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Personalised Medicine
This document discusses personalized medicine and how considering individual patient characteristics can help improve treatment outcomes. It makes the following key points: 1. Current "one-size-fits-all" drug treatment approaches do not account for individual differences and can lead to unsatisfactory response rates, increased costs, and safety issues. 2. Personalized medicine aims to use a patient's demographics, medical history, and molecular information to better define therapies through an integrated approach of diagnostics and therapeutics called "theranostics". 3. A personalized approach that considers a patient's genetics, metabolism, concurrent diseases and environment factors can help achieve improved therapeutic outcomes by providing tailored treatment.
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Personalised Medicine
- 1. Dr. Baharudin Ibrahim SeniorLecturer Department of Clinical Pharmacy School of Pharmaceutical Sciences Universiti Sains Malaysia Personalized medicine
- 2. Current Treatment Approach •Diagnostics 2009. Moving towards personalised medicine. PricewaterhouseCoopers LLP. http://pwchealth.com/ Accessed November 10, 2011. • Agency for Health Care Research and Quality (AHRQ). Reducing and preventing adverse drug events to decrease hospital costs. Research in Action, Issue 1. Rockville, Md. Available at: www.ahrq.gov/ Accessed May 29, 2010. Based on Large Cohort Studies Response rates on drugs still unsatisfactory Increased Cost and Safety concern One-Size-Fits-All Model Blockbuster medicine Do not account for individual differences Without proven Efficacy Varying widely 20% to 75% (depending on the drug and the disease)
- 3. Drug Development Failure Source:Ledford H. Nature 2011.
- 4. • Right Medication, •Right Dose, • Right Patient, • Right Time and • Right Route Five Rights of Optimum Therapy Do we treat the Right Patient??
- 5. What are thefactors affecting Patient’s Therapeutic Outcome? Patient’s Therapeutic Outcome Patient’s Genetic Drug Pharmacokinetics ADME Concomitant Diseases Environmental Factors (Age, food, gut microbiota) Drug-Drug Interaction
- 6. Personalized Medicine What isPersonalized Medicine? • Using patient’s characteristics such as: • Demographics, •Histories (medical & social) •Molecular Information (genetic, protein and metabolic profile) To better define Therapies • Integration of Diagnostics and Therapeutics Theranostics • Personalized Medicine Coalition www.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php. • Lester. DS. Will Personalized Medicine Help in 'Transforming' the Business of Healthcare? Personalized Medicine. 2009;6(5):555-565.
- 7. Personalized Medicine THERANOSTICS : ADiagnostic therapy that identifies patients most likely to be helped by a new medication, and targets drug therapy based on the test results. • Personalized Medicine Coalition www.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php. • Lester. DS. Will Personalized Medicine Help in 'Transforming' the Business of Healthcare? Personalized Medicine. 2009;6(5):555-565.
- 8. Personalized Medicine PM Philosophy EveryPatient has a unique Biology and Pathophysiology which should be reflected in the choice of Pharmacotherapy • Personalized Medicine Coalition www.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php. • Lester. DS. Will Personalized Medicine Help in 'Transforming' the Business of Healthcare? Personalized Medicine. 2009;6(5):5 Improved Treatment Outcome
- 9. Patient’s Therapeutic Outcome& PM Patient’s Therapeutic Outcome Patient’s Genetic Drug Pharmacokinetics ADME Concomitant Diseases Environmental Factors (Age, food, gut microbiota) Drug-Drug Interaction So…. How to achieve Improved Therapeutic Outcome? Personalized Medicine Based on Patient’s molecular Biology and Pathophysiology
- 10. Personalized Medicine Why isPM better than the current approach? Tailored fits better
- 11. Personalized Medicine • Treatthe Patient, NOT just the Disease • Tailored Approach (Provide for individual differences) • Predict Susceptibility and Risk Factors: • Pre-empt disease progression •Target intervention •Avoid ineffective treatments & •Prevent adverse reactions • Reduce costs in the long term • Stratify, Genotype and Phenotype Diseases Why is PM better than the current approach?
