3240 14 8 8
50mg 75mg 13 6 25 1-(1) H 3 C O OH HO H O O H OH SO H 3 Na H H N H 2 N NH OH H N O O H H O OH H 3 C H O O N H H H HO H NH CH 3 HN HO H OH O H OH H NH O N O C 56 H 70 N 9 NaO 23 S 1292.26 5-[(1S,2S)-2- [(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S, 26S)-3-[(R)-2- -1- ]-11,20,21,25- -15- [(R)-1- ]-26- - 2,5,8,14,17,23- - 18-[4-[5-(4- ) -3- ] ]-1,4,7,13,16,22- [22.3.0.0 9,13 ] -6- ]-1,2- ]-2- S o d i u m 5 - [ ( 1 S, 2 S ) - 2 - [(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)- 3-[(R)-2- carbamoyl-1-hydroxyethyl]-11,20,21,25-tetrahydroxy-15-[(r)- 1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-18-[4-[5- ( 4- pentyloxyphenyl) isoxazol-3-yl] benzoylamino] - 1,4,7,13,16,22-hexaazatri- cyclo[22.3.0.0 9,13 ]heptacos-6-yl]- 1,2-dihydroxyethyl] -2-hydroxyphenyl sulfate 1
14 8 8 50mg 75mg 13 6 25 (1) 2 150mg 3 50 150mg 1 1 1 300mg 50mg 1 1 1 300mg 75mg 30 75mg 1 150mg/ 2
14 7 1 25mg 50mg 75mg 13 6 25 25mg 1 25mg 50mg 1 50mg 75mg 1 75mg 50 150mg 1 1 50mg 1 1 1 150mg 75mg 30 75mg 1 Coleophoma empetri echinocandin B 3
B AMPH-B 5- FC MCZ FLCZ ITCZ AMPH-B MCZ FLCZ 3 AMPH-B 1,3- -D-glucan Caspofungin acetate Cancidas Merck 6 UV IR 1 H-NMR 13 C-NMR X ph mg/ml pka ph ph 7 1-0.39 UV IR 13 C-NMR ph ph 4
ph 3 22 1 173-176 1991 10% 4 4 4 5 / /27 25 /60%RH/ /6 5 2 25 /60%RH/ /27 40 /75%RH/ /6 / /3 / / /40 5
2 5w/v% / 5 15mg/mL 48 24 0.25 3.0mg/mL 24 14 5 19 2 24 6 3 5 5 ph 62.5 125 250mg/kg 100 200mg/kg 125mg/kg 250mg/kg 200mg/kg 4 3.2 10 32mg/kg/ 13 1.25 2.5 5 10mg/kg/ 26 1 3.2 10 32mg/kg/ GOT GPT 4 32mg/kg/ 2 4 13 32mg/kg/ 4 13 6
4 10 32mg/kg/ 1 4 13 26 3.2 2.5 3.2mg/kg/ 4 13 4 39 3.2 10 32mg/kg/ 39 4 13 10mg/kg/ 39 3.2mg/kg/ 4 2 3.2 10 32mg/kg/ 10mg/kg/ 3.2 10 32mg/kg/ 32mg/kg/ GPT 10mg/kg/ 32mg/kg/ 10mg/kg/ 3.2mg/kg/ 32mg/kg/ 32mg/kg/ 3.2 10 32mg/kg/ 32mg/kg/ GPT 10mg/kg/ 32mg/kg/ 3.2 10 32mg/kg/ 32mg/kg/ 1 32mg/kg/ 10mg/kg/ 32mg/kg/ 3.2 10 32mg/kg/ 32mg/kg/ 10mg/kg/ 32mg/kg/ 10mg/kg/ 3 0.02 0.025 0.05% AMPH-B 0.01% 0.02 7
0.025% 0.425% 0.05% 0.01% AMPH-B 0.425% 1.7% ASA PCA PCA PCA 30000 5 4 300mg AUC Cmax life threatening 300mg 1 300mg 1 150mg 1 300mg AUC AUC 4 13 26 32mg/kg AST GOT ALT GPT 26 32mg/kg Na Cl 10mg/kg Altered cell foci GST-P Glutathion S-transferase placental form PCNA Proliferating cell nuclear 8
