á 4 - pmda.go.jp

2.6.4

1

2.6.4 ............................................................................................................ 3

2.6.4.1 ................................................................................................................................ 3 2.6.4.2 ................................................................................................................................ 6 2.6.4.3 .................................................................................................................................... 9 2.6.4.4 .................................................................................................................................. 22 2.6.4.5 .................................................................................................................................. 25 2.6.4.6 .................................................................................................................................. 36 2.6.4.7 .......................................................................................... 36 2.6.4.8 .................................................................................................. 37 2.6.4.9 .................................................................................................................. 37 2.6.4.10 .................................................................................................................................. 41 2.6.4.11 .......................................................................................................................... 41

2.6.5 ................................................................................................................ 1

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2.6.4

2

17-(Pyridin-3-yl)androsta-5,16-dien-3 -yl acetate

N

H

H

CH3

H

HOH3C

O

CH3

(3 )-17-(3-pyridinyl)androsta-5,16-dien-3-ol

N

H

H

CH3

H

HHO

CH3

AGP 1- 1-acid glycoprotein AUC area under the concentration-time curve

AUC 0 area under the concentration-time curve from time zero to infinite time

AUCt 0 t area under the concentration-time curve from time zero to time t

BCRP breast cancer resistance protein Cmax maximum concentration CYP P450 cytochrome P450 EDTA ethylenediaminetetraacetic acid HP- -CD hydroxypropyl- -cyclodextrin HSA human serum albuminIC50 50% 50% inhibitory concentration Ki inhibition constant

LC-MS/MS liquid chromatography-tandem mass spectrometry

LSC liquid scintillation counter MRP2 multidrug resistance-associated protein 2 NaF sodium fluoride

NADPH nicotinamide adenine dinucleotide phosphate reduced form

P-gp P- P-glycoprotein

QWBA quantitative whole-body autoradiography

Radio-HPLC high performance liquid chromatography-radioactivity detection

SULT sulfotransferase t1/2 elimination half-lifetmax time to reach the maximum concentration

UGT - uridine diphosphate-glucuronyltransferase

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2.6.4

3

2.6.4

2.6.4.1

in vivo

in vitro ex vivo

in vivo Methocel A4M

Tween 80

2.6.4.1.1

Caco-2 in vitro

1 3

Cmax 9

t1/2 2 1 7 3 12

Cmax AUC

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2.6.4

4

37 8 1.5%

2.6.4.1.2 14C-

AUC /

14C-

14C-

95%

HSA 1- AGP

2.6.4.1.3

in

vitro

P450 CYP

CYP3A4 - UGT 1A4

SULT 2A1

in vivo

II

abiraterone sulphate

M45 14C-

10%

abiraterone sulphate M45 N-oxide abiraterone sulphate M31 2.7.2.2.2.1 (2) 1)

abiraterone sulphate M45

N-oxide abiraterone sulphate M31

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2.6.4

5

CYP1A2 CYP2C8 CYP2C19 CYP2D6

CYP1A2 CYP2C8 CYP2D6

CYP4A1 UGT CYP2E1

CYP CYP1A1/2 SULT2A1 CYP3A1/2 CYP2B

CYP3A1/2 SULT2A1

2.6.4.1.4

Sprague-Dawley 14C-

168

90% 168

1% 14C-

120 20%

2.6.4.1.5

Caco-2

P- P-gp

P-gp 50% IC50 10.8 μmol/L

Breast cancer resistance protein BCRP multidrug resistance-associated protein 2 MRP2

P-gp

BCRP

N-oxide abiraterone sulphate M31 BCRP

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2.6.4

6

2.6.4.2

2.6.4.2.1

2.6.4.2.1.1

4.2.2.1.1 4.2.2.1.2 4.2.2.1.3 4.2.2.1.4 4.2.2.1.5 4.2.2.1.6 4.2.2.1.7

FDA1 LC-

MS/MS 2.6.4-1

2.6.4-1 LC-MS/MS

ng/mL

A 4.2.2.1.1 4.2.2.1.2 EDTA

AA 4 1000 ABT 4 1000

4 Wistar13

a) 413

B 4.2.2.1.3 4.2.2.1.4 EDTA/NaF

AA 2 5000 ABT 2 5000 26

C 4.2.2.1.5 EDTA/NaF AA 1 1000 ABT 1 1000 39

D 4.2.2.1.6 EDTA/NaF AA 2 200

ABT 2 2000

4 Sprague-Dawley 26 b)

15a) a)

E 4.2.2.1.7 EDTA/NaF AA 0.5 100

ABT 0.5 500 4

a) GLP b) AA ABT

A

EDTA

4 1000 ng/mL

1 8 4 3

-80

35 12

60 371

NaF

NaF

1 Guidance for Industry : Bioanalytical Method Validation.U.S. Department of Health and Human

Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) and Center for

Veterinary Medicine (CVM), May 2001

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2.6.4

7

B EDTA/NaF

2 5000 ng/mL

24 4

24 3

-20 -80

6 13 13

A B

C D B 26

D A

2.6.4.2.1.2 26 39

C EDTA/NaF

1 1000 ng/mL

2 2

3

2 6

6 -60 -80

298

D EDTA/NaF

2 200 2 2000 ng/mL

1

4 24

4 15

GLP D LC-

MS/MS

2.2 0.55 1.1 ng/mL 2.2 0.55

2.2 ng/mL

GLP E

EDTA/NaF

0.5 100 0.5 500 ng/mL

1 24

0.5 1

24

4 -70

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2.6.4

8

369

315

2.6.4.2.1.2

4.2.2.1.8

26 39

D C

Cmax

7% 0 24

AUC24

9% 17 26%

Cmax

7 17% 15 24% AUC24

17 26% 27 32% 10

23% 22 45% 45%

2.6.4.2.2

in vitro in vivo 2.6.4-1 14C

* 14C

N

H

H

CH3

H

HOH3C

O

CH3

N

H

H

CH3

H

HHO

CH3

2.6.4-1 14C- 14C-

LSC

Radio-HPLC LSC

151 135 33.9 294 46.4 ng eq/g Radio-

HPLC 1 1% 2%

QWBA 882 ng eq/g

* *

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2.6.4

9

2.6.4.2.3 4.2.2.2.4 4.2.2.4.5

abiraterone sulphate

M45 N-oxide abiraterone sulphate M31

LC-MS/MS qualified research method

abiraterone sulphate M45 4 10 4 100

100 ng/mL N-oxide abiraterone sulphate M31 4 3.57 50

89.3 ng/mL

LC-MS/MS

abiraterone sulphate M45 N-oxide abiraterone sulphate M31

1 ng/mL

2.6.4.3

2.6.4.3.1 In vitro 4.2.2.2.1

Caco-2 P-gp 10 mol/L A

100 mol/L 1 30 mol/L 14C-

1 15 mol/L 14C- 37 1 4

A B B A

2.6.5.3 A

P-gp A B 3.69

10-6 cm/s B A 1.58 10-6 cm/s Efflux Ratio B A/A

B 0.38 1.31

Caco-2

P-gp A

B P-gp

P-gp A B 3.46 10-6 cm/s

B A 4.60 10-6 cm/s Efflux Ratio 0.76 1.41

Caco-2

Efflux Ratio P-gp

P-gp

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2.6.4

10

2.6.4.3.2

2.6.4.3.2.1

4.2.2.2.2

WHT 39.2 mg/kg

Tween 80

2.6.5.3 B

15 30

20 ng/mL

0.25 1 Cmax 2000 ng/mL 1.6 t1/2 0

12 AUC12 3807.0 ng·h/mL

5 1013.0 ng/mL 5 15% 1

2% t1/2 2

AUC12 10251.0 ng·h/mL

37.1%

2.6.4.3.2.2

4.2.2.2.3 4.2.2.2.4 4.2.2.2.5 4.2.2.2.6

sulfobutylether- -

cyclodextrin 2.6.5.3 C

hydroxypropyl- -cyclodextrin HP- -CD

2.6.5.3 D 2.6.5.3 E

2.6.5.3 C HP- -

CD 2.6.5.10 B

5 mg/kg 2

4.46 mg/kg

2.6.4-2 2.6.4-2

2.6.4-2

2 5 mg/kg 4.46 mg/kg

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2.6.4

11

2.6.4-2 5 mg/kg

4.46 mg/kg

+ n=3 AA ABT

2.6.4-2

±

AA ABT

5 mg/kg 4.46 mg/kg 3 /

AA ABT ABT AUC24 ng·h/mL 459±24 2025±192 1593±652 AA ABT

250 mg/

5 25 mg/kg

50 mg/kg

500 mg/ 3

2.6.4-3

2.6.4-3

± b) b) c) c) d) e) a) 250 mg/ 250 mg/ 25 mg/kg 25 mg/kg 500 mg/ 50 mg/kg

6 / 3 / 6 6 AUC24

ng·h/mL 567±805 2797±1478 3422±377f) 3656±535f) 1582±2292 4849±1347

a) 250 mg/ 25 mg/kg 500 mg/ 50 mg/kg b) FK10118 4.2.2.2.3 c) FK101214.2.2.2.4 d) FK7653 4.2.2.2.5 e) FK10014 4.2.2.2.6 f) AUC

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2.6.4

12

500 mg/

7.8 8.9% 2.6.4-2 2.6.4-3

2.6.4.3.2.3

4.2.2.2.7

250 mg/ 42 mg/kg

2

24 mg/kg HP- -CD

2.6.4-3 2.6.4-4

4 ng/mL

2 2.5 Cmax 77.8 113.0 ng/mL 7.6 9.5

t1/2 0 AUC∞

558.0 622.4 ng·h/mL

1.6 t1/2

t1/2 6.6

1.5%

2.6.4-3

+

n=6 AA ABT

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2.6.4

13

2.6.4-4

±

1 2

6 / a) 250 mg/ 24 mg/kg

ABT ABT AA Cmax ng/mL 104.6±80.48 113.0±52.76 77.8±75.70 19783.3±2291.22 10788.3±3127.97tmax h 2.5±1.22 2.0±0.00 2.3±0.82 0.22±0.07 0.083±0.00 t1/2 h 7.8±3.77 7.6±4.25 9.5±4.55 6.6±1.59 1.6±0.45 AUC∞ ng·h/mL 622.4±514.18 558.0±247.73 618.7±407.16 19763.5±2128.25 1693.7±459.14

% b) 1.6±1.13 1.5±0.50 1.6±0.98 NA NA a) 250 mg/ 42 mg/kg b) ABT / AA ABT NA

2.6.4.3.3

2.6.4.3.3.1

(1) 15

4.2.3.2.1

Swiss 2 1

2 15 125 500

2000 mg/kg/

1 15 2.6.4-4 2.6.4-5

2.2 ng/mL

1 2 Cmax

125 mg/kg 9

2

15 1 Cmax

125 mg/kg 9

2

2000 mg/kg/ tmax

9

AUC Cmax

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2.6.4

14

2.6.4-4 Swiss 125 500 2000 mg/kg/

+ n=3

2.6.4-5 Swiss 125 500 2000 mg/kg/

mg/kg/ 125 500 2000 3 /

Cmax ng/mL 2152 2047 7337 4353 9797 7523 tmax h 1.0 1.0 2.0 1.0 2.0 2.0 AUC ng·h/mL 4671 3508 30844 22666 45824 53041

1 Cmax ng/mL 1890 1363 5243 4163 7353 5827 tmax h 0.5 0.5 0.5 0.5 2.0 0.5 AUC ng·h/mL 3240 NE 33541 25240 72469 62405

15 Cmax ng/mL 973 1109 1187 1737 3672 2627 tmax h 0.5 0.5 1.0 0.5 9.0 0.5 AUC24 ng·h/mL 1839 1307 a) 5139 5414 a) 32242 13015 a) a) AUC9

NE

(2) 4

4.2.3.2.2

rasH2 26

CByB6F1 rasH2

125 375 750 1500 mg/kg/

1 27 2.6.4-

6

0.55 ng/mL

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2.6.4

15

1 1 Cmax

2 4 8

Cmax

AUC

27 1 Cmax

2 4 8

Cmax AUC

2.6.4-6 CByB6F1 125 375 750

1500 mg/kg/

1 27

3 /

mg/kg/ 125 Cmax ng/mL 754 1016 582 507 tmax h 1 0.5 1 0.5 AUC24 ng·h/mL 2260 2057 886 1327 AUC ng·h/mL 2260 2057 NE NE

mg/kg/ 375 Cmax ng/mL 2287 1697 858 660 tmax h 0.5 1 1 2 AUC24 ng·h/mL 10012 10324 3273 3690 AUC ng·h/mL 10014 10326 NE NE

mg/kg/ 750 Cmax ng/mL 2803 4363 1203 1124 tmax h 1 1 1 4 AUC24 ng·h/mL 19901 26068 5086 10971 AUC ng·h/mL 19974 27443 NE NE

mg/kg/ 1500 Cmax ng/mL 3937 3540 1862 2547 tmax h 1 0.5 0.5 1 AUC24 ng·h/mL 29819 35369 11187 20874 AUC ng·h/mL NE a) NE a) NE NE a) AUC 25% NE

2.6.4.3.3.2

(1) 4

4.2.3.2.3 4.2.3.7.6.1

Wistar 40 126 400 mg/kg/

4 27

2.6.4-7

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2.6.4

16

1 6 Cmax Cmax AUC6

4 27 Cmax AUC

126 mg/kg/ 400 mg/kg/

2.6.4-7 Wistar 40 126 400 mg/kg/

mg/kg/ 40 126 400

4 27 4 27 4 27 3 /

Cmax ng/mL 252-610 192-390 805-1630 482-1188 1092-1194 430-582 tmax h 1 1-3 3-6 1-3 3-6 3-6 AUC6 ng·h/mL 791-1695 566-1362 3485-7076 2255-3508 4302-5117 2002-3182

Sprague-Dawley 40 400 mg/kg/

1 28

2.6.4-8

2 ng/mL

1 1.33 6.67 Cmax

AUC

Cmax AUC

28 1.00 2.67 Cmax

Cmax

AUC

2.6.4-8 Sprague-Dawley 40 400 mg/kg/

±

mg/kg/ 40 400

1 28 1 28 3 /

Cmax ng/mL 703±19.6 52.2±12.6 237±95.0 44.8±14.1 3670±697 127±30.2 520±158 152±71.9tmax h 1.33±0.58 1.33±0.58 1.00±0.87 1.17±0.76 6.67±2.31 2.00±0.00 2.67±1.15 1.67±0.58AUC24

ng·h/mL NE NE 996 ±311

151 ±76.3 NE NE 4398

±527 1359 b)

AUCng·h/mL

2834 ±630

174 ±28.8 NE NE 32906

±8751 795 a) NE NE

a) n=2 b) n=1 NE

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2.6.4

17

(2) 13

4.2.3.2.5

Sprague-Dawley 250 50 750 250 2000

750 mg/kg/ 3 1 28 92

2.6.4-9

4 ng/mL

1 4 Cmax

1.44 2.26 t1/2

28 92 4 Cmax

1.45 7.23 t1/2 9 12

28 92

Cmax AUC

3 250 750 2000 mg/kg/

9 10 12

250 50 750 250 2000 750 mg/kg/

6 8 9 11

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2.6.4

18

2.6.4-9 Sprague-Dawley 250 50a) 750 250b)

