アクテムラインタビューフォーム

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1 IF FAX 80mg 1 4mL 80mg 200mg 1 10mL200mg 400mg 1 20mL400mg JAN TocilizumabGenetical RecombinationJAN 200mg 80400mg

2 IF 1 MR 63 IF 10 IF 2IF IF IF 3IF 4 9 IF IF IF 11 1 IF IF 4IF IF MR IF IF MR Drug Safety Update IF

3 CAS

4

5 IgG1 6IL-6 CDR IL-6 IgG1 CHO IL B 1986 IL-6 IL IL-6 IL C 2 1 IL-6 2RA MTX 24 ACR %29.5% DAS 28ESR % 1ACR %50%70% VASVAS VASHAQ CRP ~ 5 3 2DASdisease activity score CRPVAS 28 DAS28 1

6 DMARDs % ACR X sJIA JIA % 4JIA JIA JIA 30%50%70% %50%70%30% 1 30% VAS/VASCHAQ ESR 4pJIA JIA % 5 C CRP ESR % %LDL % %ALT(GPT) % 2

7 80mg 200 mg 400 mg ACTEMRA 80 mg for Intravenous Infusion ACTEMRA 200 mg for Intravenous Infusion ACTEMRA 400 mg for Intravenous Infusion acteffective JAN TocilizumabGenetical RecombinationJAN tocilizumabr-inn C1033H1606N278O337S6 C2181H3398N582O672S15 148, C1033H1606N278O337S623, C2181H3398N582O672S1549, ,000 MRA

8 ph luxhr 5 200Whr/m 2 (1) SDS- (2) 4

9 1 80mg80mg 200 mg200mg 400 mg400mg ph mg 200mg 400mg 4 ml 10 ml 20 ml 80 mg 200 mg 400 mg mg 2 mg 500 mg 5 mg 1000 mg 10 mg ) 25kg 50mL25kg mL 20mg/mL 25kg 50mL25kg mL 5

10 (kg) 8 (mg/kg) (ml) = 20 (mg/ml) 1) [ ] 2) 80mg200mg400mg luxhr 5 200Whr/m 2 200mg 0.1 mg/ml 8 mg/ml 24 6

11 SDS- 7

12 C MASMAS MAS MAS MAS pjia 1. sjia IL-6 sjia 2.sJIA MAS MAS IL-6 TNF-IFN-IL-1IL-8 MAS MAS MAS 8

13 MAS MAS MAS MAS NSAIDs ) MAS PLT FDP-ED-dimer 2- AST/LDH/CK ) : 2007 :, 111(8), 1103, mg/kg 4 1 8mg/kg (1) sjia 1 23 sjia 2 CRP* IL-6 3 CRP* CRP* *C 9

14 sjia MAS 1 8mg/kg 2 CRP IL-6 1 8mg/kg 2 1 CRP CRP CRP mg/kg/ CRP CRP log r= CRP CRP IL-6 CRP 4 20 mg/ml 25 kg 50 ml25 kg mL (ml) = (kg) 8 (mg/kg) 20 (mg/ml) 5 (1) (2) 1 (1) 1.2 ((2)2) ) (2) Infusion Reaction 10

15 1 Infusion Reaction (2) 10mL/hr kg 50mL 1 25kg 100mL 1 1 RA P 25.0% MTX8mg/ 16/64 MTX ACR 64 #1 20% RA 24 8mg/kg/4 MTX 80.3% MTX 49/61 61 DMARDs RA Total 52 # mg/kg/ #1: ACR #2: 2 pjia JIA 30% 50% 70% JIA #3 94.7% 94.7% 57.9% pjia 12 18/19 18/19 11/19 #3:Giannini JIA 11

16 3 sjia P 8mg/2 3 2 sjia mg/kg/ % 4/ % 16/ sjia 56 8mg/kg 2 3 JIA 30% CRP0.5mg/dL 6 2 JIA 30% CRP1.5mg/dL 4 8mg/kg 2 248mg/kg/2 CRP 3 7 CRP ESR Hb 8mg/kg/ mg/kg mg/kg/ mg/kg % mg/kg %22 1.0mg/kg %4 2.0mg/kg %10 1 8mg/kg mg/kg 2 CRP ESR 93.3% 14 /15 2mg/kg mg/kg mg/kg mg/kg 12

17 mg/kg 8mg/kg ACR 20%8mg/kg 78.2%43/55 4mg/kg 57.4%31/ %6/53 8mg/kg 2 P0.0018mg/kg 4mg/kg ACR 50%ACR 70% 8mg/kg 4mg/kg 163 8mg/kg 47/ % 166 4mg/kg 39/ % 85 26/ % 49 HDL ASTALT 4mg/kg 8mg/kg 8mg/kg 4 8mg/kg 1 8mg/kg mg/kg CRP 4mg/kg 8mg/kg 3 CRP 2mg/kg/2 CRP 3 4mg/kg/2 5 8mg/kg/2 3 JIA 30%50% 702mg/kg % %4mg/kg %87.5%50.0%8mg/kg 3 100%100%100% mg/kg 8mg/kg 2 2 8mg/kg 1 8mg/kg 3 (1) mg/kg CRP CRP 8mg/kg 13

18 2 248mg/kg % % % 25 8mg/kg 8mg/kg 8mg/kg 2 1 8mg/kg (2) 28 8mg/kg % CRPmg/dL 8.7± ±1.7** 0.9±2.0** mg/dl 639± ±149** 317±138** ESRmm/hr 114±34 63±36** 48±40** 0100mm 29.9± ±17.2* 17.7±16.5** Hbg/dL 9.2± ±1.9** 12.0±2.1** g/dl 2.7± ±0.5** 3.7±0.5** 0.05p0.01 t n=24-28sd 1 (1) 8 mg/ + + 8mg/kg/424 ACR 20% 25.0%80.3%P0.001 ADL MHAQ