antigen 13 1 4 39 39 13 3.2 10 32mg/kg 39 FLCZ ITCZ B AMPH-B Candida Saccharomyces cerevisiae Aspergillus Cryptococcus neoformans Trichosporon Fusarium solani Pseudallescheria boydii 1 Candida Aspergillus MIC 0.0313 64 µg/ml MIC 0.0078 2µg/mL 9
1 MIC Candida MIC ph HSA MIC A. fumigatus MIC ph ph8 HSA MIC HSA MIC 1 MFC C.albicans C.glabrata C.krusei AMPH-B C.tropicalis C.guilliermondii 64µg/mL Aspergillus C. albicans FP663 24 AMPH-B Candida MIC AMPH-B AMPH-B 3 6 9 AMPH-B 1 C. albicans 1 2 1,3- -D-glucan 2 6 cyclophosphamide C.albicans 0.0625 1.0mg/kg 11 0.125 mg/kg 1.0mg/kg 22 AMPH-B FLCZ 0.0625 1.0mg/kg ITCZ 20mg/kg Cyclophosphamide hydrocortisone 5-fluorouracil C. albicans 24 10
AMPH-B ED 50 1 FLCZ ED 50 3.6 AMPH-B FLCZ C. albicans AMPH-B 0.5mg/kg 0.25mg/kg FLCZ 4.0mg/kg 3 C. albicans 0.16µg/mL 0.26µg/mL 4 5 cyclophosphamide C.albicans 0.125 1.0mg/kg 7 0.5mg/kg 1.0 mg/kg 22 AMPH-B ITCZ 0.25 40 mg/kg FLCZ 20mg/kg Hydrocortisone 5-fluorouracil A.fumigatus 24 AMPH-B ED 50 1.21 0.50mg/kg 1.5 3.8 1.9 AMPH-B 5 A.fumigatus 0.55µg/mL 0.80µg/mL 4 2mg/kg/ 5mg/kg/ 8 8 5mg/kg/ 6 3 M1 M2 M5 MIC M1 M2 M5 1/128 7 C. albicans M1 M2 7 11
in vitro AMPH-B ITCZ FLCZ C. albicans 27 11 41 % 22 85 % 22 85 % A. fumigatus 30 20 67 % 26 87 % 4 13 % C. neoformans 18 AMPH-B 12 67 % 6 33 % ITCZ 15 83 % 8 A. fumigatus AMPH-B 1mg/kg AMPH-B 0.25mg/kg 8 1 10-5 1 10-3 g/ml 1 10-5 g/ml in vivo 1 10-4 g/ml 5 10-4 g/ml in vivo 9 Candida Aspergillus MIC 90 MIC 50 4 Candida Aspergillus Candida Aspergillus 12
Candida Aspergillus ICR SD 0.32 1 3.2mg/kg AUC 1mg/kg 1 AUC t 1/2 3.2 10 32mg/kg 1 1 4 t 1/2 AUC 1 3.2 10 32mg/kg 1 1 4 AUC t 1/2 AUC 14 C 1mg/kg 5 1.86 1.09 0.02 0.08 0.17 0.93 5 6 1 3 14 79.8% 2 M8 M9 M8 M9 13 18 14 C 1mg/kg 13 18 5 41 61% 1 2 25 58% 13 14 C 1mg/kg 7 1/10 13
in vitro 99.7% 4% 10 100µg/mL 10µg/mL 4% 2% M1 M2 in vitro 0.1 10µg/mL 33.2 41.5% 14 C TLC HPLC HPLC/ M1 M2 M3 M5 M6 M8 M9 M10 8 M1 M2 M1 M1 M1 M2 M1 COMT catechol O- methyltransferase M2 M2 M5 CYP1A2 2B6 2C 3A4 14 C 1mg/kg 240 83.5% 14.4% 0.0% 1mg/kg 240 83.8% 15.2% 48 43.9 13.2% 14 C 8 14 C 1mg/kg 6 24 27 2.5 50mg 2 Cmax AUC 0- M1 14
