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Akhmad Edy Purwoko
Bagian Farmakologi & Toksikologi
FKIK - UMY
Pharmacogenetics & Polymorfism
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Master of Basic Medical ScienceYogyakarta, July 2010
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Problems wih !" #rugs
• $e are all di%eren
• Mos o' us are reaed in he same way
• Trial and error
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Im(li)aions
• Money* Thousands s(en on ine%e)i+e medi)aions
• #eah,si)kness* . million serious )ases and o+er/001000 deahs.
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• Why is pharmacotreatment effective insome patients but lacks efficacy in others?
• Why suffer some patients from severeadverse drug reactions but others not?
Limitations ofpharmacotreatment?
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Serious Adverse Drug Events Reported
to the Food and Drug Administration, 1998-2005
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Adverse drug effets as ause of
hospita!i"ation
• 7% of patients are hospitalized due to adverse drugevents
JAMA 1998, 279:1200-120
•
Additional duration of hospitalization : 2!2 da"s• Additional #osts : $!000,- &'
JAMA 1997, 277:$07-$11
• (n depart)ents of ps"#hiatr" the proportion ofpatients hospitalized due to adverse drug events isesti)ated *ith 1+%
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Effia# of Drug
$reatment
Alzheimer 30
Analgetics (COX-2) 80
Asthma 60
Arrhythmias 60
Depression 62
Diaetes mellit!s "#$epatitis C %#
&ncontinence %0
'igraine (ac!te) "2
'igraine (prophylais) "0
Oncology 2"Osteoporosis %8
he!matoi* Arthritis "0
+chizophrenia 60
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2oluion3
•Pharmacogenomics:
The study of how anindividual’s geneticinheritance aects the
body’s response todrugs.
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$ha is (harma)ogenomi)s3
PHARMACOLOGYPHARMACOLOGY GENETICGENETIC+
PHARMACOGENETICPHARMACOGENETIC
PHARMACOGENOMICPHARMACOGENOMIC
http%&&'''(orn!(gov&hgmis&mediine&pharma(htm!
It is the study of how an individual’sgenetic inheritance affects the
body’s response to drugs
Ph
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Pharma)ogeno
mi)sThe study of genome-derived data including
human genetic variation!"# and protein
e$pression dierences topredict drug response inindividual patients or
groups of patients.
Pharmacogenomics includes Pharmacogenetics
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L.H. Snyder was the first to report an nsa!response to PHENYLTHIO"REA in a stdyin#o!#in$ %&& fa'i!ies (o'prisin$ )&*+ peop!e.Those who (annot taste ,PT"- are said toehi/it idiosyncratic reaction to this
(o'pond ,Ohio 0 S(i +)1*+2345+)-
History of Pharmacogenomics
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• /456 * $ason and 7ri)k des)ribe #8A9s double heli". Boni)kee al des)ribe slow and ra(id a)eylaion o' isonia:id
• /45; * Al+ing e al dis)o+er a genei) link o haemolyi)rea)ions o (rima<uine
• /45= * Moulsky (ro(oses ha >inherian)e migh e"(lain manyindi+idual di%eren)es in he e?)a)y o' drugs and in heo))urren)e o' ad+erse drug rea)ions9
• /454 * @ogel inrodu)es he erm Pharma)ogenei)s oindi)ae he inCuen)e o' herediy on drug res(onse
• /4;0 * E+ans esablishes he genei) )onrol o' isonia:ida)eylaion
• /440 * Duman genome (roe) is sared and )om(leed 006
History of Pharmacogenomics
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• /4; * Kalow (ublisheshe rs monogra(h on(harma)ogenei)s
• PDA!MA7GHE8ETI72 *Derediy and heres(onse o drugs
History of Pharmacogenomics
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• %n &'() several laboratory scientists at *t.+ary’s,ospital +edical *chool in London each ingested a mg dose of debriso/uine an anti hypertensivedrug then in clinical use.
