Disclaimer - Seoul National Universitys-space.snu.ac.kr/bitstream/10371/122336/1/000000140736.pdf · dVbfVnTVd Woc eYV XVnVd ingo]gVU in UcfX aYRcmRTokinVeiTd (GB) RnU aYRcmRToUjnRmiTd

저 시-비 리- 경 지 2.0 한민

는 아래 조건 르는 경 에 한하여 게

l 저 물 복제, 포, 전송, 전시, 공연 송할 수 습니다.

다 과 같 조건 라야 합니다:

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l 저 터 허가를 면 러한 조건들 적 되지 않습니다.

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Disclaimer

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비 리. 하는 저 물 리 목적 할 수 없습니다.

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Wcom eYV Dinidecj oW eYV BocVRn =ooU RnU ;cfX IRWVej (BD=;I) eo

VgR]fReV hYVeYVc eYVcV hVcV UidTcVaRnTiVd SVehVVn eYV ]ide oW

hieYUcRhn UcfXd Woc BocVR cVaoceVU in eYV KE :ondo]iUReVU Cided RnU

eYV RTefR] ]ide oW UcfXd hieYUcRhn in BocVR. JYV on]inV mVUiTinV ]iScRcj

oW BD=;I% hYiTY YRd To]]VTeVU dRWVej ]VeeVcd dinTV 2))1% hRd cVgiVhVU

Re Yeea3((UcfX.mWUd.Xo.kc(Yem](inUVi.[da.

). 5GtG GSGlysOs

JYV ToccV]Reion SVehVVn eYV nfmSVcd oW hieYUcRhn RnU

cVdeciTeVU UcfXd hRd bfRneiWiVU fdinX GVRcdonpd ToccV]Reion ToVWWiTiVne.

IaVRcmRnpd nonaRcRmVeciT ToccV]Reion mVeYoU hRd Raa]iVU eo VgR]fReV

eYV RddoTiReion SVehVVn eYV nfmSVc oW hieYUcRhn RnU cVdeciTeVU UcfXd

cVaoceVU eo eYV KE RnU eYV ,. YVR]eY RnU WinRnTiR] WRTeocd Wcom eYV

16

F<:; RnU eYV Moc]U 9Rnk. JYV ineVcTofnecj RXcVVmVne Woc eYV ]ided oW

hieYUcRhn UcfXd hRd RddVddVU fdinX =]Viddpd kRaaR. 8]] bfoeVU

acoSRSi]iej gR]fVd RcV eho&eRi]VU. IeReideiTR] RnR]jdid hRd aVcWocmVU Sj

eYV H IeReideiTR] GRTkRXV% gVcdion ,.1.2 P,2].

A6BDLCB

NuRHKW TL wOtNdWGwS GSd/TW WKstWOItKd dWuMs

JYVcV hVcV ,/2 UcfXd eYRe hVcV hieYUcRhn RnU 2-1 UcfXd eYRe

hVcV cVdeciTeVU (Sfe noe hieYUcRhn) in Re ]VRde 1 Tofnecj in eYV KE

:ondo]iUReVU Cided. JYV ogVcR]] nfmSVcd oW hieYUcRhn RnU cVdeciTeVU

UcfXd on R aVc&Tofnecj SRdid in eYV 2- TofneciVd hVcV 12.)2 l 1,.)0

RnU ..00 l 1./2% cVdaVTeigV]j (=iXfcV. 1&1). JYV ]ided R]do cVaoceVU eYV

UcfXd hieYUcRhn RnU cVdeciTeVU Sj eYV <fcoaVRn :ommiddion%

<fcoaVRn DVUiTinVd 8XVnTj (<D8)% RnU :ofnTi] oW <fcoaV4 eYVcV

hVcV ,% 0 RnU 1 hieYUcRhn UcfXd RnU /% -% RnU ) cVdeciTeVU UcfXd%

cVdaVTeigV]j% Woc eYVdV ocXRnikReiond. JYVcV hVcV R]do 20 RnU 2

ineVcnReionR]]j hieYUcRhn RnU cVdeciTeVU UcfXd% cVdaVTeigV]j. JYVcV hRd

R diXniWiTRne ToccV]Reion SVehVVn eYV nfmSVcd oW hieYUcRhn RnU

17

cVdeciTeVU UcfXd Woc eYV 2- TofneciVd (G 5 ).))1% c 6 ).11) (=iXfcV 1&2).

7OMuWK (-(. FOtNdWGwS GSd WKstWOItKd dWuMs wTWldwOdK. (2)

5OstWOHutOTS TS G UKW-ITuStWy HGsOs (RKGS GSd B5 dGtG) GSd (3)

ITWWKlGtOTS GIWTss 04 ITuStWOKs.

Withdrawn or restricted status

No.

of d

rugs

Withdrawn drugs Restricted drugs

05

1015

2025

30

18

7OMuWK (-). 5OstWOHutOTSs TL tNK SuRHKWs TL wOtNdWGwS GSd WKstWOItKd

dWuMs OS 33 O645 RKRHKWs GSd UGWtSKWs.

JYV WigV TofneciVd hieY eYV ]RcXVde nfmSVcd oW hieYUcRhn UcfXd

hVcV GVcmRnj% KI8% FmRn% =cRnTV% RnU KB% dYohinX /1% .2% -,% -2%

RnU -1 hieYUcRhn UcfXd% cVdaVTeigV]j. JYV WigV TofneciVd hieY eYV

]RcXVde nfmSVcd oW cVdeciTeVU UcfX hVcV GVcmRnj% KB% KI% =cRnTV% RnU

IeR]j% dYohinX .2% -2% ,1% 2/% RnU 2) cVdeciTeVU UcfXd% cVdaVTeigV]j

(=iXfcV 1&,).

●

●

●●●

●

●

●

●

●

●

●

●

●

● ●

●●●●

●

●

●

●

●

●

●●

●●

●●

●

●

●

●●●

●●

●●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●●

●

●

●

●

●

●●

●

●

●●

●

●

●

●●

●●

●

●●

●

●●

●

●●

●

●

●

●●

●

●

0 10 20 30 40 50

010

2030

4050

6070

No. of withdrawn drugs

No.

of r

estri

cted

dru

gsr = 0.807P < 0.001

19

=iXfcV 1&,. ;ideciSfeiond oW eYV nfmSVcd oW hieYUcRhn RnU cVdeciTeVU

UcfXd in 2- KE TofneciVd

20

7OMuWK (-4. 5OstWOHutOTSs TL tNK SuRHKWs TL wOtNdWGwS GSd WKstWOItKd

dWuMs OS 33 O645 RKRHKWs GSd UGWtSKWs.

8monX eYV ,2 F<:; mVmSVcd RnU aRcenVcd% RWeVc ViT]fUinX /

TofneciVd ]RTkinX UcfX cVXf]Reion&cV]ReVU inWocmReion in eYV KE

:ondo]iUReVU Cided (i.V.% :kVTY HVafS]iT% <deoniR% CfiVmSofcX% Go]RnU%

I]ogRk HVafS]iT% RnU I]ogVniR)% ,, TofneciVd hVcV inT]fUVU Woc WfceYVc

RnR]jdid. JYV ogVcR]] nfmSVcd oW hieYUcRhn RnU cVdeciTeVU UcfXd on R

aVc&Tofnecj SRdid in eYVdV ,, TofneciVd hVcV 11.2. l 1..00 RnU 11 l

12.)/% cVdaVTeigV]j (=iXfcV 1&-).

5MFs GSd O645 NKGltN GSd KITSTROI dGtG

=igV F<:; YVR]eY&RnU&hV]WRcV inUiTReocdnG;G aVc TRaieR%

GermanyUnited States

FranceUnited Kingdom

ItalyNorwaySweden

JapanTurkeyBrazil

GreeceOECD avarage

AustriaDenmark

CanadaSpain

AustraliaIndia

New ZealandIreland

SwitzerlandChile

NetherlandsBelgiumFinland

IsraelKorea

PortugalIceland

South AfricaHungary

IndonesiaMexicoChina

No. of withdrawn drugs

0 10 20 30 40 50 60 70

Coun

tries

GermanyUnited Kingdom

United StatesFrance

ItalyJapan

New ZealandBelgium

ChileIreland

SwedenAustralia

AustriaOECD avarage

CanadaSpain

NetherlandsNorway

SwitzerlandDenmark

GreeceBrazilIsrael

FinlandHungary

IndiaKorea

TurkeyIndonesia

South AfricaChina

IcelandMexico

Portugal

No. of restricted drugs

0 10 20 30 40 50 60

Coun

tries

21

G;G aVc Yofc hockVU% YVR]eY ViaVnUiefcV aVc G;G% ofe&oW&aoTkVe

aRjmVne cReV% RnU V]UVc]j aoaf]Reion cReVnhVcV diXniWiTRne]j ToccV]ReVU

hieY eYV nfmSVcd oW hieYUcRhn RnU cVdeciTeVU UcfXd (G 5 ).).%

=iXfcVd 1&. RnU 1&/). JYV nfmSVc oW cVdeciTeVU UcfXd hRd R]do

diXniWiTRne]j ToccV]ReVU hieY eYV nfmSVc oW UcfX&cV]ReVU UVReYd aVc

1))%))) aVcdond (G 5 ).).% =iXfcV 1&.(=)). Ffe&oW&aoTkVe aRjmVne

cReV dYohVU R nVXReigV ToccV]Reion hieY eYV nfmSVcd oW hieYUcRhn RnU

cVdeciTeVU UcfXd% hYi]V eYV oeYVc inUiTReocd dYohVU aodieigV ToccV]Reiond.

EGlOdGtOTS TL NKGltN GSd KITSTROI LGItTWs LWTR tNK FTWld 3GSP

dGtG

Iii WRTeocd dYohVU diXniWiTRne ToccV]Reiond hieY eYV nfmSVcd oW

UcfXd hieYUcRhn RnU(oc cVdeciTeVU Woc VRTY oW eYV ,, F<:; TofneciVd3

G;G aVc TRaieR% G;G aVc Yofc hockVU% YVR]eY ViaVnUiefcV aVc G;G%

ofe&oW&aoTkVe aRjmVne cReV% V]UVc]j aoaf]Reion cReV% RnU cReV oW UcfX&

cV]ReVU UVReYd. JYVdV ToccV]Reiond hVcV Tcodd&gR]iUReVU Sj Uohn]oRUinX

RnU RnR]jkinX eYV mReTYVU UReR Wcom eYV Moc]U 9Rnk Woc 2)1). IinTV

eYV G;G aVc Yofc hockVU RnU eYV cReV oW UcfX&cV]ReVU UVReYd hVcV

22

RSdVne Wcom eYV Moc]U 9Rnk UReR% hV TomaRcVU on]j eYV G;G aVc

TRaieR% YVR]eY ViaVnUiefcV aVc G;G% ofe&oW&aoTkVe aRjmVne cReV% RnU

V]UVc]j aoaf]Reion cReV Wcom eYV Moc]U 9Rnk UReR hieY eYV nfmSVc oW

hieYUcRhn(cVdeciTeVU UcfXd Woc VRTY Tofnecj. 8d Woc eYV F<:; inUViVd%

eYV G;G aVc TRaieR% YVR]eY ViaVnUiefcV aVc G;G% RnU V]UVc]j

aoaf]Reion cReV dYohVU diXniWiTRne aodieigV ToccV]Reiond hieY eYV

nfmSVc oW hieYUcRhn UcfXd in eYV 2- KE TofneciVd (c 6 ).-2/% G 5

).))14 c 6 ).,1,% G 6 ).))24 RnU c 6 ).,,1% G 6 ).))14 cVdaVTeigV]j) RnU

eYV nfmSVc oW cVdeciTeVU UcfXd (c 6 ).-01% G 5 ).))14 c 6 ).--2% G 5

).))14 RnU c 6 ).-10% G 5 ).))1). JYV ofe&oW&aoTkVe aRjmVne cReV hRd

nVXReigV]j ToccV]ReVU hieY eYV nfmSVc oW hieYUcRhn (c 6 m).200% G 6

).))1) RnU cVdeciTeVU (c 6 m).,-2% G 6 ).))1) UcfXd in eYV 2- KE

TofneciVd.

PTTW GMWKKRKSt HKtwKKS tNK lOsts TL wOtNdWGwS dWuMs GIWTss

ITuStWOKs

;cfXd hieYUcRhn in onV Tofnecj mRj SV acVdTciSVU in oeYVcd.

Jo VgR]fReV eYV UVXcVV oW RXcVVmVne SVehVVn eYV ]ided oW UcfXd

23

hieYUcRhn Wcom UiWWVcVne TofneciVd% =]Viddpd kRaaR gR]fVd hVcV

mVRdfcVU Woc eYV WigV TofneciVd hieY eYV ]RcXVde nfmSVcd oW hieYUcRhn

UcfXd RTTocUinX eo eYV KE :ondo]iUReVU Cided (=iXfcV 1&0(8)) (kRaaR

6 m).11-% G 5 ).))1) RnU F<:; UReR (=iXfcV 1&0(9)) (kRaaR 6 m

).11/% G 5 ).))1) RnU eYVj dYohVU ]oh RXcVVmVned. JRS]V 1&1 ]ided eYV

hieYUcRhn UcfXd ineVcnReionR]]j RnU eYV WigV TofneciVd hieY eYV ]RcXVde

nfmSVcd oW ;DMd in eYV F<:;.

24

7OMuWK (-,. :occV]Reiond SVehVVn YVR]eY(VTonomiT inUiTReocd RnU eYV

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

0 10000 20000 30000 40000 50000

010

2030

4050

6070

GDP per capita

No. o

f with

draw

n dr

ugs

IndonesiaChina

South Africa

Turkey

Mexico

Chile

HungaryPortugal

Greece

New Zealand

Spain

Israel

Italy

Korea

France

Japan

Finland

Denmark

Belgium

United Kingdom

Germany

Sweden

Iceland

CanadaAustriaAustraliaIreland

NetherlandsSwitzerland

United States

Norway

r = 0.46P < 0.01

●

●●

●

●

●

●

●

●

●

●

●

●

10 20 30 40 50 60 70

1020

3040

5060

70

GDP per hour worked

No. o

f with

draw

n dr

ugs

Mexico

Chile

Turkey

HungaryPortugal

Korea

Greece

New Zealand

Israel

Japan

Iceland

Italy

Spain

Finland

Switzerland

Canada

United Kingdom

Australia

Sweden

AustriaDenmark

Ireland

Germany

France

BelgiumNetherlands

United States

Norway

r = 0.5P = 0.007

●

●

●

●

●

●

●

●

●

●

●

●

0 10 20 30 40 50

1020

3040

5060

70

Out−of−pocket payment (% of total expenditure on health)

No. o

f with

draw

n dr

ugs

FranceUnited Kingdom

New Zealand

United States

Germany

DenmarkCanada

JapanTurkeySweden

Italy

Iceland

IrelandAustralia

Finland

Spain

Belgium

Israel

Switzerland

PortugalHungary

Greece

Chile

Korea

Mexico

r = − 0.59P < 0.001

●

●

●

●

●

●

●

●

●

●●

●

●

6 8 10 12 14 16 18

1020

3040

5060

70

Rate of health expenditure per GDP (%)

No. o

f with

draw

n dr

ugs

Turkey

Mexico

Chile

KoreaIsraelHungary

Australia

Finland

Ireland

Italy

United Kingdom

Sweden

Norway

Iceland

Greece

Spain

Japan

New Zealand

Portugal

Austria

Canada

Belgium

Denmark

Switzerland

France

Germany

Netherlands

United States

r = 0.53P = 0.004

●

●

●

●●

●

●

●

●

●

●

●

●

●

●

●

0 5 10 15 20 25

010

2030

4050

6070

Elderly population (%)

No. o

f with

draw

n dr

ugs

South Africa

India

MexicoIndonesia

Turkey

Brazil

China

Chile

IsraelKorea

Ireland

Iceland

United States

New ZealandCanadaAustralia

Norway

Netherlands

United Kingdom

Denmark

France

Hungary

Switzerland

Belgium

Finland

Spain

Portugal

Austria

Sweden

Greece

Germany

Italy

Japan

r = 0.4P < 0.05

25

nfmSVc oW UcfX hieYUcRhR]d Wcom eYV mRckVe in ,, F<:; TofneciVd.