M2 0.05µg/mL 23 25 50 75 mg 0.5 150mg 1 AUC 0- M1 50 mg 24 150mg 12 48 0.05 0.2µg/mL M2 M1 M2 1% 6 25mg 1 1 1 7 4 t 1/2 14.6 6 75mg 1 1 30 7 4 t 1/2 14.0 1 7 30 99.8% M1 M2 10 71 66 78 10 22 20 24 50mg 1 12.5 25 50 75 100 150mg 1 1 0.5 2 1 1 3 1 5 Cmax Cmin 24 2 t 1/2 t 1/2 95 65 13.5 3.1 t 1/2 13.7 2.5 13.4 3.5 148 PPK 2- CL T 2.5 150mg 30 2 CL T CL T 7 4 1 CL T 6 14 C 28.3mg 3.05MBq 1 Cmax 2.97µg/mL AUC 0-42.4µg h/ml t 1/2 13.6 Cmax 2.29µg eq./ml AUC 0-109.6µg eq. h/ml t 1/2 92.8 7 7.36% 43.80% 4 15
42 50 44 0.02 0.03µg eq./ml 0.023µg eq./ml 7 0.19µg eq./ml 2 12 HPLC M5 14 C 0.70% M5 3.62% 11.71% M3 1.75% M11 1.68% 400mg/ 12.5 25 50 75 100 150 200mg 1 1 1 7 CL T t 1/2 1 7 AUC 0-24h 34 3 4 6 8mg/kg 230 600mg 1 1 1 7 CL T t 1/2 1 7 AUC 0-24h AUC Cmax Cmin 82 59 62.8kg 82.8kg CL T 1.34 1.03 CYP 6.5µg/mL CYP1A2 2C9 2C19 2D6 2E1 3A 65µg/mL CYP3A 99.8% CYP3A 16
14 C M5 M13 2 M5 2 M5 CYP1A2 2B6 2C 3A4 M13 CYP1A1 1A2 2A6 3A4 CYP M5 168 3.71% CYP 1/100 A IC 50 31µmol/L 10µmol/L IC 50 0.14µmol/L 1/200 A M5 M13 A 100µmol/L 400mg/ CL T AUC P P P MRP2 A 30mg/kg A 5 2 4 1 100mg/ 5mg/kg Cmax/Dose AUC 0-12 /Dose 90% 80 125% Cmax AUC 0-24 AUC 0-90% 80 125% 1 17
99.8% Kragh-Hansen Biochem J 225(3);629-638,1985 4 PPK C 8 GOT 219IU GPT 153IU Al-P 1428IU -GTP 253IU CL T HIV HIV CYP3A4 CYP P in vitro CYP P ADME 3 5 1 (1) 1 P-1 2.5mg 5mg 12.5mg 25mg 50mg 2 3 6 6 6 6 27 1 BUN CPK CRP 1 18
IgE PCA in vitro 50mg 2 P-2 9 6 3 Aspergillus 25mg 1 1 1 7 1 1 BUN 2 1 BUN 2 1 3 2 4 1.14ng/mL 0.81ng/mL 0.2ng/mL 1 2 0.45ng/mL 1 7 3 FJ-463-0003 Aspergillus Candida 2 1 2 X 12.5mg 25mg 1 1 19
12.5mg 30 25mg 1 7 14 28 25mg 50mg 1 1 75mg 25mg 30 50mg 1 7 28 56 25mg 50mg 75mg 1 1 150mg 30 100mg 1 150mg 71 1 70 3 67 11 56 1 2 56 26 77 44 12 28.0 65.5kg 42 14 22 10 9 1 7 6 1 25mg 7 50mg 7 75mg 14 100mg 1 150mg 13 25mg 5 50mg 4 75mg 5 36.1 16.2 16.0 8.8 4 4 3 57.1% 24/42 78.6% 11/14 25mg 50mg 75mg 100mg 150mg 28.6% 2/7 71.4% 5/7 57.1% 8/14 0% 0/1 69.2% 9/13 25mg 50mg 75mg 60% 3/5 100% 4/4 80% 4/5 54.5% 12/22 60% 6/10 66.7% 6/9 0% 0/1 71.4% 5/7 100% 6/6 0% 0/1 60.6% 20/33 20
