2.6.3 薬理試験概要表KMD＊132 1/4.2.1.3.1 Influence on erythrocyte morphology Blood In-vit ro Schering AG A263 KM E＊57 1/4.2.1.3.2 CNS Mouse i.v. Schering AG AB40 ZNF＊0641

2.6.3 薬理試験概要表

Nihon Schering K.K.

2.6.3　　薬理試験概要表

24

2.6.3.1 薬理試験：　一覧表

Nihon Schering K.K.

2.6.3.1　　薬理試験：　一覧表

25

2.6.3.1 薬理試験：一覧表

Page 1 of 3

Nihon Schering K.K.

＊新薬承認情報提供時に置き換えた。


Test Article Gadoxetate Sodium

Location Type of Study Test System Method of Admin. Testing Facility Report No. Study No. Vol./ Section

Primary Pharmacodynamics Relaxivity measurements Water, plasma

In-vitro

Schering AG 9627 A212

KMＤ＊040,KMＤ＊111,KMＤ＊305,KMＥ＊208

1/4.2.1.1.1 1/4.2.1.1.2

MR Imaging Rats i.v. Schering AG 9947 KMＤ＊296 1/4.2.1.1.3 Comparison between S- and R- enantiomer Water, plasma

In-vitro

Schering AG 9936 KMＤ＊305,KMＥ＊068

1/4.2.1.1.4

副次的薬理試験

-- -- -- -- -- -- --

安全性薬理試験

Biochemical pharmacology Buffer In-vitro Schering AG 9863 KMＣ＊394, KMＤ＊132

1/4.2.1.3.1

Influence on erythrocyte morphology Blood In-vitro Schering AG A263 KMＥ＊57 1/4.2.1.3.2 CNS Mouse i.v. Schering AG AB40 ZNＦ＊0641 1/4.2.1.3.3 Rat Intracisternal Schering AG A238 KMＥ＊068 1/4.2.1.3.4 Mouse i.v. Nihon Schering KK A00165 Ｇ＊216 1/4.2.1.3.5 Mouse i.v. Nihon Schering KK A00176 Ｇ＊94213 1/4.2.1.3.6

26


Page 2 of 3

Nihon Schering K.K.


Mouse i.v. Nihon Schering KK A00177 Ｇ＊222 1/4.2.1.3.7 Mouse i.v. Nihon Schering KK A00178 Ｇ＊212 1/4.2.1.3.8 Mouse i.v. Nihon Schering KK A00179 Ｇ＊211 1/4.2.1.3.9 Rat i.v. Nihon Schering KK A00180 Ｇ＊217 1/4.2.1.3.10 Guinea pig In-vitro Nihon Schering KK A00181 Ｇ＊221 1/4.2.1.3.11 Cardiovascular system HERG channel In-vitro A08413 GEP_SCH_

177_00_00_02

1/4.2.1.3.12

Papillary muscle In-vitro Schering AG A08301 SP20Ｏ＊

0018 1/4.2.1.3.13

Dog i.v. Berlex Labs A879 324-Ａ＊-1051/4.2.1.3.14 Dog i.v. A08354 DERA1004 1/4.2.1.3.15 Respiratory function Rabbit i.v. Nihon Schering KK A02938 SPJ20Ｍ＊08 1/4.2.1.3.16 Renal function Rat i.v. Nihon Schering KK A02741 SPJ20Ｍ＊09 1/4.2.1.3.17 Rat i.v. Schering AG A878 NIＦ＊0002 1/4.2.1.3.18 Rabbit i.v. Schering AG A264 KMＣ＊227 1/4.2.1.3.19 Mouse i.v. Nihon Schering KK A00182 Ｇ＊343 1/4.2.1.3.20 Blood coagulation Rat i.v. Schering AG A262 KMＥ＊250 1/4.2.1.3.21 Rat i.v. Schering AG AW19 Ｈ＊504

Ｈ＊603 1/4.2.1.3.22

Rat i.v. Schering AG AW23 Ｈ＊622 1/4.2.1.3.23 General Rat i.v. Schering AG AA01 KMＧ＊026 1/4.2.1.3.24 Mouse i.v. Schering AG AA02 KMＦ＊415 1/4.2.1.3.25

27


Page 3 of 3

Nihon Schering K.K.