(8) G;G aVc TRaieR% (9) G;G aVc Yofc hockVU% (:) ofe&oW&aoTkVe

aRjmVne cReV% (;) YVR]eY ViaVnUiefcV aVc G;G% RnU (<) V]UVc]j

aoaf]Reion cReV R]] ViYiSie diXniWiTRne ToccV]Reiond hieY eYV nfmSVc oW

UcfX hieYUcRhR]d (G5).).).

26

● ●

●

●

●

●

● ●

●

●

●

●

●

●

●

0 10000 20000 30000 40000 50000

010

2030

4050

GDP per capita

No.

of r

estri

cted

dru

gs

Indonesia

ChinaSouth Africa

Turkey

Mexico

Chile

Hungary

Portugal

Greece

New Zealand

Spain

Israel

Italy

Korea

France

Japan

Finland

Denmark

Belgium

United Kingdom

Germany

Sweden

Iceland

CanadaAustriaAustraliaIreland

NetherlandsSwitzerland

United States

Norway

r = 0.34P = 0.048

●

●

●

●

●

●

●

●

●●

●

●

●

10 20 30 40 50 60 70

010

2030

4050

GDP per hour worked

No.

of r

estri

cted

dru

gs

Mexico

Chile

TurkeyHungary

Portugal

Korea

Greece

New Zealand

Israel

Japan

Iceland

Italy

Spain

FinlandSwitzerland

Canada

United Kingdom

AustraliaSweden

Austria

Denmark

Ireland

Germany

France

Belgium

Netherlands

United States

Norway

r = 0.46P = 0.037

●

●

●

●

●

●

●

●

●

●

●

●

0 10 20 30 40 50

010

2030

4050

Out−of−pocket payment (% of total expenditure on health)

No. o

f res

trict

ed d

rugs

France

United Kingdom

New Zealand

United States

Germany

Denmark

Canada

Japan

Turkey

Sweden

Italy

Iceland

IrelandAustralia

Finland

Spain

Belgium

Israel

Switzerland

Portugal

Hungary

Greece

Chile

Korea

Mexico

r = 0.5P = 0.03

●

●● ●

●

●

●

● ●

●

●●

●

6 8 10 12 14 16 18

010

2030

4050

Rate of health expenditure per GDP (%)

No.

of r

estri

cted

dru

gs

Turkey

Mexico

Chile

Korea

Israel

Hungary

Australia

Finland

Ireland

Italy

United Kingdom

Sweden

Norway

Iceland

Greece

Spain

JapanNew Zealand

Portugal

AustriaCanada

Belgium

DenmarkSwitzerland

France

Germany

Netherlands

United States

r = −0.59P = 0.003

● ●

●

●

●

●●

●

● ●

●●

●

0 5 10 15 20 25

010

2030

4050

Elderly population (%)

No.

of r

estri

cted

dru

gs

Mexico

Turkey

Chile

IsraelKorea

Iceland

United States

New Zealand

CanadaAustralia

NorwayNetherlands

United Kingdom

Denmark

France

Hungary

Belgium

Finland

Spain

Portugal

AustriaSweden

Germany

ItalyJapan

r = 0.4P = 0.007

●●

●

●

●

●

●

●

●

●

●

●

0.0 0.5 1.0 1.5 2.0 2.5

010

2030

4050

Drug Use Death per 100000 population (%)

No.

of r

estri

cted

dru

gs

Chile

Hungary

Japan

KoreaTurkey

Spain

Mexico

Netherlands

New Zealand

Australia

Israel

Italy

Portugal

Belgium

Canada

Finland

Iceland

Sweden

France

Norway

United States

Denmark

Germany

United Kingdom

Austria

r = 0.53P = 0.014

27

7OMuWK (--. :occV]Reiond SVehVVn YVR]eY RnU VTonomiT inUiTReocd RnU

eYV nfmSVc oW UcfX mRckVe cVdeciTeiond in eYV mRckVe in ,, F<:;

TofneciVd. (8) G;G aVc TRaieR% (9) G;G aVc Yofc hockVU% (:) ofe&oW&

aoTkVe aRjmVne cReV% (;) YVR]eY ViaVnUiefcV aVc G;G% (<) V]UVc]j

aoaf]Reion cReV% RnU (=) UcfX&fdV UVReYd aVc 1))%))) aVcdond R]]

ViYiSie diXniWiTRne ToccV]Reiond hieY eYV nfmSVc oW UcfX cVdeciTeVU

(G5).).).

28

7OMuWK (-.. 8XcVVmVne oW eYV ]ide oW hieYUcRhn UcfXd in eYV WigV

TofneciVd hieY eYV ]RcXVde nfmSVcd oW hieYUcRhn RnU cVdeciTeVU UcfXd.

;ideciSfeiond oW eYV nfmSVcd oW eYV UcfXd eYRe RcV (8) hieYUcRhn Wcom

A"

B"

29

eYV eoa . oW 2- KE TofneciVd RnU (9) cVdeciTeVU in eYV eoa . oW ,,

F<:; TofneciVd.

4GsK study1 KTWKG

MV aVcWocmVU R TRdV defUj oW hieYUcRhn RnU cVdeciTeVU UcfXd

Woc onV Tofnecj% BocVR. BocVR hRd cRnkVU 2/eY (n 6 /) in UcfX

hieYUcRhR]d RnU 2,eY (n 6 2) in UcfX cVdeciTeiond RmonX eYV ,, F<:;

TofneciVd (=iXfcV 2&2). Jho oW eYV 20 ineVcnReionR]]j hieYUcRhn UcfXd

hVcV SVinX acVdTciSVU in BocVR Rd oW 2)11. FnV eYV eho% ]oaVcRmiUV%

hRd hieYUcRhn ineVcnReionR]]j on]j in eYV Wocm UVdiXnVU Woc fdV Sj

TYi]UcVn% RnU eYid Wocm hRd R]do cVdeciTeVU in BocVR. JYV oeYVc UcfX%

Racoeinin% id Rn RneiWiScino]jeiT mo]VTf]V fdVU eo acVgVne mR[oc S]VVUinX

UfcinX mR[oc dfcXVcj% RnU hRd hieYUcRhn hoc]UhiUV in 2))1% RnU

TieVU Rd oJYV mRnfWRTefcVc (9RjVc InT.) YRd SVVn RUgidVU eo dfdaVnU eYV

mRckVeinX oW eYid acoUfTep in eYV KE :ondo]iUReVU Cided. JYV KE

:ondo]iUReVU Cided cVaoce eYRe dii UcfXd YRgV SVVn hieYUcRhn

(RminoaYVnRkonV% SociT RTiU RnU SocReVd% UiWVnoiin% UiaYVnoij]ReV%

WfcRko]iUonV% RnU eYiociURkinV) RnU eYcVV UcfXd YRgV SVVn cVdeciTeVU

30

(RecoainV in TomSinReion% ]oaVcRmiUV% RnU decVaeomjTin) in BocVR. 8]]

oW eYVdV UcfXd RcV in eYV 1eY KE :ondo]iUReVU Cide afS]idYVU in 2)),

(ViTVae Woc eYiociURkinV% hYiTY hRd cVaoceVU in 2)).). Jo VgR]fReV eYV

aoddiSi]iej oW fnUVccVacVdVneReion oW eYV KE :ondo]iUReVU Cided Woc

UVTidiond oW UcfX hieYUcRhn Sj eYV BD=;I% hV TomaRcVU eYV ]ide oW

hieYUcRhn UcfXd To]]VTeVU Wcom eYV on]inV ]iScRcj oW BD=;I hieY eYV

KE :ondo]iUReVU Cided. In eoeR]% 11, dRWVej ]VeeVcd hcieeVn Wcom 8fXfde

2))1 eo DRcTY 2)1. hVcV cVgiVhVU. JYV dRWVej ]VeeVcd ]ideVU 1-

inXcVUiVne UcfXd eYRe hVcV SRnnVU(hieYUcRhn in BocVR. 9VWocV FTeoSVc

2))1% hYiTY TogVcd eYV dRmV aVcioU Rd eYV KE :ondo]iUReVU Cided% eYcVV

UcfXd hVcV cVaoceVU Rd SVinX hieYUcRhn3 nVWRkoUonV YjUcoTY]ociUV (in

2)),)% eYiociURkinV (in 2)).)% RnU Racoeinin (in 2))0). 8acoeinin cV&

VneVcVU eYV mRckVe in eYV dRmV jVRc% RnU do eYVcV hVcV RTefR]]j eho

UcfXd hieYUcRhn Wcom 8fXfde 2))1 eo FTeoSVc 2))1. In eYV KE

:ondo]iUReVU Cided% dii UcfXd hVcV cVaoceVU eo SV hieYUcRhn in BocVR3

RminoaYVnRkonV (in 1201)% SociT RTiU RnU SocReVd (in 120,)% UiWVnoiin

(in 1221)% UiaYVnoij]ReV (in 1221)% WfcRko]iUonV (in 1211)% RnU

eYiociURkinV (in 2)).). 8d R cVdf]e% eYV nVWRkoUonV hieYUcRhR] UVTidion

31

in 2)), hRd noe cVaoceVU eo eYV KE.

32

TabIe 1-1. TEe IFst LC TFtEdOaTK dOuDs FK tEe tLp 5 O312 cLuKtOFes EaSFKD EFDEest KumbeO LC TFtEdOaTK dOuDs aKd tEe IFst LC

FKteOKatFLKaIIy TFtEdOaTK dOuDs

1LuKtOy (9L. LC

TFtEdOaTK dOuDs)

2OuDs

5eOmaKy (K0,.) aIbumFK, aIcILCeKac, amFKLpEeKazLKe, amFKLOeU, aKaDestLKe acetate, aOFstLILcEFcacFd,

beKzaOLKe, betaetELUyIacetaKFIFde, bLOFc acFd aKd bLOates, bucetFK, buCLOmFK, caKOeKLKe,

caKtEaUaKtEFK, caOtFIaDe eUtOact, ceII pOepaOatFLKs, cEILOLCLOm, cEILOpEeKteOmFKe, cFaKFdaKLI,

cFKcELpEeK, cFsapOFde, cILCFbOate, cILCLOeU, daKtOLK, dFCemeOFKe, dFLKaeamuscFpuIa eUtOact,

etEyIeKe dFcEILOFde, CepOazLKe, DaKDIFLsFdes, DeOmaKdeO, DFKkDL bFILba, DIaCeKFKe, DIucLsamFKe

suICate, EeOpes sFmpIeU SaccFKes, FKdLpOLCeK, FsLUFcam, ketLcLKazLIe, 8-tOyptLpEaK, meDestOLI

33

acetate, mesKa, metEapyOFIeKe, mFbeCOadFI, muzLIFmFKe, KFtOeCazLIe, KLmFCeKsFKe, LmepOazLIe,

LODLteFK, LUeIadFK, LUypEeKFsatFKeacetate, pEeKacetFK, pEeKCLOmFK, pEeKyIpOLpaKLIamFKe,

pLIySFdLKe, pLtassFum caKOeKLate, pOactLILI, pyOOLIFzFdFKe, OubFaetFKctLOumOadFU, suICacaObamFde,

suICadFcOamFde, suICadFmFdFKe, suICaDuaKFdFKe, suICameOazFKe sLdFum, suICaKFIamFde, suICFsLmFdFKe,

suILctFdFI, tFeKFIFcacFd, tOFacetyI dFpEeKLIFsatFK, uOetEaKe, SFKcamFKe

=KFted States (K059) adKOLDeKs, amaOaKtE, amCetamFKe, amFKL DIutetEFmFde, amFKLpEeKazLKe, amFpOFILse,

apEOLdFsFac dOuDs, beKzyI peKFcFIFK sLdFum tLpFcaI pOepaOatFLKs, bFtEFLKLI, bOLmCeKac,

buKamFLdyI, caIamus, cEILOmadFKLKeacetate, cEILOLCLOm, cFsapOFde, cLbaIt KLK OadFLactFSe CLOms,

cycIaKdeIate, daIkLKsEFeId, daKtOLK, depLt medOLUypOLDesteOLKe acetate (dmpa), deUamCetamFKe,

dFEydOL stOeptLmycFK, dFmazLIe, epEedOa, etEyIKFtOFte spFOFt, EaILDeKatedsaIFcyIaKFIFdes,

34

EydOLmLOpELKe EydOLcEILOFde, FKteOCeOLK Damma 0b, FLdFKatedcaseFKstOLpEaKtEFK KeL baOFKe,

I.tOyptLpEaK, IaetOFIe, IeSacetyImetEadLI, IeSamCetamFKe, metamFzLIe sLdFum, metEapyOFIeKe,

metLCLIFKe, mFbeCOadFI, LUypEeKFsatFKeacetate, pemLIFKe, peODLIFde, peUFDaKaK, pEeKacetFK,

pEeKCLOmFK, pEeKyIpOLpaKLIamFKe, pFpamazFKe, pFtuFtaOy cELOFLKFcDLKadLtOLpFK FKGectabIe,

pOasteOLKe, NuFKFKesuICate, saODOamLstFm, sLmatOLpFK pFtuFtaOy deOFSed, suICatEFazLIe,

tecEKetFum99mtc CaKLIesLmab, teOCeKadFKe, tetOacycIFKe paedFatOFc, tEeKaIFdFKe, tFeKFIFcacFd,

uOetEaKe, SaIdecLUFb, SFKaOLI aKd SFDa

4OaKce (K04() acetyI saIFcyIFc acFd (paedFatOFc), aIpFdem, amFKeptFKe, amFKLpEeKazLKe, aOFstLILcEFc acFd,

beKzbOLmaOLKe, bFsmutE saIts, bLSFKe tFssue deOFSed medFcFKes, cameIIFa sFKeKsFs, cEILOampEeKFcLI,

cILmetacFK, cLumaOFKe syKtEetFc, dFtEFazaKFKeFLdFde, DeOmaKdeO, DIaCeKFKe, FKdaIpFKe,

35

FsaULKFKepELspEate, FsLUFcam, ketLcLKazLIe, Iead LUFde aKd Iead saIts, medFCLUamFKe, metamFzLIe

sLdFum, mLUFsyIyte, mucLpLIysaccEaOFde pLIysuICuOFc acFdesteO, muzLIFmFKe, KaCtFdOLCuOyI

paOeKteOaI CLOmuIatFLKs, KaKdOLILKedecaKLate FKGectabIe, LUeIadFK, LUypEeKFsatFKe acetate,

pEeKCLOmFK, pEeKLbaObFtaI, pEeKLIpEtEaIeFK, pIaceKtaI tFssue deOFSed medFcFKe, pLdLpEyIIumOesFK,

pLtassFumcEILOFde, pLtassFumKFtOate, pOLUFbaObaI, teOCeKadFKe, tEeKaIFdFKe, tFeKFIFcacFd,

tFIbOLNuFKLI, UeKazLFcacFd

=KFted 7FKDdLm

(K041)

aIbumFK, aIcILCeKac, amCepOamLKe EydOLcEILOFde, amFKLpEeKazLKe, aOFstLILcEFa,

bFcaIutamFde, bLOFc acFd aKd bLOates, cEILOmadFKLKeacetate, cEILOLCLOm, cFsapOFde, daIkLKsEFeId,

dFKLpOLstLKe, dOLpeOFdLI, CactLOSIII, CeKcILCeKac, CepOazLKe, CILseNuFKaK, DameILKFc acFd,

DOepaCILUacFK EydOLcEILOFde, FKdLpOLCeK, I-tOyptLpEaK, mepOLbamate, metEapyOFIeKe, metOLdFK-