65.2% 15/23 20 14 3 9 2 3 25mg 2 AMPH-B FLCZ 75mg 1 AMPH-B Aspergillus A. fumigatus Candida C. albicans 57.9% 11/19 57.1% 4/7 non-albicans Candida species C. glabrata C. tropicalis C. krusei 4 3 Chemotherapy 39: 687, 1991 67 40 59.7% 117 5 4 3 11 1 43 64 12 17.9% 12 2 1 67 42 62.7% 137 8 BUN 7 K K GPT ALT 6 GOT AST LDH CRP 5 ALP 4 -GTP 3 11 16.4% 21 ALP BUN 3 GPT ALT -GTP 2 67 9 13.4% 4 5 7 5 LDH BUN K 5 7 21
1 G-CSF 3 2 FJ-463-0006 Aspergillus Candida 3 X 50mg 150mg 1 1 50mg 1 1 150mg 75mg 30 75mg 1 56 56 2002 5 16 6 8 8 150mg/ 7 2 7 14 2 43 56 3 131 1 8 3 5 3 8 1 GOT GPT Al-P -GTP 22 7 2 (2) / 4 97-0-041 FLCZ 22
FLCZ 1 1 400mg 12.5mg 25mg 50mg 75mg 100mg 150mg 200mg 8 1 1 1 C 2 Southwest Oncology Group (SWOG Toxicity Criteria Invetigational New Drugs 10: 239-253, 1992 3 Grade 3 1 48 24 500/mm 3 79 5 74 C 12 62 C 12 12.5mg 8 25mg 9 50mg 9 75mg 9 100mg 9 150mg 10 200mg 8 C 11.2 3.4 10.7 4.3 25% C 3 25% 7 11% C 6 50% 35 57% C 3 25% 14 23% C 3 25% 12 19% C 3 25% 12 19% C 1 8% 17 27% C 4 33% 17 27% C 8 67% 35 57% C 6 50% 23 37% K C 4 33% 15 24% P C 3 25% 10 16% C 3 25% 18 29% C 3 25% 13 21% C 4 33% 20 32% C 74 11 14.9% C 2 16.7% 9 14.5% C 1 1 5 27 36.5% 73 C 5 11 22 62 Grade 3 50mg 200mg K 150mg 200mg 200mg 1 4 1 200mg C 41.7% 5/12 24.2% 15/62 12.5mg 25% 2/8 25mg 33.3% 3/9 50mg 22.2% 2/9 75mg 33.3% 3/9 100mg 22.2% 2/9 150mg 10% 1/10 200mg 25% 2/8 23
/ 5 1 FG-463-21-03 3mg/kg 4mg/kg 6mg/kg 8mg/kg 10 1 1 1 SWOG Toxicity Criteria 3 Grade 3 1 2 3 500/mm 3 36 3mg/kg 10 4mg/kg 10 6mg/kg 8 8mg/kg 8 17.1 4.8 19.3 6.9 22.3 4.6 19.8 5.5 10 33 91.7% 32 88.9% K 27 75.0% 26 72.2% 25 69.4% 24 66.7% 24 66.7% 23 63.9% 19 52.8% 19 52.8% 19 52.8% 18 50.0% 17 47.2% 16 44.4% Mg 16 44.4% 15 41.7% 15 41.7% 13 36.1% 13 36.1% 12 33.3% GPT ALT 12 33.3% 12 33.3% 11 30.6% 11 30.6% BUN 10 27.8% GOT AST 10 27.8% 10 27.8% 10 27.8% 21 3mg/kg 3 10 2 Ca 1 4mg/kg 3 3 2 1 6mg/kg 1 1 1 8mg/kg 3 7 1 Grade 3 1 8mg/kg 3mg/kg 30% 3/10 4mg/kg 30% 3/10 6mg/kg 37.5% 3/8 8mg/kg 25% 2/8 6 97-7-003 MED HIV AIDS 5 1 20 1 1 1 24
