His research focuses on personalised medicine in order to optimise drug efficacy and minimise toxicity,move discoveries from the lab to the clinic, and from clinic to appication.Universidad de Málaga. Campus de Excelencia Internacional Andalucia Tech

Munir, Pirmohamed

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Repositorio Institucional Universidad de Málaga

Munir Pirmohamed David Weatherall Chair of Medicine Department of Molecular and Clinical Pharmacology Institute of Translational Medicine University of Liverpool Precision Medicine: Its Application in Clinical Investigation and Practice Innovation Definition of Precision Medicine  Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person 2015 Obama’s Precision Medicine Initiative $215 million China $8.2 billion Terminology Stratified Medicine in the NHS, ABPI, 2014 Marker of Success  We will have succeeded when this area is simply called:   A Concept of Personalised Medicine  Environmental factors Drug variability Molecular definition Phenotypic definition Current standard Disease stratification Pharmacogenomics Personalised Medicine Pirmohamed, Annu. Rev. Genomics Hum. Genet. 2014. 15:15.1–15.22 Systems Approaches Topol, Cell, 2014 Regulatory Approvals EMA SmPCs With Mandatory Genomic Testing Nov 2014: Eliglustat also approved with CYP2D6 genotyping Only 3 drugs outside the cancer area Malignant Melanoma and BRAF Inhibitor: Baseline and 2 Weeks After Source: Academy of Medical Sciences Report Somatic Gene Variants and Therapies Relling & Evans, Nature 2015  Novel trial designs – acceptability for registration  Umbrella trial – investigation of single tumour type but stratification by different mutations linked to specific candidate drugs  Basket study – in multiple tumour types but with a focus on one or few biomarkers Microbiome and Cancer Immunotherapy Science, 27 Nov 2015 Snyder et al, Science, Nov 2015  New CF drug, ivacaftor   Targets G551D mutation in the CFTR gene (4% of CF population)  Fantastic innovation with increases in FEV1 ~10% • 200 scientists • 600,000 compounds screened • In silico screening of 2.7 million compounds • 3 possible candidates Indication expanded in 2014: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, and G1349D  New Cardiovascular Targets PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)  Gain-of-function-mutations lead to high LDL-C and premature CVD; Loss-of-function mutations – lower plasma levels of LDL-C and lower CVD risk  Increased PCSK9 attenuates LDL receptor recycling resulting in higher LDL-C levels  Human monoclonal antibodies now available – lower LDL-C. Effect on mortality not clear yet.  ANGIOPOEITIN-LIKE 4 (ANGPTL4)  ANGPTL4 inhibits lipoprotein lipase (which reduced lipid levels)  Mutations in ANGPTL4 decrease triglyceride levels and patients have decreased CV risk  Monoclonal antibodies against protein in mice lead to reduce TG    Childhood motor neurone disease  Deafness, speech and swallowing problems, face and limb weakness and breathing problems   Rare, autosomal recessive  About 60 cases reported  Exome sequencing  Brown-Vialetto van Laere syndrome High dose riboflavin (Vitamin B2)  Serious Adverse Drug Reactions Toxic Epidermal Necrolysis Hepatocellular hepatitis CPT, 2012 HLA-B*1502  Faced with this choice what would you do if a patient needs to be prescribed CBZ? A. Ignore screening policy and prescribe CBZ B. Screen patient for HLA-B*15:02 and prescribe alternative drug if positive C. Avoid CBZ all together and prescribe an alternative Evidence strong and consistent Serious ADR potentially preventable Government willing to pay for the test  HLA-B*15:02 screening policy introduced in Hong Kong (Sept 16, 2008): Compared 3 years before with 3 years after (111,242 patients)  CBZ prescriptions declined from 16.2%  to 2.6% (other AEDs increased).   