19 0.32P0.001MCID (minimum clinically important differences) % 67.2%P %22/ %17/ %10/61 (2) DMARDs 8 mg/kg/4 DMARD 52 Modified Sharp Score 52 X Total 88.5%139/ P Total mg/kg 2 3 JIA 30% CRP 0.5 mg/dl JIA 30% CRP 1.5 mg/dl JIA 30% % 85.7%67.9% % %P0.001 P

20 % χ Log Rank Test: χ % mg/kg 4 3 8mg/kg ± 0.66 mg/kg/mean ± SD 0.7 mg/kg/ 8.2 mg/kg/ 1,394 1, % ACR ACR 20%70.22 ± 32.32%Mean± SD ACR 50%48.66 ± 39.07%ACR 70%27.94 ±33.88% 150/ %1,320 8 mg/kg 2 118mg/kg CRP ESR 90%100%JIA 30%50%70100% 100%90% mg mg

21 mg/kg % RA 14MRA 80CrCL CrCL CrCL ACR2028.6%4/ % % % mg/kg 4 3 JIA #2 30%50%70% 94.7%94.7%57.9% %

22 6IL-6 IL-6 IL-6R IL-6 gp130 IL-6R IL-6R IL-6 IL-6R gp130 IL-6 1) IL-6 IL-6 in vitro g/ IL-6 IL-6R IgG1 IL-6 IL-6 2) IL-6 IL-6 in vitro IL-6 IL-6 IL-6 IL-6 IL-6 3) IL-6 1% 1 IL-6 7 CRP CRP IL IL-6 4) 18

23 -1(3) mg/kg 1 Cmax kel CLtotal T1/2 MRT mg/kg n Cmax g/ml AUCfinite hrg/ml T1/2 hr kel /hr CLtotal ml/hr/kg MRT hr Vdss ml/kg ±0.6 11±6 17± ± ±2.3 25± ± ± ±73 33± ± ±0.2 47±5 58.4± ± ±222 49± ± ±0.1 69±8 57.3± ± ±569 74± ± ± ± ±8.3 AUCfinite SD kel CLtotal MRT Vdss 1 8mg/kg 2 (1) 31 8 mg/kg 1 AUCfinite = ± 5749hr g/ml ± SDT1/2 = 133 ± 25.7hr CLtotal = 0.4 ± 0.1 ml/hr/kg Vdss= 78.5 ± 16.8 ml/kg 19

24 ) (2) 1) mg/kg 2 2 CLtotal T1/2 C1hr AUCfinite T1/2 CLtotal MRT Vdss mg/kg g/ml hr g/ml hr ml/hr/kg hr ml/kg ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± SD ) 18 mg/kg 2) mg/kg ± SD 9.8 ± 7.5g/mL ± 8.6 g/ml 20 20

25 ) mg/kg C1hr AUCfinite T1/2 CLtotal MRT g/ml hr g/ml hr ml/hr/kg hr Vdss ml/kg ± ± 2511 N.A. N.A. N.A. N.A ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 13.9 ± SDN.A.: 3 7 C1hr AUCfiniten=57 15 :C1hr AUCfiniten=7 n=415 n= mg/kg g/ml

26 C1hr AUCfinite T1/2 CLtotal MRT Vdss g/ml hr g/ml hr ml/hr/kg hr ml/kg ± ± 5193 N.A. N.A. N.A. N.A ± ± ± ± ± ± ± ± 7611 N.A. N.A. N.A. N.A ± ± ± ± ± ± ± ± 3571 N.A. N.A. N.A. N.A ± ± ± ± ± ± 11.2 ± SDN.A. (2 7n= n= n=4 5) mg/kg ±17.5µg/mL 6 T1/2 MRT 6 mg/kg C1hr AUCfinite T1/2 CLtotal MRT Vdss g/ml hrg /ml hr ml/hr/kg hr ml/kg ± ± ± ± ± ± ± ± ± ± ± ± ±SD -1(3) 22

27 -1(3) -1(3) mg/kg mg/kg IgG IgG 125 I- 5mg/kg TCA

28 I- IL-6 14 TCA 125 I- 125 I- IL-6 IgG IL-6 IL-6 IL mg/kg 1 1 8mg/kg 125 I- 5mg/kg % 2.4% TCA 5.24% 24

29 125 I -6 (1) -6 (1) 25

30 IL-6 CRP IL-6 1.(3)(7) 2)4) sjia IL-6 (3)(7) 2)4 26

31 1 2 1 IL-6 EB 1(3)(7) 2)4) 2 80 (1) 1 VI VI (1) [] (2) X [ X ] (3) [] (4) (5) 27

32 3(5) 3)4) (1) IL-6R 2 1) (2) Infusion Reaction Infusion Reaction Infusion Reaction 201 Infusion Reaction % 7 3.5% 7 3.5% Infusion Reaction Infusion Reaction Infusion Reaction 5 28

33 (3) 1) 2) 500/L 3) IL-6 1) 2) 500/L 3) )4)) (4) CRP X CT IL-6 29

34 IL-6 CRP 32) CRP sjia pjia )4)) (5) X CT TNF- IL-6 IL (0.3%) TNF IL-6 30

35 (6) IL-6 6 (7) (0.6%) (8) LDL 3 LDL mg/dl93.8 mg/dl mg/dl 12 Atherogenic index 431 * % % pjia sjia 31

