25 5 31 1000 mg 24 7 12 25 5 27 6 1000mg 1000 mg 15 15 1 300 1000 mg 15 1 300 1000 mg 15 4 6 4 6 1 1 4000 mg 4000 mg 50 kg 50 kg
1 kg 1 15 mg 4 6 1 60 mg/kg 1 300 500 mg 15 4 6 1 2 1 1500 mg 2 2 1 kg 1 10 15 mg 15 4 6 1 60 mg/kg 2 2 1 kg 1 7.5 mg 15 4 6 1 30 mg/kg 1 kg 1 15 mg 4 6 1 60 mg/kg 1 300 500 mg 15 4 6 1 2 1 1500 mg 1 kg 1 10 15 mg 15 4 6 1 60 mg/kg 1 kg 1 7.5 mg 15 4 6 1 30 mg/kg
25 5 17 1000 mg 1000 mg 24 7 12 1 100 ml 1000 mg 3
25 5 17 1000 mg 1000 mg 24 7 12 15 1 300 1000 mg 15 4 6 1 4000 mg 50 kg 1 kg 1 15 mg 4 6 1 60 mg/kg 1 300 500 mg 15 4 6 1 2 1 1500 mg 1 kg 1 10 15 mg 15 4 6 1 60 mg/kg 2
1 kg 1 7.5 mg 15 4 6 1 30 mg/kg 3
1 25 4 15. 1000 mg 24 7 12 1 100 ml 1000 mg 1 2 3 15 1 1 300 1000 mg 4 6 1 4000 mg 50 kg 1 kg 1 15 mg 4 6 1 60 mg/kg 2 1 300 500 mg 1 2 1 1500 mg 3 1 kg 1 10 15 mg 4 6 1 60 mg/kg. 1. 4
1 1 4.2.1.1-1 12 3 10 30 100 200 mg/kg 3 10 30 100 200 400 mg/kg 15 PBQ 50% ID 50 39.0 mg/kg 400 mg/kg HPLC / 0.05 g/ml 1 1 4.2.2.2-1 3 20 50 100 mg/kg 6 1 4 28 C max 20 mg/kg 21.3 16.8 g/ml 50 mg/kg 49.6 50.9 g/ml 100 mg/kg 102 105 g/ml - AUC 0-6 20 mg/kg 23.4 12.1 g h/ml 50 mg/kg 56.2 49.1 g h /ml 100 mg/kg 143 133 g h /ml 28 C max 20 mg/kg 20.0 17.9 g/ml 50 mg/kg 47.8 44.6 g/ml 100 mg/kg 98.0 92.9 g/ml AUC 0-6 20 mg/kg 19.9 12.7 g h/ml 50 mg/kg 48.1 36.5 g h /ml 100 mg/kg 114 113 g h /ml AUC 0-6 28 AUC 0.74 1.05 7
50 1 1 2 4.4.3.2-1 SD 0 80 200 mg/kg/ 160 mg/kg/ 15 6 1 4 2 2 1 4 6 200 mg/kg/ 2 4 4.2.3.2-2 SD 0 80 200 400 mg/kg/ 15 6 1 4 4 400 mg/kg/ 1 400 mg/kg/ 40 ml/kg/ 400 mg/kg/ ALP 4 1 4 6 400 mg/kg/ 400 mg/kg/ 1000 mg M-1106-12 AUC 1.8 2.7 C max 1.9 2.5 2 tk 4.2.3.3-1 in vitro 4.2.3.3-2 DNA 4.2.3.3-3 tk in vitro S-9mix S-9mix DNA 79 250 350 mg/kg DNA 3 8
1 Ames Oldham JW et al. J Appl Toxicol. 6: 237-243, 1986 Burke DA et al. Mutagenesis. 9: 23-29, 1994 DNA DNA CHMP Bergman K et al. Mutat Res. 349: 263-288, 1996 tk tk S-9mix S-9mix in vivo Muller L et al. Arch Toxicol Suppl. 17: 312-325, 1995 CHMP in vivo 3 10 50 g/ml 2 in vivo 4. i 5.3.3.1 M-1106-11 2 5.3.3.1 M-1106-12 1000 mg 6 8 1 15 C max 10
