アレサガテープに関する資料...アレサガテープ 4mg アレサガテープ 8mg...

アレサガテープ 4mg アレサガテープ 8mg

に関する資料

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ることはできません。

久光製薬株式会社

4mg8mg

1.5 ................................................................................................ 5 1.5.1 ..................................................................................................................... 5 1.5.2 ..................................................................................................................................... 5

1.5.2.1 .................................................................................................................................. 8 1.5.2.2 .................................................................................................................. 8 1.5.2.3 .................................................................................................................. 8 1.5.2.4 .................................................................................................................... 10

1.5.3 ........................................................................................................................... 14 1.5.3.1 ............................................................................................................................ 14 1.5.3.2 .................................................................... 14

1.5.4 ....................................................................................................................................... 15

- 2 -

HP-3060

1cm2 0.5mg 0.5mg/cm2

1 8cm2 4mg

1 16cm2 8mg

[14C]HP-306014C 1cm2 0.5mg

0.5mg/cm2

AUC0-24 0 24 -

AUC0-t 0 t -

AUC0- 0 -

CHO chinese hamster ovary

Cmax

CYP cytochrome P450 P450

FAS full analysis set

HepG2 human hepatocellular carcinoma cells

hERGhuman ether-a-go-go related gene

IC50 50% inhibitory concentration 50%

JRQLQJapan Rhinoconjunctivitis Quality of Life Questionnaire

QOL

LOCF last observation carried forward

QOL quality of life

t1/2 log - z

TK toxicokinetics

tmax

- 3 -

01HP-3060-JP-01

02HP-3060-JP-02

03HP-3060-JP-03

04

HP-3060-JP-04

05HP-3060-JP-05

- 4 -

benzimidazole

1) 1981

1993 1996

1997 2, 3)

2

2

24)

(1) (2)

(3) 1 1 24)

2 65%

66% 14%5) 2

1 1

24

1 1

HP-3060

1.5-1

- 5 -

-6-

1.5-1

20

-7-

1.5-1

HP-3060

1 1 1

15 6 3

0603001 9

5 28 422

36

H1 H2 H3

HP-3060

HP-3060

24

HP-3060

hERG CHO hERG IC50

0.24μmol/L HP-3060

144mg/body 15.93mg/kg

in vitro

HP-3060

HP-3060 Cmax

AUC0-24

- 8 -

[14C]HP-3060

7

CYP CYP

HepG2 in vitro CYP1A2 2E1

3A4 CYP

in vitro

[14C]HP-3060

In vitro

HP-3060 4

13 39

20xx x 20xx x

20xx x

20xx x

- 9 -

4

TK

TK

4

HP-3060

HP-3060 03

8mg 14 Cmax 8.4 12

AUC0-24 7.1 10

4

13 39

12 HP-3060 1.5 3

6 12 24mg 24

2mg HP-3060

HP-3060 1.5 24mg Cmax AUC0-t AUC0-

HP-3060 tmax 16 26hr t1/2 11.7 13.8hr

tmax 4hr t1/2 7.62hr

HP-3060

HP-3060 1.5 24mg 24

20 HP-3060 8mg 5 5

24

- 10 -

HP-3060 8mg Cmax AUC0-t AUC0-

HP-3060 8mg tmax

16 28hr t1/2 12.0 15.8hr HP-3060

HP-3060 8mg

24

96 24 × 4 HP-3060

4 8 12mg 1 1 14 2

HP-3060 Cmax AUC0-24 4 12mg

2 LOCF HP-3060 8mg

HP-3060 4mg 12mg

2 LOCF

1 HP-3060

HP-3060

1 1 14 2

2

HP-3060 8mg

20xx x

- 11 -

04 05

1276 04 HP-3060 4 8mg

2

HP-3060

HP-3060 5mg

FAS 1273 383 HP-3060 4mg 384 8mg 380

126 FAS

2 LOCF HP-3060 4mg 8mg

HP-3060

HP-3060

FAS 2 LOCF

HP-3060

1

HP-3060

HP-3060

- 12 -

HP-3060 4mg

8mg 1

HP-3060

1275 384 HP-3060 4mg 384 8mg 381

126 15.4%

59/384 HP-3060 4mg 13.8% 53/384 8mg 18.1% 69/381

13.5% 17/126

10.9% 42/384 HP-3060 4mg 11.2% 43/384 8mg 14.2% 54/381

11.9% 15/126

0.5% 2/384 HP-3060 4mg 3.4% 13/384 8mg 4.7% 18/381

1.6% 2/126 0

0.5%

7.0% 27/384

HP-3060 4mg 5.2% 20/384 8mg 6.3% 24/381 4.8% 6/126

HP-3060

HP-3060 4mg 75.0% 8mg

83.3% 2

247 HP-3060 4 8mg 12 52

HP-3060

247 HP-3060 4mg 124 8mg 123

HP-3060 4mg 60.5% 75/124 8mg 61.0% 75/123

HP-3060 4mg 26.6% 33/124 8mg 23.6%

29/123

HP-3060

4mg 6.5% 8/124 8mg 10.6% 13/123 HP-3060 8mg

2%

HP-3060 4mg 20.2% 25/124

8mg 17.9% 22/123

HP-3060 4mg 72.0% 8mg 81.7% 1

- 13 -

HP-3060 52

FAS 247 HP-3060 4mg 124 8mg 123

1

52 52 HP-3060 4mg -2.65 8mg -2.39

52 / HP-3060 4mg -2.59 8mg -2.47

6 QOL JRQLQ

2 4 12

1 16, 7)

PTP

(1)

QOL

04

HP-3060 4mg 8mg

5mg

HP-3060

05

HP-3060 4mg 8mg

04 05

05 QOL JRQLQ

- 14 -

HP-3060 QOL

(2)

24

01 02

03 24

05

04

HP-3060 4mg 8mg

HP-3060 8mg 2 LOCF

1

1

HP-3060 HP-3060

HP-3060 4mg 8mg

1

24

4mg

8mg

1 4mg

24 1 8mg

1) . ® ®

.

