250 ZYTIGA Tablets 250 mg 026139
1 ZYTIGA CYP17 prednisone prednisolone 1 chemotherapy is not yet clinically indicated 2 docetaxel 3 2 2.1 ZYTIGA 1,000 4 250 prednisone prednisolone 5 1
ZYTIGA 1,000 4 250 prednisone prednisolone 5 ZYTIGA ZYTIGA 2 ZYTIGA 1 11.2 2.2 Child-Pugh Class B ZYTIGA 250 250 AUC 1,000 AUC 250 2
ALT AST ALT AST ULN 5 3 ULN ZYTIGA ZYTIGA 8.5 11.2 Child-Pugh Class C ZYTIGA ZYTIGA ALT AST 5 ULN 3 ULN ZYTIGA 5.3 AST ALT 2.5 ULN 1.5 ULN 750 3 3
酶 750 AST ALT 2.5 ULN 1.5 ULN 500 5 0 0 ZYTIGA AST ALT 20 ULN 10 ULN ZYTIGA ALT 3 ULN total bilirubin 2 ULN ZYTIGA 5.3 4
2.3 CYP3A4 ZYTIGA CYP3A4 phenytoin carbamazepine rifampin rifabutin rifapentine phenobarbital CYP3A4 CYP3A4 ZYTIGA 1,000 1,000 CYP3A4 7.1 11.2 3 ZYTIGA abiraterone acetate 250 AA250 5
4 4.1 ZYTIGA ZYTIGA ZYTIGA 8.1 5 5.1 ZYTIGA CYP17 11.1 ZYTIGA 2% 3-4 4% 3-4 6
1% 3-4 6 ACTH ZYTIGA < 50% NYHA III IV 1 NYHA II IV 3011 2 ZYTIGA 13 ZYTIGA 5.2 0.5% ZYTIGA 0.2% 7
ZYTIGA prednisone prednisone prednisone ZYTIGA 5.1 5.3 ZYTIGA 6.2 ZYTIGA 4% 3 4 8
ALT AST 5 ULN 3 ALT AST ZYTIGA 1% ZYTIGA ZYTIGA 酶 ALT AST 250 ZYTIGA ALT AST AST ALT AST ALT AST ALT 5 ULN 3 ULN ZYTIGA 9
AST ALT 2.5 ULN 1.5 ULN ZYTIGA 2.2 ALT 3 ULN total bilirubin 2 ULN ZYTIGA 2.2 AST ALT 20 ULN 10 ULN ZYTIGA 6 5.1 10
5.2 5.3 6.1 3 ZYTIGA 10% 酶 / 酶 ZYTIGA 3 abiraterone acetate 18% vs. 8% 22% vs. 16% 23% vs. 17% abiraterone acetate 6% 2% 11
CTCAE Common Terminology Criteria for Adverse Events 4 3 4 8% 5% CTCAE 4 3 4 1% 1% 3 4 LHRH ZYTIGA 1,000 prednisone prednisolone 5 10 1/10 1/100 < 1/10 1/1,000 < 1/100 1/10,000 < 1/1,000 < 1/10,000 12
1 13
* QT a 14
酶 / 酶 b ** 15
* ** a b 酶 / 酶 ALT AST 16 CTCAE 4 3 abiraterone acetate 5% 2% 酶 / 酶 4% 6% 2% 1% CTCAE 4 3 < 1% CTCAE 4 4 酶 / 酶 < 1%
3011 3011 36.7% 1 2 11.8% 20.2% 3011 20.4% 1 2 19.2% 14.9% ECOG2 75 3 6 NYHA III IV 1 II IV 3011 2 < 50% 17
LHRH 3 abiraterone acetate 2.6% vs. 2.0% 1.9% vs. 1.0% 1.7% vs. 0.8% 0.7% vs. 0.2% 0.7% vs. 0.5% abiraterone acetate ALT AST 3 3 6% abiraterone acetate 3 4 ALT AST > 5 [ULN] > 1.5 [ULN] 3011 8.4% ZYTIGA 3 4 ZYTIGA 2 3 4 3011 3 ALT AST 18
ALT AST > 5 [ULN] > 3 [ULN] abiraterone acetate ALT AST 15 40 [ULN] 2 6 [ULN] 2 abiraterone acetate 35 6.5% 3 4 ALT AST 3 2 1 abiraterone acetate 3 AST 酶 3 1.1% abiraterone acetate 0.6% ALT AST 19
3011 ALT AST > 2.5 [ULN] 1.5 [ULN] 1 ALT AST 2.5 [ULN] ALT AST > 5 [ULN] 2 ALT AST 2.5 [ULN] ALT AST > 20 [ULN] 6.2 ZYTIGA 20
7 7.1 CYP3A4 ZYTIGA CYP3A4 rifampin CYP3A4 abiraterone 55% ZYTIGA CYP3A4 CYP3A4 ZYTIGA 2.3 11.2 21