2000 750c) mg/kg/

1 28 92

3 /

mg/kg/ 250 50 Cmax ng/mL 2377 159 261 13.2 142 113 tmax h 1 0.5 1 1 0.5 0.5 t1/2 h NE 1.44 1.63 NE 1.45 1.7 AUC24 ng·h/mL 18482 629 683 45.9 664 274 AUC∞ ng·h/mL NE 623 NE NE NE NE

mg/kg/ 750 250 Cmax ng/mL 3713 312 417 50.6 291 278 tmax h 4 1 4 0.5 2 2 t1/2 h NE 2.26 NE NE NE 1.69 AUC24 ng·h/mL 42759 1777 2461 252 1770 1155 AUC∞ ng·h/mL NE 1720 NE NE NE NE

mg/kg/ 2000 750 Cmax ng/mL 3617 532 546 150 NA NA tmax h 1 1 1 1 NA NA t1/2 h NE NE 7.23 4.15 NA NA AUC24 ng·h/mL 46334 3404 4544 1034 NA NA AUC∞ ng·h/mL NE NE NE NE NA NA a) 1 9 250 mg/kg/ 10 50 mg/kg/ 1 8 250 mg/kg/

9 50 mg/kg/ b) 1 9 750 mg/kg/ 10 250 mg/kg/1 8 750 mg/kg/ 9 250 mg/kg/ c) 1 8 2000 mg/kg/ 9 11

12 48 750 mg/kg/ 1 5 2000 mg/kg/ 6 8 948 750 mg/kg/ NA NE

(3) 26

4.2.3.2.6

Sprague-Dawley 50 150 400 mg/kg/

1 183

2.6.4-10

2 ng/mL

1 0.5 4 Cmax

1.29 3.82 t1/2

183 0.5 2 Cmax

2.96 6.37 t1/2

Cmax AUC

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19

2.6.4-10 Sprague-Dawley 50 150 400

mg/kg/

mg/kg/ 50 150 400

1 183 1 183 1 183 3 /

Cmax ng/mL 729 77.1 138 132 3243 189 251 276 3537 500 494 291tmax h 1.00 1.00 2.00 1.00 4.00 2.00 1.00 2.00 4.00 0.50 2.00 0.50t1/2 h 1.29 1.99 4.99 2.96 2.49 1.72 3.67 3.88 3.34 3.82 6.37 4.64AUC24 ng·h/mL 3006 240 1132 710 16397 1063 2220 1734 49610 1889 5586 3106AUC∞ ng·h/mL 2981 244 NE NE 16413 1038 NE NE 50077 1913 NE NENE

(4)

4.2.3.5.2.2

Sprague-Dawley 10 30 100 mg/kg/

6 17 14

2.6.4-11

0.55 ng/mL

1.33 1.67 Cmax Cmax

AUC24

2.6.4-11 Sprague-Dawley 10 30 100 mg/kg/

6 17

± 9 14

mg/kg/ 10 30 100 3 /

Cmax ng/mL 10.8±1.65 33.8±4.71 55.7a) tmax h 1.67±0.58 1.33±0.58 1.5a) AUC24 ng·h/mL 34.0±5.55 109±10.5 367b) a) n=2 b) n=1

2.6.4.3.3.3

(1) 4

4.2.3.2.7

2 10 50 250 1000 mg/kg/

1 28

2.6.4-12

4 ng/mL 2 mg/kg/

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2.6.4

20

4 ng/mL

1 1.5 4.8 Cmax

2.6 4.6 t1/2

Cmax AUC

28 1.1 4.0 Cmax

4.4 5.7 t1/2

Cmax

AUC

2.6.4-12 2 a) 10 50 250 1000

mg/kg/

± 1 28

5 /

mg/kg/ 10 Cmax ng/mL 9.2±2.73 b) 9.9±5.16 b) 4.7±0.87 6.1±2.38 b) tmax h 2.0±1.41 b) 1.5±0.58 b) 4.0±1.63 1.6±0.50 b) t1/2 h 2.6±0.60 c) 4.6±2.56 b) NE NE AUC∞ ng·h/mL 37.4±10.36 c) 62.6±32.21 b) NE NE

mg/kg/ 50 Cmax ng/mL 27.2±9.68 59.6±45.08 15.3±8.19 14.7±6.88 tmax h 3.2±1.10 3.4±2.79 1.5±1.41 2.3±1.64 t1/2 h 3.2±1.19 4.3±3.60 5.0±2.07 b) 5.3±1.94 b) AUC∞ ng·h/mL 196.4±56.87 356.3±189.70 110.8±18.17 b) 144.2±51.11 b)

mg/kg/ 250 Cmax ng/mL 85.9±33.63 87.0±41.06 37.5±25.94 37.5±10.65 tmax h 1.6±0.55 2.8±1.64 1.1±0.55 2.4±1.52 t1/2 h 4.5±1.13 3.3±1.67 4.7±1.44 4.4±2.48 AUC∞ ng·h/mL 685.6±327.48 610.6±338.49 218.6±77.64 288.3±56.47

mg/kg/ 1000 Cmax ng/mL 184.6±86.34 435.0±399.61 38.5±24.71 157.1±130.48 tmax h 4.8±1.79 3.2±2.95 3.8±2.68 1.4±0.55 t1/2 h 4.0±1.63 4.5±1.38 5.2±2.76 5.7±1.43 AUC∞ ng·h/mL 1712.7±1123.13 3248.1±2686.96 317.2±153.07 884.9±561.59 a) 2 mg/kg/ b) n=4 c) n=3 NE

(2) 13

4.2.3.2.8

250 750 2000 mg/kg/

1 91

2.6.4-13

4 ng/mL

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2.6.4

21

1 1.25 2.50 Cmax

6.79 11.8 t1/2

91 1.88 8.57 Cmax

3.65 9.42 t1/2

Cmax AUC

2.6.4-13 250 750 2000 mg/kg/

±

mg/kg/ 250 750 2000

1 91 1 91 1 91 4 / 7 /

Cmax ng/mL 519 ±331

261 ±114

146 ±78

103 ±93

526 ±305

360 ±98

61.6 ±36.0

99.8 ±35.0

478 ±278

597 ±252

115 ±56

243 ±81

tmax h 1.25 ±0.50

1.25 ±0.50

8.00 ±4.62

2.50 ±3.67

2.50 ±1.73

1.25 ±0.50

1.88 ±1.55

3.75 ±3.10

2.43 ±2.51

1.29 ±0.49

5.43 ±3.41

8.57 ±1.51

t1/2 h 7.59 a) 10.7 ±0.4 b) NE 3.65

±1.01 b)6.79

±1.75 b)11.8 ±1.3 NE 8.15 c) 8.21

±2.24 d) 6.96

±2.33 e) 9.42 a) NE

AUC24

ng·h/mL

2004 ±1193

1326 ±530

1252 ±760

947 ±1233

3148 ±2524

1765 ±210

774 ±542

999 ±608

2737 ±913

4100 ±3156

1604 ±966

2961±946

AUC∞ ng·h/mL 2024 a) 1800 ±701 b) NE NE 3911

±2762 b)2169 ±309 NE NE 3154

±954 d) 5252

±4020 e) NE NE

a) n=2 b) n=3 c) n=1 d) n=6 e) n=4 NE

(3) 39

4.2.3.2.9

250 500 1000 mg/kg/

1 273

2.6.4-14

1 ng/mL

1 0.875 3.14 Cmax

5.03 6.87 t1/2

273 1.50 4.75 Cmax

5.82 9.95 t1/2

Cmax AUC 500 mg/kg

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22

2.6.4-14 250 500 1000 mg/kg/

±

mg/kg/ 250 500 1000

1 273 1 273 1 273 4 / 7 /

Cmax ng/mL 114 ±68

151 ±149

139 ±105

87.5 ±51.6

226 ±91

482 ±439

183 ±89

466 ±496

238 ±110

471 ±537

270 ±89 a)

185 ±109

tmax h 0.875 ±0.250

1.75 ±1.50

1.50 ±0.58

4.75 ±4.99

2.50 ±1.00

1.25 ±0.50

3.75 ±3.10

3.75 ±3.10

3.00 ±2.58

3.14 ±2.48

4.00 ±3.10 a)

2.86 ±2.27

t1/2 h 5.20 ±0.37 b)

6.87 ±1.91 b) 8.33 c) 7.06 d) 5.03

±1.365.73

±1.84 NE 9.95 d) 5.48 ±1.38 a)

5.13 ±1.12 e) 5.82 c) 9.48

±1.81 b)

AUC24

ng·h/mL

594 ±196

628 ±293

610 ±356

489 ±258

1577 ±874

3408 ±3808

1139 ±667

4154 ±4618

1637 ±846

2945 ±2989

2095 ±550 a)

1223±625

AUC∞ ng·h/mL 713 ±43 b)

757 ±264 b) NE NE 1628

±8723504

±3864 NE NE 1461 ±630 a)

3258 ±3512 e) NE NE

a) n=6 b) n=3 c) n=2 d) n=1 e) n=5 NE

2.6.4.4

2.6.4.4.1 QWBA 4.2.2.3.1

Sprague-Dawley Long Evans 14C-

100 mg/kg 72 168

2.6.4-15 2.6.5.5

0.5 4

8 24 882 ng eq/g 72

/ AUC

48

15 35

5 9

2 5

1 2

AUC AUC

2.6.5.5 14C-

14C-

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23

2.6.4-15 Sprague-Dawley Long Evans 14C-

Sprague-Dawley Long Evans

3 /

Cmax

ng eq/gtmax

h t1/2

h AUClast

ng eq·h/g/

AUC a)Cmax

ng eq/gtmax

ht1/2

h AUClast

ng eq·h/g /

AUC a)

38700 4.00 15.4 288289 32.4 11100 4.00 4.54 108785 27.3 3620 4.00 NE 8895 NE 1200 0.500 8.67 3987 NE

LSC 3900 4.00 1.06 17997 2.02 1350 0.500 3.23 7417 1.86 NE NE NE NE NE NE NE NE NE NE

6560 4.00 NE 14380 1.62 1050 4.00 NE 3652 0.916 13300 4.00 0.823 53429 6.01 3500 4.00 1.21 14877 3.73 12600 4.00 NE 24830 2.79 2480 4.00 NE 5394 1.35 18900 4.00 0.921 75975 8.54 4900 4.00 NE 10449 2.62 8330 4.00 NE 16618 1.87 1810 4.00 NE 4074 1.02 19400 4.00 4.19 170474 19.2 16600 8.00 20.7 233860 58.7 8620 4.00 NE 18805 2.11 1580 4.00 NE 5865 1.47

5930 4.00 1.02 24530 2.76 2240 4.00 NE 4834 1.21 6540 0.500 11.3 22320 2.51 7350 0.500 1.86 18183 4.56

18500 4.00 1.00 76155 8.56 4260 4.00 1.09 20409 5.12 914 4.00 NE 1600 0.180 1960 8.00 23.3 43394 10.9

NE NE NE NE NE 1240 4.00 NE 2170 0.544 5380 4.00 NE 10929 1.23 10900 4.00 185 519655 130

15500 4.00 1.62 66845 7.51 5670 4.00 8.93 50903 12.8 19300 4.00 1.01 79135 8.90 4670 4.00 2.34 24393 6.12

16700 4.00 0.943 67991 7.64 3180 4.00 NE 7455 1.87 18100 4.00 0.724 72701 8.17 3710 4.00 NE 10413 2.61

31200 4.00 6.56 187124 21.0 12100 4.00 4.33 99675 25.0 35400 4.00 6.65 219670 24.7 16600 4.00 5.62 136706 34.3 16600 4.00 1.18 74170 8.34 4290 4.00 2.46 26188 6.57

19400 8.00 NE 72065 8.10 17000 8.00 NE 46363 11.6 66500 4.00 3.28 430275 48.4 48100 0.500 4.41 374316 93.9

8260 4.00 0.871 34801 3.91 1740 0.500 3.04 8622 2.16 6790 4.00 NE 13623 1.53 1330 4.00 NE 3448 0.865

4250 4.00 NE 8080 0.908 470 4.00 NE 1583 0.397 10500 4.00 NE 22915 2.58 2050 0.500 9.09 6848 1.72 5310 4.00 NE 49355 5.55 2190 4.00 1.50 8899 2.23

13000 4.00 0.742 54810 6.16 2310 0.500 NE 8628 2.16 10400 4.00 NE 19434 2.18 2860 4.00 NE 5005 1.26

LSC 5970 4.00 1.03 27334 3.07 2050 0.500 1.85 11447 2.87 25000 4.00 NE 229070 25.8 9560 4.00 NE 218408 54.8 9990 4.00 1.03 41589 4.68 2640 4.00 1.44 12380 3.11 11800 4.00 NE 25290 2.84 2420 4.00 NE 8095 2.03 2580 4.00 1.74 11887 1.34 319 8.00 NE 638 0.160

6440 4.00 0.977 26182 2.94 1570 4.00 NE 3362 0.843 NA NA NA NA NA 1850 4.00 NE 3874 0.972

37500 4.00 1.93 199225 22.4 34500 4.00 2.93 217175 54.5 17000 4.00 0.929 68510 7.70 4780 4.00 1.76 22191 5.57

17300 4.00 0.689 68995 7.76 4610 4.00 NE 9884 2.48 16400 4.00 1.48 66560 7.48 5170 4.00 3.65 24228 6.08

8340 4.00 NE 18575 2.09 1660 0.500 15.5 5805 1.46 10000 4.00 43.7 139736 15.7 6490 4.00 109 253730 63.6

3700 4.00 NE 6475 0.728 1270 4.00 NE 2223 0.558 5540 4.00 NE 10979 1.23 1020 4.00 NE 2485 0.623 9810 4.00 NE 21728 2.44 3000 4.00 NE 9450 2.37

6020 4.00 1.30 26959 3.03 2930 4.00 NE 8348 2.09 a) QWBA AUClast 0 NA NE

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24

2.6.4.4.2

2.6.4.4.2.1

4.2.2.3.2

Sprague-Dawley HSA 45 mg/mL

AGP 1.0 mg/mL 0.1 10 mol/L 14C- 89.7 93.2%

37 15 2.6.5.6

A

96.3

99.0% 97.4 98.3% 98.8 99.1% HSA AGP

95.6 97.6% 94.3 95.7%

5 mol/L 14C- 95.4

98.8% 37 120 14C-

2.6.4.4.2.2

4.2.2.3.3 4.2.2.3.4

Swiss Sprague-Dawley New Zealand White

HSA 43 mg/mL AGP 0.7 2.0 mg/mL 175 3500

ng/mL 0.5 10 mol/L 14C- 99.9% 0.067 mol/L

37 1 2.6.5.6 B

99.8%

HSA AGP 99.879% 89.4 94.44%

COU-AA-011

500 ng/mL 1.4 mol/L 14C-

99.7% 0.067 mol/L 37 1

2.6.5.6 C

99.78 99.81%

99.81%

2.6.4.4.3 4.2.2.3.1

Sprague-Dawley 14C- 100 mg/kg

168

1 0.564 0.764

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25

2.6.4.4.4

2.6.4.5

in vitro in vivo

in vitro in vivo

in vitro 4.2.2.4.2 in vivo

COU-AA-007 2.7.2.2.2.1 (2) 1) 2.6.4-16

2.6.4-16 In vitro 4.2.2.4.2 in vivo COU-AA-007

In vitro code In vivo code Identification

M1 M70 O-Sulphation and N-glucuronidation of ABT M2 - Tri-oxidation of ABT (N-oxide) M3 - Tri-oxidation of ABT M4 - Di-oxidation and dehydrogenation of ABT (N-oxide) M5 - Di-oxidation of ABT (N-oxide) M6 M73 Oxidation, hydrogenation and glucuronidation of ABT M7 M31 Oxidation and O-sulphation of ABT (N-oxide) M8 M62 Di-oxidation of ABT (N-oxide)