2.72 ± 0.35 2.79 ± 0.40 5 5.3.3.3 CPI-APA-103 2009 2 3 26 2 2 Baxter-Cleveland BMS-Anagni 10 mg/ml 1000 mg 100 ml/15 C max 26.0 ± 8.0 23.8 ± 7.5 AUC 0-t 53.8 ± 14.8 51.3 ± 14.4 g h/ml t 1/2 2.90 ± 0.48 2.88 ± 0.47 2 1 5.3.3.3 CPI-APA-102 2007 6 2008 9 16 75 37 28 10 mg/ml 12.5 mg/kg 6 15 mg/kg 8 29 2 2 12 12 16 12.5 mg/kg 4 15 mg/kg 6 2 1 1.25 ml/kg/15 4 (h) 4 C max ( T max (h) AUC 0-t t 1/2 (h) C max ( T max (h) AUC 0-t 12.5 mg/kg 2 6 40.1 0.450 70.3-19.9 0.455 65.6 3.88 a 13 4 17.5 0.232 31.6 0.899 a 19.9 d 0.393 d 42.8 d 2.22 f 9 4 19.3 0.211 32.4 1.37 b 21.8 e 0.168 e 37.2 e 3.11 b 12 4 17.4 0.210 30.1 1.79 c 33.2 0.264 56.0 3.40 g 15 mg/kg 1 8 20.1 0.333 73.2-32.2 0.250 105-12 6 20.3 0.326 51.1-36.0 h 0.263 h 78.7 h 3.01 h 16 6 25.5 0.235 48.9 2.37 33.9 i 0.293 i 61.9 i 3.19 j 10 6 27.8 0.240 55.5 2.86 26.7 e 0.260 e 61.6 e 3.84 e a 1 b 3 c 5 d 12 e 6 f 8 g 10 h 9 i 15 j 14 t 1/2 (h) NONMEM PPK 2- CL Q V c V p CL Q V c V p CL 18.4 L/h/70 kg Q 97.8L/h/70 kg V c 16.0 L/70 kg V p 59.5 L/70 kg 37.4% 19.6% 61.6% 39.8% CL 0.258 0.337 L/h/kg 0.328 0.374 L/h/kg 13
0.283 L/h/kg 0.291 L/h/kg 0.176 0.205 L/h/kg 3 1 5.3.5.1 CPI-APF-302 2007 7 9 29 31 4 ng/kg 10 mg/ml 1000 mg 100 ml/15 6 ± -3.7 ± 3.58-0.7 ± 3.32p=0.0001 2 5.3.5.1 CPI-APF-303 2007 8 10 51 54 4 ng/kg 10 mg/ml 1000 mg 100 ml/15 1000 mg 2 ± 0.3 ± 0.41 0.6 ± 0.55 p=0.0039 2 2 1 AUC 24 2 29 0229 10 M-1106-13 1000 mg 1000 mg AUC 0-t AUC 0-90%0.80 1.25 C max 1000 mg C max 1000 mg 2 2 M-1106-11 M-1106-13 98051C-CIS CPI-APA-103 1000 mg 14
5 C max AUC 300 mg 650 mg C max AUC C max AUC 5 1000 mg CPI-APA-103 M-1106-11 M-1106-13 98051C-CIS BMS Baxter 8 19 24 26 26 kg 66.06 ± 8.65 63.93 ± 7.16 70.88 ± 6.69 77.47 ± 12.53 77.47 ± 12.53 mg/kg 15.36 ± 1.95 15.83 ± 1.77 14.23 ± 1.34 13.22 ± 2.03 13.22 ± 2.03 C max 46.17 ± 5.93 43.01 ± 6.62 29.94 ± 8.26 23.80 ± 7.46 26.00 ± 8.04 T max(h) 0.25 0.25 0.25 ± 0.02 0.26 ± 0.05 0.25 AUC 0-t 59.72 ± 10.83 60.01 ± 8.66-51.30 ± 14.40 53.80 ± 14.80 AUC 0-62.08 ± 11.66 62.77 ± 10.04 57.59 ± 10.39 54.10 ± 15.90 56.80 ± 16.50 t 1/2(h) 2.59 ± 0.20 2.72 ± 0.38 2.72 ± 0.35 2.88 ± 0.47 2.90 ± 0.75 CL L/h/kg 0.25 ± 0.04 0.25 ± 0.04 0.25 ± 0.04 0.26 ± 0.05 0.24 ± 0.05 Vss L/kg 0.75 ± 0.06 0.80 ± 0.06 0.89 ± 0.08 0.89 ± 0.16 0.85 ± 0.14 ± M-1106-12 CPI-APA-101 1000 mg 6 8 4 2.9 ± 0.8 2.9 ± 1.3% 2.43 ± 0.93 2.74 ± 1.06% NAPQI 1.8 ± 0.4 5.7 ± 2.0% 1.7 ± 0.7 6.6 ± 2.9% C max C max AUC 3 5.3.3.1 M-1106-11 5.3.3.1 M-1106-12 5.3.3.1 M-1106-13 4 2 5.3.5.1 CN145004 5.3.5.1 RC210 3 001 1 5.3.5.1 RC210 3 006 15