36

Ep, mFbeCOadFI, KLmFCeKsFKe, KLscapFKe, LUypEeKbutazLKe, pEeKCLOmFK, pEeKteOmFKe,

pEeKyIepEOFKe, pOactLILI, pumactaKt, pyOOLIFzFdFKe, seOtFKdLIe, sLmatOLpFK(pFtuFtaOy-deOFSed),

tEeKaIFdFKe, tLIcapLKe, tOFazLIam, tOLDIFtazLKe, UFmeIaDatOaK

6taIFa (K0)() aIcILCeKac, amFKLpEeKazLKe, aOseKFc based cLmpLuKds, baObFtaI, beKzyI peKFcFIIFK sLdFum

tLpFcaI pOepaOatFLKs, cEILOmadFKLKeacetate, cEILOLCLOm, cFaKFdaKLI, cFKcELpEeK, cIFLNuFKLI (see

aIsL EaILDeKated EydOLUyNuFKLIFKe deOFSatFSes), dFeKestOLI, dFetEyIstFIbestOLI, dFEydOL

stOeptLmycFK, dFtEFazaKFKeFLdFde, EaILDeKated EydOLUyNuFKLIFKe deOFSatFSes, EeUestOLI, FKdLpOLCeK,

FpOLKFazFd, FsLUFcam, ILbeIFa, metEapyOFIeKe, LpFumFK aKtFtussFSe pOepaOatFLKs, pEeKacetFK,

pFpeOazFKe, pLdLpEyIIumOesFK, pLIyLUyetEyIated castLOLFI, suUFbuzLKe, tetOacycIFKe (paedFatOFc),

tOaKyIcypOLmFKe, tOFacetyIdFpEeKLIFsatFK, tOFazLIam, uOetEaKe

37

6KteOKatFLKaIIy

TFtEdOaTK dOuDs (K0(-)

beKLUapOLCeK, cEILOmezaKLKe, cFaKFdaKLI, dFIeSaILI, dLmpeOFdLKe (FKGectabIe),

CeKCIuOamFKe, DIaCeKFKe, FKdLpOLCeK, FsLUFcam, ILpeOamFde, Kebacumab, KLmFCeKsFKe,

pEeKLIpEtEaIeFK, pFOpOLCeK, pLIyLUyetEyIatedcastLOLFI, pOeKyIamFKe, OemLUFpOFde, suILctFdFI,

supOLCeK, temaCILUacFK, teOLdFIFKe, tLIOestat, SaccFKes (CLO mumps, measIes, aKd OubeIIa), zFmeIdFKe,

zLmepFOac, ceOFSastatFK, apOLtFKFK

38

/4S.USS4O7

I] ]cr PSab kn]elSRUS, bVS prSaSnb abcRg Wa bVS TWrab b]

c][prSVSnaWdSlg SdOlcObS Ul]POl RrcU eWbVRrOeOla OnR rSabrWcbW]na Wn

c][pOrWa]n eWbV ]TTWcWOl VSOlbV OnR Sc]n][Wc WnRWcOb]ra. IVS rSaclba

RS[]nabrObS bVOb c]cnbrWSa eWbV VWUVSr =:F OnR/]r VWUVSr VSOlbV

SfpSnRWbcrS pSr =:F eWbVRrOe []rS RrcUa. IVS nc[PSr ]T eWbVRrOen

RrcUa eOa abr]nUlg OnR p]aWbWdSlg c]rrSlObW]n eWbV =:F pSr cOpWbO,

=:F pSr V]cr e]rkSR, OnR VSOlbV SfpSnRWbcrS pSr =:F, OnR abr]nUlg

OnR nSUObWdSlg c]rrSlObSR eWbV bVS ]cb%]T%p]ckSb pOg[Snb rObS. Ib Wa

acUUSabSR bVOb bVS nc[PSr ]T RrcU eWbVRrOeOl/rSabrWcbW]n Wa rSlObWdSlg

l]e Wn c]cnbrWSa eWbV VWUV rSaWRSnb aSlT%pOg[Snba T]r VSOlbV cOrS OnR

l]e U]dSrn[Snb%c]dSrSR pOg[Snba. FVOr[OcScbWcOl apSnRWnU Wa O

[Oj]r c][p]nSnb ]T VSOlbV cOrS SfpSnRWbcrS O[]nU []rS RSdSl]pSR

c]cnbrWSa M33N, OnR bVS nc[PSr ]T eWbVRrOen RrcUa [Og PS caSR Oa On

WnRWcOb]r ]T V]e [ccV O c]cnbrg WndSaba Wn Wba VSOlbV cOrS agabS[.

Ib Wa eWRSlg kn]en bVOb =:F pSr cOpWbO Wa c]rrSlObSR eWbV [Oj]r

VSOlbV cOrS WnRWcOb]ra accV Oa lWTS SfpScbOncg OnR WnTOnb []rbOlWbg rObS

M33N. LS SfpScbSR bVOb RrcU rSUclObW]n, Wn bVS T]r[ ]T RrcU

39

eWbVRrOeOla OnR rSabrWcbW]na, e]clR Ola] PS WnTlcSncSR Pg SOcV

c]cnbrgla Sc]n][Wc WnRSf OnR bVWa eOa c]nTWr[SR Occ]rRWnU b] ]cr

abcRg. 8cb RWaSOaS []rbOlWbg OnR lWTS SfpScbOncg eSrS n]b aWUnWTWcOnblg

c]rrSlObSR eWbV bVS nc[PSr ]T RrcU eWbVRrOeOla. Ib Wa c]ndWncWnU

Sn]cUV, PScOcaS ]T bVS [Oj]r VSOlbV WnRWcOb]r, accV Oa lWTS SfpScbOncg

]r [Oj]r RWaSOaS []rbOlWbg, eSrS WnTlcSncSR [OWnlg WnTOnbWlS []rbOlWbg

rObS, WnTScbW]n c]nbr]l, OnR [Oj]r rWak TOcb]r c]nbr]l M3,N. IVS W[pOcb

]T Oppr]prWObS RrcU rSUclObW]n ]n bVS p]pclObW]n VSOlbV c]clR PS

[SOacrSR Pg ]bVSr apScWTWc WnRSfSa accV Oa nc[PSr ]T 7:Ga ]r RrcU%

rSlObSR []rbOlWbg.

JnSfpScbSRlg, bVS nc[PSr ]T RrcU%caS RSObVa pSr )((,(((

pSra]na eOa p]aWbWdSlg c]rrSlObSR eWbV bVS nc[PSr ]T rSabrWcbSR RrcUa

(<WUcrS )%.(<)). IVWa eOa cnSfpScbSR PScOcaS ]nS e]clR SfpScb b] aSS

a[OllSr RrcU%caS RSObV rObSa Wn O c]cnbrg eWbV O VWUVSr nc[PSr ]T

rSabrWcbSR RrcUa. Ib c]clR PS p]aaWPlS bVOb bVSrS eOa O

RSbScbW]n/rSp]rbWnU PWOa Wn bVOb bVS c]cnbrWSa bVOb acrdSg OnR rSp]rb

RrcU%rSlObSR RSObV []rS OcccrObSlg c]clR rSUclObS bVS ROnUSr]ca RrcUa

[]rS abrWcblg. 8ScOcaS bVS WllWcWb RrcU caS OnR RrcU%rSlObSR []rbOlWbg OrS

40

RWTTWcclb b] acrdSg SdSn Wn RSdSl]pSR c]cnbrWSa M3-N, bVS c]cnbrWSa eWbV

[]rS eSll%]rUOnWhSR RrcU acrdSWllOncS OnR rSUclObW]n agabS[ e]clR

n]b ]nlg VOdS []rS rSabrWcbSR RrcUa Pcb Ola] VWUVSr RrcU%rSlObSR RSObV

rObSa. >]eSdSr, Wb Wa VOrR b] c]nclcRS bVOb bVSrS e]clR PS accV PWOaSa

Wn rSp]rbSR RrcU%rSlObSR RSObV ]nlg Tr][ bVWa abcRg a] TcrbVSr

SdOlcObW]n Wa nSSRSR.

IVS RrcUa lWabSR Oa PSWnU eWbVRrOen eSrS VWUVlg dOrWOPlS SdSn

O[]nU bVS b]p TWdS c]cnbrWSa. IVWa TWnRWnU Wa c]naWabSnb eWbV prSdW]ca

rSp]rba ]T [Ong aWnUlS [OrkSb eWbVRrOeOla, eVSrS []ab ]T bVSaS

eWbVRrOeOla eSrS Wn ;cr]pSOn c]cnbrWSa M)0N. IVS RWTTSrSncS [Og PS

RcS b] RWTTSrSncSa Wn bVS RrcUa caSR Pg RWTTSrSnb c]cnbrWSa, bVS c]nbr]l

bVOb [Oj]r pVOr[OcScbWcOl c][pOnWSa VOdS ]dSr bVS prSacrWpbW]n RrcU

[OrkSb, bVS RrcUa nSelg SnbSrWnU bVS [OrkSb, OnR cclbcrOl OnR

WnabWbcbW]nOl abOnROrRa rSlObSR b] bVS prSacrWPWnU ]T RrcUa.

Ie] RrcUa bVOb eSrS eWbVRrOen prW]r b] 2((0 e]rlReWRS eSrS

abWll prSacrWPSR Wn 2()) Wn A]rSO. In cOaS ]T l]pSrO[WRS, bVS eWbVRrOeOl

OpplWSR ]nlg b] bVS agrcp T]r[ T]r caS Pg cVWlRrSn, OnR Wba caS Pg

cVWlRrSn eOa Ola] rSabrWcbSR Wn A]rSO. 7pr]bWnWn eOa eWbVRrOen Wn 2((0

41

RcS b] bVS WncrSOaWnU RSObV rObS O[]nU pObWSnba, Pcb , gSOra lObSr bVS

;cr]pSOn JnW]n rSOppr]dSR Wb RcS b] Wba STTScbWdSnSaa PSWnU c]naWRSrSR

b] ]dSrrWRS Wba VOr[Tcl STTScba. IVS A]rSO <]]R OnR :rcU

7R[WnWabrObW]n Oll]eSR bVWa RrcU T]r caS ]nlg Wn lW[WbSR cOaSa Occ]rRWnU

b] O aOTSbg lSbbSr pcPlWaVSR Wn 2((0 M3.N. :rcUa bVOb eSrS eWbVRrOen

Tr][ bVS JH [OrkSb RWR n]b OppSOr SWbVSr Wn bVS eWbVRrOen ]r bVS

prSacrWpbW]n RrcU lWab Wn A]rSO. H][S RrcUa eWbVRrOen Wn ;cr]pS eSrS

T]cnR b] PS n]b eWbVRrOen Tr][ bVS prSacrWpbW]n RrcU lWab Wn A]rSO. Ib

aSS[a bVOb bVS RrcUa eWbVRrOen Wn bVS JH [Og VOdS TOWlSR b] SnbSr bVS

A]rSOn pVOr[OcScbWcOl [OrkSb OnR bVOb bVSrS [Og PS a][S OcbV]rWbg%

lSdSl WnbSrOcbW]na Wn RrcU rSUclObW]n pr]cSaaSa. 7a WnRWcObSR Wn IOPlS ),

bVS 2/ WnbSrnObW]nOllg eWbVRrOen RrcUa rSprSaSnb ,.% ]T bVS -1 RrcUa

eWbVRrOen Pg bVS JH <]]R OnR :rcU 7R[WnWabrObW]n Occ]rRWnU b] bVS

JD 9]na]lWRObSR BWaba. IVSrST]rS, Wb Wa W[p]rbOnb T]r rSUclOb]rg

OcbV]rWbWSa b] Ul]POllg []nWb]r 7:Ga OnR rSUclOb]rg RScWaW]na T]r RrcUa

OnR b] SabOPlWaV bVSWr ]en RrcU acrdSWllOncS agabS[a OnR rSUclOb]rg

UcWRSlWnSa.

Ib [Og n]b PS nScSaaOrg T]r Ong pOrbWcclOr c]cnbrg b] eWbVRrOe

42

Oll RrcUa bVOb OrS eWbVRrOen Pg ]bVSr c]cnbrWSa. IVS RScWaW]n T]r O RrcU

eWbVRrOeOl Wa WnTlcSncSR Pg dOrW]ca TOcb]ra, WnclcRWnU a]cWOl, cclbcrOl,

Sc]n][Wc, OnR SbVWcOl WaacSa. 7 :CL Wa O rSaclb ]T c][plSf p]lWbWcOl,

a]cWOl, SbVWcOl, OnR Sc]n][Wc WaacSa Oa eSll Oa 7:Ga OnR RrcU

STTScbWdSnSaa. IVSrST]rS, eS [cab OacSrbOWn bVS rSUclOb]rg RScWaW]na Wn

]bVSr c]cnbrWSa aSnaWbWdSlg OnR Ob bVS aO[S bW[S WRSnbWTg bVS l]cOl

]cccrrSncS ]T aSdSrS 7:Ga Wn O bW[Slg [OnnSr. IVS rSUclOb]rg

RScWaW]n%[OkWnU Wn A]rSO VOa lOrUSlg rSTlScbSR RScWaW]na [ORS Wn lOrUS

c]cnbrWSa accV Oa bVS JH, JOpOn, OnR ;cr]pSOn c]cnbrWSa M3/N. 8ScOcaS

7:Ga RSpSnR ]n pObbSrna ]T RrcU caS bVOb RWTTSr PSbeSSn c]cnbrWSa, Wb Wa

nScSaaOrg b] SabOPlWaV O R][SabWc acrdSWllOncS agabS[ OnR Oppr]prWObS

rSUclOb]rg UcWRSlWnSa.

7n W[p]rbOnb lW[WbObW]n ]T bVS prSaSnb abcRg Wa bVOb bVS ]PaSrdSR

c]rrSlObW]na R] n]b nScSaaOrWlg WnRWcObS cOcaOlWbg. GSUclObW]n ]T O RrcU

Wnd]ldSa O dOrWSbg ]T TcncbW]na3 lWcSnaWnU, WnapScbW]n ]T [OncTOcbcrWnU

TOcWlWbWSa OnR RWabrWPcbW]n cVOnnSla, pr]Rccb OaaSaa[Snb OnR rSUWabrObW]n,

7:G []nWb]rWnU, qcOlWbg c]nbr]l, c]nbr]l ]T RrcU pr][]bW]n OnR

ORdSrbWaWnU, OnR c]nbr]l ]T clWnWcOl RrcU brWOla M30N. In bVWa abcRg,

43

c]cnbrWSa eWbV [Ong eWbVRrOen/rSabrWcbSR RrcUa bSnR b] PS eSll

RSdSl]pSR OnR VSncS Ola] VOdS lOrUS pVOr[OcScbWcOl WnRcabrWSa. IVS

nc[PSr ]T eWbVRrOen RrcUa Wa clSOrlg c]rrSlObSR eWbV bVS nc[PSr ]T

RrcUa [OrkSbSR ]r bVS ]dSrOll [OrkSb aWhS ]T bVS c]cnbrg. IVca, bVS

rSaclba ]T bVS prSaSnb abcRg ]n VSOlbV OnR Sc]n][Wc TOcb]ra c]clR VOdS

PSSn OTTScbSR Pg [Ong c]nT]cnRSra. >]eSdSr, Wb Wa VWUVlg lWkSlg bVOb bVS

nc[PSr ]T RrcUa eWbVRrOen/rSabrWcbSR Pg O rSUclOb]rg OcbV]rWbg cOn PS

O caSTcl WnRWcOb]r T]r O c]cnbrgla ]pbW[c[ lSdSl ]T Sc]n][Wc

WndSab[Snba Wn bVS VSOlbV cOrS agabS[ OTTScbWnU RrcU rSUclObW]n

pr]cSaaSa.

7n]bVSr lW[WbObW]n Wa bVOb bVS nc[PSr ]T W[p]rbSR RrcUa eOa

n]b c]cnbSR RcS b] O lOck ]T WnT]r[ObW]n. IT O c]cnbrg ]pSrObSa O al]e

OnR c]naSrdObWdS RrcU Oppr]dOl agabS[, bVS rObS ]T p]ab[OrkSb RrcU

eWbVRrOeOla [Og PS l]eSr. ;dOlcObW]n ]T bVS RWTTSrSnb RrcU Oppr]dOl

agabS[a eOa PSg]nR bVS ac]pS ]T bVS prSaSnb abcRg. 8ScOcaS RrcU

Oppr]dOl agabS[a VOdS Sd]ldSR ]dSr bW[S, bW[S%aSrWSa OnOlgaSa ]T

Oppr]dSR OnR POnnSR RrcUa T]r RWTTSrSnb c]cnbrWSa OrSO aV]clR PS

pSrT]r[SR Wn TcbcrS c][pOrObWdS abcRWSa.