36 * 601 (9) 3 ALTGPT AST(GOT) DMARD (10) IL-6 IL-6 IL-6 IL-6R IL-6 pjia IL-6 sjia MAS IL-6 20 CRP IL-6 32

37 (11) 35 QT gp130 gp130 * gp130 IL-6 pjia sjia (MRA213JP) 61 MTX QTc pjia sjia (0.8%) 1 pjia19 sjia *(5) 33

38 % % %LDL % %ALTGPT % 1) (0.4%) ) IL-6R % (1) 2)7.8%6.4%3.4%3.3% 0.9%0.4%0.4%0.3% 0.1% IL

39 MRA009JP 16.7%(9/54 ) 8mg/kg 23.6%(13/55 ) MRA213JP MTX 25.0%(16/64 ) 39.3%(24/61 )MRA012JP 51.0%(74/145 ) 58.0%(91/157 ) (12.9%) X 3) X CT -- ) 4) X CT ) # 6 1 NSAID CRP 35

40 5) 7.0% (7.0%) / 2 sjia NCI /L 2635 DMARDs 1000/L 1 77 (2.9%) 2 9 (0.3%) (0.3%) 3 36

41 6) ) sjia IL-6 (10) IL-6 (11) 37

42 5% 1%5% 0.5%1% 90.0% 37.3% LDL HDL LDH ALTGPTAST GOTγ-GTP CKCPK Al-P T ST T TAT FDPD BUN NAG CRP DNA ) G ) ) 2 DNA % % % sjia pjia 4 (0.5%) 38

43 (94.3) 585 (97.3) 18 (94.7) 115 (89.8) 751 (95.9) (85.7) 469 (78.0) 17 (89.5) 101 (78.9) 617 (78.8) (1.0) 6 (0.8) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 2 (0.3) 1 (0.8) 3 (0.4) 4 (0.7) 4 (0.5) 4 (0.7) 4 (0.5) 3 (0.5) 1 (0.8) 4 (0.5) 23 (3.8) 2 (10.5) 20 (15.6) 45 (5.7) 1 (2.9) 29 (4.8) 1 (5.3) 7 (5.5) 38 (4.9) 2 (0.3) 2 (0.3) 1 (2.9) 2 (0.3) 3 (0.4) 2 (5.7) 1 (0.2) 3 (0.4) 2 (5.7) 23 (3.8) 1 (0.8) 26 (3.3) 1 (0.2) 1 (0.1) 9 (1.5) 1 (0.8) 10 (1.3) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 2 (5.7) 43 (7.2) 1 (5.3) 2 (1.6) 48 (6.1) 1 (2.9) 19 (3.2) 1 (5.3) 8 (6.3) 29 (3.7) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 3 (2.3) 3 (0.4) 2 (0.3) 2 (0.3) 2 (5.7) 8 (1.3) 3 (2.3) 13 (1.7) 7 (1.2) 3 (2.3) 10 (1.3) 4 (0.7) 4 (0.5) 2 (5.7) 36 (6.0) 2 (10.5) 41 (32.0) 81 (10.3) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 3 (0.5) 9 (7.0) 12 (1.5) 3 (2.3) 3 (0.4) 39

44 2 (5.7) 32 (5.3) 1 (5.3) 3 (2.3) 38 (4.9) 7 (1.2) 7 (0.9) 3 (8.6) 41 (6.8) 6 (4.7) 50 (6.4) 3 (8.6) 9 (1.5) 13 (10.2) 25 (3.2) 2 (0.3) 3 (15.8) 11 (8.6) 16 (2.0) 2 (0.3) 1 (0.8) 3 (0.4) 1 (0.8) 1 (0.1) 16 (2.7) 1 (5.3) 19 (14.8) 36 (4.6) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 3 (0.5) 4 (0.5) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (1.6) 2 (0.3) 1 (0.8) 1 (0.1) 2 (5.7) 15 (2.5) 17 (2.2) 27 (77.1) 315 (52.4) 14 (73.7) 65 (50.8) 421 (53.8) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.8) 1 (0.1) 1 (2.9) 1 (0.2) 3 (2.3) 5 (0.6) 1 (0.2) 1 (0.1) 2 (0.3) 2 (1.6) 4 (0.5) 1 (2.9) 11 (1.8) 1 (5.3) 10 (7.8) 23 (2.9) 3 (0.5) 1 (0.8) 4 (0.5) 3 (0.5) 3 (0.4) 27 (4.5) 13 (10.2) 40 (5.1) 3 (0.5) 3 (2.3) 6 (0.8) 2 (0.3) 2 (0.3) 5 (0.8) 5 (0.6) 1 (0.8) 1 (0.1) 6 (17.1) 49 (8.2) 5 (26.3) 32 (25.0) 92 (11.7) 2 (5.7) 41 (6.8) 2 (10.5) 10 (7.8) 55 (7.0) 1 (0.2) 1 (0.1) 5 (0.8) 5 (0.6) 4 (0.7) 4 (0.5) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.2) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 4 (11.4) 6 (1.0) 9 (7.0) 19 (2.4) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 40