19 10.5% 2/19 15.0% 3/20 1 1 1 2 1 5.3.5.1 CN145004 2003 6 2004 3 3 297 10 mg/ml 1000 mg 2000 mg 100 200 ml/15 297 1000 mg 132 2000 mg 132 33 Intent-to-treat ITT 297 6 PR 5 ±1000 mg 7.1 ± 5.9 2000 mg 10.2 ± 6.5 2.8 ± 4.4 2000 mg 1000 mg 2000 mg 1000 mg p<0.0001 Fisher LSD 2000 mg 1000 mg p<0.0001 p=0.0003 1000 mg 60.6% 80/132 2000 mg 56.8% 75/132 54.5% 18/33 6 3 6 4 VAS 40 mm 4 5 0=none 1=a little 2=moderate 3=a lot 4=complete 17
6 2% 1000 mg (132 ) 2000 mg (132 ) (33 ) 40 (30.3) 37 (28.0) 8 (24.2) 24 (18.2) 16 (12.1) 1 (3.0) 16 (12.1) 20 (15.2) 4 (12.1) 16 (12.1) 14 (10.6) 2 (6.1) 13 (9.8) 12 (9.1) 5 (15.2) 12 (9.1) 7 (5.3) 5 (15.2) NOS 12 (9.1) 9 (6.8) 1 (3.0) 12 (9.1) 3 (2.3) 2 (6.1) 3 (2.3) 4 (3.0) 0 3 (2.3) 3 (2.3) 1 (3.0) 3 (2.3) 2 (1.5) 0 2 (1.5) 3 (2.3) 0 2 (1.5) 2 (1.5) 1 (3.0) 3 (2.3) 1 (0.8) 0 1 (0.8) 3 (2.3) 0 1 (0.8) 3 (2.3) 0 NOS 1 (0.8) 1 (0.8) 1 (3.0) (%) 2 5.3.5.1 RC210 3 001 1999 9 12 5 150 10 mg/ml 1000 mg 20 mg/ml 2000 mg 100 ml/15 152 51 51 50 ITT 152 0.25 6 PR 5 7 6 5 18
7 6 ITT [95% ] a) a), b) p / / / 15 0.8 ± 1.0 (50) 2.1 ± 1.1 (51) 2.1 ± 1.2 (51) 1.26 [0.82, 1.70] 1.30 [0.86, 1.74] -0.04 [-0.48, 0.40] p = 0.0001 p = 0.0001 p = 0.8554 30 0.5 ± 0.8 (47) 1.9 ± 1.1 (50) 2.1 ± 1.3 (50) 1.38 [0.95, 1.82] 1.54 [1.10, 1.97] -0.15 [-0.58, 0.28] p = 0.0001 p = 0.0001 p = 0.4869 45 0.6 ± 1.0 (23) 1.7 ± 1.2 (45) 2.1 ± 1.3 (46) 1.12 [0.66, 1.59] 1.51 [1.04, 1.97] -0.38 [-0.84, 0.08] p = 0.0001 p = 0.0001 p = 0.1039 1 0.6 ± 1.1 (15) 1.5 ± 1.2 (41) 2.0 ± 1.3 (39) 0.89 [0.41, 1.36] 1.46 [0.98, 1.94] -0.57 [-1.04, -0.10] p = 0.0003 p = 0.0001 p = 0.0184 2 0.3 ± 0.8 (10) 1.4 ± 1.3 (28) 1.7 ± 1.3 (31) 1.05 [0.60, 1.50] 1.36 [0.91, 1.81] -0.31 [-0.75, 0.14] p = 0.0001 p = 0.0001 p = 0.1748 3 0.3 ± 0.7 (5) 1.1 ± 1.2 (21) 1.4 ± 1.3 (26) 0.86 [0.44, 1.27] 1.12 [0.70, 1.54] -0.27 [-0.68, 0.15] p = 0.0001 p = 0.0001 p = 0.2074 4 0.2 ± 0.6 (2) 0.9 ± 1.1 (16) 1.2 ± 1.1 (18) 0.74 [0.37, 1.11] 0.98 [0.61, 1.35] -0.24 [-0.61, 0.13] p = 0.0001 p = 0.0001 p = 0.2061 5 0.2 ± 0.5 (1) 0.9 ± 1.0 (12) 0.8 ± 0.9 (10) 0.70 [0.38, 