10 65% MED 50mg 25mg 12.5mg 3 50mg 25mg 12.5mg / 4 97-0-041 200mg/ 75mg 100mg/ 12.5mg 75mg 100mg 120 Candida 16 13 6 1 84 120 12.5mg 25mg 50mg 75mg 100mg 18 13 15 19 19 14.7 3.6 14.5 3.2 15.7 4.1 16.8 3.4 13.5 3.6 84 83 C. albicans 1 C. albicans C. tropicalis 12.5mg 66.7% 12/18 25mg 92.3% 12/13 50mg 93.3% 14/15 75mg 100% 19/19 100mg 100% 19/19 Cochran-Armitage p=0.001 12.5mg 65% MED 12.5mg/ 72 120 90 75.0% 5 18 15.0% 17 14.2% 16 13.3% 15 12.5% 13 10.8% 9 7.5% 9 7.5% 8 6.7% 7 5.8% 5 4.2% 5 4.2% 5 4.2% 5 4.2% 35 29.2% 12.5mg 26 7 26.9% 10 3 2 1 25mg 22 8 36.4% 10 GOT AST 2 1 50mg 26 8 30.8% 25 3 2 1 75mg 22 3 13.6% 5 1 100mg 24 9 37.5% 13 3 ALP 1 13 AIDS 3 2 HIV 1 25
18 15.0% 26 3 2 AIDS K 1 12.5mg 1 7 2 FG463-21-01 98-0-046 9 Aspergillus De novo 48 Efficacy failure 72 Toxicity failure De novo 50 mg 40kg 1mg/kg 1 1 1 7 25mg 0.5mg/kg 100mg 2mg/kg Efficacy failure 75 mg 40kg 1.5mg/kg 150mg 3mg/kg 150mg 7 75mg 1.5mg/kg 225mg 4.5mg/kg 200mg 188 186 186 7 18 11 157 35.4 0.2 78 60.6kg 4.7 137.4kg 111 70.7% A. fumigatus 67 42.7% A. flavus 21 13.4% Aspergillus 66 42.0% De novo 14 Efficacy failure 136 Toxicity failure 11 Efficacy failure 125 AMPH-B 89 5 AMPH-B 28 3 1 n=117 48.8 47.5 7 284 106.0 52.5mg 50.0 291.7mg n=40 0.2 15 26
68.7 80.8 7 470 55.7 36.1mg 5.4 146.2mg 1.7 0.8mg/kg 0.5 4.0mg/kg 4 6 157 40 25.5% 36 22.9% 24 15.3% 51 32.5% 63.7% 95% 56.2 71.2% De novo 92.9% n=14 Efficacy failure 60.8% n=125 Efficacy failure 36.4% n=11 Toxicity failure 100% n=7 51 De novo 1 Efficacy failure 50mg 73.3% 11/15 50mg 50.0% 3/6 50 75mg 69.0% 40/58 75 100mg 64.7% 11/17 100 150mg 64.3% 18/28 150 200mg 75.0% 6/8 200 300mg 45.8% 11/24 A. fumigatus 59.7% 40/67 A. flavus 71.4% 15/21 A. niger 85.7% 6/7 40 25.5% 32 20.4% 35 22.3% 49 31.2% 1 0.6% 14 8.9% 14 8.9% 9 5.7% 120 76.4% 6 100 2 29 68 36.6% 64 34.4% 60 32.3% K 58 31.2% 53 28.5% 52 28.0% 50 26.9% 45 24.2% 42 22.6% 40 21.5% 38 20.4% Mg 35 18.8% 33 17.7% 32 17.2% 31 16.7% 30 16.1% K 29 15.6% 27 14.5% 26 14.0% 23 12.4% 20 10.8% GOT AST 17 9.1% GPT ALT 14 7.5% 33.9% 63/186 12 6.5% 10 5.4% 7 3.8% 6 3.2% ALP 6 3.2% 16 16 34.3% 47/137 32.7% 16/49 109 58.6% 19 90 13 7.0% 12 6.5% 10 5.4% 9 4.8% 8 4.3% 5 2.7% 4 2.2% 1 27