44

IVS JD 9]na]lWRObSR BWaba ]T Fr]Rccba OrS n]b pSrTScb. H][S

W[p]rbOnb RObO OrS clSOrlg [WaaWnU, Oa SfS[plWTWSR Wn bVS cOaS abcRg ]T

A]rSO eVSrS ]nS ]T bVS be] eWbVRrOen RrcUa VOa n]b PSSn rSp]rbSR b]

bVS JD T]r 0 gSOra. DSdSrbVSlSaa, bVS lWaba OrS kn]en b] PS bVS []ab

c][prSVSnaWdS OnR OcbV]rWhSR OdOWlOPlS WnT]r[ObW]n a]crcSa. <WnOllg,

bVS clOW[a RObO T]r bVS eV]lS A]rSOn p]pclObW]n Tr][ bVS >SOlbV

InacrOncS GSdWSe 7USncg OrS rSlObSR b] prSacrWpbW]n RrcUa ]nlg, OnR

n]b ]dSr%bVS%c]cnbSr RrcUa.

In c]nclcaW]n, bVS nc[PSr ]T RrcU eWbVRrOeOla OnR rSabrWcbW]na

cOn PS caSR Oa On WnRWcOb]r ]T O c]cnbrgla lSdSl ]T WndSab[Snb Wn Wba

VSOlbV cOrS agabS[. IVS lWaba ]T eWbVRrOen OnR rSabrWcbSR RrcUa dOrg

[OrkSRlg PSbeSSn c]cnbrWSa, accV bVOb O RrcU eWbVRrOen Wn ]nS

c]cnbrg [Og PS prSacrWPSR Wn On]bVSr. ;dSn RrcUa eWbVRrOen

WnbSrnObW]nOllg Pg RrcU [OncTOcbcrSra OrS abWll PSWnU prSacrWPSR Wn a][S

c]cnbrWSa. LVWlS OcbV]rWbWSa cl]aSlg c]llOP]rObS eWbV SOcV ]bVSr, Wb aSS[a

bVOb bVSrS rS[OWna r]][ T]r W[pr]dS[Snba Wn bVS ccrrSnb RrcU

rSUclOb]rg agabS[a e]rlReWRS. DSe RrcUa eWll c]nbWnc]calg OppSOr

P]bV eWbV W[pr]dSR VSOlbV cOrS PSnSTWba OnR p]bSnbWOllg VOr[Tcl 7:Ga.

45

C]rS]dSr, nSe WnRWcObW]na T]r RrcUa eWll S[SrUS OnR bVS caOUS pObbSrna

eWll cVOnUS c]nabOnblg. <crbVSr W[pr]dS[Snba Ob P]bV bVS Ul]POl OnR

nObW]nOl lSdSla OrS rSqcWrSR Wn RrcU acrdSWllOncS agabS[a OnR rSUclOb]rg

c][[cnWcObW]n nSbe]rka.

46

.3-PTE: 2

2DLMmHc VaOHaAHlHtT aLC /ORF SaEDtT

47

47T:O/U.T4O7

IVS pSra]n%b]%pSra]n dOrWOPWlWbg Wn RrcU rSap]naS Wa O [Oj]r

cVOllSnUS T]r ccrrSnb clWnWcOl prOcbWcS, RrcU RSdSl]p[Snb, OnR RrcU

rSUclObW]n M2N. 7 RrcU eWbV pr]dSn clWnWcOl STTWcOcg Wn a][S pObWSnba

]TbSn TOWla b] e]rk Wn ]bVSra, ]r [Og SdSn cOcaS aSrW]ca aWRS STTScba,

WnclcRWnU RSObV M2j,N. IVS WncWRSncS ]T aSdSrS 7:Ga VOa PSSn

SabW[ObSR Ob ..2j../% Wn V]apWbOlWhSR pObWSnba, OnR []rS bVOn 2

[WllW]n 7:G cOaSa ]cccr OnncOllg Wn bVS JH7, WnclcRWnU )((,((( RSObVa

M,,-N. 7a O rSaclb, [Ong RrcUa cOcaWnU cnSfpScbSR aSdSrS 7:Ga OrS

SdSnbcOllg eWbVRrOen Tr][ bVS [OrkSb.

IVS W[pOcb OnR c]ab PcrRSn ]T pVOr[OcScbWcOl [OrkSb eWbVRrOeOla

OrS Sn]r[]ca. ET bVS -,0 nSe RrcUa Oppr]dSR PSbeSSn )1/- OnR )111

Wn bVS JH7, -. ()(.2%) rScSWdSR O nSe P]fSR%eOrnWnU ]r eSrS

SdSnbcOllg eWbVRrOen Tr][ bVS [OrkSb M.,/N. IeSnbg (3.0%) ]T bVS -20

nSe RrcUa Oppr]dSR PSbeSSn )11( OnR 2((1 Wn 9OnORO eSrS

eWbVRrOen T]r aOTSbg rSOa]na, OnR bVS pSrcSnbOUS ]T RrcU rS[]dOla

Tr][ bVS [OrkSb RWR n]b cVOnUS aWUnWTWcOnblg ]dSr bVOb pSrW]R,

WnRWcObWnU bVOb bVSrS eOa Ola] n] cVOnUS Wn bVS cOpOPWlWbg ]T bVS RrcU

48

rSdWSe agabS[ M0N. :SapWbS acPabOnbWOl prS[OrkSb STT]rba, WnclcRWnU dSrg

l]nU OnR c]ablg clWnWcOl brWOla, p]ab%[OrkSb RrcU eWbVRrOeOla OrS

USnSrOllg n]b prSdSnbOPlS Pg bVS ccrrSnblg OdOWlOPlS [SOna M31,,(N.

=Sn]bgpWc RWdSraWbg Wn bVS p]pclObW]n Wa lWkSlg b] cnRSrlWS pSra]n%

b]%pSra]n dOrWOPWlWbg Wn RrcU rSap]naSa. FVOr[Oc]USn][Wca pr]dWRSa

bVS WnT]r[ObW]n OP]cb bVS STTScb ]T USnSbWc dOrWObW]na ]n WnRWdWRcOl RrcU

rSap]naSa M,)N, eVWcV Wa pcb ]n bVS lOPSla ]T OP]cb )-( RrcUa Oppr]dSR

Pg bVS JnWbSR HbObSa <]]R OnR :rcU 7R[WnWabrObW]n (JH <:7) M,2N.

IVS Occc[clObW]n ]T USnSbWc RObO rSlObSR b] RrcU rSap]naS Wa O

aWUnWTWcOnb abSp b]eOrRa rSOlWhObW]n ]T bVS pSra]nOlWhSR [SRWcWnS

c]ncSpb. F]pclObW]n%POaSR USn][S%eWRS ]PaSrdObW]nOl rSaSOrcV accV

Oa =Sn][S%LWRS 7aa]cWObW]n HbcRWSa (=L7H) Wa ]nS ]T bVS []ab

p]eSrTcl b]]la T]r WndSabWUObWnU bVS rSlObW]naVWp PSbeSSn USn]bgpWc

dOrWOPWlWbg OnR RrcU rSap]naSa. >]eSdSr, bVS ccrrSnb p]pclObW]n%POaSR

Oppr]OcV Wn On OTTScbSR%dSraca%n]nOTTScbSR cOaS%c]nbr]l aSbbWnU Wa

WnVSrSnblg lW[WbSR PScOcaS bVS nc[PSra ]T USn]bgpSa, RrcUa, OnR bVSWr

Oaa]cWObW]na OrS b]] VWUV b] PS rSlWOPlg bSabSR Wn O T]rSaSSOPlS TcbcrS.

IVSrST]rS, []ab RrcUa OrS n]b SfO[WnSR Pg =L7H.

49

=Sn][S aSqcSncWnU bScVn]l]Ug VOa rSdSOlSR VcnRrSRa ]T USnSbWc

dOrWOnba bVOb OrS prSRWcbSR b] cOcaS l]aa ]T TcncbW]n (B]<) Wn pr]bSWn%

c]RWnU USnSa M,3N. IVS USnSa rSlObSR b] RrcU FA/F: VOdS [Ong B]<

dOrWOnba, eVWcV SfVWPWb aWUnWTWcOnb pSra]n%b]%pSra]n dOrWOPWlWbg Wn

RWabrWPcbW]n M,,N. IVS cnSfpScbSRlg lOrUS nc[PSr ]T RSlSbSrW]ca USnSbWc

dOrWOnba T]cnR Wn OppOrSnblg VSOlbVg acPjScba OnR bVSWr cnSdSn

RWabrWPcbW]n Ocr]aa WnRWdWRcOl USn][Sa [Og SfplOWn RScrSOaSR ]r

cncacOl acacSpbWPWlWbg b] cSrbOWn RrcUa Wn a[Oll acPp]pclObW]na. 9lWnWcOl

brWOla OrS USnSrOllg c]nRccbSR Wn Ur]cpa V][]USnS]ca Wn OUS, USnRSr,

OnR/]r SbVnWcWbg, OnR bVS rSaclba OrS bVSn SfbrOp]lObSR b] bVS USnSrOl

p]pclObW]n M,-N. >]eSdSr, bVSg [Og n]b PS OpplWcOPlS b] cSrbOWn a[Oll

acPp]pclObW]na, eVWcV [Og RS[]nabrObS cnSfpScbSR 7:Ga n]b

RSbScbSR RcrWnU pVOaS%III clWnWcOl brWOla, lSORWnU b] RrcU eWbVRrOeOl

Tr][ bVS pVOr[OcScbWcOl [OrkSb.

IVS )((( =Sn][Sa Fr]jScb pr]dWRSa cnPWOaSR RObO ]n USnSbWc

dOrWObW]n Wn 2,-(, pSra]nOl USn][Sa Tr][ rSprSaSnbObWdS p]pclObW]na

Snc][pOaaWnU 2. SbVnWc Ur]cpa M,.N. LS Vgp]bVSaWhSR bVOb bVS pSra]n%

b]%pSra]n dOrWOPWlWbg Wn bVS RWabrWPcbW]n ]T B]< dOrWOnba ]T FA/F: USnSa

50

Wn RWTTSrSnb SbVnWc Ur]cpa [Og rSdSOl acPp]pclObW]na prSRWap]aSR b]

aSdSrS 7:Ga, eVWcV [Og acPaSqcSnblg rSaclb Wn RrcU rS[]dOl Tr][ bVS

[OrkSb.

IVS TWnRWnUa ]T bVS prSaSnb abcRg acUUSab bVOb bVS pSra]n%b]%pSra]n

USnSbWc dOrWOPWlWbg Wa O abr]nU WnRSpSnRSnb prSRWcb]r ]T RrcU

eWbVRrOeOla T]r aOTSbg rSOa]na. In bVWa abcRg, eS pr]p]aS O [SbV]R b]

WRSnbWTg WnRWdWRcOla (]r acPp]pclObW]na) eWbV WncrSOaSR dclnSrOPWlWbg b]

aWRS STTScba ]T O apScWTWc RrcU OnR acUUSab n]dSl [SOacrSa b] SnacrS RrcU

aOTSbg POaSR ]n pSra]nOl USn][S aSqcSncS OnOlgaWa, eVWcV cOn W[pr]dS

RrcU RSdSl]p[Snb, caS, OnR rSUclObW]na.

6-TE:4-5 -7/ 6ET3O/S

/ORF SDlDctHML 1lMS

IVS :rcU8Onk RObOPOaS Wa O PW]WnT]r[ObWca rSa]crcS bVOb pr]dWRSa

RSbOWlSR RrcU WnT]r[ObW]n, WnclcRWnU cVS[WcOl abrccbcrS OnR

pVOr[Oc]l]UWcOl [ScVOnWa[, b]USbVSr eWbV RrcU bOrUSba, [SbOP]lWc

Snhg[Sa, cOrrWSra, OnR brOnap]rbSra M,/N. 7[]nU bVS /,/13 RrcUa Wn bVS

:rcU8Onk, -,(11 OnR ),(,) SnbWbWSa VOdS Ob lSOab ]nS ]r TWdS WRSnbWTWSR

51

FA/F: USnSa, rSapScbWdSlg (OccSaaSR HSpbS[PSr ,, 2()- Ob

Vbbp2//eee.RrcUPOnk.cO/). In bVS prSaSnb SdOlcObW]n abcRg, eS

OnOlghSR bVS ),(,) RrcUa eWbV TWdS ]r []rS FA/F: USnSa OnR 2,0(/

FA/F: USnSa kn]en b] PS Wnd]ldSR Wn RrcU rSap]naSa dWO )2,00/ RrcU%

USnS WnbSrOcbW]na (<WUcrS 2%)).

1HFROD 2-1. 1lMS CHaFOam ME CORF HLclRPHML NOMcDPP

6RltH-EtGLHc 2DLMmD /ata

LS R]enl]ORSR 2,-(, pcPlWclg OdOWlOPlS pSra]nOl USn][Sa Tr][ bVS

)((( =Sn][Sa Fr]jScb, eVWcV pr]dWRSa USn][Wc WnT]r[ObW]n ]n 2.

SbVnWc acPUr]cpa Tr][ ;cr]pS, ;Oab 7aWO, H]cbV 7aWO, 7TrWcO, OnR bVS

DrugBank (n = 7,793)

Excluding drugs without drug-gene relationship (n = 2,695)

1,041 Drugs

Excluding drugs with less than five known PK/PD genes (n =

4,058)

5,099 Drugs

52

7[SrWcOa M,0N (OccSaaSR HSpbS[PSr ,, 2()- Ob

Vbbp2//eee.)(((USn][Sa.]rU/).

SDlDctHML ME PODcaRtHMLaOT aLC 6aOIDt-SHtGCOaSL /ORFP

IVS RScWaW]n pr]cSaa ]T RrcU eWbVRrOeOla Wa VWUVlg c][plSf OnR Wa

WnTlcSncSR Pg p]lWbWcOl, c][[SrcWOl, SbVWcOl, OnR ]bVSr TOcb]ra. LS

pSrT]r[SR On Wn%RSpbV rSdWSe ]T rSa]crcSa b] crSObS O c][prSVSnaWdS

lWab ]T eWbVRrOen RrcUa2 ()) bVS 0bV, )(bV, )2bV, OnR ),bV IaacSa ]T bVS

k9]na]lWRObSR BWab ]T Fr]Rccba LV]aS 9]nac[pbW]n OnR/]r HOlS >OdS

8SSn 8OnnSR, LWbVRrOen, HSdSrSlg GSabrWcbSR, ]r D]b 7ppr]dSR Pg

=]dSrn[Snba2 FVOr[OcScbWcOlal pcPlWaVSR Pg bVS JnWbSR DObW]na (JD

9]na]lWRObSR BWaba) aWncS 2((3, M)2, 2,%2.N eVWcV OrS bVS []ab

c][prSVSnaWdS lWaba ]T eWbVRrOen OnR aSdSrSlg rSabrWcbSR RrcUa

pr]RccSR Pg Ob lSOab ]nS ]T 1, U]dSrn[Snba, (2) RScWaW]na b] eWbVRrOe

On OpplWcObW]n [ORS b] bVS ;C7 M,1N T]r O Vc[On [SRWcWnS Pg bVS

rSdWSe ]T bVS 9][[WbbSS T]r CSRWcWnOl Fr]Rccba T]r >c[On JaS

(9>CF) OnR (3) :rcU8Onk Onn]bObW]na T]r pVOr[OcScbWcOl [OrkSb

eWbVRrOeOla M,/N.