• 0hile the ma1ority of the researchers reported no
adverse side eects• !obert L. *mith e$perienced di22iness and sueredfrom about of orthostatic hypotension that lastedseveral days 3 A. Mahgoub et al., Lancet 1977;2:584-64
History of Pharmacogenomics
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$ha is Pharma)ogenomi)s3
Pharma)ogenomi)s )an bedened as he
)om(rehensi+e)om(ilaion o' in'ormaionabou genomi) se<uen)es
and se<uen)e +arians1and he a((li)aion o' hisin'ormaion o
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Pharmacogenetics-
Pharmacogenomics
C!ini(a! Goa!s
4. A#oid ad#erse dr$ rea(tions
). Mai'i6e dr$ effi(a(y
+. Se!e(t responsi#e patients
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Specific genotype
Specificdrug
Combine
The treatment based onpharmacogenetics is drug specific
5"#6loodsample
Effective drug treatment
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Master of Basic Medical Science
Yogyakarta, July 2010
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Euro(ean Medi)ines Agen)yEMEAJ /5 8o+ember 00=
The 7se of 8enomics in 9ardiovascular
9linical %ntervention Trials
"eeded documents review of the scienticmatters concerning the use of genomic data
in assessing therapeutic e;cacy and
tolerance of drugs in cardiovascular
clinical intervention trials focusing ongenetic association with clinical endpoints.
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)*!assi+ onept of pharmaogenetis
<bservation:G))urren)e o' di%eren (henoy(es
8oal:Ideni)aion o' alleli) +arians1 asso)iaed wih di%erren
(henoy(es
F r e < u e n )
y
Deriso,!ine 'etaolic ratio
oor
'etaolizers
.tensi/e 'etaolizers
Ti'e
$herapeuti area
Toi( area
C o n c e n t r a t i o n
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• 0ea= metabolism may cause adverse
drug events3active metabolites are generated to asmaller e$tent4
• #ccelerated metabolism may cause lower
or lac= of any drug eects
a! et al Clin harmacol 1her 200% #"386-343!au e al. 7lin Pharma)ol Ther 00L =5*6;-646L Kawanishie al. Eur N 7lin Pharma)ol 00L54*06-0=
,ypothesis
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2eimer e al. 7lin 7hem 005
Treatment with amitriptyline:!is= of adverse eects in relation to the
combined 9>P5@A9>P9&' genotype
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9>P5@ genotype baseddose recommendations for
antidepressants
5irchheiner et al. Acta sych +can* 200 03 -2
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Pharmacogenomics
Pharmacodynamics
•!eceptor
a;nity
•*ignaltransduction
•!egulation
Pharma)okinei)s
•#rug rans(or
•#rug meabolism
B$ogenous
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enetic variations in drug responseand drug to!icity may result from
•eneti variation in disease modif#ing genes• ER2
•
.A
•eneti variation in drug meta/o!i"ing en"#mes• hase en"#mes eg Cytochromes %"0• hase en"#mes eg 1hiop!rine +-methyltrans7erase
-acetyltrans7erases
•eneti variation in drug targets• eta-adrenergi reeptor • Angiotensin *onverting En"#me• Dopamine reeptor
•eneti variation in drug eff!u3&drug transporters• -g!#oprotien• 4Rs
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$hy do (harma)ogenomi)s resear)hin Indonesia3
• E+iden)e 'or ehni) di%eren)es in he res(onse o drugsha+e (ra)i)al im(oran)e. Indonesia )onsiss o' morehan 650 ehni)s ha shown di%eren language1 )ulure1en+ironmen.
• Digh (o(ulaion densiies.
• Mos o' he drugs used in Indonesia (rodu)ed and)lini)ally esed in U2A and Euro(e ha migh be no oour genei) ba)kgrounds.