M9 M65 /M77M35/M38 a)

Oxidation and sulphation of ABT

M10 - O-Glucuronidation of ABT M11 - N-Oxidation of ABT M12 M45 O-Sulphation of ABT M13 - Oxidation of ABT M14 - Hydroxylation of ABT M15 - Di-oxidation of ABT ABT M50 Ester hydrolysis of UD

- M23 Di-oxidation and sulphation of ABT - M75 Dehydration of ABT - M51 Hydrogenation of ABT - M52 Hydrogenation of ABT - M61 Hydrogenation, oxidation and sulphation of ABT - M69 Hydrogenation, di-oxidation and glucuronidation of ABT - M72 Di-oxidation and sulphation of ABT - M46 Hydrogenation and sulphation of ABT

a) In vitro M9 in vivoM65

- ABT UD

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2.6.4.5.1 In vitro

2.6.4.5.1.1

4.2.2.4.1 4.2.2.4.2

10 50 μmol/L 37 120

2.6.5.9 A

Swiss Sprague-Dawley New Zealand White

5 μmol/L 14C- 60 76

2.6.5.9 B

5

60

76

M12

M10 M1 M6 M7

M9 M11 M13 M14 M5 M8 M15

M2 M3

2.6.4-5

In vitro M1 M3 M6 M7 M8 M9 M10 M11 M12

M14 M15

M1

NADPH

CYP

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27

N

O

OAA

N

HOABT

N

OSO

HO O

M12

N

OO

COOHHO

HO OH

M10

N

OSO

HO O

OCOOH

OH

OHOH

M1

M13

M3

M2

M9

M4

N

HOO

OCOOH

OH

OHOH

H2M6

N

HO

SO3O

N

HO

2O

ester hydrolysis

hydroxylat ion( CY P3A4)

d i-oxidation

oxidationdehydrogenation

oxidationhydrogenation

g lucuronidation

N -glucuronidation

O-glucuronidation( UGT 1A4)

O-sulf ation

monkey mman

mouse mrabbit fdog m

rat mrabbit fmonkey mman

rabbit fdog m


rat mmonkey mman

rat mrabbit f

dog mmonkey m

man

rat mrabbit fdog mmonkey mman

mouse m,frat m,frabbit fdog mmonkey mman

mouse frat m,frabbit fmonkey mman

oxydationhydrogenation

+

O-sulf ation( SULT 2A1)

tri-oxidation

oxidation

N

HO

2 O

O

N

HO

O - 2H

O

OH

N

HO

O

O

N

HO O

OM5

N

OSO

HO O

O

M7

N

HO

OM14

N

HOHO

M15

N

HO

O

M11

oxidat ion

mouse m,frat m,f

N -oxidation( CYP3A4)


rat mrat frabbit fmonkey mman

oxidat ionsulf ation

oxidat ion

mouse mrabbit f

dog m

rat mrabbit f

dog mmonkey m

man

N

HO

O

O

M8

oxidat ion(CY P3A4)

N -oxidation

2.6.4-5 in vitro AA ABT f m

in vitro code

JEDI_DEV00 \ 0900fde9803f2acd \ 1.11 \ 2013-06-28 20:41

2.6.4

28

2.6.4.5.1.2

4.2.2.4.2 4.2.2.4.3

(1) CYP

25 mol/L 14C- CYP

37 10 14C- CYP

2.6.5.9 C

CYP3A4 14C- 14C-

CYP3A4 CYP1A2

CYP2A6 CYP2B6 CYP2C8 CYP2C9 CYP2C19 CYP2D6 CYP2E1

CYP 14C-

CYP 25 mol/L 14C- 37

10 14C- CYP

2.6.5.9 C 14C- CYP3A4

CYP1A1 CYP1A2 CYP2A6 CYP2B6 CYP2C8 CYP2C9 CYP2C19 CYP2D6 CYP2E114C-

(2) UGT

UGT 50 mol/L 14C- 37 3014C- UGT 2.6.5.9 C

14C- UGT1A4 UGT1A3

UGT1A1 UGT1A6 UGT1A7 UGT1A8 UGT1A9

UGT1A10 UGT2B4 UGT2B7 UGT2B15 UGT2B17 14C-

(3) SULT

SULT 5 mol/L 14C- 37 514C- SULT 2.6.5.9 C

14C- SULT2A1 SULT1E1

SULT1A1*1 SULT1A1*2 SULT1A3 SULT1B1 14C-

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29

CYP3A4 UGT1A4 SULT2A1 UGT1A3

SULT1E1 14C- CYP3A4 UGT1A4 SULT2A1

CYP3A4

M8 M11 N- M14 UGT1A4 M10 O-

SULT2A1 M12 O- 2.6.4-5

2.6.4.5.2 In vivo

2.6.4.5.2.1

4.2.2.3.1

Sprague-Dawley Sprague-Dawley14C- 100 mg/kg

2.6.5.10 A 2.6.5.11 B

II

(1)

21 0.25 2 Cmax

2.6.4-17 0.5

0.25 4

0.5 abiraterone sulphate M45

mono-oxy-abiraterone sulphate M31 M32 M35

M38 hydrogenated-mono-oxy-abiraterone sulphate M33 mono-oxy-abiraterone

M42 mono-oxy-abiraterone sulphate M31 M32 M36

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2.6.4-17 Sprague-Dawley

Cmax

ng eq/g a)tmax h

Cmax ng eq/g a)

tmaxh

M15 461A Di-oxy-ABT sulphate 32.5 0.5 ND NA M23 461B Di-oxy-ABT sulphate 44.3 2 22.2 2 M27 383 Hydrogenated-di-oxy-ABT 7.64 8 15.2 2 M28 Unknown 82.5 2 ND NA M30 543B Hydrogenated-mono-oxy-ABT glucuronide 29.9 0.5 33.9 1 M31 445A N-oxide ABT sulphate 184 2 227 2 M32 445B Mono-oxy-ABT sulphate 65.1 0.5 176 2 M33 447C Hydrogenated-mono-oxy-ABT sulphate 55.8 2 27.2 1 M35 445D Mono-oxy-ABT sulphate 49.8 1 33.8 8 M36 445E Mono-oxy-ABT sulphate ND NA 50.1 0.5 M37 Unknown ND NA 13.2 0.5 M38 445F Mono-oxy-ABT sulphate 97.5 2 30.7 2 M42 365A Mono-oxy-ABT 28.6 1 217 1 M45 429 ABT sulphate 1960 2 1810 2 M46 431 Hydrogenated-ABT sulphate 35.2 1 24.7 1 M47 Unknown ND NA 17.2 4 M48 365B Mono-oxy-ABT ND NA 19.8 4 M49 Unknown 73.0 1 ND NA M50 ABT 37.3 2 15.8 0.5 M53 Unknown ND NA 20.1 4 M54 Unknown 90.2 0.25 80.4 0.25 AA 29.0 0.25 9.88 0.25 a) AA AA ABT NA ND 11%

LC-MS

(2)

24 27

0.1%

N-oxide abiraterone sulphate M31 0.06%

(3)

48 27

hydrogenated-di-oxy-abiraterone sulphate M18 hydrogenated-abiraterone glucuronide M39

2% di-oxy-abiraterone sulphate M23 N-oxide

abiraterone sulphate M31 abiraterone sulphate M45 1%

(4)

48 20 30%

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31

13.1% 6%

abiraterone sulphate M45 15%

2.6.4.5.2.2

4.2.2.4.4

500 mg/kg/ 39

2.6.5.10 C 2.6.5.11 C

39

II

2.6.4.5.2.3

4.2.2.4.5

II

2.6.4-6 14C-

1000 mg/ COU-AA-007

10%


43% 2.7.2.2.2.1 (2) 1) 5.3.1.1.1

2.6%

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32

N

HO

Abiraterone (M50) 351A(M51), 351B (M52)

431(M46)

N

HO3 SO429(M45)

381A (M62)

461B (M23)

N

HO SO3 H

445C (M65), 445I (M77)

543C (M73)

4 1,2

1,2

1 = Oxidation/Hydroxylation2 = Sulfate conjugation3 = Glucuronidation4 = hydrogenation5 = Dehydration

N

331 (M75)

N

OH3C

O

Abiraterone Acetate

N

HO3SO

Gluc

605 (M70)

HO

Hydrolysis

N

HO

HOHO

HO3 S

N

O

O

HO3S

445A (M31)

N

HO

HO

445D (M35),445F(M38)HO3 S

2

447A (M61)

N

HO

HOHO

N

O2H

HO3 S

N

HO 2H

N

HO

HO

OH

HO3 S

461G (M72)

5

N

HOGluc

HO

2 H

N

HOHO3 S

HO

2H

1,2

1

3 1

4

2

N

HOGluc

2H

HOHO

1

559 (M69)

3,41

1,3

2

2.6.4-6

1000 mg/ /

COU-AA-006 8 abiraterone sulphate M45 N-oxide

abiraterone sulphate M31 28 26

39 2.6.4-18

1500 400 1000 mg/kg/



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33

2.6.4-18 27 Abiraterone sulphate M45 mg/kg/ 125 375 750 1500

/ Cmax 0.03 0.21 0.04 0.93 0.03 1.69 0.15 5.83 / AUC24 0.03 0.21 NC 1.14 0.06 NC 0.31 10.51 N-oxide abiraterone sulphate M31 mg/kg/ 125 375 750 1500

/ Cmax 0.01 0.11 0.03 0.57 0.03 1.35 0.21 6.61 / AUC24 0.01 0.04 0.02 0.27 0.02 NC 0.18 4.37 183 Abiraterone sulphate M45 mg/kg/ 50 150 400

/ Cmax 0.2 0.5 0.4 1.6 1.4 2.6 / AUC24 0.2 NC 0.5 1.3 2.7 3.9 N-oxide abiraterone sulphate M31 mg/kg/ 50 150 400

/ Cmax 0.038 0.1 0.1 0.2 0.2 0.3 / AUC24 NC NC 0.045 0.1 0.2 0.2 273 Abiraterone sulphate M45 mg/kg/ 250 500 1000

/ Cmax 1.2 1.3 2.7 3.4 7.2 5.8 / AUC24 0.8 0.4 2.2 4.7 13.1 5.7

N-oxide abiraterone sulphate M31 mg/kg/ 250 500 1000

/ Cmax 0.2 0.2 0.3 0.4 0.9 0.9 / AUC24 0.1 0.1 0.1 0.2 0.7 0.4

NC

2.6.4.5.3 4.2.2.2.4

10

25 mg/kg HP- -CD


2.6.4-7 2.6.5.10 B

5

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34

abiraterone sulphate M45 N-oxide abiraterone sulphate

M31

2.6.4-19

2.6.4-7

25 mg/kg

M45 M31

+ n=3 0.77 n=2 n=1

AA ABT M31 N-oxide abiraterone sulphate M45 abiraterone sulphate

2.6.4-19

M45 M31

AUC ng·h/mL ±

mg/kg 10 25 10 25 3 / 3 /

AA 14.7a) 156a) 61.6a) 1.56b) 21.9b) 7.88a) ABT 2317±860 7499±558 7527±1243 681±81.8 3422±377 3656±535ABT sulphate M45 - 91.6±23.5 115±36.1 30.9b) 189±38.6 201a) N-oxide ABT sulphate M31 - 54.2±27.4 101a) 17.7±5.66 93.9±36.9 173a) a) n=2 b) n=1 - AUC∞ 25% AA ABT

2.6.4.5.4

2.6.4.5.4.1 In vitro

(1)

4.2.2.4.6 4.2.2.4.7 4.2.2.4.8

CYP CYP1A2

CYP2A6 CYP2C9 S- CYP2C19

CYP2D6 CYP2E1

CYP3A4/5 0.1 10 mol/L

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35

37 CYP Ki 2.6.5.12

A


Ki 0.32 0.12 0.16 mol/L CYP2C9 CYP2E1 CYP3A4/5

Ki 17.6 31.8 6.50 11.4 mol/L CYP2A6

CYP1A2 CYP2D6 Ki

0.44 0.39 mol/L CYP2C9 CYP2C19 CYP3A4/5 Ki

29.8 46.3 8.01 10.2 mol/L CYP2A6 CYP2E1

CYP2C8

37 CYP2C8

IC50 2.6.5.12 B

CYP2C8

IC50 1.3 3.0 1.6 2.9 μmol/L

CYP2B6 CYP2C19

S-

37 CYP2B6 CYP2C19 IC50

2.6.5.12 C

CYP2B6 CYP2C19

IC50 10 μmol/L

(2)

4.2.2.4.9

0.1 10 mol/L 37 48

CYP CYP1A2 CYP3A4

30 mol/L 10 mol/L 2.6.5.12 D

CYP1A2

1.6

48 CYP2C9 CYP3A4

0.7 0.8

2.6.4.5.4.2 In vivo

4.2.2.4.10

Sprague-Dawley 40 400 mg/kg/ 4

2.6.5.12 E

40 mg/kg/ SULT2A1 400 mg/kg/

CYP CYP1A1/2 CYP4A1 UGT

in vitro M9

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36

40 mg/kg/ CYP2E1 CYP3A1/2 CYP2B

400 mg/kg/

40 mg/kg/ UGT 400 mg/kg/

CYP3A1/2 CYP4A1 400 mg/kg/

CYP2E1 SULT2A1

in vitro M9

400 mg/kg/ CYP1A1/2

2.6.4.6

2.6.4.6.1 4.2.2.3.1

Sprague-Dawley Sprague-Dawley14C- 100 mg/kg

2.6.5.13 2.6.5.14

24 85% 168

90% 168

1%

24

66% 120 75%

120 20% 1%

2.6.4.6.2

2.6.4.7

2.6.4.7.1 P-gp 4.2.2.2.1

Caco-2 0.1 30 mol/L 0.1 15 mol/L

P-gp 1 mol/L 37 1

P-gp 2.6.5.15

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37

Efflux Ratio

P-gp IC50 10.8 μmol/L

Efflux Ratio P-gp

2.6.4.7.2 4.2.2.6.1

BCRP MRP2 MDCKII P-gp LLC-PK1

MDCKII LLC-PK1 1 15 μmol/L

abiraterone sulphate M45 N-oxide abiraterone sulphate M31 37 2

2.6.5.15 B

efflux ratio

BCRP

MRP2 P-gp abiraterone sulphate M45 BCRP

MRP2 P-gp N-oxide abiraterone sulphate M31 MRP2 P-gp

BCRP 1 15 mol/L

abiraterone sulphate M45 N-oxide abiraterone sulphate M31 37

1 BCRP 2.6.5.15 B

N-oxide abiraterone sulphate M31 BCRP

BCRP N-oxide abiraterone

sulphate M31 BCRP abiraterone

sulphate M45 BCRP

2.6.4.8

2.6.4.9

2.6.4.9.1

Caco-2 in vitro

1 3 Cmax

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38

9 t1/2

2 1 7 3 12

2.3.S.1.3

37 8 1.5%

2.6.4.9.2 14C-

/ AUC 48

15 35

5 9

2 5

1 2 AUC

AUC 24

882 ng eq/g14C-

14C-

/

1 14C-

14C-

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39

96.3 99.0% 97.4 98.3% 98.8 99.1%

HSA AGP 95.6 97.6% 94.3 95.7%

HSA AGP

99.8% HSA AGP

99.879% 89.4 94.44%

14C-

89.7 93.2% 99.9%

2.6.4.9.3

in

vitro

II in vitro

abiraterone sulphate N-glucuronide in vitro code M1

NADPH

CYP

CYP3A4 UGT1A4 SULT2A1 UGT1A3 SULT1E1

in vivo

II


N-oxide abiraterone sulphate M31 0.06%

30%

in vivo COU-AA-00714C-

10% abiraterone sulphate M45 N-oxide abiraterone sulphate

M31 43% 2.7.2.2.2.1 (2) 1)