2.6.3.1 薬理試験：一覧表（続き）

Test Article Gadoxetate Sodium

Location Type of Study Test System Method of Admin. Testing Facility Report No. Study No. Vol./ Section


Pharmacodynamic Drug Interactions

MR imaging Rats i.v. Schering AG * KMＨ＊457,KMＨ＊563

1/4.2.1.4.1

*: Submitted for publication

28

2.6.3.2 効力を裏付ける試験

Nihon Schering K.K.

2.6.3.2　　効力を裏付ける試験

29


Page 1 of 2

Nihon Schering K.K.

2.6.3.2 効力を裏付ける試験 – in vitro-

Test Article： Gadoxetate Sodium Report No. Study No. Location Relaxivity Measurement Medium Field Strength

〔T〕 Concentration tested

〔mmol/L〕 T1

[L/mmol/sec]T2

〔L/mmol/sec〕Temperature

〔℃〕 Vol./Section

Water 0.47

0-1

4.9±0.2

5.7±0.2 40 9627 KMＤ＊040KMＤ＊111KMＤ＊305

1/4.2.1.1.1

plasma 0.47

0-1

8.2±0.5

8.6±0.6 40 9627 KMＤ＊040KMＤ＊111KMＤ＊305

1/4.2.1.1.1

water 2.0 0-1 6.6±0.0 7.7±0.0 RT A212 KMＥ＊208 1/4.2.1.1.2 plasma 2.0 0-1 8.1±0.1 11.6±0.1 RT A212 KMＥ＊208 1/4.2.1.1.2

RT= room temperature (≈ 21-25℃)


30


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Nihon Schering K.K.

2.6.3.2 効力を裏付ける試験（続き）

Test Article： Gadoxetate Sodium Location Vol./Section: 1/4.2.1.1.3 Report No. Study No. Dose finding imaging study, liver tumors 9947 KMＤ＊296 Species: Rat, 180-225g Gender / no of animals per dose: female, 3

MRI：SIS-85，Sisco,2T

Sequence: TR＝400msec,TE=15msec

Imaging time: 5min Method of administration: i.v.

Dose 〔mmol/kg〕

Contrast 5min Liver to tumor

Contrast 30min Liver to tumor

0 - - 0.01 + - 0.02 ++ - 0.03 +++ ++ 0.06 + ++


31

2.6.3.3 副次的薬理試験

Nihon Schering K.K.

2.6.3.3　　副次的薬理試験

32


Page 1 of 1

Nihon Schering K.K.


該当なし．

33

2.6.3.4 安全性薬理試験

Nihon Schering K.K.

2.6.3.4　　安全性薬理試験

34


Page 1 of 6

Nihon Schering K.K.



Test Article: Gadoxetate Sodium Organ Systems Evaluated

Species/ Strain Method of Admin.

Doses (mmol/kg)a

Gender and No. per Group

Noteworthy Findings GLP Report No. (Study No.)

Location Vol./ Section

補体活性化 Dog serum In-vitro 0-384.6

mmol/L

Not applicable I50: 130mmol/L no 9863(KMC＊394) 1/4.2.1.3.1

溶血阻害 Dog serum In-vitro 0-65

mmol/L

Not applicable I50: 9.5mmol/L no 9863(KMC＊394) 1/4.2.1.3.1

リゾチーム抑制 - In-vitro 0-142.9

mmol/L

Not applicable I50: 39mmol/L no 9863(KMD＊132) 1/4.2.1.3.1

ヒスタミン遊離 Rat mast cell In-vitro 0-250

mmol/L

Not applicable No effect no 9863(KMD＊132) 1/4.2.1.3.1

赤血球形態 Dog blood In-vitro 14-71

mmol/L

Not applicable No effect no A263(KME＊57) 1/4.2.1.3.2

中枢神経系 Mice/

NMRI

i.v. 0.0086-1.1 n=3 (M and F) No neurotropic

activity in Irwin

test, no toxic or

lethal findings up

to the maximum dose

no AB40 (ZNF＊0641) 1/4.2.1.3.3

Rat/

Han-Wist

Intracister-

nal

0.016-0.072 M/ 5, F/ 5, n=10 Both enantiomers

elicit no

statistically

different neural

tolerance

no A238 (KME＊068) 1/4.2.1.3.4

a 特にことわりがない限り単回投与．

35


Page 2 of 6

Nihon Schering K.K.