ketoconazole CYP3A4 abiraterone 11.2 7.2 Abiraterone ZYTIGA CYP2D6 CYP2C8 CYP2D6 dextromethorphan CYP2D6 1,000 abiraterone acetate 5 prednisone dextromethorphan Cmax AUC 2.8 2.9 abiraterone acetate CYP2D6 thioridazine CYP2D6 11.2 C Y P 2 C 8 22
pioglitazone CYP2C8 1,000 mg abiraterone acetate pioglitazone AUC 46% ZYTIGA CYP2C8 8 8.1 X 4.1 ZYTIGA ZYTIGA ZYTIGA CYP17 abiraterone acetate ZYTIGA 23
ZYTIGA 6-17 10 30 100 / / abiraterone acetate 10 / / 30 / / 100 / / 10 / / AUC AUC 0.03 0.1 0.3 8.2 24
ZYTIGA abiraterone acetate ZYTIGA 8.3 ZYTIGA 8.4 3 ZYTIGA 73% 65 30% 75 25
8.5 N=8 N=8 Child-Pugh A B 8 abiraterone 1,000 ZYTIGA abiraterone AUC 1.1 3.6 Child-Pugh Class C N=8 8 abiraterone abiraterone AUC 7 2 Child-Pugh Class B ZYTIGA 250 26
Child-Pugh Class C ZYTIGA ALT AST > 5 ULN > 3 ULN ZYTIGA 2.1 11.2 2.2 5.3 11.2 8.6 N=8 ESRD N=8 1,000 ZYTIGA PK 2.1 11.2 27
9 ZYTIGA ZYTIGA 10 ZYTIGA abiraterone acetate abiraterone acetyl ester Abiraterone CYP17 17α-hydroxylase/C17,20-lyase ZYTIGA 250 abiraterone acetate Abiraterone acetate 3β -17-3-pyridinyl androsta-5,16- dien-3-yl acetate 28
Abiraterone acetate C26H33NO2 391.55 Abiraterone acetate 5.12 Log P aromatic nitrogen pka 5.19 povidone 29
11 11.1 Abiraterone acetate ZYTIGA abiraterone 17α 酶 /C17,20 酶 17α-hydroxylase / C17,20- lyase CYP17 CYP17 1 pregnenolone progesterone 17α 酶 17α 2 C17,20 酶 dehydroepiandrosterone DHEA androstenedione DHEA androstenedione CYP17 abiraterone 5.1 30
GnRH 3 ZYTIGA ZYTIGA PSA 11.2 CRPC abiraterone acetate abiraterone abiraterone acetate Abiraterone acetate abiraterone > 99% abiraterone acetate < 0.2 ng/ml 31
CRPC abiraterone acetate abiraterone 2 abiraterone AUC 1,000 abiraterone acetate 2 CRPC 1,000 Cmax SD 226 178 ng/ml AUC 993 639 ng hr/ml 250 1,000 1,000 2,000 AUC 8% abiraterone acetate abiraterone abiraterone acetate 7% 300 abiraterone Cmax AUC0-7 5 abiraterone acetate 57% 825 32
17 10 abiraterone acetate 25% 491 2 1 abiraterone AUC0-7 1.6 CRPC abiraterone acetate 7 abiraterone 7 2 1 7 abiraterone 2 ZYTIGA ZYTIGA 2 ZYTIGA 1 2.1 Abiraterone α1 > 99% 33
SD 19,669 13,358 abiraterone acetate abiraterone P- P-gp abiraterone acetate P-gp 14 C-abiraterone acetate abiraterone acetate abiraterone 酶 酶 CYP Abiraterone abiraterone sulphate N-oxide abiraterone sulphate 43% N-oxide abiraterone sulphate CYP3A4 SULT2A1 SULT2A1 abiraterone sulphate CRPC abiraterone SD 34
12 5 14 C-abiraterone acetate 88% 5% abiraterone acetate abiraterone 55% 22% N=8 N=8 Child-Pugh A B 8 abiraterone 1,000 abiraterone 1.1 3.6 abiraterone 18 19 Child-Pugh Class C N=8 8 abiraterone 35
abiraterone AUC 7 2 2.2 8.5 ESRD N=8 N=8 abiraterone ESRD 1 1,000 ZYTIGA 96 1,000 abiraterone 8.6 36