135 72.6% 29 15.6% 22 11.8% 19 10.2% 14 7.5% 12 6.5% 10 5.4% 8 4.3% 5 2.7% 22 11.8% 4 2.2% 3 1.6% 2 1.1% 8 3 FG463-21-02 98-0-047 C.albicans non-albicans Candida species 10 7 FG463-21-01 98-0-046 De novo 48 Efficacy failure 5 De novo 50 mg 40kg 1mg/kg 1 1 1 5 25mg 0.5mg/kg 100mg 2mg/kg Efficacy failure 2 150mg 3mg/kg 5 50mg 1mg/kg 200mg 4mg/kg 200mg Germ tube non-albicans Candida species 100mg 2mg/kg 254 250 250 5 13 28 209 38.8 0.1 79 59.2kg 3.0 265kg 97 46.4% 75 35.9% C. albicans 136 65.1% non-albicans Candida species 76 36.4% Candida 12 5.7% De novo 146 Efficacy failure 63 Efficacy failure 35 AMPH-B 21 23 AMPH-B 18 AMPH-B 5-FC 1 1 28
n=187 21.8 13.3 5 77 68.8 26.3mg 33.6 200mg n=22 0.1 15 27.4 24.3 5 106 1.3 0.5mg/kg 0.7 2.4mg/kg 7 FG463-21-01 98-0-046 131 62.7% 42 20.1% 18 8.6% 15 7.2% 82.8% 95% 77.7 87.9% De novo 89.0% n=146 Efficacy failure 62.9% n=35 Efficacy failure 75.0% n=28 De novo 7 4.8% Efficacy failure 6 17.1% Efficacy failure 2 7.1% 50mg 72.2% 13/18 50mg 85.3% 64/75 51 75mg 87.0% 40/46 75 100mg 81.4% 35/43 100 150mg 88.9% 16/18 150 200mg 57.1% 4/7 200 300mg 50% 1/2 C. albicans 86.8% 118/136 non-albicans Candida species 78.9% 60/76 Candida 66.7% 8/12 136 65.1% 40 19.1% 17 8.1% 15 7.2% 1 0.5% 115 55.0% 30 14.4% 34 16.3% 30 14.4% 6 173 13 54 65 26.0% 62 24.8% Mg 54 21.6% K 48 19.2% 46 18.4% 45 18.0% 44 17.6% 43 17.2% 42 16.8% 30 12.0% 29 11.6% 28 11.2% 47.6% 119/250 GOT AST 10.8% Mg 9.2% GPT ALT 8.8% 8.4% ALP 8.4% Ca 7.6% 16 16 49.5% 109/220 33.3% 10/30 16 72 28.8% 11 61 14 5.6% 9 3.6% 7 2.8% 3 1.2% 92 36.8% 16 6.4% 13 5.2% 12 4.8% 9 3.6% 7 2.8% 6 2.4% K 5 2.0% 4 1.6% K 4 1.6% 3 1.2% 2 0.8% ALP 2 0.8% 29
1 98-0-050 FLCZ 6 50mg FLCZ 400mg 50kg 1mg/kg FLCZ 8mg/kg 1 1 1 48 500/mm 3 5 42 4 4 889 426 FLCZ 463 7 882 425 FLCZ 457 16 16 798 386 FLCZ 412 84 39 FLCZ 45 18.8 6.4 1 46 FLCZ 18.2 5.9 1 43 23.2 10.0 4 51 FLCZ 23.4 8.0 8 51 1 49.6 1.3mg/ 41.7 54.5mg/ FLCZ 390.4 30.0mg/ 194 403.8mg/ 1 1 0.6 0.1mg/kg/ 0.3 1.0mg/kg/ FLCZ 5.0 1.3mg/kg/ 1.6 9.7mg/kg/ 0.9 0.1mg/kg/ 0.6 1.0mg/kg/ FLCZ 7.7 0.7mg/kg/ 4.2 8.5/kg/ 1 80.0% 340/425 FLCZ 73.5% 336/457 6.5% 95% 0.9% 12.0% 95% 0% FLCZ 1.6% 7/425 FLCZ 2.4% 11/457 1.1% 5/425 FLCZ 1.8% 8/457 4 0.5% 2/425 FLCZ 0.7% 3/457 0.9% 4/425 FLCZ 0.4% 2/457 0.2% 1/425 FLCZ 1.6% 7/457 FLCZ Fisher 30
