2.7 臨床概要
A/G Al-P ALT AST AT- AUC AZM BIPM BP BUN CEZ CFPN-PI CFU CLcr Cmax CNS COPD CPFX CRP CS CYP CVA DBT DHP-I DIC DRPM DRPM-DC FAS γ-gtp GCP GNB GNF-GNR GPB HAM - Staphylococcus C P450 -I Full Analysis Set γ- HTLV
HIV ICU IPM ITT LAP LDH MEPM MIC MRSA NAG PaCO 2 PaO 2 PAPM PIPC PPB PPS PZFX SIRS QOL t 1/2 (β) TLC TNM TTT TUR-Bt TUR-P UTI VAP VCM WBC ZTT Intent-To-Treat Staphylococcus aureus N--β-D- Per Protocol Basis Per Protocol Set β 薄層クロマトグラフィー TNM (tumor node metastasis) 硫酸亜鉛混濁試験
A. calcoaceticus Acinetobacter calcoaceticus A. hydrophila Aeromonas hydrophila B. capillosus Bacteroides capillosus B. distasonis Bacteroides distasonis B. fragilis Bacteroides fragilis B. uniformis Bacteroides uniformis B. ureolyticus Bacteroides ureolyticus B. vulgatus Bacteroides vulgatus C. braakii Citrobacter braakii C. clostridiiforme Clostridium clostridiiforme C. difficile Clostridium difficile C. freundii Citrobacter freundii E. aerogenes Enterobacter aerogenes E. avium Enterococcus avium E. casseliflavus Enterococcus casseliflavus E. cloacae Enterobacter cloacae E. coli Escherichia coli E. corrodens Eikenella corrodens E. faecalis Enterococcus faecalis E. faecium Enterococcus faecium E. lentum Eubacterium lentum F. nucleatum Fusobacterium nucleatum G. morbillorum Gemella morbillorum H. influenzae Haemophilus influenzae H. parainfluenzae Haemophilus parainfluenzae K. oxytoca Klebsiella oxytoca K. ozaenae Klebsiella ozaenae K. pneumoniae Klebsiella pneumoniae L. cremoris Leuconostoc cremoris M (B). catarrhalis Moraxella (Branhamella) catarrhalis M. morganii Morganella morganii P. acnes Propionibacterium acnes P. aeruginosa Pseudomonas aeruginosa P. agglomerans Pantoea agglomerans P. anaerobius Peptostreptococcus anaerobius
P. asaccharolytica Porphyromonas asaccharolytica P. bivia Prevotella bivia P. cepacia Pseudomonas cepacia P. fluorescens Pseudomonas fluorescens P. gingivalis Porphyromonas gingivalis P. intermedia Prevotella intermedia P. magnus Peptostreptococcus magnus P. melaninogenica Prevotella melaninogenica P. micros Peptostreptococcus micros P. mirabilis Proteus mirabilis P. oris Prevotella oris S. agalactiae Streptococcus agalactiae S. anginosus Streptococcus anginosus S. aureus Staphylococcus aureus S. constellatus