45 1 (2.9) 22 (3.7) 1 (5.3) 3 (2.3) 27 (3.4) 4 (0.7) 1 (5.3) 2 (1.6) 7 (0.9) 9 (1.5) 7 (5.5) 16 (2.0) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 1 (2.9) 29 (4.8) 30 (3.8) 1 (2.9) 8 (1.3) 1 (5.3) 1 (0.8) 11 (1.4) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 26 (4.3) 6 (31.6) 43 (33.6) 75 (9.6) 4 (11.4) 20 (3.3) 3 (2.3) 27 (3.4) 5 (0.8) 5 (0.6) 4 (0.7) 4 (0.5) 1 (0.2) 2 (1.6) 3 (0.4) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (0.7) 4 (0.5) 1 (2.9) 1 (0.1) 2 (5.7) 2 (0.3) 6 (4.7) 10 (1.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) β 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.8) 2 (0.3) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.8) 3 (0.4) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 5 (0.8) 3 (2.3) 8 (1.0) 1 (0.2) 1 (0.8) 2 (0.3) 1 (2.9) 1 (0.1) 2 (5.7) 40 (6.7) 4 (3.1) 46 (5.9) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 3 (0.5) 3 (0.4) 4 (0.7) 4 (0.5) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (0.7) 1 (5.3) 5 (0.6) 2 (1.6) 2 (0.3) 41

46 6 (1.0) 6 (0.8) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.2) 2 (0.3) 3 (0.5) 3 (0.4) 5 (0.8) 1 (0.8) 6 (0.8) 1 (2.9) 9 (1.5) 10 (1.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 30 (5.0) 2 (1.6) 32 (4.1) (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 5 (0.8) 5 (0.6) 2 (1.6) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 3 (8.6) 27 (4.5) 1 (5.3) 9 (7.0) 40 (5.1) (2.9) 2 (0.3) 3 (2.3) 6 (0.8) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 12 (2.0) 1 (0.8) 13 (1.7) 2 (5.7) 2 (0.3) 5 (0.8) 1 (5.3) 2 (1.6) 8 (1.0) 42

47 2 (5.7) 4 (0.7) 1 (0.8) 7 (0.9) 1 (0.2) 2 (1.6) 3 (0.4) 1 (2.9) 21 (3.5) 4 (21.1) 7 (5.5) 33 (4.2) (0.2) 2 (1.6) 3 (0.4) 1 (5.3) 1 (0.8) 2 (0.3) 1 (2.9) 16 (2.7) 3 (15.8) 5 (3.9) 25 (3.2) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 2 (5.7) 7 (1.2) 9 (1.1) (2.9) 1 (0.1) 1 (2.9) 2 (0.3) 3 (0.4) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 8 (22.9) 35 (5.8) 1 (0.8) 44 (5.6) (5.7) 2 (0.3) 4 (0.5) 5 (0.8) 5 (0.6) 1 (0.2) 1 (0.1) 10 (1.7) 10 (1.3) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.1) 1 (2.9) 2 (0.3) 3 (0.4) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 2 (5.7) 2 (0.3) 1 (0.2) 1 (0.1) 2 (5.7) 13 (2.2) 15 (1.9) 1 (2.9) 15 (2.5) 1 (0.8) 17 (2.2) (0.2) 1 (0.1) 1 (2.9) 11 (1.8) 1 (0.8) 13 (1.7) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 9 (25.7) 90 (15.0) 2 (10.5) 15 (11.7) 116 (14.8) (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 43

48 1 (0.2) 1 (0.1) 25 (4.2) 1 (0.8) 26 (3.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 6 (17.1) 50 (8.3) 1 (5.3) 13 (10.2) 70 (8.9) 4 (11.4) 12 (2.0) 16 (2.0) 3 (0.5) 1 (0.8) 4 (0.5) 1 (5.3) 1 (0.1) 1 (2.9) 3 (0.5) 4 (0.5) 2 (0.3) 2 (0.3) 1 (2.9) 2 (0.3) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 8 (22.9) 93 (15.5) 1 (5.3) 26 (20.3) 128 (16.3) (2.9) 1 (0.2) 2 (0.3) 2 (1.6) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.8) 2 (0.3) 4 (0.7) 4 (0.5) 1 (2.9) 1 (0.1) 5 (0.8) 1 (0.8) 6 (0.8) 1 (0.2) 1 (0.1) 1 (2.9) 3 (0.5) 5 (3.9) 9 (1.1) 1 (0.2) 1 (0.1) 4 (11.4) 6 (1.0) 10 (1.3) 1 (2.9) 30 (5.0) 11 (8.6) 42 (5.4) 9 (1.5) 1 (5.3) 3 (2.3) 13 (1.7) 2 (0.3) 1 (0.8) 3 (0.4) 2 (0.3) 2 (0.3) 10 (1.7) 10 (1.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.2) 2 (0.3) 1 (2.9) 4 (0.7) 1 (0.8) 6 (0.8) 1 (2.9) 2 (0.3) 3 (0.4) 1 (0.2) 2 (1.6) 3 (0.4) 2 (0.3) 1 (0.8) 3 (0.4) 44

49 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.2) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (0.7) 4 (0.5) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 4 (0.7) 4 (0.5) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (2.3) 3 (0.4) 3 (8.6) 23 (3.8) 1 (0.8) 27 (3.4) (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 1 (0.8) 4 (0.5) 7 (1.2) 7 (0.9) 4 (0.7) 4 (0.5) 1 (2.9) 3 (0.5) 4 (0.5) 1 (2.9) 5 (0.8) 6 (0.8) 4 (11.4) 29 (4.8) 33 (4.2) (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 9 (1.5) 9 (1.1) 2 (0.3) 2 (0.3) 2 (5.7) 5 (0.8) 7 (0.9) 45

