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Pirmohamed rcp myogenes seminar 2018
- 1. 23/04/2018 1 Pharmacogenomics: Challenges and Opportunities Munir Pirmohamed David Weatherall Chair of Medicine, University of Liverpool Executive Director, Liverpool Health Partners Disclosures Area Disclosure Funding for studies MRC, NIHR, EU General Research Support MRC, Wolfson and Dept of Health Consultant No relevant conflicts of interest to declare Major Stockholder No relevant conflicts of interest to declare Honoraria No relevant conflicts of interest to declare Scientific Advisory Board No relevant conflicts of interest to declare Government Advisory Committees Commission on Human Medicines Pharmacovigilance Expert Advisory Group (Chair)
- 3. 23/04/2018 3 Genetic Contribution Many factors determine response to drug, some of which are environmental and clinical We do not know the overall genetic contribution to drug response The genetic effect will vary according to drug and response Definitions Pharmacogenetics (after Vogel, 1957) Pharmacogenomics (after Marshall, 1997) The study of variations of DNA and RNA characteristics as related to drug response The study of variations in DNA sequence as related to drug response ICH Topic E15, November 2007 “Variability is the law of life” Sir William Osler (1849‐1919)
- 4. 23/04/2018 4 Pharmacokinetics Absorption Distribution Metabolism Excretion Environmental factors Genetic factors Patient‐related factors Concomitant disease Pharmacodynamics Cell Organ Environmental factors Genetic factors Patient‐related factors Concomitant disease
- 5. 23/04/2018 5 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 Pythagoras (6th Century B.C.) “…..be far from fava beans consumptions” Met death in Ancient Italy because he refused to cross a field of beans Fava beans RBC haemolysis FAVISM G6PD
- 6. 23/04/2018 6 Withdrawal of Antimalarials Because of G6PD Deficiency in African Populations Chlorproguanil‐dapsone (Lapdap) and CD artesunate (CDA) As effective as other antimalarials Cheap Lower Hb in G6PD deficient patients Pharmacogenomic Variation Efficacy Cancer and non‐cancer treatments Dosing Precision dosing Safety Serious adverse drug reactions
- 8. 23/04/2018 8 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 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)
- 9. 23/04/2018 9 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 Variability in Drug Concentrations after Fixed Dosing
- 10. 23/04/2018 10 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 • CYP2D6: metabolism of 25% of drugs including codeine and psychiatry drugs • PM: lack of efficacy of codeine, while high exposure and potential for ADRs with other drugs • URM: codeine – resp depression; with other drugs – lack of efficacy 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
- 11. 23/04/2018 11 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% 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
- 12. 23/04/2018 12 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
- 13. 23/04/2018 13 Serious Adverse Drug Reactions Toxic Epidermal Necrolysis Hepatocellular hepatitis Human Leucocyte Antigens (HLA) On short arm of chromosome 6 Involved in the pathogenesis of immune‐ mediated adverse drug reactions Most work undertaken with type IV (T‐cell) mediated reactions
- 15. 23/04/2018 15 HLA Platform Mr SPOT Histomatch software Standard type of wells with the SSO spotted on to the base of the well in a set pattern which can be recognised by the Histomatch software Diagnose Predict Exclude Understand Pre‐empt Monitor Genomic testing can be used for more than prediction
- 16. 23/04/2018 16 Changing Demographics • Multiple diseases • Multiple organ systems affected • Deterioration in: • Renal function • Liver function • Respiratory function • Cognitive function • Mobility • Polypharmacy At least one high risk variant At least one actionable variant No actionable variants 91% Frequency of actionable genotypes in the first 10,000 PREDICT patients (slide courtesy of Dan Roden)
- 17. 23/04/2018 17 • 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? The Horizon 2020 U‐PGx project Ubiquitous Pharmacogenomics in the EU Thanks to the U‐PGx team and HJ Guchelaar for the slides Implement pre‐emptive PGx testing in a real world clinical setting across 7 EU sites using DPWG guidelines Evaluate patient outcome and cost effectiveness in a RCT