abiraterone CYP1A2 CYP2D6 CYP2C8 CYP2C9 CYP2C19 CYP3A4/5 dextromethorphan CYP2D6 30 1,000 abiraterone acetate prednisone 5 dextromethorphan Cmax AUC 2.8 2.9 Dextrorphan dextromethorphan AUC 1.3 7.2 abiraterone acetate 1,000 prednisone 5 100 theophylline CYP1A2 theophylline abiraterone CYP3A4 CYP3A4 rifampin 6 37
600 1,000 abiraterone acetate abiraterone AUC 55% 7.1 ketoconazole CYP3A4 abiraterone 7.1 C Y P 2 C 8 pioglitazone CYP2C8 1,000 mg abiraterone acetate pioglitazone AUC 46% 7.2 abiraterone OATP1B1 hepatic uptake transporter 11.3 QT 33 CRPC 38
ZYTIGA 1,000 1 2 prednisone 5 2 2 QTc > 20 QTc abiraterone acetate < 10 12 12.1 5 15 50 / / abiraterone acetate 15 50 150 / / abiraterone acetate abiraterone acetate interstitial cell adenoma and carcinoma abiraterone 39
AUC AUC 0.8 abiraterone acetate Tg.rasH2 6 abiraterone acetate Abiraterone acetate abiraterone Ames ZYTIGA 13 26 39 50 / / 250 / / / abiraterone 12.2 40
AUC 0.6 4 30 / / 30 / / abiraterone acetate abiraterone acetate 16 2 7 30 / / 300 / / abiraterone acetate abiraterone acetate 4 30 / / 1,000 / 0.3 41
12.2 13 26 13 39 AUC abiraterone acetate 26 50 / / AUC 39 AUC 2 abiraterone acetate 4 13 42
mhspc mcrpc ZYTIGA 3 3011 3 mhspc 3 2 1 Gleason score 8 2 3 3 ADT LHRH ZYTIGA 1,000 prednisone 5 ADT ZYTIGA prednisone ketoconazole 1 2 spironolactone 43
3011 mhspc 3011 67 n=1199 ZYTIGA 832 69.4% 246 20.5% 25 2.1% 80 6.7% / 13 1.1% 3 0.3% 97% ECOG 0 1 NYHA II-IV 3 ADT 1 OS X rpfs BPI-SF 2.0 SRE 44
PSA X X X PCWG2 CT MRI RECIST 1.1 X rpfs 2 1 45
2 X PCR3011 AA-P 597 602 239 40.0% 354 58.8% Censored 358 60.0% 248 41.2% 95% CI 33.02 29.57, NE 14.78 14.69, 18.27 0.0+, 41.0+ 0.0+, 40.6+ 46
p a < 0.0001 95% CI b 0.466 0.394, 0.550 + = NE= X X rpfs AA-P= abiraterone acetate prednisone a p ECOG 0/1 2 b < 1 AA-P 47
1 X Kaplan-Meier PCR3011 100 % 80 60 40 20 48 0 Abiraterone Acetate 00 4 8 12 16 20 24 28 32 36 40 597 533 464 400 353 316 251 177 102 51 21 602 488 367 289 214 168 127 81 41 17 7 Abiraterone Acetate
ADT OS AA-P ADT 38% HR=0.621 95% CI 0.509, 0.756 p < 0.0001 1 [OS] 0.010 3 2 49
3 PCR3011 AA-P 597 602 169 28.3% 237 39.4% Censored 428 71.7% 365 60.6% 95% CI NE NE, NE 34.73 33.05, NE 0.1, 43.5+ 1.4+, 43.5+ 50
p a < 0.0001 95% CI b 0.621 0.509, 0.756 + = NE= AA-P= abiraterone acetate prednisone a p ECOG 0/1 2 b < 1 AA-P 51
2 Kaplan-Meier PCR3011 100 % 80 60 40 20 0 00 6 12 18 24 30 36 42 Abiraterone Acetate 597 565 529 479 388 233 93 9 52 602 564 504 432 332 172 57 2 Abiraterone Acetate
ZYTIGA AA-P X rpfs ECOG 2 n=40 X rpfs ZYTIGA vs. SRE 30% HR=0.703 95% CI [0.539, 0.916] p=0.0086 ZYTIGA PCWG2 PSA PSA ZYTIGA 33.2 7.4 HR=0.299 95% CI [0.255, 0.352] p < 0.0001 53