50 1 (0.2) 1 (0.1) 3 (8.6) 4 (0.7) 7 (0.9) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (8.6) 67 (11.1) 15 (11.7) 85 (10.9) (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (0.7) 2 (1.6) 6 (0.8) 2 (0.3) 2 (0.3) 2 (5.7) 40 (6.7) 11 (8.6) 53 (6.8) 2 (1.6) 2 (0.3) 2 (0.3) 1 (0.8) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 5 (0.8) 5 (0.6) 3 (0.5) 3 (0.4) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 2 (5.7) 2 (0.3) 4 (0.5) 1 (0.2) 1 (0.1) 18 (51.4) 171 (28.5) 6 (31.6) 40 (31.3) 235 (30.0) (0.5) 1 (5.3) 1 (0.8) 5 (0.6) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 4 (11.4) 31 (5.2) 1 (0.8) 36 (4.6) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 2 (0.3) 2 (1.6) 4 (0.5) 4 (0.7) 4 (0.5) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 4 (0.7) 1 (0.8) 6 (0.8) 1 (2.9) 1 (0.1) 1 (0.8) 1 (0.1) 46

51 7 (20.0) 42 (7.0) 3 (2.3) 52 (6.6) 1 (2.9) 4 (0.7) 5 (0.6) 2 (0.3) 2 (0.3) 2 (0.3) 2 (0.3) 5 (0.8) 5 (0.6) 1 (0.2) 1 (0.1) 9 (1.5) 1 (0.8) 10 (1.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 9 (1.5) 2 (10.5) 8 (6.3) 19 (2.4) 3 (8.6) 6 (1.0) 9 (1.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.1) 5 (14.3) 66 (11.0) 3 (15.8) 27 (21.1) 101 (12.9) 1 (0.2) 1 (0.1) 3 (8.6) 3 (0.5) 2 (1.6) 8 (1.0) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 22 (62.9) 247 (41.1) 9 (47.4) 64 (50.0) 342 (43.7) (2.9) 4 (0.7) 1 (0.8) 6 (0.8) 7 (1.2) 7 (0.9) 3 (8.6) 13 (2.2) 2 (10.5) 9 (7.0) 27 (3.4) 3 (8.6) 1 (0.8) 4 (0.5) 5 (14.3) 27 (4.5) 2 (1.6) 34 (4.3) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 4 (0.7) 5 (0.6) 17 (2.8) 1 (5.3) 6 (4.7) 24 (3.1) 1 (0.2) 1 (0.1) 6 (1.0) 6 (0.8) 1 (2.9) 26 (4.3) 1 (5.3) 12 (9.4) 40 (5.1) 7 (20.0) 39 (6.5) 2 (10.5) 17 (13.3) 65 (8.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 6 (1.0) 6 (0.8) 10 (1.7) 2 (10.5) 1 (0.8) 13 (1.7) 47

52 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 5 (0.8) 5 (0.6) 4 (0.7) 4 (0.5) 1 (2.9) 21 (3.5) 2 (1.6) 24 (3.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 1 (2.9) 1 (0.1) 5 (0.8) 5 (0.6) 13 (2.2) 4 (3.1) 17 (2.2) 5 (0.8) 5 (0.6) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 5 (0.8) 2 (1.6) 7 (0.9) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (5.3) 1 (0.8) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (11.4) 19 (3.2) 1 (5.3) 5 (3.9) 29 (3.7) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 11 (1.8) 11 (1.4) 3 (8.6) 19 (3.2) 5 (3.9) 27 (3.4) 2 (1.6) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 7 (1.2) 8 (1.0) 2 (0.3) 2 (0.3) 1 (2.9) 14 (2.3) 15 (1.9) 5 (14.3) 56 (9.3) 3 (15.8) 11 (8.6) 75 (9.6) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 3 (8.6) 9 (1.5) 1 (0.8) 13 (1.7) 1 (0.2) 1 (0.1) 2 (5.7) 17 (2.8) 7 (5.5) 26 (3.3) 48

53 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 1 (2.9) 4 (0.7) 5 (0.6) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 4 (11.4) 38 (6.3) 2 (1.6) 44 (5.6) (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 5 (0.8) 5 (0.6) 1 (0.2) 1 (0.1) 2 (5.7) 3 (0.5) 2 (1.6) 7 (0.9) 2 (5.7) 25 (4.2) 27 (3.4) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 24 (68.6) 223 (37.1) 10 (52.6) 61 (47.7) 318 (40.6) (2.9) 5 (0.8) 8 (6.3) 14 (1.8) 3 (0.5) 3 (0.4) 1 (2.9) 5 (0.8) 1 (0.8) 7 (0.9) 1 (2.9) 4 (0.7) 5 (0.6) 1 (2.9) 7 (1.2) 2 (1.6) 10 (1.3) 1 (0.2) 2 (1.6) 3 (0.4) 3 (8.6) 12 (2.0) 1 (5.3) 2 (1.6) 18 (2.3) 1 (0.2) 1 (0.1) 3 (8.6) 2 (0.3) 4 (3.1) 9 (1.1) 1 (2.9) 2 (0.3) 3 (0.4) 5 (14.3) 46 (7.7) 4 (21.1) 21 (16.4) 76 (9.7) 9 (1.5) 1 (5.3) 6 (4.7) 16 (2.0) 1 (2.9) 16 (2.7) 2 (1.6) 19 (2.4) 1 (0.2) 2 (1.6) 3 (0.4) 11 (31.4) 56 (9.3) 1 (5.3) 8 (6.3) 76 (9.7) 1 (2.9) 7 (1.2) 8 (1.0) 1 (2.9) 1 (0.1) 1 (5.3) 8 (6.3) 9 (1.1) 2 (0.3) 2 (0.3) 2 (5.7) 2 (0.3) 8 (1.3) 8 (1.0) 8 (1.3) 9 (7.0) 17 (2.2) 1 (2.9) 1 (0.8) 2 (0.3) 49