- 15 -

1997; 40: 231-45.

2) MSD : 1mg, 2mg .

8 , 2013.

3) : 1mg, 2mg .

5 , 2013.

4) . 5 .

2016 8 . : ; 2015. p. 36-82.

5) , . 2

. Progress in Medicine 2008; 28:

2285-96.

6) : 1mg, 2mg . 5 , 2013.

7) : 10mg, 10mg . 15 ,

2015.

- 16 -

4mg8mg

2017 9

- 2 -

4mg8mg

-2-

1.7-1

4mg 8mg 1mg 2mg

1993 4 2

2003 3 26

1 8cm2 16 cm2 4mg8mg

1 1mg 2mg

1 4mg24

1 8mg

1 1 2mg 1 2

-3-

1.7-1

1.

2.(1)

(2) 4mg 8mg

(3)

(4)

(5)

3.

1.

2.(1)

(2) 4mg/ 2mg/

(3)

(4)

3.

-4-

1.7-1

4.1,060 201 19.0%

116 10.9%48 4.5% 21 2.0% 52

4.9%

5% 0.1% 5%

ALT GPT ASTGOT

LDH -GTP

4.14,168 1,040 7.34%

6.30% 0.61%0.23% 0.14% 0.13% 0.11%

0.10% ALT GPT0.21% AST GOT 0.16% LDH 0.13% -GTP0.10%

5% 10% 0.1% 5% 0.1%

-5-

1.7-1

5.

6.(1)

5% 10% 0.1% 5% 0.1%

AST GOTALT GPT

LDH-GTP

Al-P

5.1 1mg

6.(1)

-6-

1.7-1

(2)

7.

8.

9.

(1)(2)

(3)

(1)

(2)(3) 1

(2)

7.

8.

9.(1)(2) PTP PTP

PTP

-7-

1.7-1

2013 8 5

-8-

1.7-2

5mg0.05%

10mg10mg

1%

5mg 2010 10 270.05% 2014 1 17

10mg 2002 7 510mg 2004 2 27

1% 2007 10 19

2018 10 26 2014 3 242015 9 17

1 5mg1mL 0.5mg

1 10mg1g 10mg

-9-

1.7-2

1 5mg 1 11

10mg

7 15 1 2.5mg1 2

1 10mL 5mg 1 1

1 20mL 10mg

6 1 1 2.5mL1.25mg 1 1

1 7 1 2.5mL1.25mg 1 2

7 15 1 5mL2.5mg 1 2

1 10mg 1 1

7 1 10mg 1 1

1 10mg 1g 11

3 7 1 5mg0.5g 7 1

10mg 1g 1 1

-10-

1.7-2

10mL/min

mL/min80 50 79 30 49 10 29

5mg1 1

2.5mg1 1

2.5mg2 1

2.5mg 23 4 1

® 10mg

(1)

(2) 10mL/min

1.(1)

(2)(3)

(4)

1.(1)

(2) descarboethoxyloratadineDCL

(3)

-11-

1.7-2

2.(1)

(2)

(3)

3.

1)

1)

1)

16%

1)

1)

40%

-11%

1)

2.(1)

(2)

3.DCL CYP3A4 CYP2D6

DCLCYP3A4

CYP2D6

DCL

DCL

-12-

1.7-2

1)

1) R-

4.

R-

95mg 1292 207

16.0% 67 5.2%42 3.3% 39 3.0%

4.

® 10mg 1,653 17310.5% 105 6.4% 231.4% 15 0.9% 15 0.9% 9 0.5%

1,482 72 4.9%ALT GPT 13 0.9% AST GOT 10 0.7%

7,049 110 1.6%52 0.7% 7 0.1%

6 0.1% 5 0.1%104 5 4.8%

2 1.9%

-13-

1.7-2

1396 18913.5%

1396 140 10.0% 84 6.0%12 0.9% 9 0.6% 7 0.5%

AST GOT 1.4% 17/1182 ALTGPT 1.5% 18/1181 0.8% 9/1114

0.5% 6/11335759 163

207 3.6%149 2.6% 9 0.2% 9 0.2%

8 0.1% 6 0.1%

602 25 4.2%ALT GPT 8 1.3% 6 1.0%

R-

197 105.1% 7 3.6% 2 1.0%

197 6 3.0%ALT GPT 2 1.0% AST GOT 2 1.0%

774 6 0.8%2 0.3%

157 6 3.8%2 1.3%

-14-

1.7-2

95mg 1292 207

16.0% 67 5.2%42 3.3% 39 3.0%

6 260

1396 18913.5%

1396 140 10.0% 84 6.0%12 0.9% 9 0.6% 7 0.5%

AST GOT 1.4% 17/1182 ALTGPT 1.5% 18/1181 0.8% 9/1114

0.5% 6/11335759 163

207 3.6%149 2.6% 9 0.2% 9 0.2%

8 0.1% 6 0.1%

-15-

1.7-2

602 25 4.2%ALT GPT 8 1.3% 6 1.0%

(1)1) 2)

2) 2)

3) 0.6% 2) AST GOT ALT GPT -GTPLDH Al-P

4) 2)

2)

(1)1)

2)

3)

4) AST GOT ALT GPT -GTP Al-PLDH

-16-

1.7-2

(2)

0.1 5% 0.1%

3) 3)

3)

3)

3)

3)

3)

3) 3)

3)

(2)

1% 0.1 1% 0.1%

AST GOTALT GPT

Al-P -GTP

BUN

-17-

1.7-2

0.1 5% 0.1%

3)

ALT GPTAST GOT

Al-P

3) BUN3)

3)

3)

3)

3)

5.