- 12. Omics Genotype &Phenotype N S Genomics – study of genes Transcriptomics – study of mRNA Proteomics – study of proteins Metabolomics – study of metabolites
- 13. Genomics & Pharmacogenomics •Genomics •study of all the genes of the living organism •Pharmacogenomics •study which examines the impact of genetic variation on the response to medications • Drug Metabolizing Enzymes, Transporters and Receptors are encoded by several hundred genes, playing a Pervasive role in ADME and drug targeting • Shastry BS (2006). "Pharmacogenetics and the concept of individualized medicine". Pharmacogenomics J. 6 (1): 16–21
- 14. Genomics & Pharmacogenomics VikasKumar, The role of pharmacogenomics in drug development (http://www.pharmainfo.net/reviews/role- pharmacogenomics-drug-development) Pharmacogenomics and optimum Drug Response
- 15. • T Harumi;E Hirotoshi. Pharmacogenetics of Warfarin Elimination and its Clinical Implications. Clinical Pharmacokinetics 2001; 40(8):587-603. Warfarin Genomics & Pharmacogenomics Anticoagulant Long half life (2-3 days)-full effect 5-7 days INR change every 2-3 days Narrow therapeutic index >10-fold inter- patient variability in the doses required to attain therapeutic responses Affected by Patient’s Diet, Age, & other medications
- 16. •Schwarz UI (November2003). "Clinical relevance of genetic polymorphisms in the human CYP2C9 gene". Eur. J. Clin. Invest.. 33 Suppl 2: 23–30. • Oldenburg J, Watzka M, Rost S, Müller CR (July 2007). "VKORC1: molecular target of coumarins". J. Thromb. Haemost.. 5 Suppl 1: 1–6. Genomics & Pharmacogenomics • CYP2C9 Enzyme (Cytochrome Enzyme) •Metabolizes > 80% of the more Active S-enantiomer of warfarin to 6- and 7-hydroxy S-warfarin Warfarin
- 17. •CYP2C9 activity ismodulated by: •Genetic factors, •Stimulatory and inhibitory interactions •Age and other environmental factors •Schwarz UI (November 2003). "Clinical relevance of genetic polymorphisms in the human CYP2C9 gene". Eur. J. Clin. Invest.. 33 Suppl 2: 23–30. • Oldenburg J, Watzka M, Rost S, Müller CR (July 2007). "VKORC1: molecular target of coumarins". J. Thromb. Haemost.. 5 Suppl 1: 1–6. Genomics & Pharmacogenomics Warfarin •This lead to wide interindividual variability for elimination and/or dosage requirement • CYP2C9 hydroxylates about 16% of drugs in current clinical use including narrow therapeutic index drugs such as tolbutamide and phenytoin
- 18. •Schwarz UI (November2003). "Clinical relevance of genetic polymorphisms in the human CYP2C9 gene". Eur. J. Clin. Invest.. 33 Suppl 2: 23–30. • Oldenburg J, Watzka M, Rost S, Müller CR (July 2007). "VKORC1: molecular target of coumarins". J. Thromb. Haemost.. 5 Suppl 1: 1–6. Genomics & Pharmacogenomics • Subjects who are carriers of one or more variant alleles may be at risk for adverse drug reactions /toxicities when the prescribed drugs are extensively metabolized by CYP2C9 Warfarin • Five allelic variants of CYP2C9 produce allozymes with reduced or deficient metabolic activity causing: •Interindividual and ethnic differences (in African Americans and Asians)
- 19. • Sadee W,Dai Z. (2005), Pharmacogenetics/genomics and personalized medicine, Hum Mol Genet. 2005 October 15;14 Spec No. 2:R207-14. •TA Clayton, JC Lindon, O Cloarec, H Antti, C Charuel, G Hanton, J Provost, J Net, D Baker, RJ Walley, JR Everett, JK Nicholson. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature April 2006; 440(20) •Pharmacogenomics doesn’t reflect the variation in Metabolic Phenotype which is major factor causing inter-individual variation in drug effects Genomics & Pharmacogenomics Limitations A group of factors (Genetic & Non Genetic) gives the Metabolic phenotype