54 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 3 (0.5) 3 (0.4) 2 (0.3) 2 (0.3) 5 (0.8) 1 (5.3) 1 (0.8) 7 (0.9) 10 (28.6) 45 (7.5) 8 (6.3) 63 (8.0) 7 (1.2) 7 (0.9) 1 (0.2) 1 (0.1) 1 (2.9) 6 (1.0) 7 (0.9) 1 (0.2) 1 (0.1) 1 (2.9) 4 (0.7) 5 (0.6) 1 (0.2) 1 (0.1) 1 (2.9) 2 (0.3) 3 (0.4) 1 (2.9) 1 (0.2) 2 (0.3) 1 (0.2) 1 (0.1) 2 (5.7) 20 (3.3) 1 (0.8) 23 (2.9) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 2 (5.7) 15 (2.5) 2 (10.5) 16 (12.5) 35 (4.5) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 1 (0.8) 3 (0.4) 1 (0.2) 1 (0.1) 10 (28.6) 76 (12.6) 1 (5.3) 13 (10.2) 100 (12.8) (8.6) 6 (1.0) 9 (1.1) 1 (0.8) 1 (0.1) 1 (0.8) 1 (0.1) 6 (17.1) 15 (2.5) 1 (0.8) 22 (2.8) 1 (2.9) 1 (0.2) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 50

55 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 6 (1.0) 2 (1.6) 8 (1.0) 1 (2.9) 2 (0.3) 2 (1.6) 5 (0.6) 11 (1.8) 11 (1.4) 3 (8.6) 5 (0.8) 8 (1.0) 1 (2.9) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.8) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 5 (0.8) 1 (5.3) 7 (0.9) 1 (0.2) 1 (0.1) 4 (3.1) 4 (0.5) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 2 (5.7) 29 (4.8) 6 (4.7) 37 (4.7) (0.5) 3 (0.4) 2 (0.3) 1 (0.8) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (0.7) 4 (3.1) 8 (1.0) 2 (0.3) 2 (0.3) 4 (0.7) 1 (0.8) 5 (0.6) 1 (2.9) 1 (0.2) 2 (0.3) 2 (0.3) 2 (0.3) 51

56 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 4 (11.4) 27 (4.5) 3 (2.3) 34 (4.3) (0.8) 1 (0.1) 3 (0.5) 3 (0.4) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.2) 2 (0.3) 1 (2.9) 3 (0.5) 4 (0.5) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.2) 2 (0.3) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 6 (1.0) 6 (0.8) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.8) 2 (0.3) 21 (60.0) 84 (14.0) 14 (10.9) 119 (15.2) (0.2) 1 (0.1) 1 (2.9) 2 (0.3) 3 (0.4) 6 (17.1) 5 (0.8) 11 (1.4) 4 (11.4) 12 (2.0) 1 (0.8) 17 (2.2) 2 (5.7) 1 (0.2) 5 (3.9) 8 (1.0) 1 (0.2) 1 (0.1) 4 (0.7) 4 (0.5) 3 (8.6) 3 (0.5) 6 (0.8) 1 (2.9) 5 (0.8) 6 (0.8) 3 (8.6) 4 (0.7) 7 (0.9) 52

57 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 7 (20.0) 12 (2.0) 2 (1.6) 21 (2.7) 1 (2.9) 1 (0.1) 1 (2.9) 2 (0.3) 3 (0.4) 2 (5.7) 14 (2.3) 2 (1.6) 18 (2.3) 3 (0.5) 3 (0.4) 5 (14.3) 20 (3.3) 6 (4.7) 31 (4.0) 1 (2.9) 1 (0.2) 2 (0.3) 2 (5.7) 3 (0.5) 5 (0.6) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (1.6) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 25 (71.4) 436 (72.5) 2 (10.5) 78 (60.9) 541 (69.1) (2.9) 1 (0.1) 5 (14.3) 87 (14.5) 27 (21.1) 119 (15.2) 4 (11.4) 62 (10.3) 20 (15.6) 86 (11.0) β 8 (6.3) 8 (1.0) 1 (0.2) 1 (0.8) 2 (0.3) 1 (2.9) 29 (4.8) 3 (2.3) 33 (4.2) 1 (2.9) 4 (0.7) 5 (0.6) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 4 (11.4) 271 (45.1) 17 (13.3) 292 (37.3) 2 (5.7) 11 (1.8) 1 (0.8) 14 (1.8) 3 (0.5) 3 (0.4) 25 (4.2) 25 (3.2) 1 (2.9) 2 (0.3) 3 (0.4) 4 (11.4) 3 (0.5) 7 (0.9) 53

58 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 11 (1.8) 10 (7.8) 21 (2.7) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.1) 5 (14.3) 45 (7.5) 17 (13.3) 67 (8.6) 5 (0.8) 4 (3.1) 9 (1.1) 2 (0.3) 2 (0.3) 1 (2.9) 6 (1.0) 1 (0.8) 8 (1.0) 1 (2.9) 1 (0.1) 2 (5.7) 39 (6.5) 1 (0.8) 42 (5.4) 7 (20.0) 7 (0.9) 1 (0.2) 1 (0.1) 7 (20.0) 119 (19.8) 126 (16.1) 2 (5.7) 20 (3.3) 4 (3.1) 26 (3.3) 1 (2.9) 14 (2.3) 15 (1.9) 1 (2.9) 1 (0.1) 4 (0.7) 4 (0.5) 2 (5.7) 4 (0.7) 6 (0.8) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 5 (0.8) 5 (0.6) 1 (2.9) 2 (0.3) 1 (0.8) 4 (0.5) 1 (2.9) 13 (2.2) 14 (1.8) 19 (3.2) 19 (2.4) 2 (5.7) 14 (2.3) 16 (2.0) 2 (0.3) 2 (0.3) 4 (11.4) 2 (0.3) 6 (0.8) 5 (0.8) 5 (0.6) γ 3 (8.6) 53 (8.8) 56 (7.2) 9 (1.5) 6 (4.7) 15 (1.9) 1 (0.2) 1 (0.1) 9 (1.5) 9 (1.1) 1 (0.2) 1 (0.1) 1 (2.9) 20 (3.3) 1 (5.3) 4 (3.1) 26 (3.3) 9 (1.5) 9 (1.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.2) 2 (0.3) 54

