50mg 75mg (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
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- ただきよ なつ
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2 50mg 75mg (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 [(1S,2S)-2- [(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S, 26S)-3-[(R) ]-11,20,21, [(R)-1- ] ,5,8,14,17, [4-[5-(4- ) -3- ] ]-1,4,7,13,16,22- [ ,13 ] -6- ]-1,2- ]-2- S o d i u m 5 - [ ( 1 S, 2 S ) [(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[ ,13 ]heptacos-6-yl]- 1,2-dihydroxyethyl] -2-hydroxyphenyl sulfate 1
3 mg 75mg (1) 2 150mg mg mg 50mg mg 75mg 30 75mg 1 150mg/ 2
4 mg 50mg 75mg mg 1 25mg 50mg 1 50mg 75mg 1 75mg mg mg mg 75mg 30 75mg 1 Coleophoma empetri echinocandin B 3
5 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 UV IR 13 C-NMR ph ph 4
6 ph % / /27 25 /60%RH/ / /60%RH/ /27 40 /75%RH/ /6 / /3 / / /40 5
7 2 5w/v% / 5 15mg/mL mg/mL ph mg/kg mg/kg 125mg/kg 250mg/kg 200mg/kg mg/kg/ mg/kg/ mg/kg/ GOT GPT 4 32mg/kg/ mg/kg/
8 mg/kg/ mg/kg/ mg/kg/ mg/kg/ mg/kg/ mg/kg/ 10mg/kg/ mg/kg/ 32mg/kg/ GPT 10mg/kg/ 32mg/kg/ 10mg/kg/ 3.2mg/kg/ 32mg/kg/ 32mg/kg/ mg/kg/ 32mg/kg/ GPT 10mg/kg/ 32mg/kg/ mg/kg/ 32mg/kg/ 1 32mg/kg/ 10mg/kg/ 32mg/kg/ mg/kg/ 32mg/kg/ 10mg/kg/ 32mg/kg/ 10mg/kg/ % AMPH-B 0.01%
9 0.025% 0.425% 0.05% 0.01% AMPH-B 0.425% 1.7% ASA PCA PCA PCA mg AUC Cmax life threatening 300mg 1 300mg 1 150mg 1 300mg AUC AUC mg/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
10 antigen mg/kg 39 FLCZ ITCZ B AMPH-B Candida Saccharomyces cerevisiae Aspergillus Cryptococcus neoformans Trichosporon Fusarium solani Pseudallescheria boydii 1 Candida Aspergillus MIC µg/ml MIC µg/mL 9
11 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 FP AMPH-B Candida MIC AMPH-B AMPH-B AMPH-B 1 C. albicans 1 2 1,3- -D-glucan 2 6 cyclophosphamide C.albicans mg/kg mg/kg 1.0mg/kg 22 AMPH-B FLCZ mg/kg ITCZ 20mg/kg Cyclophosphamide hydrocortisone 5-fluorouracil C. albicans 24 10
12 AMPH-B ED 50 1 FLCZ ED 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 mg/kg 7 0.5mg/kg 1.0 mg/kg 22 AMPH-B ITCZ mg/kg FLCZ 20mg/kg Hydrocortisone 5-fluorouracil A.fumigatus 24 AMPH-B ED mg/kg 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
13 in vitro AMPH-B ITCZ FLCZ C. albicans % % % A. fumigatus % % 4 13 % C. neoformans 18 AMPH-B % 6 33 % ITCZ % 8 A. fumigatus AMPH-B 1mg/kg AMPH-B 0.25mg/kg g/ml g/ml in vivo g/ml g/ml in vivo 9 Candida Aspergillus MIC 90 MIC 50 4 Candida Aspergillus Candida Aspergillus 12
14 Candida Aspergillus ICR SD mg/kg AUC 1mg/kg 1 AUC t 1/ mg/kg t 1/2 AUC mg/kg AUC t 1/2 AUC 14 C 1mg/kg % 2 M8 M9 M8 M C 1mg/kg % % C 1mg/kg 7 1/10 13
