Farm A Kogen Etik
Farm A Kogen Etik
Farm A Kogen Etik
PHARMACOLOGY + GENETIC
PHARMACOLOGY GENETIC
PHARMACOGENETIC
PHARMACOGENETIC
PHARMACOGENOMIC
PHARMACOGENOMIC
http://www.ornl.gov/hgmis/medicine/pharma.html
Pharmacogenomics
The study of genome-derived data,
including human genetic variation,
RNA and protein expression
differences, to predict drug response
in individual patients or groups of
patients.
Pharmacogenomics includes Pharmacogenetics
History of Pharmacogenomics
Specific
genotype
DNA
Blood sample
Combine
Specific
drug
Observation:
Occurrence of different phenotypes
Goal:
Identification of allelic variants, associated with differrent phenotypes
Extensive Metabolizers
Toxic area
Concentration
Frequency
Therapeutic area
Poor
Metabolizers
Time
Debrisoquine Metabolic ratio
Hypothesis
Weak metabolism may cause adverse drug events
(active metabolites are generated to a smaller extent)
Accelerated metabolism may cause lower or lack of any
drug effects
Rau et al. Clin Pharmacol Ther 2004; 75:386-393; Kawanishi et al. Eur J Clin
Rau et al. Clin Pharmacol Ther 2004; 75:386-393 Pharmacol 2004;59:803-807
Treatment with amitriptyline:
Risk of adverse effects in relation to the combined
CYP2D6/CYP2C19 genotype
Pharmacodynamics
Pharmacokinetics
Receptor affinity
Drug transport
Signal
Drug metabolism transduction
Regulation
Exogenous factors
Genetic variations in drug response
and drug toxicity may result from
Genetic variation in drug metabolizing enzymes
Phase I enzymes e.g. Cytochromes P450
Phase II enzymes e.g. Thiopurine S-methyltransferase
N-acetyltransferases
Genetic variation in drug targets
Beta-adrenergic receptor
Angiotensin Converting Enzyme
Dopamine receptor
Genetic variation in drug efflux/drug transporters
P-glycoprotien
MRPs
CYP2D6*2
Normal activity
G1661C C2850T G4180C
CYP2D6*4
No activity
C100T G1661C G1846A G4180C
CYP2D6*10
Decrease activity
C100T G1661C G4180C
CYP2D6*17
Decrease activity
C1023T G1661C C2850T G4180C
CYP2D6*2 X N
Increase activity G1661C C2850T G4180C
Pharmaceutical substrates
of CYP2C19
Drug Reference
Haloperidol concentrations
were similar between the two
Asian groups. but significantly
higher than those observed in
Caucasians
Prolactin concentrations in
both Asian groups were
higher than the Caucasians
2-4% 3%
3%
3-5% 6% 18-20%
13%
2% 5%
11 %
15-18%
22%
5% 23%
4%
15%
8% 70%
Aborigines 26%
80
70
60 M elayu
Batak
50 Kajang
40 Sunda
Jawa
30
Dayak
20 Bima
Bugis
10
0
EM IM PM
Prevalence of CYP2C19 genotype within Geographically
Dispersed Populations
100
90 Caucasian
80 Saudi Arabian
70 African
Korean
60
Japanese
50
Chinese
40 Philippine
30 Aboriginal Australia
20 Indonesia
10 Thailand
Vanuatu
0
EM IM PM
0.04 Korean Japanese
Chinese
Thailand
Philippines
Kajang
Dayak
Malay
Caucasian
11 Bugis
Sunda
Javanese
Bima
Saudi Arabian Vanuatu
Australian Aborigine
Master of Basic Medical Science
Yogyakarta, July 2010 Yusuf .I et al, Adv Exp Med B
CYP2D6 is an Enzyme with
Polymorphisms
Proguanil
URINARY EXCRETION (% dose)
60 Cycloguanil
40
20
0 EM IM PM
Application of pharmacogenomics in clinical practice
Overall survival
of erbB2/HER2/neu
0.5
P=0.002
Examples
Oncology (PK + PD) high evidence
Psychiatry (PK) moderate evidence
Cardiovascular Diseases (PK + PD)
increasing evidence
Transplantation surgery (PK) increasing evidence
Pain treatment (PK + PD) currently low moderate
evidence
Proposed dose of anti-psychotics for patients
with different CYP2D6 phenotypes
Possible reasons:
Can pharmacogenomics
contribute to
identification of novel drug
targets
facilitated drug development
salvage of less effective
drugs
optimized drug treatment
Individualized
.....? treatment versus one fits all
Pharmacogenomics as recognized by the politics
Crohnss disease
Hypertension
Rheumatoid arthritris
Type I diabetes
Type II diabetes
Nature 2007;447:661-678
Pharmacogenomics in drug
development
Drug
DrugR&D
R&DPhase
Phase Pharmacogenomics
Pharmacogenomics
Target
Targetidentification
identification Discovery
Discoveryand
andvalidation
validationofofdisease
diseasegenes
genes
High
Highthroughput
throughputscreening
screening Screening
Screeningofofpolymorphisms,
polymorphisms,modulating
modulating
optimization
optimization(phase
(phase0)
0) compund
compundbinding
bindingproperties
properties
Phase
PhaseI I Preselection
Preselectione.g.
e.g.of
ofknown
knownCYPs
CYPs
Phase
PhaseIIII Selection
Selectionofofknown
knownSNPs
SNPs
Phase
PhaseIII
III Identification
IdentificationofofSNPs,
SNPs,involved
involvedinindrug-response
drug-response
and
andside
sideeffects
effects
Phase
PhaseIV
IV Identification
IdentificationofofSNPs,
SNPs,involved
involvedinindrug-response
drug-response
and
andside
sideeffects,
effects,individualized
individualizedtherapy
therapy
New
Newindications
indications