59 1 (2.9) 2 (0.3) 3 (0.4) 1 (2.9) 41 (6.8) 42 (5.4) 1 (0.8) 1 (0.1) 2 (5.7) 146 (24.3) 148 (18.9) 1 (2.9) 11 (1.8) 1 (5.3) 19 (14.8) 32 (4.1) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 9 (25.7) 32 (5.3) 14 (10.9) 55 (7.0) 5 (0.8) 5 (0.6) 2 (5.7) 14 (2.3) 2 (1.6) 18 (2.3) 10 (1.7) 2 (1.6) 12 (1.5) 3 (0.5) 3 (0.4) 1 (2.9) 1 (0.2) 2 (0.3) 5 (0.8) 5 (0.6) 1 (2.9) 1 (0.1) 6 (1.0) 6 (0.8) 4 (11.4) 2 (0.3) 6 (0.8) 3 (0.5) 3 (0.4) 2 (5.7) 1 (0.2) 3 (0.4) 1 (0.2) 1 (0.1) 4 (0.7) 4 (0.5) 2 (5.7) 62 (10.3) 4 (3.1) 68 (8.7) 2 (5.7) 10 (1.7) 12 (1.5) 3 (8.6) 1 (0.2) 4 (0.5) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 9 (1.5) 9 (1.1) 2 (5.7) 2 (0.3) 4 (0.5) 1 (2.9) 6 (1.0) 7 (0.9) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.2) 2 (1.6) 4 (0.5) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (5.7) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (8.6) 6 (1.0) 1 (0.8) 10 (1.3) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 55

60 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 4 (11.4) 24 (4.0) 4 (3.1) 32 (4.1) 1 (2.9) 1 (0.1) 1 (2.9) 7 (1.2) 8 (1.0) 1 (0.2) 1 (0.1) 6 (1.0) 6 (0.8) 2 (5.7) 2 (0.3) 1 (0.2) 1 (0.1) A 1 (0.2) 1 (0.1) 1 (2.9) 8 (1.3) 3 (2.3) 12 (1.5) (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.8) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) (0.8) 1 (0.1) MedDRA/J ver.8.0j 56

61 0.4% (1) (2) (1) (2)IgG IgG 57

62 sjia pjia ) 2) 1) 2) 1.2 3) 1) 80 2) 1) 2) 3) 58

63 (1) % % % % pjiasjia 1 IgE 24mg/kg

64 pjia sjia (%) % IgE (7.3) (5.3) (11.1) pjia ( N=601 N=344 (N=19) IgE IgE IgE 0/601( 0.0) 1/601(0.2) 0/344(0.0) 0/344(0.0) 0/19(0.0) 0/19(0.0) 2(mg/kg) 0/5(0.0) 0/5(0.0) 10/123(8.1) 11/123(8.9) 0/0 0/0 4(mg/kg) 0/59(0.0) 3/59(5.1) 3/112(2.7) 7/112(6.3) 0/0 0/0 8(mg/kg) 4/537(0.7) 11/537(2.0) 0/109(0.0) 0/109(0.0) 1/19(5.3) 1/19(5.3) (%) 4/601(0.7) 15/601(2.5) 13/344(3.8) 18/344(5.2) 1/19(5.3) 1/19(5.3) () sjia ( (N=128) (N=18) (N=35) (%) (N=1145) IgE IgE IgE IgE 0/128(0.0) 0/128(0.0) 0/18(0.0) 0/18(0.0) 0/35(0.0) 0/35(0.0) 0/1145(0.0) 1/1145(0.1) 2(mg/kg) 0/11(0.0) 0/11(0.0) 1/6(16.7) 0/6(0.0) 1/7(14.3) 1/7(14.3) 12/152(7.9) 12/152(7.9) 4(mg/kg) 0/0 0/0 0/6(0.0) 0/6(0.0) 0/6(0.0) 0/6(0.0) 3/183(1.6) 10/183(5.5) 8(mg/kg) 0/117(0.0) 11/117(9.4) 1/6(16.7) 0/6(0.0) 0/35(0.0) 0/35(0.0) 6/823(0.7) 23/823(2.8) (%) 0/128(0.0) 11/128(8.6) 2/18(11.1) 0/18(0.0) 1/35(2.9) 1/35(2.9) 21/1145(1.8) 46/1145(4.0) pjia ( N=601 N=344 (N=19) IgE IgE IgE - 1(0.2) (0.2) - 2(0.6) (0.7) - 8(2.3) (0.3) 1(0.3) 6(1.7) 1(5.3) - 4-3(0.5) 12(3.5) 2(0.6) * 4(0.7) 4(0.7) (5.3) (%) 4(0.7) 15(2.5) 13(3.8) 18(5.2) 1(5.3) 1(5.3) () sjia ( (N=128) (N=18) (N=35) (%) (N=1145) IgE IgE IgE IgE (0.1) 1-7( 5.5) 2( 11.1) (0.2) 10(0.9) 2-3( 2.3) - - 1(2.9) 1(2.9) 1(0.1) 16(1.4) 3-1( 0.8) (0.2) 9(0.8) (1.1) 5(0.4) 5 * (0.4) 5(0.4) (%) - 11( 8.6) 2( 11.1) - 1(2.9) 1(2.9) 21(1.8) 46(4.0) * mg/kg 1. 60