ZYTIGA 21.6 HR=0.415 95% CI [0.346, 0.497] p < 0.0001 ZYTIGA 38.9 HR=0.443 95% CI [0.349, 0.561] p < 0.0001 ZYTIGA 16.6 HR=0.695 95% CI [0.583, 0.829] p < 0.0001 abiraterone acetate prednisone AA-P 1 docetaxel CRPC 54
1,195 2:1 ZYTIGA 1,000 prednisone 5 N=797 prednisone 5 N=398 PSA / 25% X 69 39-95 93.3% 3.6% 1.7% 1.6% 89% ECOG 0-1 45% 4 24 90% 30% 70% X 30% PSA 55
70% 30% 552 ZYTIGA 4 3 775 97% 4 4 1 ZYTIGA Prednisone 56 ZYTIGA N=797 N=398 % 333 42% 219 55%
95% CI 14.8 14.1, 15.4 10.9 10.2, 12.0 p 1 < 0.0001 95% CI 2 0.646 0.543, 0.768 % 501 63% 274 69% 95% CI 15.8 14.8, 17.0 11.2 10.4, 13.1 95% CI 2 0.740 0.638, 0.859 1 P ECOG 0-1 vs. 2 vs. 1 vs. 2 PSA vs. X 2 < 1 ZYTIGA 57
3 1 Kaplan-Meier 100 80 % 60 40 20 58 0 0 3 6 9 12 15 18 21 ZYTIGA 797 736 657 520 282 68 2 0 398 355 306 210 105 30 3 0 ZYTIGA
2 CRPC 2 1088 1:1 1,000 ZYTIGA N=546 N=542 prednisone 5 X ECOG 3 70 ZYTIGA 95.4% 2.8% 0.7% 1.1% 76% ECOG 0 24% 1 59
X rpfs 24 66% 0-1 26% 2-3 X 2 2 / RECIST X rpfs 741 49 ZYTIGA 5 4 65% ZYTIGA 78% CRPC 13% ZYTIGA 44% ZYTIGA 60
5 2 ZYTIGA Prednisone ZYTIGA N=546 N=542 354 65% 387 71% 95% CI 34.7 32.7, 36.8 p 1 0.0033 2 95% CI 0.81 0.70, 0.93 30.3 28.7, 33.3 1 P ECOG 0 vs. 1 2 < 1 ZYTIGA 61
4 2 Kaplan-Meier 100 % 80 60 40 20 62 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 ZYTIGA 546 538 525 504 483 453 422 394 359 330 296 273 235 218 202 189 118 59 15 0 0 542 534 509 493 466 438 401 363 322 292 261 227 201 176 148 132 84 42 10 1 0 ZYTIGA
rpfs 150 28% ZYTIGA 251 46% X rpfs 6 5 6 2 ZYTIGA Prednisone X X ZYTIGA N=546 N=542 150 28% 251 46% rpfs 95% CI NR 11.66, NR 8.28 8.12, 8.54 p 1 < 0.0001 2 95% CI 0.425 0.347, 0.522 63
NR= 1 P ECOG 0 vs. 1 2 < 1 ZYTIGA 64
5 2 X Kaplan-Meier X % 100 80 60 40 20 0 0 3 6 9 12 15 18 ZYTIGA 546 489 340 164 46 12 0 542 400 204 90 30 3 0 ZYTIGA 65
ZYTIGA 25.2 16.8 HR=0.580 95% CI [0.487, 0.691] p < 0.0001 ZYTIGA 23.7 HR=0.686 95% CI [0.566, 0.833] p=0.0001 ZYTIGA 2014 3 31 0.806 95%CI 0.697,0.931 ZYTIGA 34.66 30.29 66
14 / ZYTIGA 250 AA250 NDC 57894-150-12 120 30 C ZYTIGA 250 ZYTIGA ZYTIGA 250 8.1 67
15 ZYTIGA prednisone prednisolone GnRH ZYTIGA prednisone prednisolone ZYTIGA ZYTIGA 2 ZYTIGA 1 ZYTIGA ZYTIGA prednisone prednisolone ZYTIGA prednisone prednisolone 68
ZYTIGA ZYTIGA ZYTIGA 250 abiraterone ZYTIGA 69
Patheon, Inc. 2100 Syntex Court Mississauga Ontario, L5N 7K9 Canada Janssen-Cilag S.P.A. Via C. Janssen 04100 Borgo S. Michele-Latina, Italy 319 8 0800-211-688 USPI_May2017+EUPI_Nov2017 mhspc _v1801 Johnson & Johnson Taiwan Ltd. 2018 1801 70