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40

28 26

39

1500 400 1000 mg/kg/ abiraterone sulphate

M45 N-oxide


CYP


Ki 0.32 0.12 0.16 mol/L CYP2C8 IC50 1.3 3.0 mol/L

CYP1A2 CYP2D6 Ki 0.44

0.39 mol/L CYP2C8 IC50 1.6 2.9 mol/L

CYP1A2

CYP2D6 COU-AA-015

Cmax AUC

Cmax AUC 2.7.2.2.2.4 (1) 3)

2.7.2.3.7.1

CYP1A2

CYP2C9 CYP3A4

40 400 mg/kg/ 4

CYP4A1 UGT CYP2E1

CYP CYP1A1/2 SULT2A1

CYP3A1/2 CYP2B CYP3A1/2

SULT2A1

2.6.4.9.4 14C-

24

85% 168 90%

168 1%

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41

14C- 120

20%

COU-AA-007

87.9% 5% 2.7.2.2.2.1 (2) 1)

2.6.4.9.5

Caco-2

P-gp P-gp

IC50 10.8 μmol/L

BCRP MRP2 P-gp

BCRP

abiraterone sulphate M45 BCRP


2.6.4.10

2.6.4.11

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1

2.6.5

2.6.5.1

CTD

Caco-2 Caco-2 In vitro 8202265 4.2.2.2.1

AA ABT -001 4.2.2.2.2

AA ABT Janssen Research & Development FK10118 4.2.2.2.3

AA ABT Janssen Research & Development FK10121 4.2.2.2.4

AA ABT Janssen Research & Development FK7653 4.2.2.2.5 AA ABT Janssen Research & Development FK10014 4.2.2.2.6

AA ABT --501648 4.2.2.2.7

AA ABT 15 Janssen Research & Development TOX9586 4.2.3.2.1 AA ABT 4 a) TOX9688 4.2.3.2.2

AA ABT 6 17 a) Janssen Research & Development TOX10115 4.2.3.5.2.2

AA ABT 4 a) 1632/1 4.2.3.2.3 AA ABT 4 a) Janssen Research & Development TOX9587 4.2.3.7.6.1 AA ABT 13 a) 7777-100 4.2.3.2.5 AA ABT 26 a) 7777-105 4.2.3.2.6 AA ABT 4 a) 1818-001 4.2.3.2.7 AA ABT 13 a) 7777-101 4.2.3.2.8 AA ABT 39 a) 7777-103 4.2.3.2.9 a) GLP AA ABT

JEDI_DEV00 \ 0900fde9803efabe \ 1.7 \ 2013-06-17 18:27

2.6.5

2

2.6.5.1

CTD

8202443 4.2.2.3.1 In vitro 8202266 4.2.2.3.2

In vitro Janssen Research & Development FK7603 4.2.2.3.3


In vitro 400380 4.2.2.4.1


In vitro 8202268 4.2.2.4.3 8202443 4.2.2.3.1 FK7532 4.2.2.4.4

Janssen Research & Development BA1732 4.2.2.4.5

In vitro 400379 4.2.2.4.6 In vitro Janssen Research & Development FK10146 4.2.2.4.7 In vitro Janssen Research & Development FK10147 4.2.2.4.8 In vitro 400378 4.2.2.4.9 Janssen Research & Development FK7476 4.2.2.4.10

8202443 4.2.2.3.1 8202443 4.2.2.3.1

P-gp Caco-2 In vitro 8202265 4.2.2.2.1

BCRP MRP2 MDCKII

P-gp LLC-PK1BCRP



2.6.5

3

2.6.5.2

2.6.4.2


2.6.5

4

2.6.5.3 A In vitro

8202265 CTD 4.2.2.2.1

Caco-2 P-gp 10 mol/L A 100 mol/L 1 30 mol/L 14C-AA 1 15

mol/L 14C-ABT 37 1 4 A B B A

P-gp 10 mol/L 100 mol/L 14C-AA

h 1 2 3 4 1 2 3 4 1 2 3 4 mol/L 1

10-6 cm/s a) A B 3.69±0.28 2.47±0.80 2.8±0.03 1.85±0.56 5.01±0.21 3.76±0.70 3.59±0.59 3.36±0.44 3.73±0.28 3.07±0.52 3.09±0.15 2.71±0.29B A 1.40±0.31 1.13±0.14 1.40±0.19 1.11±0.05 1.02±0.09 0.92±0.09 1.05±0.07 0.93±0.03 1.91±0.35 1.60±0.26 1.77±0.13 1.65±0.14

Efflux Ratio 0.38 0.46 0.50 0.60 0.20 0.24 0.29 0.28 0.51 0.52 0.57 0.61mol/L 10

10-6 cm/s a) A B 1.70±0.28 1.52±0.17 1.39±0.03 1.19±0.29 3.36±0.22 3.32±0.28 3.26±0.66 3.48±1.25 3.03±0.03 2.71±0.10 2.74±0.23 2.32±0.28B A 1.32±0.11 1.10±0.13 1.58±0.03 1.57±0.17 0.80±0.04 0.80±0.06 0.85±0.14 0.89±0.08 1.48±0.09 1.58±0.08 1.83±0.02 1.82±0.13

Efflux Ratio 0.78 0.73 1.14 1.31 0.24 0.24 0.26 0.26 0.49 0.58 0.67 0.79mol/L 30

10-6 cm/s a) A B 1.06±0.09 0.95±0.16 0.88±0.09 1.19±0.14 2.48±0.18 1.86±0.22 2.26±0.06 2.05±0.23 1.81±0.17 1.82±0.17 1.66±0.16 2.16±0.51B A 0.99±0.05 0.79±0.07 0.95±0.06 1.11±0.06 0.52±0.02 0.48±0.03 0.53±0.03 0.54±0.04 0.97±0.00 0.97±0.03 1.04±0.05 0.97±0.03

Efflux Ratio 0.93 0.84 1.08 0.94 0.21 0.26 0.23 0.26 0.54 0.53 0.62 0.45 14C-ABT

h 1 2 3 4 1 2 3 4 1 2 3 4 mol/L 1

10-6 cm/s a) A B 3.26±0.41 3.37±0.12 3.46±0.55 3.25±0.39 2.69±0.19 2.78±0.43 3.09±0.43 2.30±0.08 2.85±0.13 3.28±0.31 3.75±0.53 3.39±0.43 B A 2.49±0.04 3.41±0.29 4.08±0.42 4.60±0.22 1.91±0.18 2.26±0.05 2.70±0.06 2.62±0.05 2.77±0.47 3.75±0.15 4.76±0.22 4.79±0.29

Efflux Ratio 0.76 1.01 1.18 1.41 0.71 0.81 0.87 1.14 0.97 1.14 1.27 1.41 mol/L 5

10-6 cm/s a) A B 1.66±0.18 2.55±0.39 2.28±0.33 2.10±0.15 1.80±0.13 2.08±0.34 2.06±0.09 2.18±0.08 1.87±0.13 2.05±0.35 2.43±0.21 2.13±0.12 B A 1.56±0.11 1.93±0.01 2.16±0.02 2.28±0.12 1.20±0.02 1.32±0.11 1.55±0.17 1.50±0.01 1.74±0.19 2.38±0.04 2.60±0.11 2.72±0.20

Efflux Ratio 0.94 0.76 0.95 1.09 0.66 0.64 0.75 0.69 0.93 1.16 1.07 1.28 mol/L 15

10-6 cm/s a) A B 1.39±0.03 1.78±0.11 1.72±0.25 1.37±0.13 1.49±0.07 1.70±0.16 1.90±0.17 1.71±0.21 1.53±0.13 1.62±0.14 1.85±0.13 1.61±0.32 B A 1.43±0.08 1.47±0.11 1.52±0.01 1.57±0.09 1.06±0.05 1.07±0.05 1.15±0.05 1.12±0.05 1.38±0.08 1.59±0.05 1.68±0.09 1.76±0.01

Efflux Ratio 1.03 0.83 0.88 1.14 0.71 0.63 0.60 0.65 0.91 0.98 0.91 1.09 a) 3 ± AA ABT


2.6.5

5

2.6.5.3 B

-001 CTD 4.2.2.2.2

WHT 4 /

15.4% 3.8% Tween 80 AA

mg/kg 39.2

ABT

a) Cmax ng/mL 2000 4 5 tmax h 0.25 1 0.5 t1/2 h 1.6 2.0 AUC12 ng·h/mL 3807.0 10251.0

% b) 37.1 NA a) b) ABT / AA ABT NA


2.6.5

6

2.6.5.3 C

FK10118 CTD 4.2.2.2.3

6 / 3 /

AA 20% SBE- -CD AA

20% SBE- -CD ABT

250 mg/ 5 mg/kg 4.46 mg/kg

ABT LC-MS/MS AA LC-MS/MS ABT LC-MS/MS ABT LC-MS/MS a)

C0 ng/mL NA NA 25984±3200 3830±522 4475±655 Cmax ng/mL 116±117 1104±691 NA NA NA AUC24 ng·h/mL 567±805 2797±1478 459±24 2025±192 1593±652 AUC ng·h/mL NA NA 459±24 2166±249 1602±665 t1/2 h NA NA 0.2±0.04 15.0±11.0 3.5±1.9 Vdz L/kg NA NA 2.6±1.6 NA 13.7±1.8 Vdss L/kg NA NA 0.2±0.03 NA 4.6±0.4 CL L/h/kg NA NA 10.9±0.6 NA 3.2±1.4

a) ± AA ABT CL NA SBE- -CD sulfobutylether- -cyclodextrin Vdss Vdz


2.6.5

7

2.6.5.3 D

FK7653 CTD 4.2.2.2.5

6 /

AA

ABT LC-MS/MS 500 mg/

a) Cmax ng/mL 306±370 AUC24 ng·h/mL 1582±2292

a) ± AA ABT


2.6.5

8

2.6.5.3 E

FK10014 CTD 4.2.2.2.6

6 /

20% HP- -CD AA

ABT LC-MS/MS 50 mg/kg

a) Cmax ng/mL 1524±428 AUC24 ng·h/mL 4849±1347

a) ± AA ABT


2.6.5

9

2.6.5.3 F

- -501648 CTD 4.2.2.2.7

6 /

AA 1 AA 2 AA 40% HP- -CD AA

250 mg/ 24 mg/kg

ABT LC-MS/MS ABT LC-MS/MS AA LC-MS/MS a)

Cmax ng/mL 104.6±80.48 113.0±52.76 77.8±75.70 19783.3±2291.22 10788.3±3127.97 tmax h 2.5±1.22 2.0±0.00 2.3±0.82 0.22±0.07 0.083±0.00 t1/2 h 7.8±3.77 7.6±4.25 9.5±4.55 6.6±1.59 1.6±0.45 AUC∞ ng·h/mL 622.4±514.18 558.0±247.73 618.7±407.16 19763.5±2128.25 1693.7±459.14

% b) 1.6±1.13 1.5±0.50 1.6±0.98 NA NA a) ± b) ABT / AA ABT NA


2.6.5

10

2.6.5.4 A 15

TOX9586 CTD 4.2.3.2.1

Swiss 3 /

Methocel A4M 0.5% w/v Tween 80 0.1% w/v AA

mg/kg/ 125 500 2000

ABT LC-MS/MS

a)

Cmax ng/mL 2152 2047 7337 4353 9797 7523 tmax h 1.0 1.0 2.0 1.0 2.0 2.0 AUC ng·h/mL 4671 3508 30844 22666 45824 53041

1 Cmax ng/mL 1890 1363 5243 4163 7353 5827 tmax h 0.5 0.5 0.5 0.5 2.0 0.5 AUC ng·h/mL 3240 NE 33541 25240 72469 62405

15 Cmax ng/mL 973 1109 1187 1737 3672 2627 tmax h 0.5 0.5 1.0 0.5 9.0 0.5 AUC24 ng·h/mL 1839 1307 b) 5139 5414 b) 32242 13015 b)

a) b) AUC9

AA ABT NE


2.6.5

11

2.6.5.4 B 4

TOX9688 CTD 4.2.3.2.2

CByB6F1 3 /


mg/kg/ 125 375 750 1500

ABT LC-MS/MS

1 27 1 27 1 27 1 27 a)

Cmax ng/mL 754 1016 582 507 2287 1697 858 660 2803 4363 1203 1124 3937 3540 1862 2547 tmax h 1.0 0.50 1.0 0.50 0.50 1.0 1.0 2.0 1.0 1.0 1.0 4.0 1.0 0.50 0.50 1.0 AUC24 ng·h/mL 2260 2057 886 1327 10012 10324 3273 3690 19901 26068 5086 10971 29819 35369 11187 20874 AUC ng·h/mL 2260 2057 NE NE 10014 10326 NE NE 19974 27443 NE NE NEb) NEb) NE NE

a) b) AUC 25%

AA ABT NE


2.6.5

12

2.6.5.4 C 4

1632/1 CTD 4.2.3.2.3

Wistar 3 /

Methocel A4M 0.5% w/v Tween 80 0.1% w/v 0.9% w/v AA

mg/kg/ 40 126 400

4 27 4 27 4 27

ABT LC-MS/MS a)

Cmax ng/mL 251.5 - 609.8 191.8 - 390.2 805.4 - 1630.3 482.2 - 1187.5 1092.2 - 1194.1 430.0 - 582.4 tmax h 1 1 - 3 3 - 6 1 - 3 3 - 6 3 - 6 AUC6 ng·h/mL 790.5 - 1695.1 566.2 - 1362.1 3485.3 - 7075.9 2254.5 - 3508.3 4301.6 - 5116.9 2001.5 - 3182.3

a) AA ABT


2.6.5

13

2.6.5.4 D 4

TOX9587 CTD 4.2.3.7.6.1

Sprague-Dawley 3 /


mg/kg/ 40 400

1 28 1 28

ABT LC-MS/MS a)

Cmax ng/mL 703±19.6 52.2±12.6 237±95.0 44.8±14.1 3670±697 127±30.2 520±158 152±71.9 tmax h 1.33±0.58 1.33±0.58 1.00±0.87 1.17±0.76 6.67±2.31 2.00±0.00 2.67±1.15 1.67±0.58 AUC24 ng·h/mL NE NE 996±311 151±76.3 NE NE 4398±527 1359 c) AUC ng·h/mL 2834±630 174±28.8 NE NE 32906±8751 795 b) NE NE

a) ± b) n=2 c) n=1 AA ABT NE


2.6.5

14

2.6.5.4 E 13

7777-100 CTD 4.2.3.2.5

Sprague-Dawley 3 /


mg/kg/ 250 50 b) 750 250 c) 2000 750 d)

1 28 92 1 28 92 1 28 92

ABT LC-MS/MS a)

