FARMAKOGENETIK edit.pptx

8/17/2019 FARMAKOGENETIK edit.pptx

http://slidepdf.com/reader/full/farmakogenetik-editpptx 1/60

Akhmad Edy Purwoko

Bagian Farmakologi & Toksikologi

FKIK - UMY

Pharmacogenetics & Polymorfism



Master of Basic Medical ScienceYogyakarta, July 2010



Problems wih !" #rugs

• $e are all di%eren

• Mos o' us are reaed in he same way

• Trial and error



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.



• Why is pharmacotreatment effective insome patients but lacks efficacy in others?

• Why suffer some patients from severeadverse drug reactions but others not?

Limitations ofpharmacotreatment?



Serious Adverse Drug Events Reported

to the Food and Drug Administration, 1998-2005



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+%



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



2oluion3

•Pharmacogenomics:

The study of how anindividual’s geneticinheritance aects the

body’s response todrugs.



$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



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





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



• /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




• /4; * Kalow (ublisheshe rs monogra(h on(harma)ogenei)s

• PDA!MA7GHE8ETI72 *Derediy and heres(onse o drugs




• %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




$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



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



Specific genotype

Specificdrug

Combine

The treatment based onpharmacogenetics is drug specific

5"#6loodsample

Effective drug treatment



Master of Basic Medical Science

Yogyakarta, July 2010



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.



)*!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



• 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



2eimer e al. 7lin 7hem 005

Treatment with amitriptyline:!is= of adverse eects in relation to the

combined 9>P5@A9>P9&' genotype



9>P5@ genotype baseddose recommendations for

antidepressants

5irchheiner et al. Acta sych +can* 200 03 -2



Pharmacogenomics

Pharmacodynamics

•!eceptor

a;nity

•*ignaltransduction

•!egulation

Pharma)okinei)s

•#rug rans(or

•#rug meabolism

B$ogenous



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



$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.



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



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/





C"P#$% polymorphism

involve in the meta/o!ism of a/out 06 of a!! presri/ed drugs



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



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



Effect of C"P#$% phenotypes onpharmacokinetics of C"P#$% substrates

4 E4 44





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



Ethni variations in *odeine meta/o!ism



• *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



• 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





&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 '



Inerehni) +ariaions o'7YP7/4 genoy(e



7YP7/4 Henoy(e Fre<uen)iesin Indonesia Po(ulaions

(

1(

*(

#(

4(

!(

,(

-(

8(

.M &M +M

Melayu

Bata/

0aang

"unda

2a3a

Daya/

Bima

Bugis



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





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



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



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



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



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



%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



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



Proposed dose of anti-psychotics for patients+ith different C"P#$% phenotypes

@irhheiner et a!(, s#hiatr# 200:, 9%::2-:7



.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



.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• - -



• 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



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



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



8aure 00=L=*;;/-;=

ome-wide scan for seven disea



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



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



• 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



THANK YOU

Documents

FARMAKOGENETIK edit.pptx