15 in vitro 99.7% 4% µg/mL 10µg/mL 4% 2% M1 M2 in vitro µg/mL % 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 % 14.4% 0.0% 1mg/kg % 15.2% % 14 C 8 14 C 1mg/kg mg 2 Cmax AUC 0- M1 14
16 M2 0.05µg/mL mg mg 1 AUC 0- M1 50 mg mg µg/mL M2 M1 M2 1% 6 25mg t 1/ mg t 1/ % M1 M mg mg Cmax Cmin 24 2 t 1/2 t 1/ t 1/ PPK 2- CL T mg 30 2 CL T CL T CL T 6 14 C 28.3mg 3.05MBq 1 Cmax 2.97µg/mL AUC µg h/ml t 1/ Cmax 2.29µg eq./ml AUC µg eq. h/ml t 1/ % 43.80% 4 15
17 µg eq./ml 0.023µg eq./ml µg eq./ml 2 12 HPLC M5 14 C 0.70% M5 3.62% 11.71% M3 1.75% M % 400mg/ mg CL T t 1/2 1 7 AUC 0-24h mg/kg mg CL T t 1/2 1 7 AUC 0-24h AUC Cmax Cmin kg 82.8kg CL T CYP 6.5µg/mL CYP1A2 2C9 2C19 2D6 2E1 3A 65µg/mL CYP3A 99.8% CYP3A 16
18 14 C M5 M13 2 M5 2 M5 CYP1A2 2B6 2C 3A4 M13 CYP1A1 1A2 2A6 3A4 CYP M % CYP 1/100 A IC 50 31µmol/L 10µmol/L IC µmol/L 1/200 A M5 M13 A 100µmol/L 400mg/ CL T AUC P P P MRP2 A 30mg/kg A mg/ 5mg/kg Cmax/Dose AUC 0-12 /Dose 90% % Cmax AUC 0-24 AUC 0-90% % 1 17
19 99.8% Kragh-Hansen Biochem J 225(3); , PPK C 8 GOT 219IU GPT 153IU Al-P 1428IU -GTP 253IU CL T HIV HIV CYP3A4 CYP P in vitro CYP P ADME (1) 1 P-1 2.5mg 5mg 12.5mg 25mg 50mg BUN CPK CRP 1 18
20 IgE PCA in vitro 50mg 2 P Aspergillus 25mg BUN 2 1 BUN ng/mL 0.81ng/mL 0.2ng/mL ng/mL FJ Aspergillus Candida X 12.5mg 25mg
21 12.5mg 30 25mg mg 50mg mg 25mg 30 50mg mg 50mg 75mg mg mg 1 150mg kg mg 7 50mg 7 75mg mg 1 150mg 13 25mg 5 50mg 4 75mg % 24/ % 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/ % 6/9 0% 0/1 71.4% 5/7 100% 6/6 0% 0/1 60.6% 20/33 20
22 65.2% 15/ mg 2 AMPH-B FLCZ 75mg 1 AMPH-B Aspergillus A. fumigatus Candida C. albicans 57.9% 11/ % 4/7 non-albicans Candida species C. glabrata C. tropicalis C. krusei 4 3 Chemotherapy 39: 687, % % % BUN 7 K K GPT ALT 6 GOT AST LDH CRP 5 ALP 4 -GTP % 21 ALP BUN 3 GPT ALT -GTP % LDH BUN K
23 1 G-CSF 3 2 FJ Aspergillus Candida 3 X 50mg 150mg mg mg 75mg 30 75mg mg/ GOT GPT Al-P -GTP (2) / FLCZ 22
24 FLCZ mg 12.5mg 25mg 50mg 75mg 100mg 150mg 200mg C 2 Southwest Oncology Group (SWOG Toxicity Criteria Invetigational New Drugs 10: , Grade /mm C C mg 8 25mg 9 50mg 9 75mg 9 100mg 9 150mg mg 8 C % 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 % C % % C % 73 C Grade 3 50mg 200mg K 150mg 200mg 200mg mg C 41.7% 5/ % 15/ mg 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
25 / 5 1 FG mg/kg 4mg/kg 6mg/kg 8mg/kg SWOG Toxicity Criteria 3 Grade /mm mg/kg 10 4mg/kg 10 6mg/kg 8 8mg/kg % % K % % % % % % % % % % % % Mg % % % % % % GPT ALT % % % % BUN % GOT AST % % % 21 3mg/kg Ca 1 4mg/kg mg/kg mg/kg 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/ MED HIV AIDS
