Personalised Medicine

Dr. Baharudin Ibrahim
Senior Lecturer
Department of Clinical Pharmacy
School of Pharmaceutical Sciences
Universiti Sains Malaysia
Personalized medicine

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)

Drug Development Failure
Source: Ledford H. Nature 2011.

• Right Medication,
• Right Dose,
• Right Patient,
• Right Time and
• Right Route
Five Rights of Optimum Therapy
Do we treat the Right Patient??

What are the factors 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

Personalized Medicine
What is Personalized 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.

THERANOSTICS :
A Diagnostic therapy that identifies patients most
likely to be helped by a new medication, and targets
drug therapy based on the test results.
• Lester. DS. Will Personalized Medicine Help in 'Transforming' the Business of Healthcare? Personalized Medicine. 2009;6(5):555-565.

PM Philosophy
Every Patient has a unique Biology and Pathophysiology
which should be reflected in the choice of
Pharmacotherapy
• Lester. DS. Will Personalized Medicine Help in 'Transforming' the Business of Healthcare? Personalized Medicine. 2009;6(5):5
Improved Treatment Outcome

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?
Based on Patient’s molecular Biology and
Pathophysiology

Why is PM better than the current approach?
Tailored fits
better

• Treat the 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?

Omics Genotype & Phenotype
N
S
Genomics – study of
genes
Transcriptomics – study
of mRNA
Proteomics – study of
proteins
Metabolomics – study of
metabolites

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

Vikas Kumar, The role of pharmacogenomics in drug development (http://www.pharmainfo.net/reviews/role-
pharmacogenomics-drug-development)
Pharmacogenomics and optimum Drug Response

• T Harumi; E Hirotoshi. Pharmacogenetics of Warfarin Elimination and its Clinical Implications. Clinical Pharmacokinetics 2001; 40(8):587-603.
Warfarin
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

•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.
• CYP2C9 Enzyme (Cytochrome Enzyme)
•Metabolizes > 80% of the more Active S-enantiomer
of warfarin to 6- and 7-hydroxy S-warfarin
Warfarin

•CYP2C9 activity is modulated by:
•Genetic factors,
•Stimulatory and inhibitory interactions
•Age and other environmental factors
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

• 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)

• 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
Limitations
A group of factors (Genetic & Non Genetic) gives the Metabolic phenotype

•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.
Limitations

•It’s complex to find the genetic variation which
affect Drug response
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

•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

As the main components 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
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

• 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

•Proteins that 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
•Lester. DS. Will Personalized Medicine Help in 'Transforming' the Business of Healthcare? Personalized Medicine. 2009;6(5):55

HercepTest
HER2 protein
Trastuzumab
EGFR pharmDX Kit
Cetuximab
EGFR protein

Metabolomics & Pharmacometabonomics
•Figure Source: 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.
• 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

Metabolomics &
Pharmacometabonomics
Advantages of Metabolomics approach:
• Affected by both Genes and Environment
• Closer to Phenotype
• Simple and Non-invasive
• Relatively Ease of Analysis
• Potential to identify Novel biochemical
pathways

Metabolic fingerprint
Metabolomics
Disease Diagnosis
Ibrahim B, 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

Metabolomics
Disease Diagnosis
Metabolic fingerprint
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)
Diagnosis of Alcohol Dependence

Metabolomics
Disease Diagnosis
Scatter Plot
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)

Metabolomics
Disease Diagnosis
Accuracy, Sensitivity & Specificity
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%

•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

• Pharmacometabonomic approach can 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

•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)
Urine samples
of 10 rats NMR
Inject galactosamine
hydrochloride Liver bioassay
NMR spectra
PCA

Urine –
99 healthy male
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

COPD studyAsthma study
Discriminating principal 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

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
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Discriminating PCs derived from the models, blue triangles
show:
a) sputum eosinophils ≥ 2%; b) sputum neutrophils ≥ median
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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

Warfarin use
Scatter Plot
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
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)

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

The Role of Clinical 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

The Role of Clinical 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

Challenges
•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)

Challenges
•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?

Challenges
4)Regulations
• Patient safety and 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?

• If we can 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

• Health systems will 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

Personalised Medicine

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