2.5mg

1% 0.1 1% 0.1%

5.

-18-

1.7-2

6.(1)

(2) 1)

1) R-

7.

7

6

8.

3 5

6.(1)

(2)

7.

(1) 3 7 1%

(2) 3

3

8.

3 5

-19-

1.7-2

9.

10.

PTP PTPPTP

9.40mg 180mg

10.(1) 10mg

PTP PTPPTP

(2) ® 10mg1)

a. PTP

b.c.

®

2)

-20-

1.7-2

5mg 2017 2 60.05% 2017 2 3

10mg 10mg 2017 1 161% 2017 1 9

-21-

1.7-3

2.5 5OD 2.5 OD 5

0.5%

30mg 60mgOD 60mg

5%

2.5 5 2000 12 22OD 2.5 OD 5 2010 5 10

0.5% 2011 7 1

30mg 2006 10 2060mg 2000 9 22

OD 60mg 2010 12 145% 2014 1 17

2.5 5 2009 12 212.5 5 OD 2.5 OD 5 0.5% 7

2015 9 170.5% 2 7 2017 3 30

30mg 60mg 2011 9 292013 4 4 7

5% 6 72018 1 16

1 2.5mg 5mg1g 5mg

1 30mg 60mgOD 1 60mg

1g 50mg

-22-

1.7-3

1 5mg1 2

7 1 5mg1 2

1 5mg 1g1 2

7 1 5mg1g 1 2

2 7 12.5mg 0.5g 1 2

1 60mg 1 2

7 12 130mg 1 2 12 1

60mg 1 2

1 60mg1.2g 1 2

12 1 60mg1.2g 7 12

1 30mg 0.6g 1 2

2 7 1 30mg0.6g 6 2

1 15mg 0.3g 1 2

-23-

1.7-3

OD ODOD

9.

1.1)

2)3)

2.1)

2)

3)

4)

1.(1)

(2)

-24-

1.7-3

3.

9,620 1,05611.0% 1,402

674 7.0% ALT GPT 68 0.7%53 0.6% AST GOT 46 0.5% 36 0.4%

2.

P

3.

6,809 1,060 5,7491,093 16.1%

310 4.6% 158 2.3% 83 1.2%

3,876 61 1.6%19

0.5% 8 0.2% 5 0.1%

-25-

1.7-3

OD4,413 210

4.8% 231149 3.4% ALT GPT 20 0.5% AST

GOT 9 0.2% 7 0.2% 4 0.1%

158 13 8.2%5 3.2% ALT GPT

3 1.9% -GTP 2 1.3% 2 1.3%

3,313 23 0.69%6 0.18%

2 0.06% 2 0.06%4 174

304 10 3.3%AST GOT 5

1.6% ALT GPT 2 0.7%

212 2 0.9%1 0.5%

1 0.5%158 13 8.2%

5 3.2%ALT GPT 3 1.9% -GTP 2 1.3% 2 1.3%

-26-

1.7-3

1)AST GOT ALT

GPT -GTP LDH Al-P

3,313 23 0.69%6 0.18%

2 0.06% 2 0.06% 4174

304 10 3.3%AST GOT 5 1.6% ALT

GPT 2 0.7%

6,809 1,0605,749 1,093 16.1%

310 4.6% 158 2.3%83 1.2%

3,876 611.6%

19 0.5% 8 0.2% 5 0.1%

(1)1) 1)

2) 1) AST GOT ALT GPT -GTPAl-P LDH

-27-

1.7-3

2)

5% 0.1 5% 0.1%

ALT GPTAST GOTLDH -GTPAl-P

3) 1) 0.2% 2) 0.1%2)

1)2)

(2)3) 0.1 5% 4) 0.1% 4)

1)

2) AST GOTALT GPT

1)2)

-28-

1.7-3

5% 0.1 5% 0.1%

BUN

4.

5.1)

2)

3)4)

4.

5.(1)

(2)

-29-

1.7-3

6.

2

7.

6.

6

7.

3 5

8.

2 1800 3600mg

-30-

1.7-3

8.

1)PTP PTP

PTP

2)

OD1)

PTP PTPPTP

2)

9.

9.(1) 30mg 60mg

PTP PTPPTP

(2) OD 60mg1)

a. PTP

b.OD

c.d.

2)a.

b.

-31-

1.7-3

2.5 5 2017 4 19OD 2.5 OD 5 2017 4 8

0.5% 2017 4 5

30mg 60mg OD 60mg 2013 5 165% 2015 10 2

-32-

1.7-4

5mg 10mgOD 5mg OD 10mg

5 101.25%

5mg 10mg 2000 7 3OD 5mg OD 10mg 2007 3 14

5 10 1998 6 301.25% 2005 10 21

2010 6 292019 5 25

2008 10 32016 6 24

1 5mg 10mgOD 1 5mg 10mg

1 5mg 10mg1g 12.5mg

1 10mg 1 2 10mg1 10mg 1 1

1 20mg

-33-

1.7-4

7 1 10mg 1 2

OD

5mg

1 10mg 1 1

1 20mg

7 15 1 5mg 12

1 0.8g 10mg 1 1

1 1.6g20mg

2 7 1 0.2g 2.5mg1 2

7 15 1 0.4g 5mg1 2

10mL/min

-34-

1.7-4

mL/min80 50 79 30 49 10 29

10mg1 1

10mg1 1

5mg1 1

5mg2 1

1.

1 5mg

2.1)

2

(1)

(2) 10mL/min

1.(1)

(2)

(3)

(4)

2.(1)

-35-

1.7-4

2)

3)

4)

(2)

(3)

3.

16%

40%-11%

-36-

1.7-4

3.

