2013 03 26 2014 06 03 2015 11 25 2016 10 25 2017 09 25 ACTEMRA Tocilizumab Injection Tuozhudankang Zhusheye 6IL-6 CHO DNA C 6428H 9976 N 1720 O 2018 S 42 () 1
144 ) 985 Da ( 80 RA DMARDs MTX DMARDs sjia NSAIDs 2 2 sjia 80mg/4ml 200mg/10ml 400mg/20ml RA 8mg/kg 4 1 MTX DMARDs 4mg/kg 0.9% 100ml 1 100kg 800mg sjia sjia 2 1 1 2 <30 kg 12 mg/kg 30 kg 8 mg/kg 2
30 kg sjia 0.9% 100ml < 30 kg sjia 0.9% 50ml RA DMARDs > 13 4mg/kg ULN 4mg/kg 8mg/kg <3 ULN > 35ULN >1~3ULN ( ) >3 ULN > 5 ULN ANC 10 9 /L ANC > 1 ANC 0.51 ANC >1 10 9 /L 4mg/kg 8mg/kg ANC < 0.5 10 3 /μl 3
50100 >100 10 3 /μl 4mg/kg 8mg/kg < 50 sjia <2 10 9 /L <100 10 3 /μl, ALT AST 1.5 ULN / > 1 3 MTX ULN ALT AST > 3-5 ULN MTX < > 1-3 ULN > 5 ULN ANC 10 9 /L ANC > 1 ANC 0.5-1 ANC > 1 10 9 /L ANC < 0.5 10 3 /μl 4
50 100 MTX > 100 10 3 /μl < 50 RA 100ml 100ml sjia 30kg (0.4ml/kg) 100ml 100ml <30kg (0.6ml/kg) 50ml 50ml 5
0.9% 30 24 2~8 24 1 RA 5 III 2 4 6 2 4mg/kg MTX 774 8mg/kg MTX DMARDs 1870 8mg/kg 288 4009 3577 3296 1 2806 2 1222 3 1/100 1/10 1/1000 1/100 1 MTX DMARDs RA 6
6 8mg/kg+DMARD +DMARD 127 /100 112 /100 +DMARD 108 /100 6 8mg/kg+DMARD 5.3 /100 +DMARD 3.9 /100 3.6 /100 MTX 1.5 /100 4.7 /100 6 0.26 /100 0.28 6 24 8mg/kg+DMARD 6.9% +DMARD 5.1% 24 3778 6 4mg/kg 8mg/kg 3778 13 0.3% 2 5 7
6 2876 46 1.6% 5 30 1.1% 24 15 8 1.32 /100 +DMARD 1.37 /100 24 6 8mg/kg+DMARD 3.4% 1 10 9 /L +DMARD <0.1%ANC 1 10 9 /L 8 8mg/kg+DMARD 0.3% 0.5 10 9 /L 1 10 9 6 6 8mg/kg DMARDs 1.7% 100 10 3 /μl DMARDs <1% 6 6 8mg/kg 2.1% /ALT/AST 3 MTX 4.9% 8mg/kg+DMARD 6.5%+DMARD 1.5% MTX 0.7% ALT/AST 5 +DMARD 1.4% 8
8mg/kg+DMARD 6.2% ALT/AST 6 6 24% > 6.2mmol/L (240mg/dl) 15% 4.1mmol/L (160mg/dl) 6 sjia 112 NSAIDs 2 17 sjia 0.3 mg/kg/ 70% 12 12 75 8 12 mg/kg 12 12 5% sjia RA 12 345/100 287.0/100 73 306.6/100 12 11.4/100 73 11.3/100 RA 9
sjia sjia 24 12 4% 0% 1 12 24 16% 5% 1/112 <1 112 2 1 1 12 7% 1 10 9 /L 0% 73 17% 1 10 9 /L 1 10 9 /L 12 3% 1% 100 3 /µl 73 4% 100 10 3 /µl 10
12 5%3% ALT AST 3 ULN 0% 73 13%5% ALT AST 3 ULN 12 1.5% > 1.5-2 ULN 0% 1.9% LDL > 1.5-2 ULN 0% 73 12 2 Stevens-Johnson 11
RA sjia MTX RA 23- MTX sjia 12
sjia MAS MAS sjia MAS sjia 12 MAS 3/112 3% MAS 1 2 12 mg/kg 70 MAS 2 MAS 3 MAS 2 1 sjia MAS RA sjia 13
ANC<2 10 9 /L 0.5 10 9 /L RA 4 8 ANC sjia 100 10 3 /μl <50 10 3 /μl RA 4 8 sjia MTX ALT AST 1.5 ALT AST 5 RA 4 8 ALT AST sjia ALT AST / 14
RA sjia 4 8 RA / 3 / / 2 I~V 2644 435 65 50 75 65 65 IL -6 P450CYP450 CYP1A2CYP2B6CYP2C9CYP2C19CYP2D6 CYP3A4 mrna RA IL-6 CYP450 CYP450 CYP2C8 P-P -gp CYP450 15