When testing used, it worked: Incidence of SJS/TEN induced by carbamazepine reduced (0.24% to 0%)   SJS/TEN induced by phenytoin increased  Overall incidence of AED-induced SJS/TEN remained unchanged (0.09% [42/45,832] vs 0.07% [39/55,326]) Law of Unintended Consequences InTernational Consortium on Drug Hypersensitivity   (ITCH) EU Australia Canada US Brazil Croatia Norway EUDRAGENE Sponsored by the International Serious Adverse Event  Consortium (iSAEC)  12 international centres  50 UK centres  1500 patients SJS/TEN Patients 25 DRUGS SJS/TEN ALLOPURINOL 10 AMOXICILLIN 16 AMOXICILLIN/CLAVULANIC ACID 5 AMPICILLIN 2 BACAMPICILLIN 1 CARBAMAZEPINE 33 LAMOTRIGINE 18 OTHERS 100 PHENYTOIN 11 SULFASALAZINE 6 TRIMETHOPRIM/SULFAMETHOXAZOLE 26 Total 227 177 Caucasians Cases Associations of Serious Adverse Drug Reactions with HLA Alleles  Cost varies  Single HLA tests  Only available in some immunology laboratories in the NHS  Turnaround time is variable, and can be about 2 weeks Aim  24 HLA alleles  Lower cost than individual alleles  Turnaround time <48 hours  Development of a decision support system Problems in Implementing HLA Gene Tests Multiple HLA Biomarker Panel Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy   Paracelsus, 1493-1541 Dose = exposure  Variation in Drug Exposure as a Result of Renal Impairment  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  Variation in Drug Exposure as a Result of Genetic Polymorphism  A genetic polymorphism leading to same degree of change in drug exposure as renal impairment is often ignored and/or RCT data are required for implementation  However, many patients will have genomic data in healthcare records (for example, from 100K genome project)   Some patients may present with direct to consumer genetic tests  Should these variants be ignored, and conventional dosing used?  Or should the same principles as applied to renal/hepatic impairment be used for genetic polymorphisms to enable more precise dosing?  Eliglustat  Glucosylceramide synthetase inhibitor  Licensed for Gaucher’s disease by FDA in 2014  CYP2D6 and CYP3A4 substrate  CYP2D6 EMs or IMs: 84mg orally twice daily  CYP2D6 PMs: 84mg orally once daily   Number of users UK: 600,000  Dose (mg) range per day: 0.5-20   Fold variability in dose: 40  Major bleeding rate per 100-person years:    2.6  Ranking in ADR list:    3     Warfarin  Approved for human use in 1954  Pharmacogenetic-Based Dosing:  Warfarin Randomised Controlled Trial   FP7 sponsored EU trials  454 patients  226 in genotype arm  228 in standard care arm  Point of Care test for genotyping European Union Pharmacogenetics of AntiCoagulant Therapy Genotyped arm %TTR Standard dosing (control) arm %TTR Adjusted Difference P value ITT ANALYSIS (n= 211 vs 216) 67.4% 60.3% 7% P<0.001 PER-PROTOCOL (n=166 vs 184) 68.9% 62.3% 6.6% P=0.001 PRIMARY OUTCOME MEASURE: Percent time within therapeutic INR range 2.0-3.0 (TTR) during 12 weeks following the initiation of warfarin therapy EU-PACT Cost Effectiveness incremental cost-effectiveness ratios (ICERs) were £6,702 and 253,848 SEK per QALY  gained  Increase pace of progress which is only possible through involvement of many stakeholders  Linking of biomedical and health informatics systems  Incentives to develop stratified medicine products  Adoption  Need for collaboration    Deep phenotyping can be defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described Deep Phenotyping Delude, Nature, Nov 2015 Are our health records up to the challenge of deep phenotyping?  http://www.slideshare.net/maryam_kk/kaimrc-2014-arepathwayseffectiveakiakram Concluding Thoughts  Landscape is highly positive, but many aspects are at an early stage and thus aspirational.  The challenge will be to get them to work  Electronic health records and connectivity is very important, but key issues will need to be tackled  The focus is very much on new drugs and partnership with Pharma Industry, which is of course important.  However, most of the drugs used are off-patent, and the same issues of variability are seen.  We could learn a lot, more quickly, by more funding in this area.  Important not to forget about drug safety and drug dose  We need buy-in of healthcare systems (re-engineering of pathways and education and training) Acknowledgements Panagiotis Deloukas (Sanger Institute) Ann Daly (Newcastle University) SERIOUS ADVERSE EVENT CONSORTIUM EU-PACT Funders:  Dept of Health (NHS Chair of Pharmacogenetics) MRC, WT, DH, NIHR, EU-FP7      The University of Liverpool • B Kevin Park • Ana Alfirevic • Maike Lichtenfels • Dean Naisbitt • Andrea Jorgensen • Dyfrig Hughes  Friends in Malaga: • Liver team (Maribel Lucena, Raul Andrade, whole team • Allergy team (Miguel Blanca, Maria Torres, whole team 

Precision medicine : Its application in clinical investigation and practice innovation

Repositorio Institucional de la Universidad de Málaga

https://riuma.uma.es/xmlui/bitstream/10630/11078/2/Pirmohamed%20malaga%202016.pdf

Precision medicine : Its application in clinical investigation and practice innovation

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