p=0.071 59.5% 253/425 FLCZ 65.2% 298/457 4 25% 52.0% FLCZ 54.3% 40.9% FLCZ 37.2% 36.0% FLCZ 40.5% 32.9% FLCZ 33.9% 31.5% FLCZ 35.0% 24.0% FLCZ 27.8% 24.9% FLCZ 26.0% 26.6% FLCZ 24.5% 21.9% FLCZ 25.6% 77.9% FLCZ 80.5% 74.1% FLCZ 78.6% 70.6% FLCZ 68.9% 66.4% FLCZ 67.4% 52.7% FLCZ 50.5% 30.4% FLCZ 31.3% 28.5% FLCZ 31.1% 77.9% FLCZ 75.7% 74.8% FLCZ 70.2% 40.5% FLCZ 42.2% Mg 53.2% FLCZ 58.6% K 50.1% FLCZ 51.4% 27.3% FLCZ 24.5% 42.8% FLCZ 36.5% 35.8% FLCZ 32.4% 24.2% FLCZ 26.0% 42.8% FLCZ 40.9% 15.1% 64/425 FLCZ 16.8% 77/457 14 3.3% 10 2.4% 9 2.1% K 8 1.9% P 7 1.6% 6 1.4% Mg 5 1.2% FLCZ 15 3.3% 14 3.1% 12 2.6% GOT AST GPT ALT 9 2.0% K 8 1.8% 7 1.5% Mg 6 1.3% 2.6% 11/425 FLCZ 3.5% 16/457 18 4.2% FLCZ 26 5.7% 3 2 1 FLCZ 4 3 2 1 80 18.8% FLCZ 74 16.2% 1% 3.3% FLCZ 2.8% 3.1% FLCZ 1.3% 1.9% FLCZ 0% 2.1% FLCZ 0.7% 1.9% FLCZ 0.4% 0.7% FLCZ 1.3% 0.2% FLCZ 1.3% 0.2% FLCZ 1.1% 1.6% FLCZ 1.3% 0.7% FLCZ 1.8% 1.4% FLCZ 1.1% 0.2% FLCZ 1.3% 0.5% FLCZ 1.3% 4 4 2 1 FLCZ 10 22 31
2 GOT AST GPT AST 1 425 169 39.8% FLCZ 457 194 42.5% GOT AST GPT AST 0.65 0.38mg/dL n=159 FLCZ 0.60 0.32mg/dL n=181 1 0.82 0.85mg/dL n=131 FLCZ 0.73 0.59mg/dL n=146 2 1.17 0.92mg/dL n=155 FLCZ 1.27 2.34mg/dL n=175 3 1.60 1.66mg/dL n=119 FLCZ 1.77 2.29mg/dL n=118 4 2.15 3.84mg/dL n=52 FLCZ 2.76 5.58mg/dL n=48 46 10.8% FLCZ 53 11.6% GOT AST GPT AST (1) 14 C (1)- (2)- MTD MTD MED 3 (2)- (2)- 32
14 C MTD MTD MED 50 150mg 1 1 1 300mg 150mg 1 1 (2) 33
1 Independent Reviewer FDA NDA documents 12.5 25mg/ MTD 12.5mg/ MED 50mg/ 14 C 28.3mg 1 50mg/ 25mg/ 2.5mg/kg 100mg/ 50kg 2mg/kg 1 25mg/ 9 9 4 3 2 34
MTD 75mg/ 12.5mg 25mg/ 25mg 50mg/ 75mg/ MTD MED 50mg/ 75mg/ MTD 150mg/ 150mg/ 2 50 75mg/ 16 2 3 4 MTD 200mg/ 75mg/ 150mg/ 75mg/ 150mg/ MTD 225mg/ 200mg/ 2 MTD (3) i) 50 150mg 1 1 57.1% 24/42 25mg 50mg 75mg 100mg 150mg 28.6% 2/7 71.4% 5/7 57.1% 8/14 0% 0/1 69.2% 9/13 50 150mg/ 35
16 115 24 De novo 8 Efficacy failure 9 Toxicity failure 7 91 Efficacy failure 24 75.0% 18/24 50 75mg 75 100mg 100 150mg 150 200mg 225mg 300mg 70.0% 7/10 75.0% 3/4 100% 4/4 50.0% 1/2 75.0% 3/4 150 300mg 66.7% 4/6 75 300mg/ 50 150mg 1 1 1 300mg 150mg 6 150mg 150mg 8mg/kg 600mg 300mg ii) 50mg 1 1 1 150mg 78.6% 11/14 25mg 50mg 75mg 60% 3/5 100% 4/4 80% 4/5 50mg 4 1 3 75mg 3 1 50mg 50mg 50mg 50 75mg 75 100mg 100 150mg 150 200mg 200 250mg 1/1 89.9% 62/69 92.5% 37/40 86.5% 32/37 100% 7/7 1/3 1/2 150mg/ 5 150mg nonalbicans Candida species 36