1,446137 9.5% 83 5.7% 16

1.1% 12 0.8% 7 0.5% 7 0.5%6 0.4% 4 0.3% 4 0.3%

1,225 64 5.2% ALT GPT 1,209 252.1% 1,020 11 1.1% -GTP 1,130 10

0.9% AST GOT 1,210 8 0.7%4,453

89 2.0% 591.3%

1) 5 15 1,31614 1.1%

5 0.4% 2 0.2% 2 0.2%7 15

615 14 2.3%5 0.8% 2 0.3% AST GOT

2 0.3%

4.

1,396 18913.5%

1,396 140 10.0% 84 6.0%12 0.9% 9 0.6% 7 0.5%

AST GOT 1.4% 17/1,182 ALTGPT 1.5% 18/1,181 0.8% 9/1,114

0.5% 6/1,1335,759

163 207 3.6%149 2.6% 9 0.2% 9

0.2% 8 0.1% 6 0.1%

602 25 4.2%ALT GPT 8 1.3% 6 1.0%

3,157 42 1.3%22 0.7%

5 1.25%

(1)1)

-37-

1.7-4

0.1 5% 0.1%

AST GOT ALTGPT -GTP

LDH

2) 0.1%

3)AST GOT ALT GPT -GTP LDH Al-P

4)

(2)

0.1% 5% 0.1%

-38-

1.7-4

0.1 5% 0.1% 0.1% 5% 0.1%

ALT GPTAST GOT

Al-P

BUN

-39-

1.7-4

4.

5.1)

2)

6. 1)

5.

5mg

6.(1)

(2)

7.

(1) 2 71.25%

(2) 2

2

-40-

1.7-4

7.

PTP PTPPTP

OD(1)

PTP PTPPTP

(2)1)

2)

8.

3 5

9.

10.

PTP PTPPTP

-41-

1.7-4

5mg 10mg 2017 10 16OD 5mg OD 10mg 2017 10 8

5 10 2016 10 251.25% 2016 10 25

-42-

1.7-5

10 20

10 20 1994 4 1

2003 1 17

1 10mg 20mg

1.

1 20mg 1 1

2.1 10 20mg 1 1

-43-

1.7-5

1.

2.(1)

(2)

(3)

(4)

(5)

3.8,443

263 3.12%102 1.21% 28 0.33% 27 0.32%

17 0.20% 15 0.18%

-44-

1.7-5

(1)1) AST GOT ALT GPT -GTP Al-P

LDH

2)

(2)

0.1 5% 0.1%1)

2)

-45-

1.7-5

0.1 5% 0.1%

2)

1)2)

4.

10mg/

5.(1)

(2)

-46-

1.7-5

6.

7.

PTP PTPPTP

8.

10 20 2011 9 8

4mg8mg

1.8 .................................................................................................................................... 4 1.8.1 ......................................................................................... 4

1.8.1.1 .................................................................................................................. 4 1.8.1.2 .............................................................................................. 4

1.8.2 ......................................................................................... 4 1.8.2.1 .................................................................................................................. 4 1.8.2.2 .............................................................................................. 4

1.8.3 ............................................. 7 1.8.4 ............................................. 7 1.8.5 ..................................................................................... 7

1.8.5.1 .......................................................................................................................................... 7 1.8.5.2 .......................................................................................................................................... 7 1.8.5.3 .................................................................................................................................. 7 1.8.5.4 .................................................................................................................................. 7 1.8.5.5 .................................................................................................................. 8 1.8.5.6 .................................................................................................................................. 8 1.8.5.7 ...................................................................................................................................... 9 1.8.5.8 ...................................................................................................................... 9 1.8.5.9 ........................................................................................ 10 1.8.5.10 .................................................................................................................... 10 1.8.5.11 ................................................................................................ 10 1.8.5.12 ................................................................................................................................ 10 1.8.5.13 ........................................................................................................................ 11 1.8.5.14 ........................................................................................................................ 11

1.8.6 ....................................................................................................................................... 12 1.8.7 ........................................................................................................................... 12

- 2 -

HP-3060

1cm2 0.5mg 0.5mg/cm2

1 8cm2 4mg

1 16cm2 8mg

FAS full analysis set

JRQLQJapan Rhinoconjunctivitis Quality of Life Questionnaire

QOL

LOCF last observation carried forward

QOL quality of life

tmax

01HP-3060-JP-01

02HP-3060-JP-02

03HP-3060-JP-03

04

HP-3060-JP-04

05HP-3060-JP-05

- 3 -

1276 04 HP-3060 4 8mg

2

FAS 2 LOCF -0.45 HP-3060 4mg -1.22

8mg -1.50 HP-3060 4mg 8mg

HP-3060

p < 0.0001 Dunnett

HP-3060

4mg 8mg 2.5.4.3.2

247 05 HP-3060 4 8mg 12

52

52 /

HP-3060 4mg 8mg -2.59 -2.47

1 52

QOL JRQLQ

2.5.4.3.3

04

05

1 4mg

24 1 8mg

- 4 -

(1)

12 HP-3060 1.5 3

6 12 24mg 24 01

tmax 16 26hr 2.5.3.3.1.1 16 26

1 24

96 HP-3060

4 8 12mg 14 2 03

24 7 14

2.5.3.3.2.1

HP-3060 1

1

20 5 5 HP-3060 8mg

24 02

HP-3060 8mg 24

2.5.3.3.1.2

(2)