53

1HFROD 2-2. /ORFP SHtGCOaSL aLC NODcaRtHMLaOT EOMm tGD maOIDt

<]r bVS pcrp]aS ]T bVS prSaSnb abcRg, O RrcU eOa RSTWnSR Oa

eWbVRrOen WT Wb VOR PSSn rS[]dSR, POnnSR, ]r RWaOppr]dSR Pg Ob lSOab

]nS c]cnbrg T]r Ong rSOa]n. LS [OncOllg aSlScbSR 3-( RrcUa

eWbVRrOen Pg Ob lSOab ]nS c]cnbrg Occ]rRWnU b] bVS JD 9]na]lWRObSR

BWaba M)2, 2,%2.N, )/, RrcUa eWbVRrOen Tr][ JOncOrg 2((. b]

HSpbS[PSr 2()- Occ]rRWnU b] bVS ;C7 M,1N, OnR )0) eWbVRrOen RrcUa

Onn]bObSR Pg :rcU8Onk, M,/N rSapScbWdSlg. In ORRWbW]n, eS Ola] aSlScbSR

277

51

0 115

67

113

UN withdrawn drugs (n=350)

DrugBank withdrawn

drugs (n=181)

EMA withdrawn

drugs (n=121)

n=578

25 112123FDA PGx drugs

(n=148)

Beers criteria drugs

(n=137)

n=260

Withdrawn Drugs Precautionary Drugs

34544 226Precautionary drugs (n=260)

Withdrawn drugs (n=578)

n=804

54

prScOcbW]nOrg RrcUa Pg OpplgWnU bVS 8SSra crWbSrWO (n 5 )3/) M-(N OnR

JH <:7 pVOr[Oc]USn][Wc PW][OrkSr WnT]r[ObW]n Wn RrcU lOPSla (n 5

),0) M,2N (<WUcrS 2%2). IVS 8SSra crWbSrWO T]r F]bSnbWOllg InOppr]prWObS

CSRWcObW]n JaS Wn ElRSr 7Rclba VOdS PSSn WaacSR Wn 2((3 Pg bVS

7[SrWcOn =SrWObrWc H]cWSbg OnR OrS eWRSlg caSR Wn clWnWcOl cOrS b]

prSdSnb 7:Ga Wn bVS SlRSrlg p]pclObW]n.

IOPlS )%) aV]ea bVOb bVS RWabrWPcbW]n ]T eWbVRrOen ]r

prScOcbW]nOrg RrcUa Occ]rRWnU b] bVS TWlbSrWnU pr]cSaa ]T nc[PSr ]T

FA/F: USnSa rSlObSR b] RrcUa. <WUcrS 2%3 aV]ea bVOb O[]nU bVS ),(,)

aSlScbSR RrcUa eWbV Ob lSOab TWdS FA/F: USnSa, 201 eSrS clOaaWTWSR Oa

eWbVRrOen ]r prScOcbW]nOrg. 7[]nU bVS )-, eWbVRrOen RrcUa, ). OnR

)0 eSrS Ola] rSRcnROnblg clOaaWTWSR Oa prScOcbW]nOrg Occ]rRWnU b] bVS

8SSra crWbSrWO (n 5 1() OnR JH <:7 pVOr[Oc]USn][Wc PW][OrkSr

WnT]r[ObW]n (n 5 1.) (<WUcrS 2%3).

55

TaAlD 2-1. 7RmADO ME SHtGCOaSL aLC NODcaRtHMLaOT CORFP accMOCHLF

tM tGD EHltDOHLF AT tGD LRmADO ME FDLDP ODlatDC tM CORFP.

1HFROD 2-3. /ORF PDlDctHML ElMS aLC tGD CHPtOHARtHML ME SHtGCOaSL,

NODcaRtHMLaOT, aLC MtGDO CORFP

124

144

12

576117

Withdrawn (n=154)

Beers criteria(n=90)

Drugs labelled with FDA-approved

pharmacogenomic information (n=96)

Excluding drugs with poor PK/PD (n<5) information

DrugBank (n = 7,793)

Drugs with at least five known PK/PD genes

(n=1,041)

Other drugs(n = 752)

Withdrawn or Precautionary drugs(n = 289)

(The%1,041%study%drugs%have%2,807%PK/PD%genes%%connected%by%12,887%drug–gene%interac@ons.)

752

289

515Total Withdrawn or

Precautionary drugs, n=804

56

In b]bOl, ),(,) RrcUa Tr][ bVS :rcU8Onk eWbV Ob lSOab TWdS WRSnbWTWSR

USnSa Wnd]ldSR Wn RrcU pVOr[Oc]kWnSbWca (FA) OnR pVOr[Oc]RgnO[Wca

(F:) eSrS WnclcRSR Wn bVS abcRg. 7 c][prSVSnaWdS lWab ]T eWbVRrOen

RrcUa (n 5 )-,) eOa ]PbOWnSR Pg rSdWSeWnU bVrSS rSa]crcSa2 ()) bVS 0bV,

)(bV, )2bV, OnR ),bV IaacSa ]T bVS k9]na]lWRObSR BWab ]T Fr]Rccba LV]aS

9]nac[pbW]n OnR/]r HOlS >OdS 8SSn 8OnnSR, LWbVRrOen, HSdSrSlg

GSabrWcbSR, ]r D]b 7ppr]dSR Pg =]dSrn[Snba2 FVOr[OcScbWcOlal

pcPlWaVSR Pg bVS JnWbSR DObW]na3 (2) OpplWcObW]na T]r eWbVRrOeOl Tr][

;C73 OnR (3) bVS :rcU8Onk Onn]bObW]na T]r eWbVRrOeOla.

FrScOcbW]nOrg RrcUa (n 5 ).-) eSrS WRSnbWTWSR POaSR ]n bVS 8SSra

crWbSrWO OnR JH <:7 bOPlS ]T pVOr[Oc]USn][Wca PW][OrkSra. IVS

rS[OWnWnU /-2 RrcUa eSrS clOaaWTWSR Oa ]bVSr RrcUa.

/DlDtDOHMRPLDPP ScMODP EMO 2DLDP, VaOHaLtP, /ORFP, aLC

PMNRlatHMLP

7n WnRWdWRcOlla rSap]naS b] O RrcU Wa OTTScbSR Pg bVS USnSa Snc]RWnU

RrcU bOrUSba, rSlObSR [SbOP]lWc Snhg[Sa OnR RrcU brOnap]rbSra. Ib VOa

PSSn RS[]nabrObSR bVOb bVS W[pOcb ]T n]nagn]ng[]ca acPabWbcbW]na ]n

57

pr]bSWn abrccbcrS OnR TcncbW]n cOn PS rSlWOPlg prSRWcbSR Pg OpplgWnU

abrOWUVbT]reOrR S[pWrWcOl rclSa caWnU apScWTWc OlU]rWbV[a accV Oa HI<I

M-)N, F]lgFVSn%2 M-2N, CcbObW]n7aaSaa]r M-3N, 97:: M-,N, OnR

9]nRSl M--N.

LS caSR bVS HI<I OlU]rWbV[ M-)N b] c][pcbS bVS dOrWOnb

RSlSbSrW]canSaa ac]rS (K) T]r Oll n]nagn]ng[]ca c]RWnU dOrWOnba T]cnR

Wn bVS 2,0(/ FA/F: USnSa ]T bVS 2,(-, pSra]nOl USn][Sa aSlScbSR Tr][

bVS )((( =Sn][Sa Fr]jScb.

IVS USnS RSlSbSrW]canSaa ac]rS (=) eOa RSTWnSR Oa bVS US][SbrWc

[SOn ]T bVS K ac]rSa T]r Oll n]nagn]ng[]ca c]RWnU dOrWOnba ]T bVS

USnS (<WUcrS 2%,). HW[WlOrlg, bVS RrcU RSlSbSrW]canSaa ac]rS (:) eOa

RSTWnSR Oa bVS US][SbrWc [SOn ]T bVS = ac]rSa T]r Oll RrcU%rSlObSR

FA/F: USnSa (<WUcrS 2%,). IVS US][SbrWc [SOn eOa caSR b] WRSnbWTg

bVS cSnbrOl bSnRSncg Wn bVS cVOnUS ]T bVS OnOlghSR pOrO[SbSra. IVS K,

=, OnR : RSlSbSrW]canSaa ac]rSa rOnUS Tr][ ( b] )3 l]e K OnR = ac]rSa

WnRWcObS aSdSrSlg OlbSrSR abrccbcrS OnR/]r TcncbW]n ]T bVS c]rrSap]nRWnU

USnS, eVWlS l]e : dOlcS WnRWcObSa WncrSOaSR prSRWap]aWbW]n b] 7:Ga.

58

1HFROD 2-4. /DlDtDOHMRPLDPP ScMODP EMO 2DLDP, VaOHaLtP, /ORFP, aLC

PMNRlatHMLP

IVS dOrWOnb ac]rS, K Wa bVS HI<I ac]rS. IVS USnS RSlSbSrW]canSaa ac]rS,

= eOa cOlcclObSR Pg US][SbrWc [SOn ]T bVS K ac]rSa ]T bVS USnS OnR bVS

RrcU%eWaS RSlSbSrW]canSaa ac]rS, : eOa RSTWnSR Oa bVS US][SbrWc [SOn

]T bVS = ac]rSa T]r Oll RrcU%rSlObSR FA/F: USnSa. IVS RrcU%USnS

rSlObW]naVWpa c][S Tr][ :rcU8Onk RObOPOaS. IVS p]pclObW]n

RSlSbSrW]canSaa ac]rS, F ]r bVS OrSO cnRSr bVS ccrdS (7J9) T]r bVS

RWabrWPcbW]n ]T bVS : ac]rS T]r O RrcU k Wn O p]pclObW]n cOn PS

c][pcbSR Pg OdSrOUWnU pSra]nOlWhSR : ac]rSa ]T bVS eV]lS p]pclObW]n.

v1 v2

Ga=(V1%x%V2%x%V3)1/3

Dk=(Ga%x%Gb%x%Gc)1/3

v3 v4 v5 v6 v7 v8 v9 v10 v11 v12 v13

Genea Geneb Genec Gened

S4

S3

S2

S1

……

……

……

……

……

Gb=(V4%%x%V6)1/2 Gc=(V7%x%V8%x%V9%x%V10)1/4 Gd%=(V11%x%V13)1/2

Dj=(Gb%x%Gd%x%…)1/|G|

…… Gene$–wise$$Deleteriousness$$Score,$G

Drug$–wise$Deleteriousness$Score,$D

……

P:$Popula7on–wise$Deleteriousness$Score,$P$(=*AUC*of*D*distribu7on*in*a*popula7on*

=*average*of*Ds*in*a*popula7on)*

……

S1

S1

……

SN

Dk Dj S2

Popula7on

S3 SN

Dk%for%S1 Dj%for%S1 !! = !"#! =

1! !!

!

!!! !! = !"#! =

1! !!

!

!!!

59

<WUcrS 2%, (l]e pOnSla) aV]ea bVS RWabrWPcbW]na ]T bVS : ac]rSa T]r

SOcV RrcU (W.S., :k, :j, Sbc.) O[]nU bVS 2,(-, pSra]nOl USn][Sa. IVS

p]pclObW]n RSlSbSrW]canSaa ac]rS (F) ]r bVS OrSO cnRSr bVS ccrdS (7J9)

T]r bVS RWabrWPcbW]n ]T bVS : ac]rS T]r O RrcU k Wn O p]pclObW]n cOn PS

c][pcbSR Pg OdSrOUWnU pSra]nOlWhSR : ac]rSa ]T bVS eV]lS p]pclObW]n

(<WUcrS 2%,)2

!!"

#$$%

&== '

=

N

pkkk DN

AUCP1

1

LS c][pOrSR bVrSS bgpSa ]T [SOna, OrWbV[SbWc, US][SbrWc, OnR

VOr[]nWc [SOn. LWbV Oll bVrSaV]lR c][pOrWa]n, Tr][ b]bOl -(11 RrcUa

b] )(,) RrcUa VOdWnU rSlObSR USnSa []rS bVOn TWdS, eS T]cnR ]cb bVOb WT

bVS nc[PSr ]T USnSa rSlObSR b] RrcUa WncrSOaWnU, bVS bVrSS bgpSa ]T

[SOna aV]e aW[WlOr cSnbrOl bSnRSncg. (<WUcrS 2%-)

60

1HFROD 2-5. .MmNaOHPML ME tGODD tTNDP ME mDaLP

StatHPtHcal -LalTPHP

7DEK7 OnR p]ab%V]c IckSg OnOlgaWa eSrS caSR b] c][pOrS bVS

7J9a O[]nU bVS T]cr RrcU cObSU]rWSa2 eWbVRrOen, prScOcbW]nOrg Pg

8SSra crWbSrWO, prScOcbW]nOrg Pg <:7 pVOr[Oc]USn][Wca lOPSlWnU, OnR

]bVSr RrcUa. I] c]nbr]l bVS STTScb ]T nc[PSr ]T USnSa rSlObSR b] SOcV

RrcU, 7D9EK7 OnOlgaWa eOa Ola] OpplWSR b] c][pOrS bVS 7J9a O[]nU

, cObSU]rWSa. GSlObWdS TrSqcSncWSa ]T RrcU eWbVRrOeOla OnR prScOcbW]na

eSrS c][pcbSR Ocr]aa 7J9 ac]rS PWna T]r TcrbVSr OnOlgaWa. IVS

61

9]cVrOnS%7r[WbOUS IrSnR bSab eOa pSrT]r[SR Ocr]aa 7J9 ac]rS PWna

b] SabW[ObS bVS STTScb ]T bVS 7J9 ac]rSa ]n bVS TrSqcSncWSa ]T RrcU

eWbVRrOeOl OnR prScOcbW]n. 7ll F dOlcSa eSrS be] aWRSR, OnR

c]naWRSrSR abObWabWcOllg aWUnWTWcOncS Ob 4 (.(-. 7ll abObWabWcOl OnOlgaSa

eSrS c]nRccbSR caWnU bVS G abObWabWcOl pOckOUS (dSr. 3.()) M32N.

:ESU5TS

/ORF WHtGCOaSalP aLC PODcaRtHMLP

LS OnOlghSR ),(,) RrcUa eWbV Ob lSOab TWdS FA/F: USnSa aSlScbSR

Tr][ bVS :rcU8Onk). (<WUcrS 2%3). EdSrOll, )-, (),.0%) ]T bVS ),(,)

OnOlghSR RrcUa eSrS SdSnbcOllg eWbVRrOen Tr][ bVS [OrkSb Pg Ob lSOab

]nS c]cnbrg. 7[]nU bVS )3/ RrcUa Wn bVS 8SSra lWab OnR ),0 RrcUa eWbV

<:7 pVOr[Oc]USn][Wc lOPSla, 1( (.-./%) OnR 1. (.,.1%), rSapScbWdSlg,

eWbV Ob lSOab TWdS FA/F: USnSa eSrS Wn bVS lWab ]T bVS ),(,) abcRg RrcUa,

OnR 3( ()0.2%) ]T bVSaS prScOcbW]nOrg RrcUa eSrS Ola] eWbVRrOen Tr][

bVS [OrkSb Pg Ob lSOab ]nS c]cnbrg (<WUcrS 2%3).

62

TGD P ScMOD aLC /ORF WHtGCOaSalP/PODcaRtHMLP

1HFROD 2-6. .MmNaOHPML ME NMNRlatHML CDlDtDOHMRPLDPP PcMODP ADtSDDL

SHtGCOaSL, NODcaRtHMLaOT, aLC MtGDO CORFP

<WUcrS 2%. RS[]nabrObSa bVOb bVS eWbVRrOen RrcUa (7J9 5 (.--0 i

(.)/() Oa eSll Oa prScOcbW]nOrg RrcUa Wn bVS 8SSra lWab (7J9 5 (.-,1 i

(.)-3) OnR eWbV <:7 pVOr[Oc]USn][Wc lOPSla (7J9 5 (.-,2 i (.),-)

SfVWPWbSR aWUnWTWcOnblg l]eSr 7J9a c][pOrSR b] ]bVSr RrcUa (7J9 5

(..3- i (.)0/) Oa WnRWcObSR Pg 7DEK7 eWbV p]ab%V]c IckSg OnOlgaWa

(F 4 (.(()).