CYP3A4 OATP1B1 12 RA 40mg 4~10 2 10mg/kg 57%39% RA CYP3A4 CYP2C19 CYP3A4 RA 10mg 2 RA 8mg/kg 1 10mg AUCinf 0 N=5N=5 12% N=8 28% CYP2D6 CYP3A4 13 RA 30mg 8mg/kg 1 5%2 1 40mg/kg 1 28mg/kg 28mg/kg 5 RA 5 ~ 18 ACR 8 6 4 MTX I DMARDs 16
673 6 MTX MTX 67% MTX 8mg/kg 4 MTX 7.5 mg/ 8 20mg/ 24 ACR20 2 24 52 1196 MTX 4 8mg/kg 52 MTX10~25mg/ 24 ACR20 52 MTX 623 MTX 4 8mg/kg MTX10~25mg/ 1220 DMARDs 8 mg/kg DMARD 499 TNF TNF 4 8mg/kg MTX10~25mg/~ 24 ACR20 ~ ACR20ACR50ACR70 2 2 MTX/ ACR MTX MTX DMARD TNF MTX TCZ MTX TCZ TCZ TCZ TCZ 8mg/k 8mg/k 8mg/k 8mg/k +DMA 8mg/k +MTX +MTX +MTX g g+mt g+mt g+dm RD g+mt X X ARD X N=286 N=284 N=398 N=393 N=205 N=204 N=803 N=413 N=170 N=158 ACR20 24 52 ACR50 70%*** 52% 56%*** 27% 59%*** 26% 61%*** 24% 50%*** 10% 56%*** 25% 24 44%** 33% 32%*** 10% 44%*** 11% 38%*** 9% 29%*** 4% 17
52 ACR70 24 52 52 MCR 36%*** 10% 28%** 15% 13%*** 2% 22%*** 2% 21%*** 3% 12%** 1% 20%*** 4% 7% 1% TCZ= N=28 6 DAS28 *p0.05 +MTX/DMARD **p0.01 +MTX/DMARD ***p0.0001 +MTX/DMARD MCR = ACR70 24 8mg/kg 6 ACR205070 2 3 8mg/kg ACR +MTX/DMARDs HAQ C CRP 8mg/kg DAS28+DMARD EULAR +DMARD 3 MAX TCZ MTX 8mg/k g N=28 4 3 24 DAS EULAR DMARD TNF MTX MTX +MTX TCZ 8mg/kg +MTX N=398 TCZ +MTX 8mg/kg +MTX N=393 N=205 [ SE ] 18 TCZ 8mg/kg +MTX +DMAR D N=204 N=803 TCZ +DMAR 8mg/kg D +MTX N=170 N=413 24-3.31-2.05-3.11-1.45-3.43-1.55-3.17-1.16-3.16-0.95 N=15 8
(0.12) (0.12) (0.09)*** (0.11) (0.12) (0.15) (0.07) (0.09) (0.14) (0.22) *** *** *** DAS2.6% 24 33.6% 12.1% 33.3%** * 3.8% 27.5%** * 0.8% 30.2%** * 3.4% 30.1%* ** 1.6% EULAR % 18% 35% 26% 65% 20% 65% 20% 62% 32% 84% 42% 48% 34% 29% 41% 32% 40% 33% 31% 15% 40% 17% 41%*** 6% 38%*** 3% 40%*** 4% 37%*** 2% TCZ= p EULAR *p0.05 +MTX/DMARD **p0.01 +MTX/DMARD ***p0.0001 +MTX/DMARD II 47% 52 DAS28 < 2.6 24 33% /MTX 2 14% 24 II MTX Sharp-Genant MTX II +MTX 4 II 52 104 X PBO + MTX 52 (+ 16 TCZ) 19 TCZ 8 mg/kg + MTX N 294 353 Sharp-Genant 1.17 0.25
0.76 0.15 JSN 0.41 0.10 52 104 N 294 353 Sharp-Genant 0.79 0.12 0.48 0.07 JSN 0.31 0.05 PBO - MTX - TCZ - JSN - II 24 52 80 104 104 MTX 1 TSS 0 83% MTX 67% 83% 52 104 93% 8mg/kg DMARDs MTX/DMARDs HAQ-DIFACIT - PCSMCS 36SF -36 5 24 8mg/kg HAQ-DI 0.25+MTX/DMARDs II MTX TCZ 8mg/kg N=286 5 24 SF-36HAQ FACIT- MTX N=284 MTX TCZ 8mg/kg + MTX N=398 +MTX N=393 MTX TCZ 8mg/kg+ MTX N=205 PCS SE 20 +MTX N=204 DMARD TCZ 8mg/kg + DMARD N=803 + TCZ 8mg/kg DMARD + MTX N=413 N=170 TNF +MTX N=15 8