Cmax ng/mL 2377 159 261 13.2 142 113 3713 312 417 50.6 291 278 3617 532 546 150 NA NA tmax h 1.00 0.50 1.00 1.00 0.50 0.50 4.00 1.00 4.00 0.50 2.00 2.00 1.00 1.00 1.00 1.00 NA NA t1/2 h NE 1.44 1.63 NE 1.45 1.70 NE 2.26 NE NE NE 1.69 NE NE 7.23 4.15 NA NA AUC24 ng·h/mL 18482 629 683 45.9 664 274 42759 1777 2461 252 1770 1155 46334 3404 4544 1034 NA NA AUC∞ ng·h/mL NE 623 NE NE NE NE NE 1720 NE NE NE NE NE NE NE NE NA NA

a) b) 1 9 250 mg/kg/ 10 50 mg/kg/ 1 8 250 mg/kg/ 9 50 mg/kg/ c)1 9 750 mg/kg/ 10 250 mg/kg/ 1 8 750 mg/kg/ 9 250 mg/kg/ d) 1 8 2000 mg/kg/

9 11 12 48 750 mg/kg/ 1 5 2000 mg/kg/ 6 8 9 48 750 mg/kg/ AA ABT NA NE


2.6.5

15

2.6.5.4 F 26

7777-105 CTD 4.2.3.2.6

Sprague-Dawley 3 /


mg/kg/ 50 150 400

1 183 1 183 1 183

ABT LC-MS/MS a)

Cmax ng/mL 729 77.1 138 132 3243 189 251 276 3537 500 494 291 tmax h 1.00 1.00 2.00 1.00 4.00 2.00 1.00 2.00 4.00 0.50 2.00 0.50 t1/2 h 1.29 1.99 4.99 2.96 2.49 1.72 3.67 3.88 3.34 3.82 6.37 4.64 AUC24 ng·h/mL 3006 240 1132 710 16397 1063 2220 1734 49610 1889 5586 3106 AUC∞ ng·h/mL 2981 244 NE NE 16413 1038 NE NE 50077 1913 NE NE

a) AA ABT NE


2.6.5

16

2.6.5.4 G 4

1818-001 CTD 4.2.3.2.7

5 /


ABT LC-MS/MS mg/kg/ 2 10 50

1 28 1 28 1 28 a)

Cmax ng/mL NE b) NE b) NE b) NE b) 9.2 ±2.73 c)

9.9 ±5.16 c)

4.7 ±0.87

6.1 ±2.38 c)

27.2 ±9.68

59.6 ±45.08

15.3 ±8.19

14.7 ±6.88

tmax h NE b) NE b) NE b) NE b) 2.0 ±1.41 c)

1.5 ±0.58 c)

4.0 ±1.63

1.6 ±0.50 c)

3.2 ±1.10

3.4 ±2.79

1.5 ±1.41

2.3 ±1.64

t1/2 h NE b) NE b) NE b) NE b) 2.6 ±0.60 d)

4.6 ±2.56 c) NE NE 3.2

±1.19 4.3

±3.60 5.0

±2.07 c) 5.3

±1.94 c)

AUC∞ ng·h/mL NE b) NE b) NE b) NE b) 37.4 ±10.36 d)

62.6 ±32.21 c) NE NE 196.4

±56.87 356.3

±189.70 110.8

±18.17 c)144.2

±51.11 c)

mg/kg/ 250 1000 1 28 1 28

a)

Cmax ng/mL 85.9 ±33.63

87.0 ±41.06

37.5 ±25.94

37.5 ±10.65

184.6 ±86.34

435.0 ±399.61

38.5 ±24.71

157.1 ±130.48

tmax h 1.6 ±0.55

2.8 ±1.64

1.1 ±0.55

2.4 ±1.52

4.8 ±1.79

3.2 ±2.95

3.8 ±2.68

1.4 ±0.55

t1/2 h 4.5 ±1.13

3.3 ±1.67

4.7 ±1.44

4.4 ±2.48

4.0 ±1.63

4.5 ±1.38

5.2 ±2.76

5.7 ±1.43

AUC∞ ng·h/mL 685.6 ±327.48

610.6 ±338.49

218.6 ±77.64

288.3 ±56.47

1712.7 ±1123.13

3248.1 ±2686.96

317.2 ±153.07

884.9 ±561.59

a) ± b) 4 ng/mL c) n=4 d) n=3 AA ABT NE


2.6.5

17

2.6.5.4 H 13

7777-101 CTD 4.2.3.2.8

4 / 7 /


mg/kg/ 250 750 2000

1 91 1 91 1 91

ABT LC-MSMS a)

Cmax ng/mL 519 ±331

261 ±114

146 ±78

103 ±93

526 ±305

360 ±98

61.6 ±36.0

99.8 ±35.0

478 ±278

597 ±252

115 ±56

243 ±81

tmax h 1.25 ±0.50

1.25 ±0.50

8.00 ±4.62

2.50 ±3.67

2.50 ±1.73

1.25 ±0.50

1.88 ±1.55

3.75 ±3.10

2.43 ±2.51

1.29 ±0.49

5.43 ±3.41

8.57 ±1.51

t1/2 h 7.59 b) 10.7 ±0.4 c) NE 3.65

±1.01 c) 6.79

±1.75 c) 11.8 ±1.3 NE 8.15 d) 8.21

±2.24 e) 6.96

±2.33 f) 9.42 b) NE

AUC24 ng·h/mL 2004 ±1193

1326 ±530

1252 ±760

947 ±1233

3148 ±2524

1765 ±210

774 ±542

999 ±608

2737 ±913

4100 ±3156

1604 ±966

2961 ±946

AUC∞ ng·h/mL 2024 b) 1800 ±701 c) NE NE 3911

±2762 c) 2169 ±309 NE NE 3154

±954 e) 5252

±4020 f) NE NE

a) ± b) n=2 c) n=3 d) n=1 e) n=6 f) n=4 AA ABT NE


2.6.5

18

2.6.5.4 I 39

7777-103 CTD 4.2.3.2.9

4 / 7 /


mg/kg/ 250 500 1000

1 273 1 273 1 273

ABT LC-MS/MS a)

Cmax ng/mL 114 ±68

151 ±149

139 ±105

87.5 ±51.6

226 ±91

482 ±439

183 ±89

466 ±496

238 ±110

471 ±537

270 ±89 b)

185 ±109

tmax h 0.875 ±0.250

1.75 ±1.50

1.50 ±0.58

4.75 ±4.99

2.50 ±1.00

1.25 ±0.50

3.75 ±3.10

3.75 ±3.10

3.00 ±2.58

3.14 ±2.48

4.00 ±3.10 b)

2.86 ±2.27

t1/2 h 5.20

±0.37 c) 6.87

±1.91 c) 8.33 d) 7.06 e) 5.03 ±1.36

5.73 ±1.84 NE 9.95 e)

5.48 ±1.38 b)

5.13 ±1.12 f) 5.82 d)

9.48 ±1.81 c)

AUC24 ng·h/mL 594 ±196

628 ±293

610 ±356

489 ±258

1577 ±874

3408 ±3808

1139 ±667

4154 ±4618

1637 ±846

2945 ±2989

2095 ±550 b)

1223 ±625

AUC∞ ng·h/mL 713

±43 c) 757

±264 c) NE NE 1628 ±872

3504 ±3864 NE NE 1461

±630 b) 3258

±3512 f) NE NE

a) ± b) n=6 c) n=3 d) n=2 e) n=1 f) n=5 AA ABT NE


2.6.5

19

2.6.5.5

8202443 CTD 4.2.2.3.1

Sprague-Dawley 3 /

Methocel A4M 0.5% w/v Tween 80 0.1% w/v 0.9% w/v 14C-AA

mg/kg 100 14C kBq/mg 42.9

14C QWBA

ng eq/g a) 0.5 h 4 h 8 h 24 h 72 h

10300 1700 38700 29600 7010 1240 1410 320 306b) 531 108000 37000 355000 223000 41000 10900 0.00b) 0.00 0.00b) 0.00 1280 210 3620 2420 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00

0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 1450 250 6560 5090 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 1320 390 13300 9400 457b) 791 0.00b) 0.00 0.00b) 0.00 1390 560 12600 9800 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 1620 410 18900 12600 930 1610 0.00b) 0.00 0.00b) 0.00 1020 120 8330 6230 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 1880 270 19400 14700 8850 940 683b) 1180 0.00b) 0.00

0.00b) 0.00 2290000 940000 1630000 330000 15400 10100 350b) 606 516000 594000 343b) 595 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 0.00b)c) NA 1970000d) NA 47900 20800 858b) 827 1810000 2150000 1440000 1340000 106000 38000 5870 1270 377b) 652

6730000 2240000 54300 54000 470b) 814 0.00b) 0.00 0.00b) 0.00 1860 400 8620 6230 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00

756b) 680 5930 2630 390b) 675 0.00b) 0.00 0.00b) 0.00 6540 3590 5280 3110 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00

2230 370 18500 13700 1160 200 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 914 915 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00

0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 757b) 655 5380 4080 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00

a) AA b) c) n=2 d) n=1 AA NA


2.6.5

20

2.6.5.5

8202443 CTD 4.2.2.3.1

ng eq/g a) 0.5 h 4 h 8 h 24 h 72 h

1560 470 15500 10200 2800 1430 0.00b) 0.00 0.00b) 0.00

2140 500 19300 13500 1240 300 0.00b) 0.00 0.00b) 0.00 1800 420 16700 13600 883 771 0.00b) 0.00 0.00b) 0.00 2020 530 18100 14800 393b) 681 0.00b) 0.00 0.00b) 0.00

6030 540 31200 14000 5060 1270 933 862 0.00b) 0.00 6520 700 35400 18300 6420 2070 1210 1080 0.00b) 0.00 4370 1240 16600 15000 1590 315 0.00b) 0.00 0.00b) 0.00

1670 290 7980 5110 19400 10900 0.00b) 0.00 0.00b) 0.00 41400 3560 66500 28800 9550 1540 325b) 563 0.00b) 0.00

1570 330 8260 7430 343b) 595 0.00b) 0.00 0.00b) 0.00 870b) 754 6790 5270 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00

321b) 556 4250 3060 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 2270 260 10500 8800 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00

0.00b) 0.00 5310 3210 777b) 698 0.00b) 0.00 903 1560 2720 540 13000 11400 310b) 537 0.00b) 0.00 0.00b) 0.00

617b) 1070 10400 9100 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 1370 520 25000 15000 6050 650 1210 1230 1390c) NA 1380 210 9990 7580 683b) 592 0.00b) 0.00 0.00b) 0.00 2320 240 11800 9800 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 583b) 1010 2580 1050 523b) 906 0.00b) 0.00 0.00b) 0.00

639b) 558 6440 3310 377b) 652 0.00b) 0.00 0.00b) 0.00 20400 23200 37500 27700 8900 2280 0.00b) 0.00 0.00b) 0.00 1520 210 17000 9600 860b) 845 0.00b) 0.00 0.00b) 0.00

1750 160 17300 11700 310b) 538 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 16400 6300 2530 1170 0.00b) 0.00 0.00b) 0.00

1990 330 8340 6780 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 7360 3450 10000 7900 1990 170 1570 280 724b) 654

0.00b) 0.00 3700 1830 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 642b) 556 5540 4020 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00

2280 110 9810 7100 0.00b) 0.00 0.00b) 0.00 0.00b) 0.00 1480 520 6020 1830 712b) 625 0.00b) 0.00 0.00b) 0.00

13400 13500 22000 5300 3650 3130 0.00b) 0.00 0.00b) 0.00 a) AA b) c) n=2 d) n=1 AA


2.6.5

21

2.6.5.5

8202443 CTD 4.2.2.3.1

Long Evans 3 /


mg/kg 100 14C kBq/mg 42.9

14C QWBA

ng eq/g a) 0.5 h 4 h 8 h 24 h 48h 72 h 168 h

8930 2500 11100 3300 4610 810 400 b) 693 0.00 0.00 0.00 0.00 0.00 0.00 172000 47000 143000 62000 34300 1900 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1200 220 907 787 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

0.00 b) 0.00 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 907 881 1050 960 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 523 b) 906 3500 2020 353 b) 612 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 527 b) 912 2480 2190 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 937 874 4900 2920 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 453 b) 785 1810 1570 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1210 1320 10800 9700 16600 3400 983 1700 440b) 762 0.00 0.00 0.00 0.00

0.00 b) 0.00 4150000 1350000 1250000 190000 9580 10800 1330 2310 14400 24900 0.00 0.00 205000 107000 1120 1940 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 b) 0.00 673000 1170000 2010000 850000 15800 10900 403b) 699 0.00 0.00 0.00 0.00 2010000 400000 521000 231000 61200 59100 1930 1030 0.00 0.00 0.00 0.00 0.00 0.00

5190000 790000 87100 136000 1000 870 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1550 620 1580 1490 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

457 b) 791 2240 2170 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 7350 4640 1990 2400 0.00 0.00 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00

1880 1060 4260 2820 337 b) 583 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 b) 0.00 1930 1070 1960 660 640 b) 1110 313b) 543 0.00b) 0.00 0.00 0.00

0.00 b) 0.00 1240 2150 0.00 b) 0.00 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1720 380 10900 4600 6890 2170 3960 1530 2900 1420 2790 940 1880 660

908 900 5670 2550 2260 1160 653 b) 571 0.00b) 0.00 0.00b) 0.00 0.00 0.00 a) AA b) AA


2.6.5

22

2.6.5.5

8202443 CTD 4.2.2.3.1

ng eq/g a)

0.5 h 4 h 8 h 24 h 48h 72 h 168 h

2010 670 4670 2900 1430 1370 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 945 966 3180 2180 0.00 b) 0.00 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1960 1030 3710 2610 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

5540 1930 12100 3800 4070 1550 315 b) 546 0.00 b) 0.00 0.00 b) 0.00 0.00 0.00 6000 2120 16600 3800 5620 1900 782 b) 711 0.00 b) 0.00 0.00 0.00 0.00 0.00 3660 1420 4290 1550 1390 110 0.00 b) 0.00 0.00 b) 0.00 0.00 0.00 0.00 0.00

1400 500 2550 1450 17000 7200 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 48100 7500 45200 17100 10200 2700 827 b) 716 0.00 b) 0.00 0.00 b) 0.00 0.00 0.00

1740 500 1200 1060 321 b) 555 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 560 b) 970 1330 1240 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

380 b) 658 470 b) 814 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2050 960 1570 1410 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

0.00 b) 0.00 2190 950 343 b) 595 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2310 1030 2290 1250 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

0.00 0.00 2860 3240 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 747 b) 1290 9560 4510 4690 2720 1790 370 3790 2410 617 b) 1070 0.00 0.00 853 b) 754 2640 1280 387 b) 670 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1930 840 2420 1130 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 b) 0.00 0.00 b) 0.00 319 b) 553 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

307 b) 532 1570 1930 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 318 b) 550 1850 1000 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

30500 32700 34500 25800 13400 8900 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1140 370 4780 2940 993 888 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

908 868 4610 3520 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 b) 0.00 5170 3070 2420 980 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

1660 730 1420 1250 0.00 b) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 3900 1120 6490 4360 5100 4240 1590 310 1220 30 1330 60 619 b) 537

0.00 b) 0.00 1270 350 0.00 b) 0.00 0.00 b) 0.00 0.00 b) 0.00 0.00 b) 0.00 0.00 b) 0.00 350 b) 606 1020 960 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