Popu

latio

n−wi

se d

elet

erio

usne

ss s

core

(AUC

)

Withdrawn Beers criteria FDA PGx Other

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

P <0.001P <0.001

P <0.001

63

IVS RrcUa eWbVRrOen Tr][ bVS [OrkSb (7J9 5 (.--0 i (.)/() OnR

prScOcbW]nOrg RrcUa Occ]rRWnU b] bVS 8SSra crWbSrWO (7J9 5 (.-,1 i

(.)-3) OnR <:7 pVO[Oc]USn][Wc WnT]r[ObW]n (7J9 5 (.-,2 i (.),-)

SfVWPWbSR aWUnWTWcOnblg l]eSr 7J9 dOlcSa bVOn ]bVSr RrcUa (7J9 5

(..3-i (.)0/3 F 4 (.((), ]nS%eOg 7DEK7 T]ll]eSR Pg p]ab%V]c

IckSg%bSaba). In c]nbrOab, bVS RWTTSrSncS O[]nU bVS bVrSS

eWbVRrOen/prScOcbW]nOrg RrcU Ur]cpa RWR n]b rSOcV abObWabWcOl

aWUnWTWcOncS (F 6 (.(-). 7J9, OrSO cnRSr bVS RrcU RSlSbSrW]canSaa ac]rS

ccrdS3 <:7 F=f, <:7%Oppr]dSR RrcUa eWbV pVOr[Oc]USn][Wc

WnT]r[ObW]n ]n RrcU lOPSla. <WUcrS 2%/ aV]eSR bVS nc[PSr ]T USnSa

Occ]rRWnU b] bVS bVrSS cObSU]rWSa ]T RrcUa.

64

1HFROD 2-7. .MmNaOHPML ME tGD LRmADO ME FDLDP ODlatDC tM CORFP

accMOCHLF tM tGD tGODD catDFMOHDP, SHtGCOaSL, NODcaRtHMLaOT, aLC MtGDO

CORFP

<WUcrS 2%0 aV]ea rSlObWdS TrSqcSncg VWab]UrO[a ]T bVS eWbVRrOen

RrcUa Occ]rRWnU b] bVS JD 9]na]lWRObSR BWaba M)2, 2,j2.N, ;C7 M,1N,

OnR :rcU8Onk M,/N. 8ScOcaS SOcV c]cnbrg VOa RWTTSrSnb p]lWcg

rSUOrRWnU bVS Oppr]dOl ]T pVOr[OcScbWcOl pr]Rccba, eS OnOlghSR bVSaS

rSa]crcSa aSpOrObSlg Oa eSll Oa Wn c][PWnObW]n. IVS rSaclba WnRWcObS bVOb

l]eSr 7J9 dOlcSa aWUnWTWcOnblg c]rrSlObSR eWbV VWUVSr rSlObWdS

65

TrSqcSncWSa ]T RrcU eWbVRrOeOla Tr][ bVS [OrkSb Wn SdSrg c]nTWUcrObW]n

(F 4 (.(-, 9]cVrOnS%7r[WbOUS IrSnR bSab3 IOPlS 2%2). IVS aO[S brSnR

eOa c]naWabSnblg ]PaSrdSR T]r prScOcbW]nOrg RrcUa Pg bVS 8SSra crWbSrWO

(F 5 (.((13 <WUcrS 2%1(7)) Oa eSll Oa Pg <:7 pVOr[Oc]USn][Wca

lOPSla (F 4 (.((), 9]cVrOnS%7r[WbOUS IrSnR bSab3 <WUcrS 2%1(8) OnR

IOPlS 2%)).

66

T-.le 2-2. Cochr-n-Armit-ge test 2or trend 2or drug withdr-w-ls -nd prec-utions.

AUC score .ins S0.1 S0.2 S0.3 S0.4 S0.5 S0.6 S0.7 S0., S0.- S1.0 :um. 9 T

No. o2 Withdr-wn Drugs

;oNal 1 4 7 13 30 34 3- 16 6 4 154 .010 <8 or 571 1 3 7 11 26 31 34 15 4 2 134 .00- <8 or 4ruC2anF 1 3 5 5 25 26 2, 12 5 3 113 .033 571 or 4ruC2anF. 1 4 3 11 16 14 26 , 5 3 -1 .007 <8 1 2 5 3 21 23 23 11 3 1 -3 .016 571 0 1 2 , 6 , 12 4 1 1 43 .066 4ruC2anF 1 3 1 3 10 6 14 4 4 2 4, .02,

No. o2 Prec-ution-ry

Drugs

2AArM crENArEa 0 1 6 7 16 25 25 6 3 1 -0 .00- 641

pDarmacoCAnomEcM

0 0 6 11 17 32 1- 7 3 1 -6 0.00

1

No. o2 Tot-l Study Drugs 5 14 34 6, 144 217 234 167 ,, 70 70

T9-PaluAM by 3ocDran-1rmENaCA NAMN Bor NrAnd. 1bbrAPEaNEonM. 1<3, 1rAa undAr NDA druC-wEMA dAlANArEouMnAMM-McorA

67

curPA; <8, NDA <nENAd 8aNEonM; 571, NDA 5uropAan 7AdEcEnAM 1CAncy; 641, NDA <nENAd :NaNAM 6ood and 4ruC

1dmEnEMNraNEon

68

EMA only withdrawn drugs, n=41UN only withdrawn drugs, n=63DrugBank only withdrawn drugs, n=20Withdrawn drugs at least two databases, n=30

Population−wise deleteriousness score (AUC)

Rel

ative

freq

uenc

y of

dru

g w

ithdr

awal

05

1015

2025

30

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

EMA only withdrawn drugs, n=48UN only withdrawn drugs, n=43UN and EMA withdrawn drugs, n=2


Rel

ative

freq

uenc

y of

dru

g w

ithdr

awal

05

1015

20

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

UN only withdrawn drugs, n=65DrugBank only withdrawn drugs, n=20UN and DrugBank withdrawn drugs, n=28


Rel

ative

freq

uenc

y of

dru

g w

ithdr

awal

05

1015

20

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

EMA only withdrawn drugs, n=43DrugBank only withdrawn drugs, n=48


Rel

ative

freq

uenc

y of

dru

g w

ithdr

awal

05

1015

2025

30

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

UN withdrawn drugs, n=93


Rel

ative

freq

uenc

y of

dru

g w

ithdr

awal

05

1015

20

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

EMA withdrawn drugs, n=43


Rel

ative

freq

uenc

y of

dru

g w

ithdr

awal

02

46

810

12

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

DrugBank withdrawn drugs, n=48


Rel

ative

freq

uenc

y of

dru

g w

ithdr

awal

05

1015

20

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

A B C D

E F G

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

Samples

Da

0 500 1000 1500 2000 2500

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

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Samples

Db

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0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●

Samples

Dc

0 500 1000 1500 2000 2500

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

69

FiguGe 2-8. FGeFueC9y :isIGi8uIiDC Df :Gug LiIh:GaLals a99DG:iCg ID

EDEulaIiDC :eleIeGiDusCess s9DGes

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-, ;O= iYeh[ b_di ef [gkWb i_p[i* (;% ;bb jhh[[ h[iekhY[i7 (<wD% fW_h[Z

h[iekhY[i7 (?wA% _dZ_l_ZkWb h[iekhY[i6 OH (?%( ?G; (F%( WdZ

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m_jhZhWmd fhec jh[ cWha[j (i[[ NWbb[ -%* Nh[ jhh[[ _Yedi _d ; (bem[h

fWd[b% ihem Zhk] Z[b[j[h_ekid[ii iYeh[ Ykhl[i jof_YWb feh jh[

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Od_j[Z HWj_edi*

Beers criteria drugs, n=90


Rel

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05

1015

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

FDA pharmacogenomic drugs, n=96


Rel

ative

freq

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pre

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rugs

05

1015

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

A B

70

FiguGe 2-9. DisIGi8uIiDC Df GelaIive fGeFueC9y Df :Gug EGe9auIiDCs

a99DG:iCg ID EDEulaIiDC :eleIeGiDusCess s9DGes

L[bWj_l[ fh[gk[dY_[i ef Zhk] fh[YWkj_edi WYYehZ_d] je (;% OM FD;

fhWhcWYe][dec_Yi bWb[bi WdZ (<% jh[ <[[hi Yh_j[h_W m[h[ i_]d_f_YWdjbo

h_]h[h _d bem[h jhWd _d h_]h[h ;O= iYeh[ b_di (J 8 ,*,-( =eYhhWd)

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Z[b[j[h_ekid[ii iYeh[ Ykhl[*

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de Z[b[j[h_eki lWh_Wdji WYheii jh[ [dj_h[ hkcWd fefkbWj_ed( mh_Yh _i

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fefkbWj_ed( m[ h[h[ fhefei[ jme ][dec_Y fWhWc[j[hi je Wii[ii Zhk]

iWf[jo( ;O= WdZ Pj( mh_Yh cWo fWY_b_jWj[ Zhk] Z[l[befc[dj( ki[( WdZ

h[]kbWj_ed( WdZ [l[djkWbbo fh[l[dj Zhk] m_jhZhWmWb*

71

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je jh[ ;dWjec_YWb Nh[hWf[kj_Y =h[c_YWb (;N=% YbWii_f_YWj_ed ioij[c*

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y][d[j_YWbbo _Z[Wbz Zhk] (s+t+u+v%( mh_Yh cWo b[ [gkWb je -*,*

Nhki( s (eh -);O= ef gk_d_Z_d[% h[fh[i[dji jh[ Z_ijWdY[ ef

Z_iefohWc_Z[ fhec W y][d[j_YWbbo _Z[Wbz Zhk] _d j[hci ef ][dec[

i[gk[dY[ lWh_Wj_ed WdZ _i icWbb[h jhWd jhWj ef fheYW_dWc_Z[ (-)Tu+vU%

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WdZ gk_d_Z_d[*

F_]kh[ .)-, Z[cedijhWj[i jhWj Wced] jh[ .(1,0 _dZ_l_ZkWbi( /1

(-*0"%( /,. (-.*-"%( WdZ -(3// (25*."% hWl[ _dYh[Wi[Z h_iai feh ;DLi

YWki[Z bo Z_iefohWc_Z[( fheYW_dWc_Z[( WdZ( gk_d_Z_d[ h[if[Yj_l[bo( _f

,*/ _i jh[ h_ia jhh[ihebZ feh jh[ D iYeh[ (P,*/%* Pj _i Z[f_d[Z Wi jh[

72

fhefehj_ed ef f[efb[ ][d[j_YWbbo lkbd[hWbb[ feh ;DLi ef W Y[hjW_d Zhk](

mhe hWl[ D iYeh[i bem[h jhWd jh[ h_ia jhh[ihebZ( j* Nh[ Z_ijh_bkj_edi ef

P,*/ WdZ P,*3 feh jh[ jhh[[ Zhk]i Wh[ ihemd _d F_]kh[ .)-,*

FiguGe 2-10. 2GDEDse: measuGes Df :Gug safeIy ID EGeveCI EGe9auIiDCs

aC: :Gug LiIh:GaLals fGDm Ihe maGkeI

(;% Dhk] Z[b[j[h_ekid[ii iYeh[i feh jhh[[ Zhk]i( Z_iefohWc_Z[

(]h[[d%( fheYW_dWc_Z[ (bbk[%( WdZ gk_d_Z_d[ (h[Z% m_jh jh[ iWc[ ;N=

YeZ[ (=,-<; feh ;dj_Whhojhc_Yi YbWii CW% m[h[ Yecfkj[Z feh .(,10

][dec[i ef jh[ -,,, A[dec[i Jhej[Yj WdZ iehj[Z _d jh[ WiY[dZ_d]

V0.3 = 35 (1.4%)

V0.7 = 564 (22.5%) V0.3 = 302 (12.1%)

V0.7 = 2283 (91.2%)

V0.3 = 1733 (69.2%) V0.7 = 2498 (99.8%)

A

C

α

β

γ

δ

B

Disopyramide, Procainamide, Quinidine,

DisopyramideProcainamideQuinidine

α

β

γ

δ

73

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h[if[Yj_l[bo* (=% Qh[d jh[ h_ia jhh[ihebZ _i i[j Wj ,*/( jh[d /1 (-*0"%(

/,. (-.*-"%( WdZ -(3// (25*."% Wced] jh[ .(1,0 _dZ_l_ZkWbi YWd b[

YbWii_f_[Z Wi ][d[j_YWbbo lkbd[hWbb[ je i_Z[ [ff[Yji ef Z_iefohWc_Z[(

fheYW_dWc_Z[( WdZ( gk_d_Z_d[ h[if[Yj_l[bo (P,*/%* ;bbh[l_Wj_edi6 ;O=(

Wh[W kdZ[h jh[ Zhk] Z[b[j[h_ekid[ii iYeh[ Ykhl[7 ;N=( ;dWjec_YWb

Nh[hWf[kj_Y =h[c_YWb =bWii_f_YWj_ed Moij[c*

D.SCUSS.10

Cd jh_i ijkZo( m[ hWl[ Z[cedijhWj[Z jhWj jh[ f[hied)je)f[hied

][dec[ lWh_Wb_b_jo _i W ijhed] _dZ[f[dZ[dj fhe]deij_Y fWYjeh ef Zhk]

m_jhZhWmWb fhec jh[ fhWhcWY[kj_YWb cWha[j( mh_Yh hWi bed] b[[d

Yedi_Z[h[Z kdfh[Z_YjWbb[* Q[ fhefei[ del[b c[Wikh[i ef Zhk] iWf[jo

Wii[iic[dj bWi[Z ed f[hiedWb ][dec[ i[gk[dY[ WdWboi_i( mh_Yh mekbZ

_cfhel[ Zhk] Z[l[befc[dj( ki[( WdZ h[]kbWj_ed* Nh[ fhefei[Z c[jheZ

YWd b[ h[WZ_bo Wffb_[Z je _Z[dj_fo _dZ_l_ZkWbi m_jh _dYh[Wi[Z ][d[j_Y

74

lkbd[hWb_b_jo je WZl[hi[ i_Z[ [ff[Yji ef W if[Y_f_Y Zhk]* Jhoi_Y_Wdi YWd

ki[ jh_i c[jheZ Wi W jeeb je ikffehj Yb_d_YWb Z[Y_i_edi WdZ fh[l[dj

kd_dj[dZ[Z Zhk] h[WYj_edi* Nh[ fhefei[Z ][dec_Y c[Wikh[i YWd b[

ki[Z feh [ff_Y_[dj iYh[[d_d] ef YWdZ_ZWj[ fhWhcWY[kj_YWbi( Z[l[befc[dj

ef iWf[h Zhk]i( ][dec[)bWi[Z fhWhcWYel_]_bWdY[( WdZ h[]kbWj_ed ef

Zhk] iWf[jo*

=h_j_Yi hWl[ Wh]k[Z jhWj W Yb_d_YWb jh_Wb _dlebl_d] Wbekj .(,,,q/(,,,

fWhj_Y_fWdji YWddej h[b_Wbbo Z[j[Yj hWh[ ;DLi m_jh Wd _dY_Z[dY[ ef b[ii

jhWd - f[h -,(,,, T12U* ;bjhek]h _dYh[Wi_d] jh[ dkcb[h ef jh_Wb

fWhj_Y_fWdji _i dej _cfhWYj_YWb( _j cWo ij_bb b[ _dWZ[gkWj[ je WZZh[ii jh[

Yecfb[n_jo ef f[hiedWb ][dec[ i[gk[dY[ lWh_Wj_edi T13U* Nh[ Ykhh[dj

Wff[Yj[Z)l[hiki)kdWff[Yj[Z YWi[)Yedjheb WffheWYh ki[Z _d

fhWhcWYe][dec_Yi h[i[WhYh T14U YWddej fhel_Z[ Yecfh[h[di_l[

WdWboi_i ef ckbj_fb[ Yecfb[n WiieY_Wj_edi b[jm[[d dkc[heki ][dejof[i

WdZ Zhk]i* Cd YedjhWij( jh[ fhefei[Z Wb _d_j_e c[jheZ _i iYWbWbb[ je

_dYh[Wi_d] dkcb[hi ef ][dejof[i WdZ Zhk]i WdZ h[b_[i edbo ed

_dj[]hWj[Z fkbb_Y h[iekhY[i6 f[hiedWb ][dec[ i[gk[dY[ ZWjWbWi[i

75

Yel[h_d] Z_ff[h[dj [jhd_Y ]hekfi( Zhk] JE+JD _dfehcWj_ed( WdZ jh[

h[YehZi ef m_jhZhWmd WdZ+eh fh[YWkj_edWho Zhk]i*

Geh[ _cfehjWdjbo( fkjkh[ Yb_d_YWb jh_Wb Z[i_]d cWo b[ b[d[f_j[Z bo

_dYehfehWj_d] [jhd_Y_jo)h[bWj[Z ZWjW h[]WhZ_d] ][dec[ i[gk[dY[

lWh_Wb_b_jo( mh_Yh YWd Wff[Yj Zhk] iWf[jo* Feh [nWcfb[( mh[d W ikb)