- 20. • Sadee W,Dai Z. (2005), Pharmacogenetics/genomics and personalized medicine, Hum Mol Genet. 2005 October 15;14 Spec No. 2:R207-14. •TA Clayton, JC Lindon, O Cloarec, H Antti, C Charuel, G Hanton, J Provost, J Net, D Baker, RJ Walley, JR Everett, JK Nicholson. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature April 2006; 440(20) •Metabolic Phenotype is influenced not only by genotype but also by environmental factors such as •Nutritional status, •Gut microbiota, •Age •Disease and •Co- or pre-administration of other drugs which modulate drug pharmacokinetic (ADME), efficacy and toxicity. Genomics & Pharmacogenomics Limitations
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- 22. • Sadee W,Dai Z. (2005), Pharmacogenetics/genomics and personalized medicine, Hum Mol Genet. 2005 October 15;14 Spec No. 2:R207-14. •TA Clayton, JC Lindon, O Cloarec, H Antti, C Charuel, G Hanton, J Provost, J Net, D Baker, RJ Walley, JR Everett, JK Nicholson. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature April 2006; 440(20) •It’s complex to find the genetic variation which affect Drug response Genomics & Pharmacogenomics Limitations Thus, although genetic variation is clearly important, it seems unlikely that personalised drug therapy will be enabled for a wide range of major diseases using genomic knowledge alone
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- 24. •American Medical Association.AMA Science U.S. Department of Energy Office of Science, Office of Biological and Environmental Research, Human Genome Program JainPharmaBiotech - http://www.ama-assn.org/ Accessed: 05/11/11 Proteomics & Pharmacoproteomics • Proteins – relatively large molecules made up of strings of amino acids linked like a chain • 20 amino acids - combined in different ways to form thousands of proteins, each with a unique, genetically defined sequence that determines the Protein’s specific Shape and Function
- 25. As the maincomponents of the Physiological Pathways of the Cells, proteins serve vital functions in the body such as: •American Medical Association. AMA Science U.S. Department of Energy Office of Science, Office of Biological and Environmental Research, Human Genome Program JainPharmaBiotech - http://www.ama-assn.org/ Accessed: 05/11/11 Proteomics & Pharmacoproteomics Acting as messengers Catalyzing various biochemical reactions Acting as control elements that regulate cell reproduction Influencing growth and development of various tissues Transporting oxygen in the blood Defending the body against disease
- 26. Proteomics & Pharmacoproteomics •Proteomics •Comprehensive analysis and characterization of all of the proteins and protein isoforms • Genome •Relatively static, the proteome changes constantly in response to tens of thousands of intra- and extracellular environmental signals • The proteome varies with health or disease, the nature of each tissue, the stage of cell development and effects of drug treatments •Personalized Medicine Coalition www.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php. •Lester. DS. Will Personalized Medicine Help in 'Transforming' the Business of Healthcare? Personalized Medicine. 2009;6(5):55
- 27. Proteomics & Pharmacoproteomics •Proteinsthat do the work of the cell: •The functional aspects, not genes • Most of the FDA approved targeted therapeutics are directed at proteins • Estrogen receptor - 1960s: •Anti-estrogen tamoxifen in the 1970s - more personalized treatment of patients with breast cancer •Personalized Medicine Coalition www.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php. •Lester. DS. Will Personalized Medicine Help in 'Transforming' the Business of Healthcare? Personalized Medicine. 2009;6(5):55