10.2 8.4 0.7(0.7) 8.1 9.5 5.0 5.6 0.6 0.81.0 0.7 ** *** 8.9 (0.4)*** 4.1 (0.6) 8.0 (0.9)** 2.2 (1.3) MCS SE 6.7 5.0 0.9(0.9) 2.7 4.2 2.8 7.3 1.3 0.8 0.9 1.1** 5.3 (0.6)** 2.3 (0.7) 4.1 (1.3) 4.1 (1.9) HAQ-DI SE -0.70 (0.05) -0.52 (0.05) -0.5 (0.04)** -0.3 (0.04) -0.55 (0.06)** -0.34 (0.07) -0.47 (0.03)*** -0.2 (0.03) -0.39 (0.05)** * -0.05 (0.07) FACIT- SE 9.3 7.0 0.8(0.8) 6.4 5.4 0.7(0.8) 8.6 0.91.0 *** 4.0 8.0 (0.5)*** 3.6 (0.7) 8.8 (1.0)* 4.2 (1.6) TCZ= *p0.05 +MTX/DMARD **p0.01 +MTX/DMARD ***p0.0001 +MTX/DMARD II,TCZ 8 mg/kg+mtx PCSMCSFACIT- 52 10.1p0.00015.4 8.4p0.01+MTX 5.63.85.5 52 TCZ 8 mg/kg+mtx HAQ-DI - 0.58 +MTX - 0.39TCZ 8 mg/kg+mtxhaq-di 104-0.61 24 8mg/kg DMARD/MTX +MTX/DMARD p 0.0001 RA 2 24 CRPESR A sjia 21
12 := 2:1 2 MTX 75 2 30 kg 8 mg/kg < 30 kg 12 mg/kg 37 2 JIA ACR70 6 12 12 JIA JIA ACR ACR30 30% 7 37.5 C JIA ACR 6 3 30%50%70% 1 30% ESR - CHAQ85% 64/75 24.3%9/37 JIA ACR 30,50,70 90 6 12 JIA ACR N=75 N=37 ACR 30 90.7%* 24.3% ACR 50 85.3%* 10.8% ACR 70 70.7%* 8.1% ACR 90 37.3%* 5.4% * p<0.0001, vs. JIA ACR JIA AC 44 35/41 85% sjia 12 14 37.5 C 5/24 21% 14/22 64% 2/18 11% 44 22
8/31 26% 48/7069% 6 8 JIA ACR70 17 24 1 3 20 12 JIA ACR30 44 44/103 43% 44 50% 18 HAQ -DI 12 CHAQ-DI 0.13 77 58/75 19 7/37 CRPESR A IL-6 2~28 mg/kg 3~5 IgG1 6IL -6 IL-6 sil-6r mil-6r sil-6r mil-6r IL -6 T IL -6 IL-6 23
50mg/kg/ 4 100mg/kg/ 6 8~10 IL-6 6 IL-6 IL-6 IL-6 50mg/kg/ / 100 / IL-6 RA 1793 4mg/kg 8mg/kg 4 24 RA 4 4mg/kg 8mg/kg AUC C min 24
C max 8mg/kg AUC C min 4 mg/kg 2.7 6.5 4 8mg/kg AUCC min C max ±SD 35000±15500h μg/ml9.74±10.5μg/ml 183±85.6μg/ml AUC C max 1.22 1.06 C min 2.35 8 20 C maxaucc min AUCC min C max 100kg AUC C min C max (±SD) 55500±14100mcg h/ml19.0±12.0mcg/ml269±57mcg/ml 100 kg 800mg 4 4mg/kg AUCC C max (± SD) 13000±5800µg h/ml 1.49±2.13μg/ml 88.3± 41.4µg/mlAUCC max 1.11 1.02C min 1.96 C max AUC 16 C sjia min min sjia 75 sjia 2 8 mg/kg 30 12 mg/kg <30 AUC 2 C max C min ± SD 32200 ± 9960 mcg h/ml245 ± 57.2 mcg/m l 57.5 ± 23.3 mcg/ml C min 12 /2 3.2 ± 1.3 12 12 3.5L 2.9L 6.4L sjia 0.94L 1.60L 2.54L RA 12.5ml/hsJIA 7.1ml/h 25
RA t 1/2 RA 4 t 1/2 4 mg/kg 11 8 mg/kg 13 sjia 8 mg/kg 30 kg 12 mg/kg <30 kg t 1/2 12 23 Cockcroft-Gault 80ml/min 50ml/min 28 80mg/4ml1/ 4 / 200mg/10ml1/ 4 / 400mg/20ml1/ 4 / 30 JS20170010 80mg/4mlS20171024 200mg/10mlS20171025 400mg/20mlS20171026 26
Roche Pharma (Schweiz) Ltd. Schoenmattstrasse 2, 4153 Reinach, Switzerland Chugai Pharma Manufacturing Co., Ltd. 16-3, Kiyohara Kogyodanchi, Utsunomiya-city, Tochigi, 321-3231, Japan F. Hoffmann -La Roche Ltd. : Wurmisweg, 4303 Kaiseraugst, Switzerland 1100 021-28922888 400 820 8780 800 820 8780 www.roche.com.cn 27