fefkbWj_ed eh [jhd_Y ]hekf _i el[hh[fh[i[dj[Z kdZ[h jh[ h_ia jhh[ihebZ

(Pj% feh W jh_Wb Zhk]( h[Yhk_j_d] ceh[ ikbj[Yji fhec Wdejh[h ikb]hekf

][d[j_YWbbo lkbd[hWbb[ feh Zhk] i_Z[ [ff[Yji cWo b[WZ je W ceh[ hWj_edWb

jh_Wb Z[i_]d( kbj_cWj[bo _cfhel_d] Zhk] iWf[jo* Fkhjh[hceh[( je h[b_Wbbo

Z[j[Yj ;DLi b[feh[ cWha[j_d]( Zhk]i m_jh bem ;O= lWbk[i (_*[*( bWh][

][dec_Y Z_ijWdY[ fhec W y][d[j_YWbbo _Z[Wbz Zhk]% ihekbZ b[ j[ij[Z _d

bWh][h fefkbWj_ed jhWd Zhk]i m_jh h_]h ;O= lWbk[i*

=ecfkjWj_ed ef jh[ D iYeh[i YedZkYj[Z _d jh[ fh[i[dj ijkZo _i

ikbj[Yj je iec[ b_c_jWj_edi( fWhj_Wbbo Zk[ je jh[ _cf[hf[Yj ademb[Z][

Wbekj Zhk] JE+JD WdZ jh[ [ff[Yji ef dediodedoceki YeZ_d] lWh_Wdji

ed fhej[_d ijhkYjkh[ WdZ fkdYj_ed T1-)11U* ;dejh[h b_c_jWj_ed _i

_dikff_Y_[dj fkbb_Y h[iekhY[i fhel_Z_d] jh[ _dfehcWj_ed ed f[hiedWb

][dec[ i[gk[dY[i ef Z_ff[h[dj [jhd_Y ]hekfi WdZ ijWdZWhZ_p[Z h[fehji

76

ef m_jhZhWmd WdZ fh[YWkj_edWho Zhk]i* Fkhjh[h [nfWdi_ed ef jh[i[

Yh_j_YWb h[iekhY[i mekbZ mWhhWdj jh[ _cfhel[c[dj ef Zhk] iWf[jo

ijhWj[]_[i*

OdfehjkdWj[bo( m[ fekdZ jhWj cWdo Zhk]i [b_]_bb[ feh _dYbki_ed _d

ekh ijkZo bWYa[Z JE+JD _dfehcWj_ed* A_l[d jh[ ikbijWdj_Wb [ff[Yj ef

][dec_Y lWh_Wb_b_jo ed Zhk] h[ifedi[i( ceh[ WYYkhWj[ WdZ

Yecfh[h[di_l[ JE+JD ZWjW ihekbZ b[ WlW_bWbb[ feh fkjkh[ Zhk]

Z[l[befc[dj( ki[( WdZ h[]kbWj_ed* Geh[el[h( dedYeZ_d] h[]_edi ef jh[

hkcWd ][dec[ YedjW_d kf je 44" ef m[Wabo fh[dejof[)WiieY_Wj[Z

lWh_Wdji _Z[dj_f_[Z bo jh[ AQ;M T15U WdZ ?H=ID? (?H=oYbef[Z_W If

DH; ?b[c[dji% T2,U* Nh[ _dj[]hWj_ed ef jh[ YeZ_d] WdZ dedYeZ_d] ][d[

_dfehcWj_ed cWo fkhjh[h _cfhel[ jh[ fh[i[dj iYeh_d] ioij[c*

77

C10CLUS.10

Nh[ ijhed] Yehh[bWj_ed b[jm[[d jh[ fefkbWj_ed Z[b[j[h_ekid[ii iYeh[

(eh ;O=% WdZ fhWhcWY[kj_YWb cWha[j m_jhZhWmWb hWj[ mWi Yedi_ij[djbo

ebi[hl[Z _d Z_ff[h[dj ZWjWbWi[i WdZ b_iji ef Zhk] m_jhZhWmWbi WdZ

fh[YWkj_edi( _dYbkZ_d] OH =edieb_ZWj[Z F_iji( Dhk]<Wda( ?khef[Wd

G[Z_Y_d[i ;][dYo( <[[hi ]k_Z[b_d[i( WdZ OM FD;* Id[ _dj[h[ij_d]

bofheZkYj ef jh[ fh[i[dj ijkZo _i jhWj jh[ fhefei[Z c[jheZ cWo h[iYk[

d[Y[iiWho Zhk]i jhWj hWl[ Wbh[WZo b[[d m_jhZhWmd fhec jh[ cWha[j feh

iWf[jo h[Wiedi( Wbjhek]h _j ihekbZ b[ Z[f[hh[Z kdj_b jh[ ][d[j_Y YWki[ ef

;DLi _d W lkbd[hWbb[ ikbfefkbWj_ed _i Yb[Whbo _Z[dj_f_[Z WdZ

Yehh[ifedZ_d] Z_W]deij_Y j[ij_d] fheY[Zkh[i Z[l[bef[Z*

78

REFERE0CES

-* Iib[h Q* Nh[ Jh_dY_fb[i WdZ JhWYj_Y[ ef G[Z_Y_d[* H[m Reha6

;ffb[jed7 -45.*

.* GW K( Fk ;R* JhWhcWYe][d[j_Yi( fhWhcWYe][dec_Yi( WdZ

_dZ_l_ZkWb_p[Z c[Z_Y_d[* JhWhcWYebe]_YWb L[l* .,--72/(.%60/3)15*

/* Qoiemia_ DE( MmWhjp F* ;Zl[hi[ Zhk] [l[dj ikhl[_bbWdY[ WdZ Zhk]

m_jhZhWmWbi _d jh[ Od_j[Z MjWj[i( -525).,,.6 jh[ _cfehjWdY[ ef

h[fehj_d] ikif[Yj[Z h[WYj_edi* ;hYh Cdj[hd G[Z* .,,17-21(-.%6-/2/)5*

0* FWpWhek D( Jec[hWdp <B( =eh[o JH* CdY_Z[dY[ ef WZl[hi[ Zhk]

h[WYj_edi _d heif_jWb_p[Z fWj_[dji6 W c[jW)WdWboi_i ef fheif[Yj_l[

ijkZ_[i* D;G;* -5547.35(-1%6-.,,)1*

1* Q_ba_died AL* Dhk] c[jWbeb_ic WdZ lWh_Wb_b_jo Wced] fWj_[dji _d

Zhk] h[ifedi[* H[m ?d]b D G[Z* .,,17/1.(.-%6..--).-*

2* FWii[h E?( ;bb[d JD( QeebhWdZb[h MD( B_cc[bij[_d DO( Qebf[ MG(

<eh DB* N_c_d] ef d[m bbWYa ben mWhd_d]i WdZ m_jhZhWmWbi feh

fh[iYh_fj_ed c[Z_YWj_edi* D;G;* .,,.7.43(-3%6..-1).,*

3* H_dWd <( Q[hjh[_c[h ;C* Q_jhZhWm_d] Dhk]i _d jh[ OM P[hiki Ijh[h

=ekdjh_[i* Cdel JhWhc* .,-.7/(/%6-)-.*

79

4* F[nYh_d D* Bem iWf[ Wh[ d[m Zhk]i: GWha[j m_jhZhWmWb ef Zhk]i

Wffhel[Z _d =WdWZW b[jm[[d -55, WdZ .,,5* If[d G[Z_Y_d[*

.,-074(-%6-0)5*

5* Fh_[ZcWd G;( QeeZYeYa D( Fkcfa_d GG( Mhkh[d D?( BWii ;?(

Nhecfied FD* Nh[ iWf[jo ef d[mbo Wffhel[Z c[Z_Y_d[i6 Ze h[Y[dj

cWha[j h[celWbi c[Wd jh[h[ _i W fhebb[c: D;G; -5557.4-6-3.4)/0*

-,* <Waa[ IG( GWdeYYh_W G( Z[ ;bWje F( EW_j_d EC( FWiW]dW F* Dhk]

iWf[jo Z_iYedj_dkWj_edi _d jh[ Od_j[Z E_d]Zec( jh[ Od_j[Z MjWj[i( WdZ

MfW_d fhec -530 jhhek]h -55/6 W h[]kbWjeho f[hif[Yj_l[* =b_d

JhWhcWYeb Nh[h -5517146-,4)-3*

--* D_[ff[ J;( ?bhWh_c M( GWhj_d LG( Dkd_ J* F[iiedi fhec jh[

m_jhZhWmWb ef hef[Yen_b* <GD .,,07/.56423)4*

-.* O*H* D[fWhjc[dj ef ?Yedec_Y WdZ MeY_Wb ;ffW_hi* =edieb_ZWj[Z F_ij

ef JheZkYji Qhei[ =edikcfj_ed WdZ+eh MWb[ BWl[ <[[d <Wdd[Z(

Q_jhZhWmd( M[l[h[bo L[ijh_Yj[Z eh dej ;ffhel[Z bo Ael[hdc[dji6

JhWhcWY[kj_YWbi ?_]hjh Ciik[* H[m Reha6 Od_j[Z HWj_edi Jkbb_YWj_ed7

.,,/*

-/* SWd][h OG* JhWhcWYe][d[j_Yi ) YhWbb[d][i WdZ effehjkd_j_[i

80

Wh[WZ* Fhedj_[hi _d fhWhcWYebe]o .,-,( -6--.*-0* GWb_[fWWhZ( GWhY(

[j Wb* JhWhcWYe][d[j_Yi _d jh[ [lWbkWj_ed ef d[m Zhk]i6 W ckbj_h[]_edWb

h[]kbWjeho f[hif[Yj_l[* HWj L[l Dhk] D_iY -.*. (.,-/%6 -,/)--1*

-1* IdWafeoW CD( B[d[]hWd =D( ;hedied DE* D[bWoi _d jh[ feij)

cWha[j_d] m_jhZhWmWb ef Zhk]i je mh_Yh Z[Wjhi hWl[ b[[d Wjjh_bkj[Z6 W

ioij[cWj_Y _dl[ij_]Wj_ed WdZ WdWboi_i* <G= G[Z .,-17-/6.2*

-2* Ahebh_Wb CG( LWjakcWh MP* GWdW][c[dj ef jhWb_Zec_Z[ jen_Y_jo* D

Mkffehj IdYeb .,,/7-6-50).,1*

-3* D_[ff[ J;( ?bhWh_c M( GWhj_d LG( Dkd_ J* F[iiedi fhec jh[

m_jhZhWmWb ef hef[Yen_b* <GD .,,07/.56423)4*

-4* Fkd] G( Nhehdjed ;( Gob[Ya E( Qk DB( BehdbkYab[ E( Gkd_p ?*

?lWbkWj_ed ef jh[ YhWhWYj[h_ij_Yi ef iWf[jo m_jhZhWmWb ef fh[iYh_fj_ed

Zhk]i fhec mehbZm_Z[ fhWhcWY[kj_YWb cWha[ji)-52, je -555&* Dhk]

Cdf D .,,-7/16.5/)/-3*

-5* H_dWd <( Q[hjh[_c[h ;C* Q_jhZhWm_d] Zhk]i _d jh[ OM l[hiki ejh[h

Yekdjh_[i* Od_l[hi_jo ef G_dd[iejW( =ebb[][ ef JhWhcWYo* L[jh_[l[Z

fhec jh[ Od_l[hi_jo ef G_dd[iejW D_]_jWb =edi[hlWdYo(

hjjf6++fkhb*kcd*[Zk+-/3---* .,-.*T;YY[ii[Z ed 5( Dkd[( .,-0U

81

.,* GWakYh LQ( Mh_ L* =ecfWh_ied ef Zhk] WffhelWbi _d [khef[

l[hiki jh[ Od_j[Z MjWj[i6 ;d WdWboi_i ef Z_iYh[fWdY_[i b[jm[[d Zhk]

fheZkYji h[l_[m[Z bo ?G; WdZ FD;* Nh[h Cddel L[]kb MY_

.,-07046/2.)2*

.-* ;bhWhWc D( DWl_i =* ; YecfWhWj_l[ WdWboi_i ef Zhk] iWf[jo

m_jhZhWmWbi _d jh[ OE WdZ jh[ OM (-53-)-55.%6 _cfb_YWj_edi feh

Ykhh[dj h[]kbWjeho jh_da_d] WdZ feb_Yo* MeY MY_ G[Z .,,172-644-)5.*

..* =ebecW JG( MYhk[c_[ GD( Nh_f_h A( A_d_ L( B[h_d]i L(

B_ff_ib[o) =en D( GWppW]b_W A( A_Wgk_dje =( =ehhWe A( J[Z[hi[d F*

=ecb_d_d] [b[Yjhed_Y h[WbjhYWh[ ZWjWbWi[i _d ?khef[ je Wbbem feh

bWh][)iYWb[ Zhk] iWf[jo ced_jeh_d]6 jh[ ?O ;DL Jhej[Yj*

JhWhcWYe[f_Z[c_eb Dhk] MWf .,--7.,6-)--*

./* <[hhcWd L?( <[dd[h DM( <hemd DM( GY=b[bbWd G( QeeZYeYa D(

JbWjj L* D[l[bef_d] jh[ M[dj_d[b Moij[cxW dWj_edWb h[iekhY[ feh

[l_Z[dY[ Z[l[befc[dj* H?DG .,--7/206054)5*

.0* OH( =edieb_ZWj[Z F_ij ef JheZkYji Qhei[ =edikcfj_ed WdZ+eh

MWb[ BWl[ <[[d <Wdd[Z( Q_jhZhWmd( M[l[h[bo L[ijh_Yj[Z eh dej

;ffhel[Z bo Ael[hdc[dji6 JhWhcWY[kj_YWbi* (D[fWhjc[dj ef

82

?Yedec_Yi WdZ MeY_Wb ;ffW_hi( .,,0%*









.3* I?=D* I?=D MjWj_ij_Yi* ;lW_bWbb[ Wj hjjf6++mmm*e[YZ)