2.6.3.4 安全性薬理試験（続き）



Doses (mmol/kg)a


Noteworthy Findings

GLP Report No. (Study No.)



Mice/ICR i.v. 0.1-1.0 M7 No effects on

acetic acid-induced

writhing up to

1mmol/kg

no A00165(G＊216) 1/4.2.1.3.5


maximum

electroshock

seisure up to

1mmol/kg

no A00176(G＊213) 1/4.2.1.3.6


pentetrazole-

induced convulsion

up to 1mmol/kg

no A00177(G＊222) 1/4.2.1.3.7

Mice/ICR i.v. 0.1-1.0 M5 No hypnotic and

convulsive effects

up to 1mmol/kg

no A00179(G＊211) 1/4.2.1.3.9

Rats/Wist i.v. 0.1-1.0 M5 No effect on

spontaneous

motility up to

1mmol/kg

no A00180(G＊217) 1/4.2.1.3.10

Mice/ICR i.v. 0.1-1.0 M7 No effect on

hexobarbital-

induced hypnosis up

to 1mmol/kg

no A00178(G＊212) 1/4.2.1.3.8

36


Page 3 of 6

Nihon Schering K.K.




Doses (mmol/kg)a


Noteworthy Findings




自律神経系平滑筋 Guinea pigs/

Hartley

In-vitro 0.2-5.0

mmol/L

Not applicable No effects on Ach-,

Hist-, 5-HT- and

Ba-induced

contraction of

isolated ileum up

to 5.0mmol/L

no A00181(G＊221) 1/4.2.1.3.11

循環器 CHO cells In-vitro 1– 100

mmol/L

Not applicable Dose dependent

inhibition of the

human HERG

potassium channel

with an IC50 of

about 30mmol/L

no A08413

(GEP_SCH_177_00_

00_02)

1/4.2.1.3.12

Guinea pig/

Ducan-Hartley

In-vitro 0.1-10

mmol/L

Not applicable No effects on

action potential

duration(APD) up to

10mmol/L

hyperpolarization

of – 5mV at

10mmol/L

A08301 (SP20M＊

0018)

1/4.2.1.3.13

Dog/

mongrel

i.v. 0.05-0.25 Sex unselected,

n=6

No hemodynamic

side-effects up to

doses of 0.25

mmol/kg

no A879 (324-A＊-

105

Berlex)

1/4.2.1.3.14

37


Page 4 of 6

Nihon Schering K.K.




Doses (mmol/kg)a


Noteworthy Findings




Dog/

Beagle

i.v. 0.025-0.5 F/ 2, M/ 2 No hemodynamic

side-effects up to

doses of 0.5

mmol/kg

yes A08354

(DERA1004)

1/4.2.1.3.15

呼吸器 Rabbit/

White New

Zealand

i.v. 0.1-1.0 M/ 8 1.0mmol/kg

increases

respiratory

frequency and

decreases tidal

volume and

resistance but does

not cause

esophageal pressure

difference,

compliance, blood

pressure and heart

rate. The lower

doses do not show

any effect on

respiratory

function, blood

pressure and heart

rate

No A02938

(SPJ20008)

1/4.2.1.3.16

38


Page 5 of 6

Nihon Schering K.K.




Doses (mmol/kg)a


Noteworthy Findings




腎 Rat/Wist i.v. 0.1-1.0 M/ 5 per dose No effect on renal

excretory function

(urine volume and

urinary

electrolytes,

creatinine

clearance and BUN

no A02741

(SPJ200009

NSKK)

1/4.2.1.3.17

Rat/Wist i.v. 0.33-1.0 M/ 8 per dose No effect on

urinary volume,

protein and

potassium

excretion. Highest

dose caused some

temporary elevation

of sodium excretion

no A878 (NIF＊0002) 1/4.2.1.3.18

Rabbits/ White

New Zealand

i.v. 1.0 F/ 2, M/3, 5 per

dose

Gadoxetate exhibits

no renal toxicity

no A264 (KMC＊227) 1/4.2.1.3.19

消化器系 Mice/ICR i.v. 1.0 M/8 per dose No effect on

gastrointestinal

transit

no A00182(G＊343) 1/4.2.1.3.20

血液凝固 Rat /Hans-Wist i.v. 0.1-0.5 F/ 2, M/ 3 Only at the very

high dose of

0.5mmol/kg a slight

prolongation of the

bleeding time was

recorded

no A262 (KME＊250) 1/4.2.1.3.21

39


Page 6 of 6

Nihon Schering K.K.