26 10 65% MED 50mg 25mg 12.5mg 3 50mg 25mg 12.5mg / mg/ 75mg 100mg/ 12.5mg 75mg 100mg 120 Candida mg 25mg 50mg 75mg 100mg 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= mg 65% MED 12.5mg/ % % % % % % 9 7.5% 9 7.5% 8 6.7% 7 5.8% 5 4.2% 5 4.2% 5 4.2% 5 4.2% % 12.5mg % mg % 10 GOT AST mg % mg % mg % 13 3 ALP 1 13 AIDS 3 2 HIV 1 25
27 % AIDS K mg FG Aspergillus De novo 48 Efficacy failure 72 Toxicity failure De novo 50 mg 40kg 1mg/kg mg 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 kg kg % A. fumigatus % A. flavus % Aspergillus % De novo 14 Efficacy failure 136 Toxicity failure 11 Efficacy failure 125 AMPH-B 89 5 AMPH-B n= mg mg n=
28 mg mg mg/kg mg/kg % % % % 63.7% 95% % 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/ mg 69.0% 40/ mg 64.7% 11/ mg 64.3% 18/ mg 75.0% 6/ mg 45.8% 11/24 A. fumigatus 59.7% 40/67 A. flavus 71.4% 15/21 A. niger 85.7% 6/ % % % % 1 0.6% % % 9 5.7% % % % % K % % % % % % % % Mg % % % % % K % % % % % GOT AST % GPT ALT % 33.9% 63/ % % 7 3.8% 6 3.2% ALP 6 3.2% % 47/ % 16/ % % % % 9 4.8% 8 4.3% 5 2.7% 4 2.2% 1 27
29 % % % % % % % 8 4.3% 5 2.7% % 4 2.2% 3 1.6% 2 1.1% 8 3 FG C.albicans non-albicans Candida species 10 7 FG De novo 48 Efficacy failure 5 De novo 50 mg 40kg 1mg/kg mg 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 kg kg % % C. albicans % non-albicans Candida species % Candida % De novo 146 Efficacy failure 63 Efficacy failure 35 AMPH-B AMPH-B 18 AMPH-B 5-FC
30 n= mg mg n= mg/kg mg/kg 7 FG % % % % 82.8% 95% % 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 % Efficacy failure 2 7.1% 50mg 72.2% 13/18 50mg 85.3% 64/ mg 87.0% 40/ mg 81.4% 35/ mg 88.9% 16/ mg 57.1% 4/ mg 50% 1/2 C. albicans 86.8% 118/136 non-albicans Candida species 78.9% 60/76 Candida 66.7% 8/ % % % % 1 0.5% % % % % % % Mg % K % % % % % % % % % 47.6% 119/250 GOT AST 10.8% Mg 9.2% GPT ALT 8.8% 8.4% ALP 8.4% Ca 7.6% % 109/ % 10/ % % 9 3.6% 7 2.8% 3 1.2% % % % % 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
31 FLCZ 6 50mg FLCZ 400mg 50kg 1mg/kg FLCZ 8mg/kg /mm FLCZ FLCZ FLCZ FLCZ FLCZ FLCZ mg/ mg/ FLCZ mg/ mg/ mg/kg/ mg/kg/ FLCZ mg/kg/ mg/kg/ mg/kg/ mg/kg/ FLCZ mg/kg/ /kg/ % 340/425 FLCZ 73.5% 336/ % 95% 0.9% 12.0% 95% 0% FLCZ 1.6% 7/425 FLCZ 2.4% 11/ % 5/425 FLCZ 1.8% 8/ % 2/425 FLCZ 0.7% 3/ % 4/425 FLCZ 0.4% 2/ % 1/425 FLCZ 1.6% 7/457 FLCZ Fisher 30
32 p= % 253/425 FLCZ 65.2% 298/ % 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/ % % 9 2.1% K 8 1.9% P 7 1.6% 6 1.4% Mg 5 1.2% FLCZ % % % 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/ % FLCZ % FLCZ % FLCZ % 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% FLCZ
