CTD 2 2.6 5.3mg 0.4mg 0.6mg 0.8mg 1.0mg 1.2mg 1.4mg 1.6mg 1.8mg 2.0mg 12mg
2.6 Page 3 2.6.6...5 2.6.6.1...6 2.6.6.2...9 2.6.6.3...9 2.6.6.4... 11 2.6.6.5... 11 2.6.6.6... 11 2.6.6.7... 11 2.6.6.8... 11 2.6.6.9...12 2.6.7...15
2.6 Page 4
2.6.6 Page 5 2.6.6 2.6.6.1 2.6.6.1 AGHD AUC 0-24h Cmax F 0 F 1 GH IGF-I IU PCA 24 1 I IU IU mg 1 mg = 3 IU
2.6.6.1 Page 6 2.6.6.1 AGHD 12 OECD FDA GLP 0.13 0.65 3.23 mg 0.4 2 10 IU /kg/day 52 IGF-I 0.13mg/kg/day 0.65 mg/kg/day 0.65 mg/kg/day 3.23 mg/kg/day 3.23 mg/kg/day 3.23 mg/kg/day 1 3.23 mg/kg/day GH 12 3.23 mg/kg/day 0.65 mg/kg/day AUC 0-24h 2.66 µg (8.22 miu) h/ml 2.32 µg (7.19 miu) h/ml 1 AGHD 0.04 IU/kg/day 0.013 mg/kg/day 75 kg 1 mg/body/day AUC 0-24h 115.4 ng h/ml 23 20 1 mg/body/day 0.05 mg/kg/day 2.7.3.1 3 2.6.6.1.1 560 40 IU/kg 1120 80 IU/kg 2240 160 IU/kg 16 IU/kg 200 2.6.6.1.2 1 GH 0.625 mg (1.7 IU)/kg/day
2.6.6.1 Page 7 3.125 mg (8.4 IU)/kg/day 1 0.125 mg (0.34 IU)/kg/day 3 1 IU/kg/day 3 0.125 mg (0.33 IU)/kg/day 3.125 mg (8.33 IU)/kg/day 0.125 mg (0.33 IU)/kg/day 2.6.6.1.3 Ames L5178Y 2.6.6.1.4 GH 2 ng/iu 2.6.6.1.5 2.6.6.1.5.1. F0 3 IU/kg 10 IU/kg F1 3 IU/kg 1 IU/kg 3 IU/kg 10 IU/kg 2.6.6.1.5.2. 1 IU/kg F1 10 IU/kg 1 IU/kg 4 IU/kg
2.6.6.1 Page 8 0.25 IU/kg 1 IU/kg 2.6.6.1.5.3. F0 F1 10 IU/kg F1 3 IU/kg 2.6.6.1.6 2.6.6.1.7 3 GH PCA
2.6.6.4 Page 9 2.6.6.2 p.124 2.6.6.1 2.6.6.3 2.6.6.3.1. 12 4.2.3.2 3 p.126 3.125 mg (8.33 IU)/kg/day 8 3.23 mg (10 IU)/kg/day 0.13 mg (0.4 IU)/kg/day 0.175 0.35 mg/kg/week 0.025 0.05 mg/kg/day 2.6 5.2 5 0.65 mg (2 IU)/kg/day 1 1 52 3.23 mg/kg/day 12 1 27 50 0.13 mg/kg/day 1 210 5 IGF-I 0.13mg/kg/day 0.65 mg/kg/day 0.65 mg/kg/day 3.23 mg/kg/day GH
2.6.6.4 Page 10 49 0.13 mg/kg/day 3.23 mg/kg/day 0.65 mg/kg/day 3.23 mg/kg/day 3.23 mg/kg/day 1 0.65 mg/kg/day 5 1 7 3 5 0.65 mg/kg/day 1 3.23 mg/kg/day 7 6 13 2 3.23 mg/kg/day GH 3.23 mg/kg/day 52 26 52 3.23 mg/kg/day 0.65 mg/kg/day AUC 0-24h 2.66 µg (8.22 miu) h/ml 2.32 µg (7.19 miu) h/ml 1 AGHD 0.04 IU/kg/day 0.013 mg/kg/day 75 kg 1 mg/body/day AUC 0-24h 115.4 ng h/ml 1) 23 20