Doses (mmol/kg)a


Noteworthy Findings




肝 Rat/SD i.v. 0.3 F/5 No effect on liver

function

no AW19(H＊504,

H＊603)

1/4.2.1.3.22

Rat/SD i.v. 0.3 F/5-6 No effect on liver

function

no AW23(H＊622) 1/4.2.1.3.23

急性毒性 Rat/Han-Wist i.v. 2.5-15.0 F/6, M/6, 12 per

dose

LD50 in male: 5.3

mmol/kg, in female:

8.5mmol/kg, The

death occurred

within the first

three hours

no AA01(KMG＊026) 1/4.2.1.3.24

Mice/NMRI i.v. 0.05-10 of

chelates

Sex unselected,

3-6 per dose

LD50 of chelates:

ZK155141 = (EOB-

DTPA) ≈0.1 ZK 43649 =(DTPA)

≈0.1 ZK155116 =(Ca-EOB-

DTPA) ≈1

no AA02(KMF＊415) 1/4.2.1.3.25

40

2.6.3.5 薬力学的薬物相互作用

Nihon Schering K.K.

2.6.3.5　　薬力学的薬物相互作用

41

2.6.3.5 薬力学的薬物相互作用試験

Page 1 of 2

Nihon Schering K.K.



Test Article： Gadoxetate Sodium Location Report No. Study No. Vol./ Section 1), 2) KMＨ＊457,

KMＨ＊563 1/4.2.1.4.1

Species: Rat, Wistar Han Gender/no of animals per dose: Female, 3 MRI: SIS-Sisco, 2T Sequence: TR=50msec, TE=3.7msec, α=80° Imaging time: 0-30 min post injection Method of administration: intravenous Dose: 25μmol/kg Drug (generic name) Dose 〔mg/kg〕 Relative Liver Enhancement Rifampicin, i.v. 40 Strong inhibition of contrast enhancement Prednisolon, i.v. 40 Slightly longer lasting enhancement than volume control Cisplatin, i.v. 2 Slightly longer lasting enhancement than volume control Doxorubicin, i.v. 7 Slightly longer lasting enhancement than volume control Propranolol hydrochloride, i.v. 4 Slightly longer lasting enhancement than volume control Ampicillin, i.v. 35 Not different to volume control 1) Hesiki A, Weinmann H.-J. Intaction between Gd-EOB-DTPA and Clinical Drugs in Normal Rats. Scientific Assembly and Annual Meeting of the

Radiological Society of North America (RSNA), 1997, Chicagl, IL

42


Page 2 of 2

Nihon Schering K.K.

2.6.3.5 薬力学的薬物相互作用試験（続き）

Test Article： Gadoxetate Sodium Location Report No. Study No. Vol./ Section 1), 2) KMＨ＊457,

KMＨ＊563 1/4.2.1.4.1


2) Kato et. Al., Gd-EOB-DTPA interaction with clinical drugs in rats. Investigative Radiology 2002; 37 (12): 680-684.

Drug (generic name) Dose 〔mg/kg〕 Relative Liver Enhancement Cefotaxime sodium, i.v. 140 Not different to volume control Verapamil hydrochloride, i.v. 0.5 Not different to volume control Scopolamine butylbromide, i.v. 2.5 Not different to volume control Theophyllin, i.v. 15 Not different to volume control Butylscopolaminiumbromide, i.v. 2.5 Not different to volume control Diazepam, i.v. 2.5 Not different to volume control 1) Hesiki A, Weinmann H.-J. Interaction between Gd-EOB-DTPA and Clinical Drugs in Normal Rats. Scientific Assembly and Annual Meeting of

the Radiological Society of North America (RSNA), 1997, Chicagl, IL

2) Kato et. Al., Gd-EOB-DTPA interaction with clinical drugs in rats. Investigative Radiology 2002; 37 (12): 680-684.

43

Documents

2.6.3 薬理試験概要表KMD＊132 1/4.2.1.3.1 Influence on erythrocyte morphology Blood In-vit ro Schering AG A263 KM E＊57 1/4.2.1.3.2 CNS Mouse i.v. Schering AG AB40 ZNF＊0641