needsConsistency in evidence standardsStreamlined processes for adoption into NHSInnovation into practice a major driver for the AHSNPoste, Nature, 2011
24 Acknowledgements Collaborators Wellcome Trust Sanger Institute (Panos Deloukas, Stephane Bourgeois, Trevor Lawley, Gordon Dougan)University of Bangor (Dyfrig Hughes)Epigen, DILIGEN, iSAECFundersDepartment of Health (NHS Chair of Pharmacogenetics), NIHR programme, MRC, EU-FP7, Wellcome TrustDept of PharmacologyAna Alfirevic, Dean Naisbitt, Andrea Jorgensen, Dan Carr, Mas Chaponda, Fabio Miyajima, Kevin Park plus many others