2100 890 3000 1910 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1610 1860 2930 1290 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

29700 33500 6680 1590 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 a) AA b) AA


2.6.5

23

2.6.5.6 A In vitro

8202266 CTD 4.2.2.3.2

Sprague-Dawley 3 3 HSA 45 mg/mL AGP 1.0 mg/mL

14C-ABT % a) ABT mol/L HSA 45 mg/mL AGP 1.0 mg/mL

0.1 96.3 b) 97.4±0.9 99.0±0.3 95.6±0.8 94.9±0.7 0.5 99.0±0.2 97.5±0.6 99.1±0.2 96.6±0.2 94.9±0.2 1 98.9±0.1 98.3±0.4 99.1±0.2 96.8±0.2 94.6±0.1 5 98.9±0.1 97.6±0.2 98.8±0.1 97.6±0.1 94.3±0.4 10 98.9±0.1 98.1±0.3 99.0±0.1 97.5±0.2 95.7±0.0

a) 3 ± b) 2 ABT


2.6.5

24

2.6.5.6 B In vitro

FK7603 CTD 4.2.2.3.3

Swiss Sprague-Dawley New Zealand White HSA 43 mg/mL w/v AGP 0.7 2.0 mg/mL w/v

14C-ABT % a)

ABT ng/mL 43 mg/mL HSA

AGP 43 mg/mL HSA

+0.7 mg/mL AGP

0.7 mg/mL 1.0 mg/mL 2.0 mg/mL

175 - - - - 99.914 - - - - - 350 99.889 99.818 99.853 99.853 99.921 - - - - - 1750 - - - - 99.923 99.879 89.4 92.43 94.44 99.886 3500 99.899 99.819 99.835 99.872 - - - - - -

a) - ABT 175 ng/mL 0.5 mol/L 350 ng/mL 1 mol/L 1750 ng/mL 5 mol/L 3500 ng/mL 10 mol/L


2.6.5

25

2.6.5.6 C In vitro

FK7448 CTD 4.2.2.3.4

8 /

14C-ABT

% a) 99.78 99.81 99.81

a) ABT


2.6.5

26

2.6.5.7

TOX10115 CTD 4.2.3.5.2.2

Sprague-Dawley 3 /


6 17 12

mg/kg/ 10 30 100 9 14

ABT LC-MS/MS

a) Cmax ng/mL 10.8±1.65 33.8±4.71 55.7 b) tmax h 1.67±0.58 1.33±0.58 1.5 b) AUC24 ng·h/mL 34.0±5.55 109±10.5 367 c)

a) ± b) n=2 c) n=1 AA ABT


2.6.5

27

2.6.5.8


2.6.5

28

2.6.5.9 A In vitro

400380 CTD 4.2.2.4.1

10 50 μmol/L AA 37 120

AA m/z of [M+H]+ AA 392 19.8 deacetylation ABT 350 13.6 O-monosulphation 430 17.6 O-monoglucuronidation 526 9.4 O-monoglucuronidation/ N-oxidation/ dehydrogenation 540 6.3 O-monoglucuronidation/ N-oxidation 542 6.5 Monohydroxylation 366 15.2 N-oxidation/dehydrogenation 364 13.6 N-oxidation/monohydroxylation 382 12.2

AA ABT


2.6.5

29

2.6.5.9 B In vitro

FK7389 CTD 4.2.2.4.2

mol/L 5 14C-AA

Radio-HPLC LC-MS/MS

60 76

Swiss SD NZW

Swiss SD NZW

% of sample radioactivity

M1 - - - - - - - - - - - - - - 3.50 M2 - - - - 17.1 7.80 - - 8.20 - - - 6.60 4.00 - - M3 - - - 4.70 - 5.20 2.20 - - - - - - - - M4 - - - - 5.00 1.80 - - - - - - - - - - M5 - - - - 14.9 4.70 - - 10.2 - - - 3.70 14.3 - - M6 - - - - - - - - - - 5.50 - 10.2 - 9.20 9.20 M7 - - - - - - - - - - 13.1 - M8 - - 8.60 - 6.10 15.3 26.8 10.0 - - - - - -

2.00 2.80 M9 - - - - - - - - - - - - - M10 - - - - - - - - - - - 2.40 5.70 10.9 1.00 M11 4.90 1.90 3.70 4.30 3.90 2.40 11.5 8.00 - - - - - - - - M12 - - - - - - - - - 7.20 24.7 68.3 26.3 - 48.7 38.5 M13 8.30 6.50 2.70 3.50 - - - - - - - - - - - - M14 2.80 3.80 6.40 2.60 6.50 19.9 8.40 16.4 - - - - - 6.00 2.00 5.50 M15 - - - 1.60 3.60 - - - - - - - - ABT 72.5 66.9 26.2 80.0 6.20 11.7 15.0 49.7 - - 20.3 1.60 4.00 13.1 3.10 18.3

AA - - - - - - - - - - - - - - - - - AA ABT NZW New Zealand White SD Sprague-Dawley

14C- CYP3A4 UGT1A4 SULT2A1 2.6.5.9 C 4.2.2.4.3CYP3A4 M8 M11 N- M14 UGT1A4 M10 O- SULT2A1 M12 O-


2.6.5

30

2.6.5.9 C In vitro

8202268 CTD 4.2.2.4.3

mol/L 25 14C-ABT

10

CYP g/mL Tris % a) CYP1A2 CYP2A6 CYP2B6 CYP2C8 CYP2C9 CYP2C19 CYP2D6 CYP2E1 CYP3A4

CYP M1/M2b) 2 93.2 120 89.3 59.4 81.1 90.0 92.2 76.5 41.3 5 85.4 84.0 97.2 95.7 91.1 73.0 79.4 35.2 40.2 10 116 68.7 84.7 67.6 143 103 71.5 90.4 28.8

CYP M3b) 2 142 103 107 137 120 92.9 88.8 120 143 5 112 122 88.3 99.5 91.9 115 126 107 131 10 106 94.9 72.6 114 135 123 104 116 70.1 CYP M4b) 2 71.8 116 85.7 73.3 98.9 88.8 87.2 102 37.2 5 97.8 86.1 125 101 100 69.6 82.6 91.9 17.6 10 67.4 124 69.6 83.5 108 114 77.1 81.3 14.5

a) 3 b) ABT


2.6.5

31

2.6.5.9 C In vitro

8202268 CTD 4.2.2.4.3

CYP

mol/L 25 14C-ABT

10

CYP pmol/min/pmol CYP a)

CYP M1/M2b) CYP M3b) CYP M4b)

CYP1A1 0.29±0.06 0.58±0.06 0.21±0.02 CYP1A2 0.35±0.03 0.58±0.07 0.15±0.02 CYP2A6 0.39±0.02 0.54±0.04 0.18±0.03 CYP2B6 0.29±0.03 0.55±0.06 0.19±0.01 CYP2C8 0.34±0.04 0.56±0.04 0.19±0.01 CYP2C9 0.37±0.02 0.53±0.04 0.22±0.04 CYP2C19 0.33±0.02 0.53±0.03 0.18±0.01 CYP2D6 0.33±0.02 0.87±0.01 0.21±0.06 CYP2E1 0.35±0.07 0.54±0.05 0.19±0.02 CYP3A4 1.87±0.21 2.47±0.35 6.06±0.81

a) 3 ± b) ABT


2.6.5

32

2.6.5.9 C In vitro

8202268 CTD 4.2.2.4.3

UGT

mol/L 50 14C-ABT

30

UGT pmol/min/mg protein a)

UGT M1b) UGT M2b)

c) 3.7±1.3 1.8±0.6

UGT1A1 4.2±0.3 2.6±0.7

UGT1A3 13.4±1.3 4.3±0.3

UGT1A4 51.3±1.3 56.6±1.3

UGT1A6 4.5±0.6 2.2±0.8

UGT1A7 4.1±0.4 2.2±0.5

UGT1A8 4.9±0.2 2.8±0.6

UGT1A9 4.4±0.9 1.8±0.4

UGT1A10 4.6±0.8 1.7±0.2

UGT2B4 4.1±0.3 1.9±0.6

UGT2B7 4.7±0.2 3.1±0.3

UGT2B15 4.7±0.6 2.0±0.3

UGT2B17 4.2±0.2 2.4±0.3a) 3 ± b) c) ABT


2.6.5

33

2.6.5.9 C In vitro

8202268 CTD 4.2.2.4.3

SULT

mol/L 5 14C-ABT

5

SULT pmol/min/ g protein a)

SULT M1b)

SULT1A1*1 0.0±0.0

SULT1A1*2 0.0±0.0

SULT1A3 0.0±0.0

SULT1B1 0.0±0.0

SULT1E1 16.6±1.8

SULT2A1 44.2±2.7a) 3 ± b) ABT


2.6.5

34

2.6.5.10 A In vivo

8202443 CTD 4.2.2.3.1

Sprague-Dawley 3 3


mg/kg 100 kBq/mg 14C 42.9

Radio-HPLC

ng eq/g a)

h 0.25 0.5 1 2 4 8 12 0.25 0.5 1 2 4 8 12 M15 461A Di-oxy-ABT sulphate 15.3 32.5 29.0 ND ND ND ND ND ND ND ND ND ND ND M23 461B Di-oxy-ABT sulphate 18.7 33.3 29.3 44.3 19.1 16.2 ND 17.7 13.7 15.5 22.2 12.7 10.7 ND M27 383 Hydrogenated-di-oxy-ABT ND ND ND ND ND 7.64 ND ND ND ND 15.2 10.9 11.7 7.06 M28 Unknown ND 49.8 54.6 82.5 34.5 5.78 ND ND ND ND ND ND ND ND M30 543B Hydrogenated-mono-oxy-ABT glucuronide 25.5 29.9 ND ND ND ND ND 20.9 28.2 33.9 25.4 13.8 6.83 ND M31 445A N-oxide ABT sulphate ND 100.0 127 184 149 36.9 6.89 28.2 68.6 159 227 173 59.9 17.6 M32 445B Mono-oxy-ABT sulphate 47.7 65.1 23.7 39.1 24.5 ND ND 69.9 117 134 176 75.4 8.43 ND M33 447C Hydrogenated-mono-oxy-ABT sulphate ND 28.7 41.9 55.8 37.8 ND ND ND 23.1 27.2 21.9 23.0 17.4 ND M35 445D Mono-oxy-ABT sulphate 17.0 ND 49.8 ND 46.0 16.5 6.89 11.2 13.9 20.0 22.7 27.3 33.8 17.6 M36 445E Mono-oxy-ABT sulphate ND ND ND ND ND ND ND 28.1 50.1 35.8 20.8 9.06 5.54 ND M37 Unknown ND ND ND ND ND ND ND 10.6 13.2 ND ND ND ND ND M38 445F Mono-oxy-ABT sulphate ND 23.9 62.9 97.5 80.3 14.5 ND ND 10.9 18.4 30.7 22.0 ND ND M42 365A Mono-oxy-ABT ND ND 28.6 22.3 ND ND ND ND 13.0 217 10.4 11.7 5.81 ND M45 429 ABT sulphate 141 597 1300 1960 1630 212 49.2 195 486 1190 1810 1020 167 52.9 M46 431 Hydrogenated-ABT sulphate ND ND 35.2 27.3 29.5 6.83 3.95 ND ND 24.7 19.5 18.0 21.6 7.06 M47 Unknown ND ND ND ND ND ND ND ND ND ND ND 17.2 6.92 ND M48 365B Mono-oxy-ABT ND ND ND ND ND ND ND ND ND ND ND 19.8 12.8 ND M49 Unknown ND 24.0 73.0 66.7 44.1 ND ND ND ND ND ND ND ND ND M50 ABT 13.6 12.2 30.6 37.3 29.0 ND ND 12.4 15.8 ND ND ND ND ND M53 Unknown ND ND ND ND ND ND ND ND ND ND ND 20.1 9.45 ND M54 Unknown 90.2 ND ND ND ND ND ND 80.4 ND ND ND ND ND ND AA 29.0 21.9 ND ND ND ND ND 9.88 ND ND ND ND ND ND

a) AA AA ABT ND 1 1% LC-MS Peak Designation


2.6.5

35

2.6.5.10 A In vivo

8202443 CTD 4.2.2.3.1

Sprague-Dawley Radio-HPLC

% of dose

h 0-24 M1 Unknown 0.01 ND ND M2 Unknown 0.01 0.01 ND M3 Unknown 0.03 0.01 ND M5 415A Hydrogenated-tetra-oxy-ABT 0.02 0.01 ND M6 415B Hydrogenated-tetra-oxy-ABT 0.02 0.02 0.01 M7 477A Tri-oxy-ABT sulphate 0.01 0.01 0.01 M9 479A Hydrogenated-tri-oxy-ABT sulphate 0.01 0.01 ND M11 477D Tri-oxy-ABT sulphate 0.02 0.02 ND M13 479D Hydrogenated-tri-oxy-ABT sulphate 0.02 0.02 ND M15 461A Di-oxy-ABT sulphate 0.01 0.01 0.02 M16 Unknown 0.01 ND ND M17 Unknown 0.02 0.02 0.01 M18 463A Hydrogenated-di-oxy-ABT sulphate 0.02 0.02 0.03 M19 Unknown 0.04 0.03 0.01 M20 Unknown 0.03 0.02 ND M21 Unknown 0.01 0.03 0.01 M23 461B Di-oxy-ABT sulphate 0.02 ND 0.01 M24 Unknown 0.02 0.02 0.01 M25 Unknown ND ND 0.01 M26 461C Di-oxy-ABT sulphate ND ND 0.01 M29 Unknown ND ND 0.01 M30 543B Hydrogenated-mono-oxy-ABT glucuronide ND ND 0.01 M31 445A N-oxide ABT sulphate ND ND 0.06 M32 445B Mono-oxy-ABT sulphate ND ND 0.02 M38 445F Mono-oxy-ABT sulphate ND ND 0.01 M45 429 ABT sulphate ND ND 0.01 M54 Unknown ND ND 0.01

ABT ND 1 2% LC-MS Peak Designation


2.6.5

36

2.6.5.10 A In vivo

8202443 CTD 4.2.2.3.1


% of dose

h 0-8 8-24 0-48 M4 493B Tetra-oxy-ABT sulphate 0.11 ND ND M5 415A Hydrogenated-tetra-oxy-ABT 0.07 ND ND M6 415B Hydrogenated-tetra-oxy-ABT 0.08 ND ND M7 477A Tri-oxy-ABT sulphate 0.10 0.18 0.39 M8 477B Tri-oxy-ABT sulphate 0.08 ND ND M9 479A Hydrogenated-tri-oxy-ABT sulphate 0.08 ND 0.19 M10 477C Tri-oxy-ABT sulphate 0.11 ND ND M11 477D Tri-oxy-ABT sulphate 0.16 ND 0.37 M12 479B Hydrogenated-tri-oxy-ABT sulphate ND 0.20 0.22 M13 479D Hydrogenated-tri-oxy-ABT sulphate 0.08 ND ND M14 477E Tri-oxy-ABT sulphate 0.19 0.10 0.19 M15 461A Di-oxy-ABT sulphate 0.21 0.11 0.25 M18 463A Hydrogenated-di-oxy-ABT sulphate 1.07 0.84 2.20 M22 463B Hydrogenated-di-oxy-ABT sulphate ND 0.24 0.21 M23 461B Di-oxy-ABT sulphate 0.43 0.54 1.27 M26 461C Di-oxy-ABT sulphate 0.17 0.26 0.49 M27 383 Hydrogenated-di-oxy-ABT ND 0.16 0.20 M30 543B Hydrogenated-mono-oxy-ABT glucuronide 0.09 0.32 0.49 M31 445A N-oxide ABT sulphate 0.59 0.52 1.07 M32 445B Mono-oxy-ABT sulphate 0.15 0.35 0.70 M33 447C Hydrogenated-mono-oxy-ABT sulphate ND 0.11 ND M35 445D Mono-oxy-ABT sulphate ND 0.13 0.23 M36 445E Mono-oxy-ABT sulphate 0.08 ND 0.23 M38 445F Mono-oxy-ABT sulphate 0.24 0.24 0.61 M39 527 Hydrogenated-ABT glucuronide 0.49 2.01 2.85 M45 429 ABT sulphate 0.50 0.44 0.96 M46 431 Hydrogenated-ABT sulphate ND 0.25 0.26