65 (2)(DMARD) DMARD 3 ALTGPT ASTGOTDMARD 8 mg/kg+dmard 103/1582 (6.5%)+DMARD 18/1170 (1.5%) 8 mg/kg 6/288 (2.1%)MTX 14/284 (4.9%) (9) (3) pjiasjia MTX DMARDs 1.1 (4) in vitro IL-6 CYPs IL-6 CYPs IL-6 CYPs IL-6 CYP3A4CYP2C19 CYP2D6 IL-6 CYPs in vitro IL-6 CYP IL-6 CYP1A2CYP2CCYP2E1CYP3A mrna IL-6 CYP3A4 mrna IL-6 -naphthoflavone CYP1A1 CYP1A2 rifampicin CYP3A4 mrna CYP3A4 IL-6 rifampicin phenobarbital CYP3A4 61

66 CYP2B6CYP2C8CYP2C9 mrna in vitro IL-6 CYP3A4 mrna CYP2D6CYP1A2CYP2B6CYP2C9 CYP2C19 IL-6 IL-6 CYP IL-6 CYP IL-6 CYP CRP1.5mg/dL IL-6 CYP3A4 CYP2C19 (CYP3A4/CYP2D6 )CYP2C19 AUC 40% CYP3A4 CYPs CYPs TDM (5)gp130 gp130 IL-6 IL-6 IL-6 IL-6CT-1LIFIL-11CNTF gp130 KO gp130 conditional KO IL-6 gp130 KO conditional KO gp130 IL-6 IL-6 IL-6KO IL-6 62

67 (11) 6) IL-6 IL-6Cardiotropin1CT-1Leukemia Inhibitory FactorLIF IL-11Ciliary Neurotrophic FactorCNTFOncostatin MOSM (6) IL-6 IL-6 IL IL

68 (mg/kg) Slc:ddY Slc:ddY Slc:ddY Slc:Wistar Slc:Hartley Slc:Hartley Beagle/CSK Slc:ddY Slc:SD a b250mm NaCl, 20mM, ph7.0 0 b, 1.33, 13.34, M 0 b, 1.33, 13.34, M 0 b, 1.33, 13.34, M 0 b, 1.33, 13.34, M in vitro 20, 67, 200 µg/ml 7M in vitro 200 µg/ml 7M 0 b, M 0 b, M, 2F 1, 10, M CPKCPK 3 0 b, 1.33, 13.34, M 0 b, M, 2F 0 c, 1.33, 13.34, M ph Na K Cl c175mm NaCl, 18mM, ph6.7 64

69 0, 6, 30, 150 mg/kg 0, 1, 10, 100 mg/kg (mg/kg) >150 >100 2 () 0, 2, 10, 50 mg/kg/ 1 2 () 0, 2, 10, 50 mg/kg/ 0, 0.4, 2, 10, 50 mg/kg/ (mg/kg) , 2, 10, 50 mg/kg/ , 1, 10, 100 mg/kg/ 100 0, 5, 16, 50 mg/kg/ 50 () 0, 5, 16, 50 mg/kg/ 0, 5, 50 mg/kg/ (mg/kg) 50 0, 0.5, 5, 50 mg/kg/ 50 0, 2, 10, 50 mg/kg/ 10 in vitro 0, 47.3, 96.4, 189, 379, 757 µg/plate in vitro 0, 47.3, 96.4, 189, 379, 757 µg/plate in vitro 0, 189.3, 378.5, 757 µg/ml 0.5 ml (30 mg/ml) 0.2 ml (30 mg/ml) 10µg/animal 1, 10 mg/kg 65

70 mg mg1 400 mg mg AMX

71 200 mg AMX AMZ mg AMX mg mg mg mg mg 1 8 mg/kg 4 1 8mg/kg

72 80mg A mg a mg a

73 1Yoshizaki KJ.Immunol.1296,1982 2Hirano TNature 73,1986 3Gabay C,et.al.N.Engl.J.Med.448, MTX MRA213JP 5Nishimoto N,et al.ann.rheum.dis.1162, MRA318JP 7Giannini EH,et al.arthritis Rheum.1202,1997 8Yokota S,et al.lancet 998,2008 9MRA005JP 10MRA006JP 11) MRA001JP 12MRA002JP 13MRA009JP 14MRA011JP 15MRA012JP 16MRA316JP 17 MRA010JP 18 MRA221JP , Mihara M,et al.int.immunopharmacol.1731, Shinkura H,et al.anticancer Res. 1217, Mihara M, et al.: Clin Immunol.319, MRA220JP , Abdel-Razzak, Z, et al.: Molecular Pharmacology 707, Jover R, et al.the FASEB Journal 1799, Muntane-Relat J, et al.: Hepatology 1143, Pascussi JM, et al.: Biochem. Biophys. Res. Commun. 707,

74 37Hirota H, et al.: Cell 189, Kopf M, et al.: Nature 339,

75 EU

76 http//www.chugai-pharm.co.jp 72

77 ACT

200mg 2005 3 876179 2002 3 3 200mg VFEND for Intravenous Use (1) (2) [4.1 ] (3) [4.2 ] (1) [1] (2) (3) [1] 3

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