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Pharma)ogenomi)s o'7YP7/4
• 9>P9&' is the isoen2ymes of cytochrome p) thatcataly2e hydro$ylation of several important groups ofdrugs
• 8enetic variations of 9>P9&' gene aects the
metabolism of the drugs therapeuticmanagement
• 8enetic variations of 9>P9&' shows interethnicvariation
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Cre/uent 3D&-E4 !are 3F&E4
7YPA; Fla+in monoo"ygenase7YP7 FMG61 sh odor syndromeJ7YP74 #P# dihydro(yrimidine
dehydrogenaseJ7YP7/4 me(henyoin-y(eJ TPMT hio(urin 2-mehylrans'eraseJ7YP#; debriso<uine,s(areine-y(eJ 2u))inyl-7holineserase7YP6A57YP6A=8AT/ & arylamine 8-a)eylrans'erasesJ
A#D/ al)ohol dehydrogenase y(e IJAO#D aldehyde dehydrogenaseJParao"onaseUHT/A/ U#P-glu)uronylrans'erase /A/JH2Ts gluahione-2-rans'erasesJ
ymorphisms of 5rug +etaboli2ing Bn2ymes
E+ans and !elling1 2)ien)e /4441 ;*=-4/
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Master of Basic Medical Science
Yogyakarta, July 2010
C"P#$% polymorphism
involve in the meta/o!ism of a/out 06 of a!! presri/ed drugs
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C2850T G4180C G1661C
CYP2D6*2 X
!ncrease acti"it#
5 ; = / 4CYP2D6*1ormal acti"it#
CYP2D6*4
C100T G4180C G1661C G1846$o acti"it#
CYP2D6*10
C100T G4180C G1661C Decrease acti"it#
C2850T G4180C
CYP2D6*1%
C102&T G1661C Decrease acti"it#
CYP2D6*2
C2850T G4180C
ormal acti"it#
G1661C
6
Common C"P#$% alleles4ore than 70 a!!e!es have /een identified
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Pharma)eui)al subsraeso' 7YP7/4
Drug Reference
Amitriptyline Melstrom et al , 1988
Barbiturates Adedoyin et al , 1994
Chlorproguanil right et al , 199!
Citalopram "indrup et al , 199#
Clomipramine $ielsen et al , 1994
Dia%epam Bertillson et al , 1989
&mipramine 'aefeli et al , 199(
Mephenytoin de Morias et al , 1994
)mepra%ole Anderson et al , 199*+roguanil Anderson et al , 199(
+ropranolol ard et al , 1989
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Effect of C"P#$% phenotypes onpharmacokinetics of C"P#$% substrates
4 E4 44
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Master of Basic Medical Science
Yogyakarta, July 2010
Differene in the distri/ution of de/risouin & :-h#dro3#de/risouinmeta/o!i ratio among Asians and *auasians
ndividua! 'ith !o' *;2D< ativit#
=4> % high meta/o!i ratio
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Ethni variations in *odeine meta/o!ism
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• *erum haloperidol and
prolactin concentrations weremeasured in male
9aucasians #merican-born
#sians and foreign-born
#sians after administration of
haloperidol
Ethnic differences in pharmacokinetics of haloperidol
Lin et al. G 9lin Psychopharmacol. &'HHIH:&')-&
a!operido! onentrations
'ere simi!ar /et'een the t'o
Asian groups( /ut signifiant!#
higher than those o/served in*auasians
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• Prolactin
concentrations in
both #sian groups
were higher than
the 9aucasians
Ethnic differences in pharmacodynamics of haloperidol
Lin et al. G 9lin Psychopharmacol. &'HHIH:&')-
•$hese resu!ts indiate that
/oth pharmao?inetis and
pharmaod#namis of
ha!operido! 'ere differene
/et'een *auasians and
Asians
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Master of Basic Medical Science
Yogyakarta, July 2010
&re'uency of C"P#C() P*s in variousethnics
11 6
18-20616
15-186
156
226
26
-56
2-:6 6
<6
6
26 56
86
56
:6706
A/origines 2<6
I h i i i '
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Inerehni) +ariaions o'7YP7/4 genoy(e
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7YP7/4 Henoy(e Fre<uen)iesin Indonesia Po(ulaions
(
1(
*(
#(
4(
!(
,(
-(
8(
.M &M +M
Melayu
Bata/
0aang
"unda
2a3a
Daya/
Bima
Bugis
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Pre+alen)e o' 7YP7/4 genoy(e wihinHeogra(hi)ally #is(ersed Po(ulaions
(
1(
*(
#(
4(
!(
,(
-(
8(
9(
1((
.M &M +M
Caucasian
"audi Arabian
African
0orean2apanese
Chinese
+hilippine
Aboriginal Australia
&ndonesia
hailand
5anuatu
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Master of Basic Medical Science
Yogyakarta, July 2010
00%
Sunda
ima
Da#a?