ABT ND 1 1% LC-MS Peak Designation


2.6.5

37

2.6.5.10 A In vivo

8202443 CTD 4.2.2.3.1


% of dose

h 0-24 24-48 0-24 24-48 0-24 24-48 M28 Unknown ND 0.04 0.04 ND ND ND ND ND ND M31 445A N-oxide ABT sulphate 0.83 0.05 0.88 ND ND ND 1.34 0.09 1.43 M33 447C Hydrogenated-mono-oxy-ABT sulphate ND 0.04 0.04 ND ND ND ND ND ND M34 Unknown 1.37 0.23 1.60 ND ND ND ND ND ND M36 445E Mono-oxy-ABT sulphate ND ND ND ND ND ND ND 0.09 0.09 M37 Unknown ND ND ND ND ND ND ND 0.13 0.13 M39 527 Hydrogenated-ABT glucuronide 1.72 0.08 1.79 ND ND ND 1.09 0.16 1.26 M40 Unknown ND 0.04 0.04 ND ND ND ND ND ND M41 Unknown ND 0.18 0.18 ND ND ND ND ND ND M43 Unknown ND 0.05 0.05 ND ND ND ND ND ND M44 Unknown ND 0.17 0.17 ND ND ND ND ND ND M45 429 ABT sulphate 16.3 0.16 16.5 ND ND ND 23.0 1.99 25.0 M46 431 Hydrogenated-ABT sulphate 1.27 0.04 1.31 ND ND ND 1.05 0.23 1.28 M47 Unknown ND 0.04 0.04 ND ND ND ND ND ND M49 Unknown ND 0.16 0.16 ND ND ND ND 0.19 0.19 M50 ABT 5.38 0.22 5.60 12.1 0.94 13.1 5.17 0.53 5.70 M51 351A Hydrogenated-ABT 6.66 0.92 7.57 5.60 1.60 7.20 3.11 1.58 4.69 M52 351B Hydrogenated-ABT 2.54 0.30 2.84 2.59 0.68 3.27 1.89 0.43 2.33 M53 Unknown ND ND ND ND 0.12 0.12 ND 0.08 0.08 M54 Unknown ND ND ND ND ND ND ND 0.16 0.16 AA 31.5 0.53 32.0 31.5 1.78 33.2 31.7 1.08 32.8

AA ABT ND 1 1% LC-MS Peak Designation


2.6.5

38

2.6.5.10 B In vivo

FK10121 CTD 4.2.2.2.4

3 /

20% HP- -CD AA

AA ABT ABT sulphate M45 N-oxide ABT sulphate M31 LC-MS/MS

mg/kg 10 25 25 10 25 25

AUC ng·h/mL a) AA 14.7b) 156b) 61.6b) 1.56c) 21.9c) 7.88b) ABT 2317±860 7499±558 7527±1243 681±81.8 3422±377 3656±535 ABT sulphate M45 - 91.6±23.5 115±36.1 30.9c) 189±38.6 201b) N-oxide ABT sulphate M31 - 54.2±27.4 101b) 17.7±5.66 93.9±36.9 173b)

a) ± b) n=2 c) n=1 - AUC∞ 25% AA ABT


2.6.5

39

2.6.5.10 C In vivo

FK7532 CTD 4.2.2.4.4

4


mg/kg/ 500

LC-MS/MS h 0.5 1 2 4 8

M18 463A Dihydro-di-oxy-ABT sulphate ND x x x x M23 461B Di-oxy-ABT sulphate x x x x x M27 383 Dihydro-di-oxy-ABT x x x x x M30 543B Dihydro-mono-oxy-ABT glucuronide x x x x x M31 445A N-oxide ABT sulphate x x x x x M35 445D Mono-oxy-ABT sulphate ND x x x x M38 445F Mono-oxy-ABT sulphate x x x x x M42 365A Mono-oxy-ABT ND x x x x M45 429 ABT sulphate x x x x x M46 431 Dihydro-ABT sulphate x x x x x M50 ABT x x x x x M51 351A Dihydro-ABT x x x x x M52 351B Dihydro-ABT x x x x x M61 447A Dihydro-mono-oxy-ABT sulphate ND x x x x M62 381A Di-oxy-ABT x x x x x M65 445C Mono-oxy-ABT sulphate x x x x x M69 559B Dihydro-di-oxy-ABT glucuronide x x x x x M70 605 Sulphated-ABT glucuronide ND x x x x M72 461G Di-oxy-ABT sulphate x x x x x M75 331 Dehydrated-ABT x ND x ND x M77 445I Mono-oxy-ABT sulphate x x x x x

AA ABT ND x LC-MS Peak Designation


2.6.5

40

2.6.5.10 C In vivo

FK7532 CTD 4.2.2.4.4

LC-MS/MS

h 0.5 1 2 4 8 M78 383B Dihydro-di-oxy-ABT ND x x x x M79 463D Dihydro-di-oxy-ABT sulphate x x x x x M80 381D Di-oxy-ABT x x x x x M81 445G Mono-oxy-ABT sulphate x x x x x M82 541 Mono-oxy-ABT glucuronide x x x x x M83 541B Mono-oxy-ABT glucuronide ND x x x x M84 525B ABT glucuronide x x x x x M85 527 Dihydro-ABT glucuronide x x x x x M86 527B Dihydro-ABT glucuronide x x x x x M87 367C Dihydro-mono-oxy-ABT ND x x x x M88 365C Mono-oxy-ABT ND x x x x M89 367D Dihydro-mono-oxy-ABT ND x x x x M90 367A Dihydro-mono-oxy-ABT ND x x x x M91 365B Mono-oxy-ABT x x x x x M92 367B Dihydro-mono-oxy-ABT ND ND x x x M93 431B Dihydro-ABT sulphate ND ND ND x x M94 347 3-keto-17-(3-pyridyl)-androsta-4,16-diene x x x x x M95 349 5-alpha-17-(3-pyridyl)-16-androstene-3-one ND x x x x M96 351C Dihydro-ABT x x x x x AA ND ND x x x

AA ABT ND x LC-MS Peak Designation


2.6.5

41

2.6.5.11 A In vitro

AA ABT f m

N

O

OAA

N

HOABT

N

OSO

HO O

M12

N

OO

COOHHO

HO OH

M10

N

OSO

HO O

OCOOH

OH

OHOH

M1

M13

M3

M2

M9

M4

N

HOO

OCOOH

OH

OHOH

H2M6

N

HO

SO3O

N

HO

2O

ester hydrolysis

hydroxylat ion( CY P3A4)

d i-oxidation

oxidationdehydrogenation

oxidationhydrogenation

g lucuronidation

N -glucuronidation

O-glucuronidation( UGT 1A4)

O-sulf ation

monkey mman

mouse mrabbit fdog m


rabbit fdog m


rat mmonkey mman

rat mrabbit f

dog mmonkey m

man

rat mrabbit fdog mmonkey mman


mouse frat m,frabbit fmonkey mman

oxydationhydrogenation

+

O-sulf ation( SU LT 2A1)

tri-oxidation

oxidation

N

HO

2 O

O

N

HO

O - 2H

O

OH

N

HO

O

O

N

HO O

OM5

N

OSO

HO O

O

M7

N

HO

OM14

N

HOHO

M15

N

HO

O

M11

oxidat ion

mouse m,frat m,f

N -oxidation( CYP3A4)


rat mrat frabbit fmonkey mman

oxidat ionsulf ation

oxidat ion

mouse mrabbit f

dog m

rat mrabbit f

dog mmonkey m

man

N

HO

O

O

M8

oxidat ion( CY P3A4)

N -oxidation


2.6.5

42

2.6.5.11 B


2.6.5

43

2.6.5.11 C

N

HO

Abiraterone/M50

N

HO OH

365A/M42, 365B/M91, 365C/M88

N

HOHO3S

HO

445D/M35, 445F/M38

447A/M61

463A/M18

N

HO

HOHO

HO3S

461B/M23

N

HO

2H

OH

367A/M90,367B/M92,367C/M87,367D/M89

N

HO

HO

HO

381A/M62,381D/M80

N

HO 2H

351A/M51,351B/M52,351C/M96

N

HSO4

429/M45

N

H SO4

2H

431/M46,431B/M93

N

HSO4

Gluc

605/M70

N

HSO4

O

445A/M31

N

OGluc

N

O 2HGluc

525B/M84

527/M85,527B/M86

541/M82,541B/M83543B/M30

559B/M69463D/M79

461G/M72

N

HO

SO3H

OH

445G/M81

N

HO SO3H

OH

445C/M65,445I/M77

N

331/M75

N

HO

Gluc

N

H O 2H

Gluc

OR

OR

N

O

349/M95

N

O

347/M94

1 = Oxidation2 = Sulfate conjugation3 = Glucuronide conjugation4 = hydrogenation5 = dehydration

5

4

1

3

2

11

4

1

141

3

1

4

1

2

3

4

11,2

1,2

3

4

383/M27,383B/M78

N

HO

Gluc

HO

N

HOHO3S

HOHO

2H

N

HO

HO3S

HO

2HN

HO

HO

Gluc

2H

N

OH3C

O

N

HO

Hydrolysis

Abiraterone Acetate Abiraterone

N

HO

OH

2H

HO

SO3H

OR

N

HO

OH

2H

O

SO3H

N

HO

OHHO

SO3H

N

HO

OH

O

SO3H

OR

N

HOGluc

2H

HO

HO

N

HOGluc

2H

HOO

OR

N

HO 2H

HO

OR

N

HO 2H

HOO

HO


2.6.5

44

2.6.5.12 A In vitro

400379 CTD 4.2.2.4.6

CYP 0.1 10 mol/L AA ABT 37 CYPKi

CYP Ki mol/L AA ABT

CYP1A2 O- 0.32 0.44 CYP2A6 7- CYP2C9 17.6 29.8 CYP2C19 S- 4’- 0.12 46.3 CYP2D6 O- 0.16 0.39 CYP2E1 6- 31.8 CYP3A4/5 1- 11.4 10.2 CYP3A4/5 6 - 6.50 8.01

AA ABT


2.6.5

45

2.6.5.12 B In vitro

FK10146 CTD 4.2.2.4.7

CYP2C8 AA ABT 37CYP2C8 IC50

CYP Assay 1 0.06 60 μmol/L Assay 2 0.03 30 μmol/L

IC50 μmol/L % IC50 μmol/L %

CYP2C8

AA 1.3 80 3.0 83 ABT 1.6 67 2.9 59

0.03 – 30 μmol/L

1.6 91 1.3 96

AA ABT triplicate

Assay 1 0 0.06 0.18 0.6 1.8 6 18 60 μmol/L Assay 2 0 0.03 0.09 0.3 0.9 3 9 30 μmol/L Assay 1 Assay 2


2.6.5

46

2.6.5.12 C In vitro

FK10147 CTD 4.2.2.4.8

CYP2B6 CYP2C19 S- AAABT 37 CYP2B6 CYP2C19 IC50

CYP Assay 1 0.06 60 μmol/L Assay 2 0.03 30 μmol/L

IC50 μmol/L % IC50 μmol/L %

CYP2B6

AA > 20 43 10 54ABT > 60 47 > 30 39

0.005 – 5 μmol/L

0.10 94 0.069 95

CYP2C19

AA > 10 45 > 10 48ABT 10 58 > 30 39

N-3- 0.002 – 2 μmol/L

0.064 92 0.066 93

AA ABT triplicate

Assay 1 0 0.06 0.18 0.6 1.8 6 18 60 μmol/L Assay 2 0 0.03 0.09 0.3 0.9 3 9 30 μmol/L Assay 1 Assay 2


2.6.5

47

2.6.5.12 D In vitro

400378 CTD 4.2.2.4.9

AA 37 48 CYP CYP1A2 CYP3A430 mol/L 10 mol/L

AA CYP a) CYP1A2 CYP2C9 CYP3A4

7- O- 4- 6 - 30 120 60

0 1.0 b) 1.0 1.0 b) 0.1 mol/L 1.6 1.0 0.8 1 mol/L 1.6 0.9 0.7 10 mol/L 1.3 1.0 0.7 30 mol/L 48.0 - - 10 mol/L - - 10.2

a) 3 CYP b) 6 CYP - AA


2.6.5

48

2.6.5.12 E In vivo

FK7476 CTD 4.2.2.4.10

Sprague-Dawley AA 40 400 mg/kg/ 1 a)

0 40 mg/kg/ 400 mg/kg/ 0 40 mg/kg/ 400 mg/kg/

g/100g BW 2.71±0.22 2.72±0.13 4.36±0.59*** 2.93±0.09 2.93±0.26 3.52±0.30** mg/g liver 16.4±2.4 16.1±1.6 15.1±1.1 17.3±1.9 20.3±2.6 19.3±1.6

CYP nmol/mg protein 0.648±0.092 0.695±0.098 0.821±0.102* 0.592±0.077 0.669±0.104 0.648±0.036 7- O- CYP1A1/2

nmol/min/mg protein 0.072±0.013 0.073±0.008 0.113±0.018** 0.107±0.027 0.107±0.026 0.088±0.011nmol/min/nmol CYP 0.113±0.027 0.106±0.013 0.138±0.014 0.179±0.032 0.159±0.031 0.137±0.020#

7- O- CYP2B nmol/min/mg protein 0.022±0.004 0.017±0.003# 0.016±0.004 0.018±0.004 0.022±0.006 0.009±0.004 nmol/min/nmol CYP 0.034±0.004 0.024±0.004## 0.020±0.004### 0.030±0.007 0.035±0.013 0.014±0.006

CYP2E1 nmol/min/mg protein 1.058±0.118 0.891±0.168 0.722±0.224# 0.812±0.074 0.752±0.095 0.612±0.050## nmol/min/nmol CYP 1.647±0.221 1.278±0.120# 0.871±0.226### 1.377±0.053 1.159±0.300 0.949±0.103###

N- CYP3A1/2 nmol/min/mg protein 8.943±0.572 3.938±1.429### 5.138±1.355### 3.560±0.482 3.290±0.302 5.002±0.539** nmol/min/nmol CYP 13.943±1.555 5.594±1.424### 6.274±1.571### 6.027±0.600 4.972±0.581# 7.749±1.047*

12- CYP4A1 nmol/min/mg protein 0.794±0.079 0.860±0.116 1.449±0.230*** 0.968±0.105 1.138±0.340 1.451±0.410* nmol/min/nmol CYP 1.238±0.171 1.243±0.130 1.814±0.518* 1.651±0.242 1.719±0.478 2.241±0.601