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- 29. HercepTest HER2 protein Trastuzumab EGFR pharmDXKit Cetuximab EGFR protein Proteomics & Pharmacoproteomics
- 30. Metabolomics & Pharmacometabonomics •FigureSource: American Society for Pharmacotherapy & Therapeutics http://www.ascpt.org/My-ASCPT/Special-Interest-Groups/Pharmacometabolomics-Interest-Group •TAClayton, JC Lindon, O Cloarec, H Antti, C Charuel, G Hanton, J Provost, J Net, D Baker, RJ Walley, JR Everett, JK Nicholson. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature April 2006; 440(20) • Ian D. Wilson1 . Drugs, bugs, and personalized medicine: Pharmacometabonomics enters the ring. PNAS August 2009; 106(34):14187– 14188 • Metabolomics: • A descriptive study of all the metabolites (metabolome) in a cellular system • Metabonomics: •Interactions between metabolic property of an organism and the biological and genetic changes • Metabolomics approach not only may able to diagnose diseases but also phenotype them
- 31. Metabolomics & Pharmacometabonomics Advantages ofMetabolomics approach: • Affected by both Genes and Environment • Closer to Phenotype • Simple and Non-invasive • Relatively Ease of Analysis • Potential to identify Novel biochemical pathways
- 32. Metabolic fingerprint Metabolomics Disease Diagnosis IbrahimB, Marsden P, Smith JA, Custovic A, Nilsson M, Fowler SJ. Breath metabolomic profiling by nuclear magnetic resonance spectroscopy in asthma. Allergy. 2013 Aug;68(8):1050-6. Diagnosis of Asthma
- 33. Metabolomics Disease Diagnosis Metabolic fingerprint HamzaMohamed Amin Mostafa, Arwa Mohamed Amin Mostafa, Nor Hayati Arif, Teh Chin Hoe, Vikneswaran a/l Murugaiyah, & Ibrahim, B. (2014). METABOLOMIC ANALYSIS OF BLOOD AND URINE TO IDENTIFY ALCOHOL-DEPENDENCE BIOMARKERS. The Medical Journal of Penang Hospital(Supplement 2014). (Poster Abstract) Diagnosis of Alcohol Dependence
- 34. Metabolomics Disease Diagnosis Scatter Plot Diagnosisof Alcohol Dependence The OPLS-DA model of 3 groups each12 subjects of AD, social drinkers and healthy control groups was done. Hamza Mohamed Amin Mostafa, Arwa Mohamed Amin Mostafa, Nor Hayati Arif, Teh Chin Hoe, Vikneswaran a/l Murugaiyah, & Ibrahim, B. (2014). METABOLOMIC ANALYSIS OF BLOOD AND URINE TO IDENTIFY ALCOHOL- DEPENDENCE BIOMARKERS. The Medical Journal of Penang Hospital(Supplement 2014). (Poster Abstract)
- 35. Metabolomics Disease Diagnosis Accuracy, Sensitivity& Specificity Diagnosis of Alcohol Dependence OPLS-DA model Hamza Mohamed Amin Mostafa, Arwa Mohamed Amin Mostafa, Nor Hayati Arif, Teh Chin Hoe, Vikneswaran a/l Murugaiyah, & Ibrahim, B. (2014). METABOLOMIC ANALYSIS OF BLOOD AND URINE TO IDENTIFY ALCOHOL- DEPENDENCE BIOMARKERS. The Medical Journal of Penang Hospital(Supplement 2014). (Poster Abstract) Type of Analysis Specificity Sensitivity Accuracy OPLS-DA in (AD vs Social drinkers vs Healthy control) 81.82% 90.91% 57.58% OPLS-DA in (AD vs Social drinkers+Healthy control) 90.91% 90.91% 90.91%
- 36. Pharmacometabonomics •TAClayton, JC Lindon,O Cloarec, H Antti, C Charuel, G Hanton, J Provost, J Net, D Baker, RJ Walley, JR Everett, JK Nicholson. Pharmaco- metabonomic phenotyping and personalized drug treatment. Nature April 2006; 440(20) • Ian D. Wilson1 . Drugs, bugs, and personalized medicine: Pharmacometabonomics enters the ring. PNAS August 2009; 106(34):14187–14188 • Pharmacometabonomics •The prediction of a drug or xenobiotic intervention outcome in an individual based on a mathematical model of Pre- intervention metabolite signatures •i.e. Prediction of: •Efficacy •Toxicity • One of the major factors influencing patient’s response to any medication is drug Pharmacokinetic (ADME). •Differences in the balance of Pharmacokinetic leading to detoxification vs. toxicity are the difference between a treatment being Safe and Effective or causing an adverse drug reaction