@aang
$hai!and
4a!a#
Bavanese
ugis
hi!ippines
Austra!ian A/origine
Canuatu
*auasian
Saudi Ara/ian
*hinese @orean Bapanese
Yusuf .I et al, Adv Exp Med B
9>P5@ is an Bn2yme with
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9>P5@ is an Bn2yme withPolymorphisms
•A((ro"imaely =0 nu)leoide (olymor(hisms areknown
•Four (henoy(e sub(o(ulaions o' meaboli:er
• Poor meaboli:er PMJ• Inermediae meaboli:er IMJ
• E"ensi+e meaboli:er EMJ
• Ulra ra(id meaboli:er UMJ
•@ariaions a))ording o ra)ial ba)kground
•More han ;5 )ommonly used drugs aresubsraes
•7odeine is a well known subsrae
Medi)al and Publi) Dealh
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Medi)al and Publi) DealhIm(li)aions
• The mos signi)an (oenial im(a) o' 7YP7/4 PM in(aien )are1 here'ore1 would be in 2EA where here is a)ombinaion o' high (o(ulaion densiies and signi)anlyin)reased risk asso)iaed wih PM.
• The re)ogniion o' he high 're<uen)y o' IM and PM
indi+iduals amongs 2EA is im(oran 'or medi)al(ra)iioners in 2EA bu also hose in Euro(e1 Middle Eas1and U2A where he 're<uen)ies o' EM indi+iduals(redominae.
• !a)ial di%eren)es in he res(onse o drugs no only ha+e
(ra)i)al im(oran)e 'or he )hoi)e and dose o' drugs bushould also aler (hysi)ians o he im(oran underlyinggenei) deerminans o' drug res(onse i' used in (o(ulaionswih di%eren genei) ba)kgrounds.
U i E i ' P il
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Urinary E")reion o' Proguaniland 7y)loguanil
0
0
0
;0
0
.' &' ' 9 & 8 A : . X C . 1 & O
8 ( ; *
o s e ) +roguanil
Cycloguanil
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App!iation of pharmaogenomis in !inia! pratie
25-06 of /reast tumor speimens
sho' amp!ifiation&overe3pression
of er/2&ER2&neu
A!! patients
4onths
D v e r a ! !
s u r v i v a !