- UGT pmol/min/mg protein 4.847±2.512 6.945±1.414 14.240±2.757*** 3.419±1.052 8.725±1.682*** 9.476±1.866***

mg/g liver 68.0±3.3 66.5±2.3 63.6±2.1# 78.2±4.6 76.5±6.7 70.1±5.9# DHEA SULT2A1

nmol/min/mg protein 0.063±0.007 0.295±0.030*** 0.327±0.005*** 1.304±0.130 1.065±0.318 0.924±0.216## ABT b),c),d)

nmol/min/mg protein 0.073±0.005 0.172±0.002 0.223±0.013 0.824±0.154 0.713±0.044 0.537±0.013 ABT c),d),e)

nmol/min/mg protein 0.157±0.037 0.088±0.042 0.117±0.034 - - - a) ± n=5 b) in vitro M9 c) 5 d) 3 ± e) in vitro M12 AA ABT BW body weight DHEA dehydroepiandrosterone - * p 0.05; ** p 0.01; *** p 0.001 # p 0.05; ## p 0.01; ### p 0.001


2.6.5

49

2.6.5.13

8202443 CTD 4.2.2.3.1

Sprague-Dawley 3 /

3 Methocel A4M 0.5% w/v Tween 80 0.1% w/v 0.9% w/v 14C-AA

mg/kg 100

14C kBq/mg 42.9

LSC % of dose a)

0 8 h 0.21±0.08 85.2±7.2 0.08±0.06

0.22±0.07 85.8±5.1 0.04±0.01

8 24 h 0.22±0.10 0.10±0.03 24 48 h 0.08±0.06 4.15±2.23 0.02±0.01 0.04±0.02 7.45±5.24 0.01±0.01 48 72 h 0.02±0.01 0.37±0.29 0.01±0.01 0.00±0.01 0.13±0.09 0.00±0.00 72 96 h 0.01±0.01 0.11±0.10 0.00±0.01 0.00±0.00 0.02±0.01 0.00±0.00 96 120 h 0.00±0.01 0.06±0.06 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 120 144 h 0.00±0.01 0.03±0.04 0.00±0.00 0.00±0.00 0.01±0.01 0.00±0.00 144 168 h 0.00±0.00 0.02±0.03 - 0.00±0.00 0.00±0.00 -

0.53±0.26 89.9±4.7 0.11±0.09 0.37±0.11 93.4±0.4 0.05±0.01 168 h 0.05±0.07 0.03±0.03

168 h 0.03±0.05 0.03±0.01 168 h 0.07±0.12 0.00±0.00

90.9±3.8 93.8±0.5 a) ± - AA


2.6.5

50

2.6.5.14

8202443 CTD 4.2.2.3.1

Sprague-Dawley 3

3 Methocel A4M 0.5% w/v Tween 80 0.1% w/v 0.9% w/v 14C-AA

mg/kg 100

14C kBq/mg 42.9

LSC % of dose a)

0 2 h 0.20±0.02

66.4±5.8

0.66±0.26

0.05±0.01 2 4 h 2.30±0.90 4 8 h 4.21±0.46 8 24 h 0.20±0.03 9.87±3.10 24 48 h 0.34±0.20 7.70±2.95 1.41±0.51 0.03±0.02 48 72 h 0.08±0.08 0.32±0.21 0.18±0.18 0.02±0.02 72 96 h 0.02±0.03 0.11±0.09 0.08±0.10 0.01±0.01 96 120 h 0.00±0.01 0.03±0.03 0.01±0.02 -

0.84±0.23 74.6±4.1 18.7±4.4 0.11±0.05 120 h 0.09±0.12

120 h 0.41±0.70 120 h 0.00±0.00

120 h 0.02±0.01 120 h 0.02±0.04

94.8±3.1 a) ± - AA


2.6.5

51

2.6.5.15 A P-gp

8202265 CTD 4.2.2.2.1

Caco-2 0.1 30 mol/L AA 0.1 15 mol/L ABT P-gp 1 mol/L37 1 P-gp P-gp 10 mol/L A 100 mol/L

10-6 cm/s a)

Efflux Ratio A B B A

AA 0 1.25±0.09 11.0±0.4 8.830.1 mol/L 1.08±0.11 9.03±0.13 8.391 mol/L 1.09±0.02 10.3±0.6 9.465 mol/L 1.60±0.14 9.98±0.66 6.2510 mol/L 2.40±0.37 8.64±0.12 3.5930 mol/L 2.41±0.31 7.50±0.30 3.1110 mol/L A 3.63±0.05 3.85±0.16 1.06100 mol/L 2.75±0.10 4.08±0.32 1.48

ABT 0 1.51±0.09 12.2±2.5 8.060.1 mol/L 1.43±0.01 11.0±0.1 7.710.5 mol/L 1.39±0.03 10.6±0.3 7.651 mol/L 1.81±0.26 11.4±0.3 6.325 mol/L 2.39±1.09 10.7±0.4 4.4915 mol/L 1.74±0.02 11.4±0.5 6.5710 mol/L A 3.79±0.17 5.32±0.44 1.40100 mol/L 3.34±0.71 4.65±0.15 1.39

a) 3 ± AA ABT


2.6.5

52

2.6.5.15 B

FK10223 CTD 4.2.2.6.1

BCRP MRP2 MDCKII P-gp LLC-PK1 1 15 μmol/L ABT ABT sulphate M45 N-oxide ABT sulphate M31 37 2

MDCKII BCRP MDCKII

Papp 10-6 cm/s a) Efflux Ratio Papp 10-6 cm/s a) Efflux Ratio

1 μmol/L 3H- A B 1.38±0.00

0.96±0.03 0.64±0.00

5.85±0.32 B A 1.33±0.00 3.76±0.06

1 μmol/L 3H- + 1 μmol/L KO143 b)

A B 1.51±0.07 0.88±0.09

1.43±0.01 0.74±0.03

B A 1.33±0.00 1.06±0.00

1 μmol/L ABT A B 8.51±0.61

0.61±0.06 9.25±1.00

0.63±0.07 B A 5.19±0.55 5.79±0.74

1 μmol/L ABT + 1 μmol/L KO143 b)

A B 10.4±0.02 0.49±0.03

9.23±0.24 0.58±0.04

B A 5.05±0.26 5.37±0.42

15 μmol/L ABT A B 10.1±0.07

0.57±0.01 10.1±0.27

0.59±0.02 B A 5.75±0.03 5.94±0.05

15 μmol/L ABT + 1 μmol/L KO143 b)

A B 8.31±0.15 0.50±0.02

8.00±0.18 0.64±0.03

B A 4.16±0.01 5.14±0.07

1 μmol/L ABT sulphate M45 A B BQL

- BQL

- B A BQL BQL

1 μmol/L ABT sulphate M45 + 1 μmol/L KO143 b)

A B BQL -

BQL -

B A BQL BQL

15 μmol/L ABT sulphate M45 A B 0.03±0.00

0.85±0.05 0.02±0.00

3.12±0.24 B A 0.03±0.00 0.06±0.00

15 μmol/L ABT sulphate M45 + 1 μmol/L KO143 b)

A B 0.03±0.00 0.84±0.05

0.02±0.00 1.18±0.07

B A 0.03±0.00 0.03±0.00

1 μmol/L N-oxide ABT sulphate M31 A B BQL

- BQL

- B A BQL BQL

1 μmol/L N-oxide ABT sulphate M31 + 1 μmol/L KO143 b)

A B BQL -

BQL -

B A BQL BQL

15 μmol/L N-oxide ABT sulphate M31 A B 0.02±0.00

- BQL

- B A BQL 0.02 c)

15 μmol/L N-oxide ABT sulphate M31 + 1 μmol/L KO143 b)

A B 0.02±0.00 -

BQL -

B A BQL BQL a) 3 ± b) BCRP c) BQL n=1 ABT BQL < 1.00 ng/mL Papp<0.2 10-6 cm/s 1 μmol/L ABT sulphate Papp<0.02 10-6 cm/s 15 μmol/L N-oxide ABT sulphate Papp , -


2.6.5

53

2.6.5.15 B

FK10223 CTD 4.2.2.6.1

MDCKII MRP2 MDCKII


1 μmol/L 3H- A B 1.87±0.00

1.70±0.11 0.66±0.01

17.6±1.30 B A 3.17±0.12 11.7±0.49

1 μmol/L 3H- + 500 μmol/L b)

A B 1.53±0.02 5.14±0.36

0.65±0.00 19.9±0.91

B A 7.85±0.32 13.0±0.36

1 μmol/L ABT A B 8.69±0.07

0.65±0.07 9.29±0.70

0.56±0.03 B A 5.61±1.01 5.21±0.10

1 μmol/L ABT + 500 μmol/L b)

A B 9.85 c) 0.50 8.98±0.17

0.57±0.02 B A 4.94±0.04 5.08±0.08

15 μmol/L ABT A B 8.92±0.06

0.65±0.02 10.1±0.19

0.58±0.02 B A 5.81±0.12 5.83±0.03

15 μmol/L ABT +500 μmol/L b)

A B 10.5±0.54 0.56±0.03

10.2±0.34 0.52±0.03

B A 5.90±0.11 5.36±0.19

1 μmol/L ABT sulphate M45 A B BQL

- BQL

- B A BQL BQL 1 μmol/L ABT sulphate M45 +500 μmol/L b)

A B BQL -

BQL -

B A BQL BQL


4.05±2.01 0.05±0.00

1.62±0.74 B A 0.23±0.01 0.09±0.00

15 μmol/L ABT sulphate M45 +500 μmol/L b)

A B 0.39±0.06 0.83±0.35

0.20±0.01 1.07±0.38

B A 0.32±0.01 0.21±0.00


- BQL

- B A BQL BQL 1 μmol/L N-oxide ABT sulphate M31 +500 μmol/L b)

A B BQL -

BQL -

B A BQL BQL


2.80±1.60 0.02±0.00

- B A 0.23±0.01 BQL 15 μmol/L N-oxide ABT sulphate M31 +500 μmol/L b)

A B 0.21±0.01 0.47±0.35

0.28±0.10 0.63±0.52

B A 0.10±0.01 0.18±0.02 a) 3 ± b) MRP2 c) n=1 ABT BQL < 1.00 ng/mL Papp<0.2 10-6 cm/s 1 μmol/L ABT sulphate Papp<0.3 10-6 cm/s 1 μmol/L N-oxide ABT sulphate Papp<0.02 10-6 cm/s 15 μmol/L N-oxide ABT sulphate Papp , -


2.6.5

54

2.6.5.15 B

FK10223 CTD 4.2.2.6.1

LLC-PK1 P-gp LLC-PK1


30 nmol/L 3H- A B 1.82±0.01

3.08±0.15 0.40±0.00

23.8±2.78 B A 5.60±0.11 9.43±0.94

30 nmol/L 3H- +5 μmol/L GF120918 b)

A B 2.69±0.08 1.12±0.12

2.55±0.02 0.95±0.04

B A 3.00±0.24 2.43±0.01

1 μmol/L ABT A B 9.31±0.39

0.47±0.02 9.18±0.32

0.56±0.03 B A 4.34±0.01 5.19±0.06

1 μmol/L ABT +5 μmol/L GF120918 b)

A B 8.54±0.01 0.55±0.01

9.47±0.30 0.47±0.02

B A 4.67±0.01 4.49±0.06

15 μmol/L ABT A B 11.3±0.15

0.48±0.01 12.6±0.33

0.40±0.01 B A 5.36±0.02 5.06±0.05

15 μmol/L ABT +5 μmol/L GF120918 b)

A B 11.5±1.24 0.41±0.02

9.67±0.53 0.48±0.03

B A 4.72±0.01 4.62±0.06

0.73 μmol/L ABT sulphate M45 A B BQL

- BQL

- B A BQL BQL 0.73 μmol/L ABT sulphate M45 +5 μmol/L GF120918 b)

A B BQL -

BQL -

B A 0.47 c) BQL


6.34±2.36 0.04±0.00

2.45±0.63 B A 0.29±0.03 0.09±0.00

11 μmol/L ABT sulphate M45 +5 μmol/L GF120918 b)

A B 0.04±0.00 1.94±0.62

0.16±0.01 1.22±0.61

B A 0.08±0.00 0.19±0.01


- BQL

- B A BQL BQL 1 μmol/L N-oxide ABT sulphate M31 +5 μmol/L GF120918 b)

A B BQL -

BQL -

B A BQL BQL


2.65±1.61 0.21±0.01

0.55±0.29 B A 0.26±0.02 0.12±0.00

15 μmol/L N-oxide ABT sulphate M31 +5 μmol/L GF120918 b)

A B 0.03 c) 1.33 0.04 d) 3.39 B A 0.04±0.00 0.15±0.01

a) 3 ± b) P-gp BCRP c) BQL n=1 d) n=1 ABT BQL < 1.00 ng/mL Papp<0.3 10-6 cm/s 0.73 μmol/L ABT sulphate Papp<0.2 10-6 cm/s 1 μmol/L N-oxide ABT sulphate Papp<0.01 10-6 cm/s 15 μmol/L N-oxide ABT sulphate Papp , -


2.6.5

55

2.6.5.15 B

FK10223 CTD 4.2.2.6.1

BCRP 1 15 mol/L ABT ABT sulphate M45 N-oxide ABT sulphate M31 37 1 BCRP

- ATP + ATP

BCRP BCRP 3H-Estrone-3-Sulphate cpm a)

1 μmol/L 3H-Estrone-3-Sulphate 548±25.0 753±32.0 643±18.8 4604±334 1 μmol/L 3H-Estrone-3-Sulphate + 1 μmol/L KO143 b) 507±6.66 698±28.0 584±33.2 739±51.1

ABT ng/mL a) 1 μmol/L ABT 88.0±32.1 59.7±4.90 55.6±5.76 65.1±3.35 1 μmol/L ABT + 1 μmol/L KO143 b) 82.5±6.31 81.6±11.5 75.9±5.00 112±30.2

15 μmol/L ABT 1327±476 899±62.1 847±92.8 996±52.4 15 μmol/L ABT + 1 μmol/L KO143 b) 1247±92.9 1240±168 1157±75.1 1723±469

ABT sulphate ng/mL a) 1 μmol/L ABT sulphate M45 55.5±6.46 73.7±11.1 62.4±5.90 61.3±11.5 1 μmol/L ABT sulphate M45 + 1 μmol/L KO143 b) 54.6±4.36 99.4±43.8 65.8±1.19 87.0±5.42

15 μmol/L ABT sulphate M45 844±77.0 1037±37.9 1087±160 1480±184 15 μmol/L ABT sulphate M45 + 1 μmol/L KO143 b) 1025±48.8 1347±41.6 961±176 1517±170

N-oxide ABT sulphate ng/mL a) 1 μmol/L N-oxide ABT sulphate M31 0.954±0.153 1.15±0.181 1.09±0.138 4.35±0.277 1 μmol/L N-oxide ABT sulphate M31 + 1 μmol/L KO143 b) 0.780±0.215 1.18±0.156 0.901±0.0335 1.15±0.141

15 μmol/L N-oxide ABT sulphate M31 12.2±1.27 15.9±2.84 14.3±0.833 57.1±4.55 15 μmol/L N-oxide ABT sulphate M31 + 1 μmol/L KO143 b) 11.7±2.73 15.8±2.17 11.0±0.777 15.4±2.54

a) 3 ± b) BCRP ABT


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