- 37. Pharmacometabonomics • Pharmacometabonomic approachcan amounts to: •Response-targeted Pre-dose phenotyping, might provide the basis of a future population-screening tool for selecting individuals according to their suitability for treatment with particular drugs, drug classes or drug doses •Potentially avoiding Adverse drug reactions by Pre- dose phenotyping and drugs and dose levels could be targeted more effectively according to the metabolic and other characteristics of each individual •TAClayton, JC Lindon, O Cloarec, H Antti, C Charuel, G Hanton, J Provost, J Net, D Baker, RJ Walley, JR Everett, JK Nicholson. Pharmaco- metabonomic phenotyping and personalized drug treatment. Nature April 2006; 440(20) • Ian D. Wilson1 . Drugs, bugs, and personalized medicine: Pharmacometabonomics enters the ring. PNAS August 2009; 106(34):14187–14188
- 38. Pharmacometabonomics •TA Clayton, JCLindon, O Cloarec, H Antti, C Charuel, G Hanton, J Provost, J Net, D Baker, RJ Walley, JR Everett, JK Nicholson. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature April 2006; 440(20) Urine samples of 10 rats NMR Inject galactosamine hydrochloride Liver bioassay NMR spectra PCA
- 39. Pharmacometabonomics Urine – 99 healthymale volunteers •TA Clayton, D Baker, JC Lindon, JR Everettc, and JK Nicholson. Pharmacometabonomic identification of a significant host- microbiome metabolic interaction affecting human drug metabolism. PNAS August 2009; 106(34):14728–14733 Pre-dose NMR analysis Acetaminophen 1g Post-dose NMR analysis • High predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide • p-cresol known to be produced from protein-derived tyrosine in reactions involving gut bacteria • In individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen • Gut bacteria might influence both drug-induced responses and disease development
- 40. COPD studyAsthma study Discriminatingprincipal components, blue triangles show subjects on ICS • Ibrahim B, Basanta M, Cadden P, Singh D, Douce D, Woodcock A, Fowler SJ. (2011). Non-invasive phenotyping using exhaled volatile organic compounds in asthma. Thorax 2011;66:804-809. • M Basanta, B Ibrahim, R Dockry, D Douce, M Morris, D Singh, A Woodcock and SJ Fowler. Exhaled volatile organic compounds for phenotyping chronic obstructive pulmonary disease; a cross-sectional study. Respiratory Research 2012;13(1);72 Inhaled steroid use Scatter Plot
- 41. Eosinophils and Neutrophils no yes Eosinophils>=1% 0.0 1.0 2.0 3.0 Factor score 2 -1.0 0.0 1.0 2.0 Factorscore1 Discriminating PCs derived from the models, blue triangles show: a) sputum eosinophils ≥ 2%; b) sputum neutrophils ≥ median a b M Basanta, B Ibrahim, R Dockry, D Douce, M Morris, D Singh, A Woodcock and SJ Fowler. Exhaled volatile organic compounds for phenotyping chronic obstructive pulmonary disease; a cross-sectional study. Respiratory Research 2012;13(1);72 Scatter Plot
- 42. Warfarin use Scatter Plot AbdulkaderAhmad Bawadikji, Forough Ebrahimi, Muhamad Ali Bin Sheikh Abdul Kader, Omar Ismail, Premalosini Ramanathan, Azizah Binti Yusuf, . . . Ibrahim, B. (2014). Differentiation of plasma metabolite profiles of the patients on Warfarin with stable and un-stable International Normalized Ratio. The Medical Journal of Penang Hospital(Supplement 2014). Poster Abstract The OPLS-DA analysis of the Stable, Un-stable Patients on Warfarin Unstable 12 Patients (INR <2 or >3 during 6-months) Stable 12 Patients (INR 2-3 during 6- months)