1(0
0(0
0(5
0 <0 120 180
0(002
c-er<-2 negati/e (80=28)c-er<-2 positi/e (30=4)
Agrup et al. Breast Cancer Res Treat 2000
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%mpact of polymorphic drug metaboli2ingen2ymes for cancer therapies
En"#me Drug oor Re!evane
meta/o!i"ersC:2D6 1amoi7en #-0; possile
C:2C4 Cyclophosphami*e 3-"; !nclear
DD "->l!oro!racil ?; @ea
1'1 AzathioprineB 6-' 06; high
91A &rinotecan 0-"; high
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B$amples
• Gn)ology PK P#J high e+iden)e
• Psy)hiary PKJ moderae e+iden)e
• 7ardio+as)ular #iseases PK P#Jin)reasing e+iden)e
• Trans(lanaion surgery PKJ in)reasing e+iden)e
• Pain reamen PK P#J )urrenly low Qmoderae e+iden)e
macogenomics J 9urrent #pplicati
P d d f i h i f i
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Proposed dose of anti-psychotics for patients+ith different C"P#$% phenotypes
@irhheiner et a!(, s#hiatr# 200:, 9%::2-:7
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.imitations of pharmaogenetis
Alhough here is a huge numbero' sudies1 (harma)ogenei)s has
been a))e(ed only in a 'ew)ases in )lini)al (ra)i)e
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.imitations of pharmaogenetis
Possible reasons:
• Lac= of =nowledge on the clinicaloutcome J need of prospective studies
• Low positive predictive value of asingle genetic trait
• 9omple$ genetic bac=ground
•
+inor clinical relevance 3e.g. there isan inKuence on the =inetic but theclinical outcome is not aected4
• #vailability of alternative drugs
bypassing polymorphic pathways• - -
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• Indi+idual drug arge sele)ion in on)ologi)al diseases is(er'ormed already o dae in )ases o' o+er-e"(ression o')an)er-relaed genes*
• Esrogen re)e(or α amo"i'enJ•
DE!,neu rasu:umabJ• EHF!/ geinibJ• B7!-ABO imainibJ
• Indi+idual dose ada(aion o' )hemohera(eui)s should be
(er'ormed in )ases relaed o )learly (olymor(hi) drugmeaboli:ing en:ymes
• TPMT a:ahio(rine1 ;-mer)ao(urineJ• UHT/A/ irinoe)anJ
%ndividuali2ed therapy: fact or ction?
h i i
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roaches to 5rug %nnovation: 8eneti
*an pharmaogenomis
ontri/ute to
• identifiation of nove! drug
targets
• fai!itated drug deve!opment
• sa!vage of !ess effetive
drugs
• optimi"ed drug treatment
• (((((iduali2ed treatment versus one
i i d b th liti
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U2 senaor Bara)k Gbama (ro(osed a Henomi)sand Personali:ed Medi)ine A) o' 00;1 whi)hshould i be ena)ed1 would esablish a
Henomi)s and (ersonali:ed Medi)ine Inera)ing$orking Hrou( o )oordinae (ersonali:edmedi)ine e%ors1 'und genomi)s resear)h oim(ro+e drug sa'ey and esablish a U2Biobanking !esear)h Iniiai+e1
rmacogenomics as recogni2ed by the politics
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8aure 00=L=*;;/-;=
ome-wide scan for seven disea
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ome wide scan for seven disea
8aure 00=L=*;;/-;=
<ipolar *isor*er
Coronary artery *isease
Crohnss *isease
$ypertension
he!matoi* arthritris
1ype & *iaetes
1ype && *iaetes
harmaogenomis in drug
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Drug RGD hase harmaogenomis
1arget i*enti7ication Disco/ery an* /ali*ation o7 *isease genes
$igh thro!ghp!t screening +creening o7 polymorphismsB mo*!lating
optimization (phase 0) comp!n* in*ing propertieshase & reselection eg o7 no@n C:s
hase && +election o7 no@n +s
hase &&& &*enti7ication o7 +sB in/ol/e* in *r!g-response
an* si*e e77ects
hase &E &*enti7ication o7 +sB in/ol/e* in *r!g-response
an* si*e e77ectsB in*i/i*!alize* therapy
e@ in*ications
harmaogenomis in drug
deve!opment
according to Essioux et al. 2002
harmaogenomis-/ased
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• helps to i*enti7y reasons o7 inter-in*i/i*!al /ariaility in *r!g response
• helps to i*enti7y the important 7actors eing in/ol/e* in
pharmacoinetics an* pharmaco*ynamics
•But, the positi/e pre*icti/e /al!e o7 genetic traits is o7ten lo@
• 1here is a strong nee* o7 prospecti/e o!tcome st!*ies
• +electe* genetic traits sho!l* e consi*ere* in pharmacotherapy
alrea*y no@
•9se o7 m!lti-genetic signat!res sho!l* e pre7erre* (microarrays)
• Consi*eration o7 no/el genetic traits i*enti7ie* in @hole genome scans
harmaogenomis /ased
ne' therapeuti onepts
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