33 2 GOT AST GPT AST % FLCZ % GOT AST GPT AST mg/dL n=159 FLCZ mg/dL n= mg/dL n=131 FLCZ mg/dL n= mg/dL n=155 FLCZ mg/dL n= mg/dL n=119 FLCZ mg/dL n= mg/dL n=52 FLCZ mg/dL n= % FLCZ % GOT AST GPT AST (1) 14 C (1)- (2)- MTD MTD MED 3 (2)- (2)- 32
34 14 C MTD MTD MED mg mg 150mg 1 1 (2) 33
35 1 Independent Reviewer FDA NDA documents mg/ MTD 12.5mg/ MED 50mg/ 14 C 28.3mg 1 50mg/ 25mg/ 2.5mg/kg 100mg/ 50kg 2mg/kg 1 25mg/
36 MTD 75mg/ 12.5mg 25mg/ 25mg 50mg/ 75mg/ MTD MED 50mg/ 75mg/ MTD 150mg/ 150mg/ mg/ MTD 200mg/ 75mg/ 150mg/ 75mg/ 150mg/ MTD 225mg/ 200mg/ 2 MTD (3) i) mg % 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/ mg/ 35
37 De novo 8 Efficacy failure 9 Toxicity failure 7 91 Efficacy failure % 18/ mg mg mg mg 225mg 300mg 70.0% 7/ % 3/4 100% 4/4 50.0% 1/2 75.0% 3/ mg 66.7% 4/ mg/ mg mg 150mg 6 150mg 150mg 8mg/kg 600mg 300mg ii) 50mg mg 78.6% 11/14 25mg 50mg 75mg 60% 3/5 100% 4/4 80% 4/5 50mg mg mg 50mg 50mg 50 75mg mg mg mg mg 1/1 89.9% 62/ % 37/ % 32/37 100% 7/7 1/3 1/2 150mg/ 5 150mg nonalbicans Candida species 36
38 C. albicans non-albicans Candida species 25mg mg 150mg 75mg 150mg 150mg iii) % % % 21/ mg 25mg 50mg 75mg 150mg 31.3% 5/ % 2/ % 7/ % 7/ mg 46.2% 146/ mg 300mg 25% 10/40 300mg 0/1 150mg 8.2% 26/ mg 7.3% 3/41 150mg Al-P GOT AST GPT ALT mg 150mg 75mg 1 150mg mg 150mg 300mg 150mg 150mg mg 37
39 50 150mg mg Jpn J Antibiotics 42:47-54,1989 Jpn J Antibiotics 46: ,
40 % 6/ % 15/ % 15/ % 141/316 (4) Al-P mg/kg i.v. bolus g/ml 75mg 30 75mg mg 39
41 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
42 60.6% 20/ % 15/ AMPH-B 11 AMPH-B AMPH-B 10 AMPH-B 2 Efficacy failure / % 76/ % 21/ % 22/ % Efficacy failure Harrison s Principles of Internal Medicine, 15 th ed ITCZ 6 12 FLCZ AMPH-B
43 5 (6) mg/kg/
44 11.7% 9/ Cmax AUC Cmax Cmin AUC 1mg/kg/ 50mg/ 14 4 GCP GCP GCP mg mg 43
45 50 150mg mg 150mg/ 44
46 mg 75mg mg/ 50mg/ 300mg/ 150mg/ 300mg/ 150mg/ 40% 2/5 150mg/ 150mg/ 150mg/ mg/ 45
47 300mg/ 300mg/ 150mg CL T 300mg/ 50kg 6mg/kg 50kg 1 6mg( )/kg MTD 8mg/kg 25mg ICH
48 X % % in vitro 47
49 in vitro Cryptococcus neoformans Candida albicans Aspergillus fumigatus mg mg Seg. I mg/kg GST-P PCNA 10mg/kg/ 48
50 mg mg 50mg mg 75mg 30 75mg 1 49
51 150mg/ 50
52 mg 75mg mg/kg 100mg/kg 10 1
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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Aspergillus β Table1 Laboratoryfindingsonadmission Hematology WB Seg Band Lymph Eos Baso RB Hb Hct Plt Biochemistry AST ALT LD ALP γ-gtp K 17,700 /mm 3 70.0 % 7.0 % 17.0 % 2.0 % 1.0 % 337 10 4 /mm 3 11.5g/dl
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