2.6.6.4 Page 11 2.6.6.3.2. 1 3 3 p.125 131 2.6.6.1 2.6.6.4 Ames L5178Y p.138 144 2.6.6.1 2.6.6.5 GH 2 ng/iu p.145 2.6.6.6 p.133 135 p.25 34 2.6.6.1 2.6.6.7 p.146 2.6.6.1 2.6.6.8 3 p.136 137 2.6.6.1
2.6.6.9 Page 12 2.6.6.9 1 3 GH 12 IGF-I GH IGF-I 075 2.7.3.3.2.2.3 19 GH GH GH 3.23 mg/kg/day GH 3.23 mg/kg/day 1 AUC 0-24h 17051 ng h/ml 15687 ng h/ml AGHD AUC 0-24h 115.4 ng h/ml 1) 148 136 075 076 2.7.4.2.1.1.1 6 3.23 mg/kg/day 0.65 mg/kg/day 12 3 GH 12
2.6.6.9 Page 13 0.65 mg/kg/day AUC 0-24h AGHD 1 mg/body/day 20 23 12 GH 20 23
Page 14 1) SM-9500 25, 505-517, 1997
2.6.7.2 mg/kg GLP 52 0, 0.13, 0.65, 3.23 GLP 570 004-XFI 4.4.2.1 2.6.7 Page 16
2.6.7.3 1 1) mg/kg AUC 0-24h (ng h/ml) 2) AUC 0-24h (ng h/ml) 1 27 50 1 27 50 1 0 69 12 47 58 35 51 0.013 115.4 0.13 628 466 417 380 567 434 0.65 2655 2337 2294 2323 2088 2372 3.23 17051 14266 12798 15687 11913 12731 1) 4.4.2.1 2) 2.6.6 1) 2.6.7 Page 17
2.6.7 Page 19 2.6.7.5 2.6.7.6
2.6.7.7 570-004 (mg/kg/day) 0 0.13 0.65 3.23 M: 7 F: 7 M: 5 F: 5 M: 5 F: 5 M: 7 F: 7 52 ng/ml 7.6 10.0 9.5 b) 11.0 5.7 4.7 0.9* 3.0* µiu/ml 33 68 b) 95* 145* a) ng/ml 1 ND 446 ND 448 ND 227 ND 61* 4 ND 267 ND 263 ND 309 ND 64 7 ND 334 ND 577 ND 108 ND 43 10 ND 335 ND 609 ND 585 ND 77 IGF-I ng/ml 673 445 1285* b) 575 1324* 1152* 1932* 926* ml/min 49 7.8 4.0* 7.2 7.0 5 5 4 5 5 5 5 5 0 0 0 0 0 0 1 0 2 1 1 3 3 3 3 4 *p<0.05 Dunnett Wilcoxon a) b) n=4 ND 2.6.7 Page 21
2.6.7.7 570-004 (mg/kg/day) 0 0.13 0.65 3.23 M: 7 F: 7 M: 5 F: 5 M: 5 F: 5 M: 7 F: 7 5 5 4 5 5 5 5 5 0 1 2 2 3 b) 5 5 4 0 0 0 3 0 3 0 3 0 0 0 0 0 0 1 2 3 3 2 5 4 3 3 4 4 3 1 3 2 5 4 4 0 1 0 0 2 0 0 1 2 1 2 4 3 3 4 3 2 2 1 3 3 2 3 3 ND ND ND ND ml 52 19.72 c) ND 16.49 b) ND 11.04* ND 20.05 ND a) ND 5 ND 1 ND 1 ND 13 ND 0 ND 0 ND 1 ND 2 GH 1 d) 0 0 0 0 0 1 e) 0 ND a) b) n=4 c) n=6 d) 52 e) 26 *p<0.05 Dunnett Wilcoxon 2.6.7 Page 22
2.6.7.7 570-004 (mg/kg/day) 0 0.13 0.65 3.23 M: 7 F: 7 M: 5 F: 5 M: 5 F: 5 M: 7 F: 7 2 2 0 0 0 0 2 2 0 0 ND ND ND ND 0 1 0 2 ND ND ND ND 1 a) 2 1 2 ND ND ND ND 1 a) 2 0 1 ND ND ND ND 1 a) 1 ND a) n=1 2.6.7 Page 23
2.6.7 Page 24 2.6.7.8 In Vitro 2.6.7.9 In Vivo 2.6.7.10 2.6.7.11 2.6.7.12 2.6.7.13 2.6.7.14 2.6.7.15 2.6.7.16 2.6.7.17