- 43. Warfarin use Accuracy, Sensitivity& Specificity Abdulkader Ahmad Bawadikji, Forough Ebrahimi, Muhamad Ali Bin Sheikh Abdul Kader, Omar Ismail, Premalosini Ramanathan, Azizah Binti Yusuf, . . . Ibrahim, B. (2014). Differentiation of plasma metabolite profiles of the patients on Warfarin with stable and un-stable International Normalized Ratio. The Medical Journal of Penang Hospital(Supplement 2014). Poster Abstract OPLS-DA analysis of the Stable, Un-stable Patients on Warfarin OPLS-DA Accuracy 91.67% Sensitivity 100% Specificity 85.71% R2 (cum) 0.9620 Q2 (cum) 0.5422
- 44. The Role ofClinical Pharmacist in Future • Apply specialized knowledge of the scientific and clinical use in medication action, dosing, adverse effects, and drug interactions, and in performing patient care activities in collaboration with other members of the health care team. • Dose adjustment not just based on therapeutic drug monitoring but also based on molecular information. •TAClayton, JC Lindon, O Cloarec, H Antti, C Charuel, G Hanton, J Provost, J Net, D Baker, RJ Walley, JR Everett, JK Nicholson. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature April 2006; 440(20) • Ian D. Wilson1 . Drugs, bugs, and personalized medicine: Pharmacometabonomics enters the ring. PNAS August 2009; 106(34):14187–14188
- 45. The Role ofClinical Pharmacist in Future • Equipped with the knowledge on Genomics, Proteomics and Metabolomics which can be incorporated into undergraduate or postgraduate curriculum of pharmacy. •TAClayton, JC Lindon, O Cloarec, H Antti, C Charuel, G Hanton, J Provost, J Net, D Baker, RJ Walley, JR Everett, JK Nicholson. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature April 2006; 440(20) • Ian D. Wilson1 . Drugs, bugs, and personalized medicine: Pharmacometabonomics enters the ring. PNAS August 2009; 106(34):14187–14188
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- 47. Challenges •Personalized Medicine Coalitionwww.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php. •Lester. DS. Will Personalized Medicine Help in 'Transforming' the Business of Healthcare? Personalized Medicine. 2009;6(5):555-565. 1)Patient • Demand? • Safety • Privacy- data shared • Peace of mind? • Employers discrimination? • Ethnic discrimination? - • e.g BIDIL – (Isosorbide Dinitrate & Hydralazine HCL) – for congestive heart failure in African Americans)
- 48. Challenges •Personalized Medicine Coalitionwww.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php. •Lester. DS. Will Personalized Medicine Help in 'Transforming' the Business of Healthcare? Personalized Medicine. 2009;6(5):555-565. 2) Clinician • New knowledge • Cost 3)Industries • Pharmaceuticals, diagnostics, biotechnology • New business model – reduced market size, profit? • Disease prevention doesn’t pay?
- 49. Challenges 4)Regulations • Patient safetyand privacy, • High quality and clinical utility • Genetic Information Nondiscrimination Act of 2005 (GINA) – In USA 5)Insurance • Genetically susceptible patient – coverage? • Forced Patient to go for genetic testing?
- 50. • If wecan say Genetic contribute to a disease, of course it can also contribute to Drug Response. •Limitations of Pharmacogenomics lead to the new approach known as Pharmacometabonomics. •This method has high potential to Personalize Treatment as it looks at the contribution of both Genetics and Environmental factors to the drug effects. Conclusion
- 51. • Health systemswill turn from Reactive medicine to Proactively understanding and supporting individuals in managing their own health. • Increasing the number of alliances between Diagnostic and Pharmaceutical companies. • Move from Mass market therapies to Specialist Therapies • Clinical Pharmacist role? Conclusion