_b_bhWho*eh]+ijWj_ij_Yi TWYY[ii[Z ed - D[Y[cb[h .,-0U*

.4* QehbZ <Wda* QehbZ D[l[befc[dj CdZ_YWjehi .,-,* ;lW_bWbb[ Wj

hjjf6++ZWjW*mehbZbWda*eh]+_dZ_YWjeh TWYY[ii[Z ed -1 F[bkbWho .,-1U*

.5* MB HWc( RM E_c( RM Dk* ; ijkZo ef Yecfei_j[ _dZ[n ed h[Wbjh

WdZ m[bfWh[* Eeh[W Cdij_jkj[ feh B[Wbjh WdZ MeY_Wb ;ffW_hi6 M[ekb 7.,-.*

/,* ED F_c( MG F_c( EB M[e* ;dWboi_i ef jh[ I?=D B[Wbjh DWjW

.,-.* L[i[WhYh Cdij_jkj[ feh B[WbjhYWh[ Jeb_Yo6 M[ekb7 .,-/*

/-* E_c F( E_c D;( E_c M* ; ]k_Z[ feh jh[ kj_b_pWj_ed ef B[Wbjh

83

CdikhWdY[ L[l_[m WdZ ;ii[iic[dj M[hl_Y[ HWj_edWb JWj_[dj MWcfb[i*

?f_Z[c_eb B[Wbjh .,-07/26[.,-0,,4*

/.* N[Wc L=* L6 ; bWd]kW][ WdZ [dl_hedc[dj feh ijWj_ij_YWb

Yecfkj_d]* P_[ddW( ;kijh_W* .,-.*

//* I?=D* F_f[ [nf[YjWdYo Wj b_hjh WdZ ADJ f[h YWf_jW( .,-- (eh

d[Wh[ij o[Wh%* B[Wbjh Wj W AbWdY[* I?=D Jkbb_ih_d]( JWh_i7 .,-/*

/0* RWd] M( EhWd] R)B( BWhf[h M( DWl[o Mc_jh A( F[ed D;( FodYh D*

OdZ[hijWdZ_d] jh[ LWf_Z CdYh[Wi[ _d F_f[ ?nf[YjWdYo _d Mekjh Eeh[W*

;c D Jkb B[Wbjh .,-,7-,,6452)5,/*

/1* BWbb Q( DehWd =( D[][dhWhZj F( Mh[fWhZ D* Cbb_Y_j If_Wj[ ;bki[*

Cd6 DWc_ied DN( <h[cWd DA( G[WihWc ;L( ;bb[od[ A( =bW[ied G(

?lWdi D<( [j Wb*( [Z_jehi* D_i[Wi[ =edjheb Jh_eh_j_[i _d D[l[bef_d]

=ekdjh_[i* .dZ [Z* QWih_d]jed D=7 .,,2*

/2* Eeh[W FeeZ WdZ Dhk] ;Zc_d_ijhWj_ed( D[Wh B[WbjhYWh[ Jhef[ii_edWb

F[jj[h (;fhej_d_d%** .,,4*

hjjf6++Zhk]*cfZi*]e*ah+hjcb+Whj_Yb[F_da<eZo*jif:fVc[dkCZ9,2,.&fVi

kbVc[dkCZ9,2,.,-&fVde9---

/3* =he_ D( =he_ G( Ee ;* =khh[dj ijWjki ef fhWhcWY[kj_YWb iWf[jo

84

cWdW][c[dj _d Eeh[W* D Eeh[Wd G[Z ;iieY .,-.71164.3)/0*

/4* LWjWdWm_j_jhWi_d M( QedZ[cW][]d[hk ?* "?ff[Yj_l[ Zhk] h[]kbWj_ed*"

; ckbj_Yekdjho ijkZo* A[d[lW( Mm_jp[hbWdZ6 QehbZ B[Wbjh

Ih]Wd_pWj_ed .,,.*

/5* MhWh LL* =Wd fhWhcWYe][d[j_Yi h[bf h[iYk[ Zhk]i m_jhZhWmd fhec

jh[ cWha[j: JhWhcWYe][dec_Yi* .,,273(2%6445)5,4*

Ze_6-,*..-3+-02..0-2*3*2*445*

0,* DW]]kcWbb_ DMP( GWhj_d CA* ;h[ JhWhcWY[kj_YWb GWha[j

Q_jhZhWmWbi Jh[l[djWbb[: ; Jh[b_c_dWho ;dWboi_i* Dhk] Cdf D*

.,-.702(2%6250)3,,*

0-* QWd] F( GYF[eZ BF( Q[_dih_bbekc LG* A[dec_Yi WdZ Zhk]

h[ifedi[* H[m ?d]b D G[Z* .,--7/20(-.%6--00w1/*

0.* FD;* NWbb[ ef fhWhcWYe][dec_Y b_ecWha[hi _d Zhk] bWb[b_d]*

hjjf6++mmm*fZW*]el+Dhk]i+MY_[dY[L[i[WhYh+L[i[WhYh;h[Wi+JhWhcWYe

][d[j_Yi+kYc,4//34*hjc( ;YY[ii[Z M[fj[cb[h 4( .,-1*

0/* GWY;hjhkh DA( <WbWikbhWcWd_Wd M( FhWda_ih ;( BkWd] H( Gehh_i

D( QWbj[h E [j Wb* ; ioij[cWj_Y ikhl[o ef beii)ef)fkdYj_ed lWh_Wdji _d

hkcWd fhej[_d)YeZ_d] ][d[i* MY_[dY[* .,-.7//1(2,3,%64./)4*

85

00* LeZ[d DG( A[eh][ Dh ;F* Nh[ ][d[j_Y bWi_i ef lWh_Wb_b_jo _d Zhk]

h[ifedi[i* HWj L[l Dhk] D_iYel* .,,.7-(-%6/3)00*

01* B[_Wj ;( Aheii =J( Ehkchebp BG* L[fh[i[djWj_ed ef jh[ [bZ[hbo(

mec[d( WdZ c_deh_j_[i _d h[Whj fW_bkh[ Yb_d_YWb jh_Wbi* ;hYh Cdj[hd G[Z*

.,,.7-2.(-1%*

02* -,,, A[dec[i Jhej[Yj =ediehj_kc( ;b[YWi_i AL( ;kjed ;( [j Wb*

;d _dj[]hWj[Z cWf ef ][d[j_Y lWh_Wj_ed fhec -(,5. hkcWd ][dec[i*

HWjkh[* .,-.705-(30..%612)21*

03* Q_ihWhj DM( Eden =( Ake ;=( [j Wb* Dhk]<Wda6 W Yecfh[h[di_l[

h[iekhY[ feh _d i_b_Ye Zhk] Z_iYel[ho WdZ [nfbehWj_ed* HkYb[_Y ;Y_Zi

L[i* .,,27/0(DWjWbWi[ _iik[%6D224)23.*

04* -,,, A[dec[i Jhej[Yj =ediehj_kc( ;b[YWi_i AL( ;kjed ;( [j Wb*

;d _dj[]hWj[Z cWf ef ][d[j_Y lWh_Wj_ed fhec -(,5. hkcWd ][dec[i*

HWjkh[* .,-.705-(30..%612)21*

05* ?khef[Wd G[Z_Y_d[i ;][dYo6 ?G;+G<+255./+.,-,);ddkWb

h[fehj ef jh[ ?khef[Wd G[Z_Y_d[i ;][dYo .,,5*

hjjf6++mmm*[cW*[khefW*[k+ZeYi+[dVA<+ZeYkc[djVb_bhWho+;ddkWbVh[

fehj+.,-,+,1+Q=1,,,5,3-.*fZf( ;YY[ii[Z M[fj[cb[h -4( .,-1*

86

1,* <o jh[ ;c[h_YWd A[h_Wjh_Yi MeY_[jo <[[hi =h_j[h_W OfZWj[ ?nf[hj J*

;c[h_YWd A[h_Wjh_Yi MeY_[jo .,-1 OfZWj[Z <[[hi =h_j[h_W feh Jej[dj_Wbbo

CdWffhefh_Wj[ G[Z_YWj_ed Oi[ _d IbZ[h ;Zkbji* D ;c A[h_Wjh MeY* .,-1*

1-* EkcWh J( B[d_aeff M( H] J=* Jh[Z_Yj_d] jh[ [ff[Yji ef YeZ_d] ded)

iodedoceki lWh_Wdji ed fhej[_d fkdYj_ed ki_d] jh[ MCFN Wb]eh_jhc* HWj

JhejeY* .,,570(3%6-,3/)4-*

1.* LWc[diao P( <eha J( MkdoW[l M* BkcWd ded)iodedoceki MHJi6

i[hl[h WdZ ikhl[o* HkYb[_Y ;Y_Zi L[i* .,,.7/,(-3%6/450)5,,*

1/* L[lW <( ;dj_f_d R( MWdZ[h =* D[j[hc_dWdji ef fhej[_d fkdYj_ed

h[l[Wb[Z bo Yecb_dWjeh_Wb [djhefo efj_c_pWj_ed* A[dec[ <_eb*

.,,374(--%6L./.*

10* E_hYh[h G( Q_jj[d DG( DW_d J( [j Wb( ; ][d[hWb fhWc[meha feh

[ij_cWj_d] jh[ h[bWj_l[ fWjhe][d_Y_jo ef hkcWd ][d[j_Y lWh_Wdji* HWj

A[d[j* .,-0 GWh702(/%6/-,)/-1*

11* Aedp b[p)J h[p ;( F f[p)<_]Wi H* Ccfhel_d] jh[ Wii[iic[dj ef jh[

ekjYec[ ef dediodedoceki MHPi m_jh W Yedi[diki Z[b[j[h_ekid[ii

iYeh[( =edZ[b* ;c D Bkc A[d[j* .,--744(0%600,)5*

12* Mjhec <F* Bem jh[ OM Zhk] iWf[jo ioij[c ihekbZ b[ YhWd][Z*

87

D;G;* .,,27.51(-3%6.,3.)1*

13* <[hb_d D;( AbWii[h M=( ?bb[db[h] MM* ;Zl[hi[ [l[dj Z[j[Yj_ed _d

Zhk] Z[l[befc[dj6 h[Yecc[dZWj_edi WdZ ebb_]Wj_edi b[oedZ fhWi[ /*

;c D Jkbb_Y B[Wbjh* .,,4( 54(4%6-/22)-/3-*

14* ;b[hd[jho D( QeeZYeYa D( F[iae F* JhWhcWYebe]_YWb c[YhWd_ic)

bWi[Z Zhk] iWf[jo Wii[iic[dj WdZ fh[Z_Yj_ed* =b_d JhWhcWYeb Nh[h*

.,--745(2%635/)3*

15* MYhWkb G;( <eob[ ;J( EkdZWj[ ;( <Wjpe]bek M( MdoZ[h G* F_da_d]

Z_i[Wi[ WiieY_Wj_edi m_jh h[]kbWjeho _dfehcWj_ed _d jh[ hkcWd ][dec[*

A[dec[ L[i* .,-.7..(5%6-304)15*

2,* =ediehj_kc ?J* Nh[ ?H=ID? (?H=oYbef[Z_W ef DH; [b[c[dji%

fhej[Yj* MY_[dY[* .,,07/,2(1252%62/2)0,*

88

PS 초록

VR6 많은 환자에서 임상적인 효용을 입증 받은 약이라 할지라도 종종

다른 환자들에서 –료에 실패하거나 사망을 포함한 심각한 γ작용을

일으— 수 있다* 이러한 약물 반응의 개인차는 임상 현장( 약물 개발 단계와

의약품 규제 단계 모두에서 주요 해결 과제이다* α 연구는 약물 안전성에

중요한 결정 요인인 국가별 약물 규제관련 요인을 δ석해보고( 개인

유전체 염기서열 변이 δ석을 ’해 인구 집단의 약물 유전학적 안전성이

실제 약물의 위험성을 예측할 수 있는지 확인하고자 하였다*

방U: 우선 거시적으로 국가별 약물 안전성 평가 및 그에 따른 규제의

차이를 나타내는 지표로서 국가별 퇴출 및 제한 약물의 수를 OH

보고서에서 리뷰하여 조사하였다* 또한 이러한 약물 규제와 연관된 국가별

경제( 사회( 보건( 복지 및 건강 지표들을 알아보기 위해 QehbZ <Wda 와

I?=D 지표 조사를 이용하였다* 다른 한편으로( 개인 유전체 변이의

변이성의 정도가 인구 집단 약물 안전성에 반영되는지 확인하기 위해

.1,0 명의 건강한 개인으로 이루어진 -,,, A[dec[i Jhej[Yj 로γ터 개인

유전체 데이터를 δ석하여 약물의 약동학 및 약력학에 영향을 미–는 모든

단백질 손상 변이의 총합을 δ석하였다* 그리고 각 약물마다 약물 유전

89

안전성 점수를 산출하여 이를 위험 약물 리스트 (퇴출 혹은 사용 주의 약물%

와 비교하여 위험한 약물군과 그렇지 않은 약물군 사이에 인구집단 약물

유전 안전성 점수가 어떻게 다른지 확인하였다* 이때 사용된 위험 약물

리스트는 퇴출)OH 보고서( ?G;( Dhk]<Wda 에서 퇴출 약물로 표시한

경우 혹은 사용 주의) <[[hi Yh_j[h_W 혹은 OM FD; fhWhcWYe][dec_Yi

라벨 약물이었다* 연구에 포함된 전체 약물은 Dhk]<Wda

데이터베이스로γ터 약물 관련 약동학+약력학 유전자가 최소 1 개 이상

연결되어 있는 약물 -,0- 개였다*

NO: 국가별 약물 규제에 관해 가장 포±적인 정보를 제공하는 OH

=edieb_ZWj[Z b_ij ef fheZkYj 를 ’해 -51, 년γ터 .,-, 년까지 기간 동안(

50 개 나라로γ터 한번이라도 퇴출된 /2. 개 약물과 .04 개의 제한 약물을

확인하였다* 국가별 퇴출 약물과 제한 약물 수의 평균은 각각 -.*,. r

-/*,3 ( 1*33 r 4*25 (c[Wd r MD%였다* 국가별 사용 규제 (퇴출 및 제한%

약물의 수는 ADJ( ADJ f[h YWf_jW( ADJ f[h hekh meha[Z( B[Wbjh

[nf[dZ_jkh[ f[h ADJ( [bZ[hbo fefkbWj_ed hWj[ 와 유의하게 양의

상관관계를 보였고( ekj)ef)feYa[j fWoc[dj 와는 유의하게 음의

상관관계를 보였다* 또한 약물 제한 수의 경우 약물 γ작용으로 인한

사망률과 유의한 양의 상관관계를 보였다*

90

한편 집단 유전체 δ석을 ’해 구한 약물 유전학적 안전성 점수는 퇴출+

제한 약물 모두에서 유의하게 (J 8,*,,-% 낮았다* 약물 손상 점수가 낮아질

수록( 즉 약물 관련 손상 변이가 많을 수록( 퇴출 약물 혹은 <[[hi Yh_j[h_W

나 FD; 약물 유전학 데이터베이스에 속한 약물의 비율이 유의하게

증가하였다* (J 8,*,1% 이러한 경향은 나눠서 ?G;( OH( Dhk]<Wda 의

데이터베이스의 약물 리스트를 개별적으로 δ석하거나 혹은 조합해서

δ석해도 모두 같은 경향을 보였다* NR: 국가별로 규제 대상 약물 수와

프로파일은 매우 다양했지만( 규제 약물의 수와 ADJ 등 경제지표 및 국가

의료비 지출이 비례하고 개인 의료비 지출 수준과 반비례함을 β 때(

적절한 약물 규제는 국가 의료시스‘의 수준을 반영한다고 β 수 있다*

또한 인구집단 유전 변이 δ석을 ’해 위험 약물 및 시장 퇴출 약물을 예측

할 수 있었다* 각 개인과 민족의 약물 관련 유전자의 손상 프로파일의

변동성을 ~안할 때( 우리는 이를 이용해 모든 사람들의 위한 위험한

약물의 조합을 추정할 수 있다* 특정 약물의 경우 사람 사이 변이가 적은

동시에 거의 모든 사람에게 위험한 것으로 나타난 약물도 있었다* JE+JD

유전자와 약물의 상관관계가 좀 더 밝혀지고 누적된다면( 이 예측 모델은

더욱 정확해질 것이다* 약물 γ작용의 개인 차이와 인종간 차이를

91

고려했을 때 국가별 약물 γ작용 ~시시스‘의 활성화와 약물 γ작용 및

규제 정보의 교류가 더욱 활발해져야 할 것이다*

)))))))))))))))))))))))))))))))))))))

주요어 6 약물 γ작용( 유전 변이( 유전자( 약물 유전학( 위험 약물 퇴출(

약물 퇴출과 철수( 국가별 사회경제적요인평가

학 번 6 .,-/)/--34

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