96 03 2 LOCF

HP-3060 8mg

p = 0.0185 HP-3060

4mg 2.5.4.3.1

HP-3060 4mg 8mg

2.7.6.3.4.11 1 1 14 2

2.5.5.2

03 HP-3060 4 8mg

1276 04 HP-3060 4 8mg 2

FAS 2 LOCF

- 5 -

95% HP-3060 4mg -0.77 -1.02 0.51 8mg -1.05 -1.30 0.80

HP-3060 4mg 8mg HP-3060 4mg p < 0.0001

8mg p < 0.0001 Dunnett 2.5.4.3.2 HP-3060

4mg 8mg 2.5.5.2

247 05 HP-3060 4 8mg 12

52 1

52

52 HP-3060 4mg -2.65 8mg -2.39 HP-3060 4mg

-2.59 8mg -2.47 2.5.4.3.3 HP-3060 4mg 8mg

HP-3060 8mg 2.5.5.2 05

HP-3060 8mg HP-3060 4mg 2

2 4 12 HP-3060

2.5.3.3.2.2

4 8mg

4 8mg

4mg 03 04 4mg

8mg 03 HP-3060 8mg

4mg 8mg

4mg 8mg

1 4mg

24

1 8mg

- 6 -

(1)

(2) 4mg 8mg

(3)

(4)

(5)

(1)

(2) 8mg

4mg

8mg

8mg

(3)

1)

(4)1)

(5)

- 8 -

1,060 201 19.0%

116

10.9% 48 4.5% 21 2.0%

52 4.9%

5% 0.1% 5%

ALT GPTAST GOT

LDH -GTP

- 9 -

(1)

(2)

2)

- 10 -

(1)

(2)

(3)

(1)

(2)

(3) 1

(1)

2.6.4.3.1.4

(2)

(3)

(1)

(2)

(3) 1 24

- 11 -

1) . 5 . . .

2016 8 . :

; 2015. p. 66-70.

2) Sakai T, Takahashi H, Hamada T, Awata N, Watanabe J. The biological fate of 1-(2-ethoxyethyl)

-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413) III Transfer to fetus and milk

in rats. 1987; 2: 147-54.

- 12 -

201 1 87449

36

ALLESAGA®TAPE

4mg 8mg

1

4mg

1

8mg

1

22.3mm × 36.1mm 31.5mm × 51.0mm

8cm2 16cm2

HP3204T HP3208T

1 4mg

24

1 8mg

(1)

(2) 4mg 8mg

(3)

(4)

(5)

- 13 -

1,060 201 19.0%

116 10.9% 48

4.5% 21 2.0% 52 4.9%

ALT GPT

AST GOT

LDH -GTP

(1)

(2)

(1)

(2)

(3)

(1)

(2)

(3) 1

1)

12

1.5 3 6 12 24mg 24

Cmax AUC0-t AUC0- 1.5 24mg

1 4 8mg

- 14 -

Cmax

(ng/mL)AUC0-t

(ng hr/mL)AUC0-

(ng hr/mL)tmax

a)

(hr)t1/2

(hr)1.5mg(12)

0.320± 0.112

8.48± 3.03

9.15± 2.97

2611.7

± 3.193mg(12)

0.642± 0.235

18.4± 5.44

19.3± 5.41

16, 2613.2

± 2.006mg(12)

1.59± 0.567

43.8± 13.2

46.2± 13.1

2613.8

± 2.2912mg(12)

3.09± 1.01

86.4± 25.3

90.5± 24.9

1613.0

± 2.4724mg(12)

5.43± 1.89

156± 53.3

164± 52.7

2613.0

± 2.84

a) 2)

20

8mg 24

AUC0-t

0.930 1.000 0.923 0.740

AUC0-t

3)

4 8 12mg 1 1 14

Cmax AUC0-24 4 12mg

7

1 4 8mg

Cmax

(ng/mL)AUC0-24

(ng hr/mL)tmax

a)

(hr)t1/2

(hr)

1

4mg(23)

1.16± 0.419

16.3± 7.54

20 -

8mg(24)

2.32± 0.832

31.7± 14.9

20 -

12mg(24)

2.94± 1.49

38.8± 24.1

20 -

7

4mg(22)

1.80± 0.579

36.0± 10.9

16 -

8mg(24)

3.98± 1.18

79.5± 23.8

12 -

12mg(24)

5.49± 2.62

112± 57.1

16 -

14

4mg(21)

2.03± 0.641

40.6± 12.3

12, 1615.5

± 2.368mg(24)

4.42± 1.40

88.8± 30.3

12, 1615.5

± 1.5912mg(24)

6.28± 2.86

128± 62.1

1216.2

± 2.83

a)

4, 5)

[14C]

8

7

6)

[14C]

in vitro 7, 8)

CYP1A2 2E1

3A41)

12

1.5 3 6 12 24mg 24

0 96

6- 5-

2.9 4.4% 12.4

15.9%

9)

4 8mg 1 1 2

a)

95%CI

3836.45

± 1.636.16

± 2.03-0.29± 1.86

4mg384

6.56± 1.65

5.46± 1.98

-1.10± 1.89

-0.77-1.02 -0.51

p < 0.0001b)

8mg380

6.47± 1.61

5.12± 2.13

-1.35± 1.98

-1.05-1.30 -0.80

p < 0.0001b)

a)

b) Dunnett p 5%

- 15 -

10)

4 8mg 1 1 52

1 52

4mg124

6.45 ± 1.81 3.86 ± 1.99 -2.59 ± 1.93

8mg123

6.35 ± 1.58 3.88 ± 1.84 -2.47 ± 1.99

2411)

in vitro 12)

in vitro 13)

H1

H2 H3

in vitro 14, 15)

C4

P

in vitro 16)

B4

Emedastine Fumarate JAN

1-(2-Ethoxyethyl)-2-(4-methyl-1,4-diazepan-1-yl)-

1H-benzimidazole difumarate

C17H26N4O 2C4H4O4

534.56

99.5 100

149 152

4mg 70 1 / 1 × 70

8mg 70 1 / 1 × 70

1) I

2) I

3) I/II

4)

5)

6) Sakai, T., et al.: 1987; 2: 147-154.

7) in vitro

8) : 1997; 31: 3089-3093.

9) III

10) III

11)

12) Fukuda, T., et al.: Arzneimittelforschung 1984; 34: 801-805.

13) Sharif, NA., et al.: J. Ocul. Pharmacol. 1994; 10: 653-664.