Streptococcus constellatus S. epidermidis Staphylococcus epidermidis S. intermedius Streptococcus intermedius S. maltophilia Stenotrophomonas maltophilia S. marcescens Serratia marcescens S. mitis Streptococcus mitis S. oralis Streptococcus oralis S. pneumoniae Streptococcus pneumoniae S. pyogenes Streptococcus pyogenes S. rubidaea Serratia rubidaea S. salivarius Streptococcus salivarius S. sanguis Streptococcus sanguis S. vestibularis Streptococcus vestibularis V. parvula Veillonella parvula Y.L.O Yeast like organism DRPM
_ 頁 2.7 2.7.1... 1 2.7.1.1... 1 2.7.1.1.1... 1 2.7.1.1.2 Bioassay HPLC... 3 2.7.1.2... 3 2.7.1.3... 4 2.7.1.4... 4 2.7.2... 5 2.7.2.1... 5 2.7.2.2... 6 2.7.2.2.1... 6 2.7.2.2.1.1... 6 2.7.2.2.1.1.1... 6 2.7.2.2.1.1.2 6 (Bioassay )... 2.7.2.2.1.1.3 1 3 (Bioassay )... 12 2.7.2.2.1.2... 14 2.7.2.2.2 (Bioassay )... 16 2.7.2.2.3 (Bioassay HPLC )... 17 2.7.2.2.4 (Bioassay )... 20 2.7.2.2.5... 22 2.7.2.2.5.1 (Bioassay HPLC )... 22 2.7.2.2.5.2 (Bioassay )... 22 2.7.2.2.5.3 (Bioassay )... 23 2.7.2.2.5.4 (Bioassay )... 24 2.7.2.2.5.5 (Bioassay )... 24 2.7.2.2.5.6 (HPLC )... 25 2.7.2.2.5.7 (Bioassay )... 26 2.7.2.2.5.8 (Bioassay )... 29 2.7.2.2.5.9 (Bioassay HPLC )... 29 2.7.2.2.5. (Bioassay )... 30 2.7.2.2.6 (Bioassay HPLC )... 31 2.7.2.3... 38 2.7.2.4... 38 2.7.2.5... 38 2.7.3... 39 2.7.3.1... 39
_ 頁 2.7.3.2... 39 2.7.3.2.1... 44 2.7.3.2.1.1... 44 2.7.3.2.1.2... 46 2.7.3.2.2... 48 2.7.3.2.2.1... 48 2.7.3.2.2.2... 49 2.7.3.2.3... 51 2.7.3.3... 55 2.7.3.3.1... 55 2.7.3.3.2... 55 2.7.3.3.3... 55 2.7.3.4... 58 2.7.3.5... 58 2.7.3.6... 58 2.7.4... 59 2.7.4.1... 59 2.7.4.1.1... 59 2.7.4.1.2... 59 2.7.4.1.3... 59 2.7.4.2... 62 2.7.4.2.1... 62 2.7.4.2.1.1... 99 2.7.4.2.1.2...4 2.7.4.2.1.3...5 2.7.4.2.1.4...7 2.7.4.2.1.5...7 2.7.4.2.2...7 2.7.4.3...7 2.7.4.4...9 2.7.4.5...9 2.7.4.5.1...9 2.7.4.5.2...1 2.7.4.5.3...1 2.7.4.5.4...1 2.7.4.5.5...1 2.7.4.5.6...1 2.7.4.5.7...1
_ 頁 2.7.4.5.8...1 2.7.4.6...1 2.7.4.7...111 2.7.4.7.1 (AST)...111 2.7.4.7.2 (ALT)...116 2.7.4.7.3 (Al-P)...121 2.7.4.7.4 ()...126 2.7.4.7.5 (-GTP)...131 2.7.5...136 2.7.6...139 2.7.6.1...142 2.7.6.1.1 1 ()...142 2.7.6.1.2 1 ()...146 2.7.6.1.3 1 ()...150 2.7.6.1.4 1 ()...156 2.7.6.1.5 1 (500 mg 3 )...160 2.7.6.2...163 2.7.6.2.1 ()...163 2.7.6.2.2 ()...167 2.7.6.2.3 ()...171 2.7.6.2.4 ()...175 2.7.6.2.5 ()...179 2.7.6.2.6 ()...183 2.7.6. ()...187 2.7.6.2.8 ()...191 2.7.6.3...195 2.7.6.3.1...195 2.7.6.3.2...198 2.7.6.4...201 2.7.6.4.1...201 2.7.6.5...205 2.7.6.5.1...205 2.7.6.5.2...225 2.7.6.6...243 2.7.6.6.1...243 2.7.6.6.2...267 2.7.6.7...296