1.02] 0.64 [0.32, 0.96] 0.06 [-0.26, 0.38] p = 0.0001 p = 0.0001 p = 0.7179 6 0.1 ± 0.4 (1) 0.8 ± 1.0 (8) 0.7 ± 0.9 (3) 0.66 [0.36, 0.97] 0.58 [0.28, 0.89] 0.07 [-0.22, 0.38] p = 0.0001 p = 0.0002 p = 0.6114 ± a) b) 3 Fisher LSD p p=0.0001 27.5% 14/51 60.8% 31/51 28.0% 14/50 8 49.0% 25/51 3 8 2 (51 ) (51 ) (50 ) 0 24 (47.1) 0 5 (9.8) 6 (11.8) 2 (4.0) 4 (7.8) 5 (9.8) 3 (6.0) 4 (7.8) 2 (3.9) 1 (2.0) 2 (3.9) 2 (3.9) 3 (6.0) 0 3 (5.9) 3 (6.0) 2 (3.9) 1 (2.0) 2 (4.0) 0 3 (5.9) 1 (2.0) 1 (2.0) 2 (3.9) 0 (%) 3 5.3.5.1 RC210 3 006 2000 11 2001 10 6 180 6 VAS 30 mm 1 12 19
10 mg/ml 15 mg/kg 20 mg/ml 30 mg/kg 1.5 ml/kg/15 185 96 89 183 95 88 ITT Visual Analog Scale VAS 7 PID 9 6 9 6 PID ITT 95 88 52.0 ± 17.0 52.2 ± 17.1 15 25.6 ± 20.0 25.8 ± 23.3 30 38.1 ± 22.1 38.8 ± 20.4 1 38.8 ± 22.8 41.5 ± 21.2 2 40.4 ± 22.9 38.1 ± 23.1 3 41.3 ± 23.7 38.9 ± 24.0 4 40.3 ± 24.0 38.7 ± 24.5 5 41.0 ± 23.9 37.9 ± 24.5 6 40.9 ± 24.1 38.1 ± 24.6 ± 21.1% 20/95 43.2% 38/88 2 14.7% 14/95 33.0% 29/88 5.3% 5/95 5.7% 5/88 1.1% 1/95 2.3% 2/88 0 3.4% 3/88 36.4% 32/88 14.7% 14/95 4 5.3.5.1 CN145-001 2001 6 2003 1 92 10 mg/ml 15 mg/kg 20 mg/ml 30 mg/kg 1.5 ml/kg/15 7 20
67 35 32 ITT 2 65 PPS per protocol set 6 ± 1.93±0.77 2.22±0.97 95%0.13-0.53, 0.27 95% -0.5 14.3% 5/35 40.6% 13/32 2 5.7% 2/35 25.0% 8/32 2.9% 1/35 6.3% 2/32 1 420 mg 2000 mg 28.1% 9/32 5.7% 2/35 1 AUC Gibb IA and Anderson BJ. Arch Dis Child. 93: 241-247, 2008 Kozer E et al. Ther Drug Monit. 29: 819-823, 2007- EC 50 10 17 g/ml Anderson BJ et al. Eur J Clin Pharmacol. 57: 559-569, 2001 McNeil's background package on acetaminophen for the September 19, 2002 5 g/ml Brown RD et al. J Pharmacokinet Biopharm. 26: 559-579, 1998 1000 mg C max 42.05 1000 mg EC 50 2 10 g/ml EC 50 10 17 Singla NK et al. Pain Pract. 12: 523-532, 2012 2 21
i 2 M-1106-13 C max CPI-APA-101 2 10 3 CPI-APF-303 2 11 CPI-APF-303 12 CPI-APF-302 2001 2009 1 31 5300 150 250 mg/kg 1 7.5 g/.. 16: 285-297, 2003 1 4 g M-1106-13 1000 mg C max 43.01 ± 6.62 1000 mg C max 23.56 ± 8.51 2 RM 4 150 M-1106-13 CPI-APA-101 1000 mg 1000 mg NAPQI 22