14) Nishimura, N., et al.: Immunopharmacol. Immunotoxicol.

1987; 9: 511-521.

15) Saito, T., et al.: Jpn. J. Pharmacol. 1993; 62: 137-143.

16) : 1993; 55: 1081-1085.

100-6330 4 1

0120-381332

FAX. (03)5293-1723

9:00 17:50

841-0017 408

- 16 -

4mg8mg

62 6 25 1 16 19 8 6

0806001

Emedastine Fumarate

- 2 -

4mg8mg

1 1 2mg 1 2

1 1.14mg*

1mg 1 1mg

2mg 1 2mg

LD50 mg/kg

2547 712 101

2206 609 93

2151 666 72

1854 643 77

193

mg/kg/ mg/kg/

3 10, 50, 250,

1250

10 ChE GPT AlP

A/G LDH BUN Ca2+

P K+

3 3, 15, 75 15

AlP

TG

2mg

- 2 -

mg/kg/ mg/kg/

1 1, 3, 10, 50 10 ChE

1 1, 3, 15, 45

15

AlP

1 +

3

0.3, 1, 3, 45

192 / 1229 = 15.6%

155

19

9

6

4

- 3 -

1 4mg

24 1 8mg

4mg 1 8cm2 4mg

8mg 1 16cm2 8mg

mg/kg/day mg/kg/day

4

+ 4

0, 4.5, 9, 18 18

4 0, 1, 3, 9 9

181 / 1060 = 17.1% 21 / 1060 = 2.0%

116 7

52

48 4

21

3

3

- 4 -

4mg8mg

/

3.2.S

3.2.P.1

3.2.P.2 2020

3.2.P.3 2020

3.2.P.4 2020

3.2.P.5 2020

3.2.P.6

3.2.P.7

3.2.P.820

20

3.2.A 2020

アレサガテープ

1.12 添付資料一覧

Page 2

3.3-1 26 12 5 34 .

3.3-2 28 1 22 170 .

3.3-3 Iemura R, Hori M, Ohtaka H. Syntheses of the metabolites of 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazole difumarate(KG-2413) and related compounds. Chem Pharm Bull 1989; 37: 962-6.

3.3-4 2 in silico 947-15-K-0196 . 2016.



Page 3

/

4.2.1.1-1 HP-3060 2020

4.2.1.3-1 Effects of emedastine difumarate on hERG currents 2020

4.2.1.3-2 HP-3060 2020

4.2.2.1-1 Bioanalytical method validation and stability study for determination of emedastine inmouse (ICR) plasma by LC/MS/MS

2020

4.2.2.1-2 Bioanalytical method partial validation for determination of emedastine in mouse (B6C3F1)plasma by LC/MS/MS

2020

4.2.2.1-3 Bioanalytical method validation and stability study for the determination of emedastine inrat plasma by LC/MS/MS

2020

4.2.2.1-4 Partial validation for the determination of emedastine in F344 rat plasma by LC/MS/MS 2020

4.2.2.1-5 Bioanalytical method validation and stability study for the determination of emedastine inrabbit plasma by LC/MS/MS

2020

4.2.2.1-6 Bioanalytical method validation and stability study for the determination of emedastine indog plasma by LC/MS/MS

2020

4.2.2.2-1 Pharmacokinetic study of oral administration of emedastine difumarate and percutaneousadministration of HP-3060 patch to rats

2020

4.2.2.2-2 Pharmacokinetic study of emedastine difumarate in rats after single subcutaneous orintravenous administration

2020

4.2.1.4

4.2.2.1

4.2.2.2

4.2.1.3

4.2.1.1

4.2.1.2



Page 4

/

4.2.2.2-3 Pharmacokinetics study of single percutaneous administration of [14C]-HP-3060 patch torats

2020

4.2.2.2-4 Pharmacokinetic study of single intravenous administration of emedastine difumarate andpercutaneous administration of HP-3060 patch to dogs

2020

4.2.2.3-1 Pharmacokinetics study of repeated percutaneous administration of [14C]-HP-3060 patch torats

2020

4.2.2.4-1 In vitro metabolism study of [14C]emedastine difumarate20

20

4.2.2.4-2 Identification of enzymes involved in glucuronidation of 5-hydroxyemedastine and 6-hydroxyemedastine

2020

4.2.2.6-1 Inhibitory effects of emedastine difumarate on drug metabolizing enzyme activities inhuman liver microsomes

2020

4.2.2.6-2 In vitro studies on emedastine difumarate transport of MDR1, BCRP, OATP1B1,OATP1B3 and OCT1

2020

4.2.2.6-3 In vitro inhibitory effects of emedastine difumarate on the transport activity 2020

4.2.3.2-1 A 4-week repeated dose percutaneous toxicity study of HP-3060 patch in rats followed by a4-week recovery period

2020

4.2.3.2-2 A four-week repeated dose percutaneous toxicity study of HP-3060 patch in dogs 2020

4.2.3.2

4.2.2.3

4.2.2.4

4.2.2.5

4.2.2.6

4.2.2.7

4.2.3.1



Page 5

/

4.2.3.4.2-1 A 4-week repeated dose range finding study for a medium-term skin carcinogenesisbioassay of emedastine fumarate in mice

2020

4.2.3.4.2-2 A medium-term skin carcinogenesis bioassay of emedastine fumarate in mice 2020

4.2.3.5.2-1 A 7-day repeated dose subcutaneous study of emedastine fumarate in non-pregnant rabbits 2020

4.2.3.5.2-2 A preliminary study for effects of emedastine fumarate on embryo-fetal development bysubcutaneous administration in pregnant rabbits

2020

4.2.3.5.2-3 Reproductive and developmental toxicity study of emedastine fumarate in rabbits bysubcutaneous administration - Study for effects on embryo-fetal development -