C. albicans non-albicans Candida species 25mg 3 2 50mg 150mg 75mg 150mg 150mg iii) 12 17.9% 12 11 16.4% 21 31.3% 21/67 1 75mg 25mg 50mg 75mg 150mg 31.3% 5/16 12.5% 2/16 33.3% 7/21 53.8% 7/13 2 16 150mg 46.2% 146/316 150mg 300mg 25% 10/40 300mg 0/1 150mg 8.2% 26/316 150mg 7.3% 3/41 150mg Al-P GOT AST GPT ALT 3 4 50mg 150mg 75mg 1 150mg 150 300mg 150mg 300mg 150mg 150mg 41 150 300mg 37
50 150mg 1 1 1 300mg 1995 6 7 Jpn J Antibiotics 42:47-54,1989 Jpn J Antibiotics 46:374-387, 1989 7 4 7 24 9 14 12 28 3 29 56 11 7 14 28 14 7 90 5 42 90 28 90 14 42 38
65 16 64 20.0% 6/30 40.5% 15/37 36.6% 15/41 44.6% 141/316 (4) 2001 9 1268 2001 10 17 67 54 5 4 Al-P 3 1 4 67 1 100mg/kg i.v. bolus 1 1 5 10-4 g/ml 75mg 30 75mg 1 13 300mg 39
AUC Cmax (5) Aspergillus Candida Mucor and Rhizopus Cryptococcus neoformance Blastomyces dermatidis Coccidioides immitus Hisoplasma capsulatum Sporothrix schenckii Candida Sporothrix schenckii Aspergillus Candida AMPH-B K AMPH-B 5-FC 5- DNA AMPH-B CYP 14 - MCZ FLCZ ITCZ MCZ FLCZ FLCZ AMPH-B 1980 FLCZ C.albicans HIV Cecil: Textbook of Medicine, 21 st Edition 1,3- -D- 40
60.6% 20/33 65.2% 15/23 56 6 30 AMPH-B 11 AMPH-B 4 45 29 17 AMPH-B 10 AMPH-B 2 Efficacy failure 72 5 11/18 61.1% 76/125 60.8% 21/28 75.0% 22/35 62.9% Efficacy failure 2 1 28 Harrison s Principles of Internal Medicine, 15 th ed. 2001 ITCZ 6 12 FLCZ 10 14 AMPH-B 8 10 41
5 (6) 12 12 15 1334 1982 9 10 8 25 743 1 2 17 0.5 4mg/kg/ 1 1 1 4 42
11.7% 9/77 2 12 13 17 Cmax AUC 4 12.1 15.2 Cmax Cmin AUC 1mg/kg/ 50mg/ 14 4 GCP GCP GCP 150 300mg 150 300mg 43
50 150mg 1 1 1 300mg 150mg/ 44
14 8 8 50mg 75mg 13 6 25 50 150mg/ 50mg/ 300mg/ 150mg/ 300mg/ 150mg/ 40% 2/5 150mg/ 150mg/ 150mg/ 6 5 300mg/ 45
300mg/ 300mg/ 150mg CL T 300mg/ 50kg 6mg/kg 50kg 1 6mg( )/kg MTD 8mg/kg 25mg ICH 5 12 2 104 65 10 8 25 743 65 74 75 79 80 3 77 79 80 4 9 46
1 2 1 24 14 28 11 7 14 X -2-3 71 62 87.3% 5 45 5 14 35 15 28 20 29 42 7 157 145 92.4% 5 14 28 56 57 1 1 in vitro 47
in vitro Cryptococcus neoformans 18 15 Candida albicans 26 22 4 Aspergillus fumigatus 30 1 25 4 150mg 80 150mg Seg. I 3.2 10 32mg/kg GST-P PCNA 10mg/kg/ 48
6 50 150mg 1 1 1 300mg 50mg 1 1 1 300mg 75mg 30 75mg 1 49
150mg/ 50
14 8 28 50mg 75mg 13 6 25 125mg/kg 100mg/kg 10 1