10 CPI-APA-101 2 1000 mg 4 38 1000 mg 6 38 1000 mg 4 38 1000 mg 6 38 1 (2.6) 2 (5.3) 3 (7.9) 6 (15.8) 1 (2.6) 2 (5.3) 1 (2.6) 2 (5.3) 1 (2.6) 2 (5.3) 1 (2.6) 1 (2.6) 0 2 (5.3) 1 (2.6) 1 (2.6) 2 (5.3) 1 (2.6) 0 0 1 (2.6) 2 (5.3) 0 0 0 2 (5.3) 0 0 % 11 CPI-APF-303 2 1000 mg (54 ) 1000 mg (51 ) 6(11.1) 13(25.5) 5(9.3) 4(7.8) 4(7.4) 5(9.8) 2(3.7) 0 0 2(3.9) (%) 12 CPI-APF-303 1000 mg (54 ) 1000 mg (51 ) - 26(48.1) 20(39.2) 14(25.9) 7(13.7) 10(18.5) 4(7.8) 8(14.8) 6(11.8) 2(3.7) 1(2.0) (%) C max CPI-APA-102 RC210 3 006 CN145-001 CPI-APA-352 8 CPI-APA-102 AST 8 37 18 30 50 mg/kg/ 6 8 40 75 mg/kg/ 4 6 23
1 CPI-APA-352 3 9 4 5 2001 2009 1 31 7 25 8 8 9 140 mg/kg 5 3 1 N-acetylcysteine mg ml 10 mg/ml NAPQI P450 NAPQI Pineiro-Carrero VM et al. Liver Pediatrics. 113: 1097-1106, 2004 AST Allegaert K et al. Paediatr Anaesth. 18: 388-92, 2008 3 1 10 mg/ml 100 ml/15 1000 mg 100 ml/15 10 98051C-CIS CPI-APA-101 CPI-APF-302 CPI-APF-303 CPI-APA-301 CPI-APA-304 CPI-APA-351 CN 145-004 RC 210 3 001 RC 210 3 002 65 65 65 1.2% 65 8.5% 65 24
10 mg/ml 15 1000 mg 100 ml/15 10 mg/ml 15 2 50 kg 1 15 mg/kg M-1106-11 M-1106-12 M-1106-13 98051C-CIS CPI-APA-101 CPI-APA-103 2 50 kg 100 kg C max AUC 3 15 mg/kg 67.7 87.1 kg 15 mg/kg 50 kg 15 mg/kg 6 12.5 kg/kg 4 33 kg 50 kg 15 mg/kg 4 50 kg 1 15 mg/kg 50 kg 15 mg/kg AUC 6h/mL 9 M-1106-13 62.77 ± 10.04 h/ml 57.11 ± 12.55 h/ml 9 C max 25
2 3 C max AUC 50 kg 1 15 mg/kg 3 10 kg 1 7.5 mg/kg 4 1 30 mg/kg 2 33 50% 2 CPI-APA-101 CPI-APA-102 Palmer RB et al. NACCT Meeting. Abstract 203, 2003 2 26
28 1 2 50% 33% 6 AUC 13 13 1000 mg 15 mg/kg AUC h/ml C max t 1/2 h CL L/h/kg Vss L/kg 62±11 25±4 7.0±2.7 0.12±0.04 1.1±0.2 57±54 29±23 4.2±2.9 0.29±0.15 1.1±0.3 38±8 29±7 3.0±1.5 0.34±0.10 1.2±0.3 41±7 31±9 2.9±0.7 0.29±0.08 1.1±0.3 43±11 28±21 2.4±0.6 0.27±0.08 0.8±0.2 ± 2 10 kg 1 7.5 mg/kg 4 1 30 mg/kg 4 1 2 3 27
5. 1. 5.3.3.1 M-1106-12 5.3.3.1 M-1106-13 GCP 2. GCP. 28
29
2 25 5 17. 1000 mg 1000 mg 24 7 12. 20 12 25 20 8 1 2 3 30
15 1 300 1000 mg 15 4 6 1 4000 mg 50 kg 1 kg 1 15 mg 4 6 1 60 mg/kg 1 300 500 mg 15 4 6 1 2 1 1500 mg 1 kg 1 10 15 mg 15 4 6 1 60 mg/kg 1 kg 1 7.5 mg 15 4 6 1 30 mg/kg 4 1 31
2 3 C max C max 4 15 5 C max 300 C max 100. 32
6 15 1 300 1000 mg 15 4 6 1 4000 mg 50 kg 1 kg 1 15 mg 4 6 1 60 mg/kg 1 300 500 mg 15 4 6 1 2 1 1500 mg 1 kg 1 10 15 mg 15 4 6 1 60 mg/kg 1 kg 1 7.5 mg 15 4 6 1 30 mg/kg 33