2020

4.2.3.6-1 A primary skin irritation study of HP-3060 patch in rabbits 2020

4.2.3.6-2 A 13-week cumulative skin irritation study of HP-3060 patch in minipigs 2020

4.2.3.6-3 A 39-week cumulative skin irritation and 4-week recovery study of HP-3060 patch inminipigs

2020

4.2.3.3

4.2.3.44.2.3.4.1

4.2.3.4.2

4.2.3.4.3

4.2.3.54.2.3.5.1

4.2.3.5.2

4.2.3.5.3

4.2.3.5.4

4.2.3.6



Page 6

/

4.2.3.6-4 A skin sensitization study of HP-3060 patch in guinea pigs 2020

4.2.3.7.7-1 A skin phototoxicity study of emedastine fumarate in guinea pigs 2020

4.2.3.7.7-2 A skin photosensitization study of HP-3060 patch in guinea pigs 2020

4.2.3.7.7-3 Toxicokinetic study of emedastine fumarate in mice after single oral dose 2020

4.2.3.7.7-4 Toxicokinetics study of a single oral administration of emedastine difumarate to F344 rats 2020

4.2.3.7.7-5 Toxicokinetics study of a single oral administration of emedastine difumarate to SDpregnant rats

2020

4.2.3.7.7-6 Toxicokinetics study of a single oral administration of emedastine difumarate to dogs 2020

4.2.3.7.7-7 Toxicokinetics study of a repeat oral administration of emedastine difumarate to SD rats 2020

4.2.3.7.1

4.2.3.7.3

4.2.3.7.7

4.2.3.7.6

4.2.3.7.5

4.2.3.7.4

4.2.3.7.2

4.2.3.7



Page 7

4.3-1 . ® , ®

. 1997; 40: 231-45.

4.3-2 . 1 . 2016 8 .: ; 2015. p. 2-5.

4.3-3 . 3 . 20168 . : ; 2015. p. 16-8.

4.3-4 Fukuda T, Morimoto Y, Iemura R, Kawashima T, Tsukamoto G, Ito K. Effect of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole difumarate(KB-2413), a new antiallergic, on chemical mediators. Arzneimittelforschung 1984; 34: 801-5.

4.3-5 Nishimura N, Ito K, Tomioka H, Yoshida S. Inhibition of chemical mediator release from human leukocytes and lung in vitro by a novel antiallergic agent, KB-2413. Immunopharmacol Immunotoxicol 1987; 9: 511-21.

4.3-6 Saito T, Hagihara A, Igarashi N, Matsuda N, Yamashita A, Ito K, et al. Inhibitory effects of emedastine difumarate on histamine release. Jpn J Pharmacol 1993;62: 137-43.

4.3-7 Spangler DL, Brunton S. Efficacy and central nervous system impairment of newer-generation prescription antihistamines in seasonal allergic rhinitis. SouthMed J 2006; 99: 593-9.

4.3-8Sharif NA, Su SX, Yanni JM. Emedastine: a potent, high affinity histamine H1-receptor-selective antagonist for ocular use: receptor binding and secondmessenger studies. J Ocul Pharmacol 1994; 10: 653-64.

4.3-9 , , , , . Emedastine Difumarate . 1993;55: 1081-5.

4.3-10 Saito T, Fukuda T, Sukamoto T, Yoshidomi M, Morimoto Y, Shimohara K, et al. General pharmacology of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate. 1st communication: Effects on the central nervous system. Arzneimittelforschung 1988; 38: 66-9.

4.3-11Tasaka K, Kamei C, Katayama S, Kitazumi K, Akahori H, Hokonohara T. Comparative study of various H1-blockers on neuropharmacological and behavioraleffects including 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413), a new antiallergic agent. Arch Int Pharmacodyn Ther1986; 280: 275-91.

4.3-12 Saito T, Fukuda T, Tajima S, Sukamoto T, Yamashita A, Kanazawa T, et al. General pharmacology of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate. 2nd communication: Effects on the circulation and the other systems. Arzneimittelforschung 1988; 38: 267-72.

4.3-13 , , . KG-2413 . 1989; 23: 3145-7.

4.3-14 EMADINE® Review documents, Clinical pharmacology and biopharmaceutics review(s) (NDA 20-706).

4.3-15 Sakai T, Takahashi H, Hamada T, Awata N, Watanabe J. The biological fate of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate(KB-2413) I Absorption and excretion after oral administration to rats and guinea pigs. 1987; 2: 123-31.

4.3-16 Sakai T, Hamada T, Awata N, Watanabe J. Interspecies differences in pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1,4-diazepin-1-yl)benzimidazole difumarate (KG-2413) after intravenous administration to rats, guinea pigs and dogs. Chem Pharm Bull 1989; 37: 753-6.

4.3-17 Sakai T, Takahashi H, Hamada T, Awata N, Watanabe J. The biological fate of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate(KB-2413) III Transfer to fetus and milk in rats. 1987; 2: 147-54.



Page 8

4.3-18 , , , , , . 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazole difumarate KG-2413 . 1989; 4: 459-70.

4.3-19 , , , , . 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazoledifumarate KG-2413 , . 1989; 4: 471-80.

4.3-20 , , , , . 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazoledifumarate KG-2413 . 1989; 109: 318-28.

4.3-21 Hamada T, Awata N. Metabolism of a new antiallergic agent, emedastine difumarate, in human. 1990; 5: 871-81.

4.3-22 , , , . in vitro . . 1990;110: 40-8.

4.3-23 , , , . P450 . 1997; 31: 3089-92.

4.3-24 Sakai T, Hamada T, Awata N, Watanabe J. Pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazole difumarate (KG-2413) after oral administration: interspecies differences in rats, guinea pigs and dogs. J Pharmacobio-Dyn 1989; 12: 530-6.

4.3-25 Sakai T, Hamada T, Awata N, Watanabe J. Binding of 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1,4-diazepin-1-yl)benzimidazole difumarate (KG-2413) toserum or plasma proteins in man, guinea pig and rat. J Pharmacobio-Dyn 1988; 11: 262-7.

4.3-26 , , . / ,KG-2413 , . 1989; 109: 749-54.

4.3-27 EMADINE® Review documents, Pharmacology Review(s) (NDA 20-706).

4.3-28 Sakai T, Takahashi H, Hamada T, Awata N, Watanabe J. The biological fate of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate(KB-2413) II Distribution after single and multiple oral administration to rats. 1987; 2: 133-45.

4.3-29 , , , , , . Emedastine Difumarate KG-2413 3. 1990; 39: 231-68.


4.3-31 , , , , , . Emedastine Difumarate KG-2413. 1990; 39: 209-14.




4.3-35 , , , , , . Emedastine Difumarate KG-2413 . 1990; 39: 329-42.



Page 9


4.3-37 Remmer H. Induction of drug metabolizing enzyme system in the liver. Euro J clin Pharmacol 1972; 5: 116-36.

4.3-38 , , , , , . . 2015;56: 42-8.



Page 10

/

5.3.1.4-1 Bioanalytical method validation and stability study for the determination ofemedastine in human plasma by LC/MS/MS

2020

5.3.1.4-2 Bioanalytical method validation and stability study for the determination ofemedastine and its metabolites in human urine by LC/MS/MS

2020

5.3.2.2-1 In vitro metabolism study of [14C]emedastine difumarate20

20

5.3.2.2-2 Identification of enzymes involved in glucuronidation of 5-hydroxyemedastineand 6-hydroxyemedastine

2020

5.3.2.2-3 Inhibitory effects of emedastine difumarate on drug metabolizing enzymeactivities in human liver microsomes

2020

5.3.2.2-4 In vitro studies on emedastine difumarate transport of MDR1, BCRP,OATP1B1, OATP1B3 and OCT1

2020

5.3.2.2-5 In vitro inhibitory effects of emedastine difumarate on the transport activity 2020

5.3.3.1-1 HP-3060 2020

5.3.3.1-2 HP-3060 2020

5.3.3.1 PK

5.3.1.3 In Vitro -In Vivo

5.3.1.4

5.3.2.1

5.3.2.2

5.3.2.3

5.3.1.1 BA

5.3.1.2 BA BE



Page 11

/

5.3.5.1-1 HP-3060 2020

5.3.5.1-2 HP-3060

21

2020

5.3.5.2-1 HP-306011

2020

5.3.7.15.3.7.25.3.7.35.3.7.45.3.7.5

5.3.5.1

5.3.5.2

5.3.5.3

5.3.5.4

5.3.3.2 PK

5.3.3.3 PK

5.3.3.4 PK

5.3.3.5 PK



Page 12

5.4-1 . 1 . 2016 8 .: ; 2015. p. 2-5.

5.4-2 . 1 . . . : ; 2005. p. 16-21.

5.4-3 . : QOL . 2015; 4734: 20-1.

5.4-4 . 2 . 2016 8 . :; 2015. p. 8-13.

5.4-5 . 3 . 20168 . : ; 2015. p. 16-8.

5.4-6 . 5 . 2016 8 . :; 2015. p. 36-82.

5.4-7 , . 2. Progress in Medicine 2008; 28: 2285-96.

5.4-8 . ® ®

. 1997; 40: 231-45.

5.4-9 MSD : 1mg, 2mg . 8 , 2013.

5.4-10 : 1mg, 2mg . 5 , 2013.

5.4-11 EMADINE® Review documents, Clinical pharmacology and biopharmaceutics review(s) (NDA 20-706).



5.4-14 Herranz U, Rusca A, Assandri A. Emedastine-ketoconazole: pharmacokinetic and pharmacodynamic interactions in healthy volunteers. Int J Clin PharmacolTher 2001, 39: 102-9.

5.4-15 Sakai T, Hamada T, Awata N, Watanabe J. Binding of 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1,4-diazepin-1-yl)benzimidazole difumarate (KG-2413) toserum or plasma proteins in man, guinea pig and rat. J Pharmacobio-Dyn 1988; 11: 262-7.

5.4-16 , , , , . 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazoledifumarate KG-2413 . 1989; 109: 318-28.

5.4-17 Hamada T, Awata N. Metabolism of a new antiallergic agent, emedastine difumarate, in human. 1990; 5: 871-81.



Page 13

5.4-18 , , , . P450 . 1997; 31: 3089-92.

5.4-19 MSD : 1mg, 2mg . 7 , 2013.

5.4-20 , . 1 CKD . CKD 2012. 1 . : ; 2012. p. 1-4.

5.4-21 Malmstrom K, Schwartz J, Reiss TF, Sullivan TJ, Reese JH, Jauregui L, et al. Effect of montelukast on single-dose theophylline pharmacokinetics. Am J Ther1998; 5: 189-95.

5.4-22 . 5 . . 20137 . : ; 2013. p. 60-3.

5.4-23 Guidance for Industry. Allergic rhinitis: Clinical development programs for drug products. Draft guidance. FDA. April 2000.

5.4-24 . 1 . . 20137 . : ; 2013. p. 2.

5.4-25 . 4 . . 5. QOL . 2013 7 . : ; 2013. p. 27-9.

5.4-26 , , , , , . OHIO ChamberOD . 2011; 60: 2216-29.

5.4-27 : 30mg, 60mg, OD 60mg . 20 , 2014. p. 20.

5.4-28 : 10mg . p. 526-60.

5.4-29 : 1mg, 2mg . 5 , 2013.

5.4-30 : 10mg, 10mg . 15 , 2015.



Page 14

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アレサガテープに関する資料...アレサガテープ 4mg アレサガテープ 8mg...