_ 頁 2.7.6.7.1 2...296 2.7.6.7.2 2 ()...309 2.7.6.7.3 2 ()...323 2.7.6.7.4 2 ()...336 2.7.6.7.5 2 ()...347 2.7.6.7.6 3 ()...358 2.7.6.7.7 3 ()...366 2.7.6.7.8 3 ()...376 2.7.6.7.9 3 ()...386 2.7.6.7. 3 ()...395 2.7.6.7.11 3 ()...404 2.7.6.7.12 3 [ ()]...412 2.7.6.7.13 3 ()...432
2.7.1 2.7.1.1 2.7.1.1.1 (DRPM) DRPM (Bioassay ) 1 () Bioassay HPLC Bioassay HPLC DRPM (DRPM-DC) HPLC 2.7.1-1 1) Bioassay 5.3.1-Report 01 Bioassay (2.6.4.2.2 ) 2) HPLC 5.3.1-Report 02
2.7.1-1 Matrix (µg/ml) CV (%) Bias (%) CV (%) Bias (%) DRPM DRPM-DC Bioassay HPLC HPLC 0.06 0.07.8 0.0.9 1.25.2 0.09.2 0.3 1.46.4 0.719.2 1.611.6 1.98.3 0.200 0.92.3-2.711.2 1.18.7-6.62.0 1.0 1.23.4-8.23.2 2.66.8-1.83.5 0.200 1.37.9 -.33.3 3.66.3-5.23.2 5.0 0.916.8-6.93.4 2.1.9-5.04.4 2.7.1.1.2 Bioassay HPLC 48 55 Bioassay HPLC DRPM Bioassay/HPLC 1.09 0.96 2.7.1.2
2.7.1.3 in vitro 2.7.1.4
2.7.2 2.7.2.1 1) DHP-I 4.2.2.4-Report 04 -I (DHP-I) DHP-I DRPM DRPM (IPM) (MEPM) DHP-I 37 C band-culture IPM 80%DRPM MEPM 20% DRPM DHP-I IPM MEPM DRPM MEPM (2.6.4.5.4 ) 2) 4.2.2.4-Report 05 P450 (CYP) DRPM in vitro DRPM 0.3300 µm CYP1A22A62B62C82C92C192D62E13A4/5 4A11 CYP DRPM 30 DRPM CYP (2.6.4.5.5 ) DRPM 25500 mg ( 12525050000 mg ) 1 2 6 ( 500 mg 00 mg) 13 1 3 ( 500 mg) 2 3 2
() () () () 3 () () () () () () 2.7.2.2 2.7.2.2.1 2.7.2.2.1.1 2.7.2.2.1.1.1 5.3.3-Report 02 DRPM 12525050000 mg 30 DRPM 2.7.2-1 2.7.2-2 2.7.2-1 (Cmax) 12 (AUC) 2-β (t 1/2 (β)) 24 2.7.2-2 Cmax AUC 2.7.2-3 70 (µg/ml) 60 50 40 30 20 00mg 500mg 250mg 125mg 0 2 4 6 8 時間 (hr) ( 平均値 ± 標準偏差,n=6) 2.7.2-1DRPM (Bioassay )
4000 0 尿中濃度 (µg/ml) 3000 2000 00 125mg 250mg 500mg 00mg 80 60 40 20 累積尿中排泄率 (%) 0 0-2 2-4 4-6 6-8 8 - - 12 12-24 時間 (hr) ( 平均値,n=6) 0 2.7.2-2 DRPM (Bioassay ) 2.7.2-1 DRPM (Bioassay ) (mg) 0-2 hr 2-4 hr 4-6 hr 6-8 hr 8- hr -12 hr 12-24 hr 0-24 hr 125 (µg/ml) 403 ± 173 111 ± 13 35.4 ± 9.1 5.91 ± 3.91 1.52 ± 0.86 0.71 ± 0.26 < 0.3 (%) 64.7 ± 4.5 7.6 ± 1.5 3.4 ± 1.7 0.7 ± 0.3 0.2 ± 0.1 0.1 ± 0.0 0.0 76.7 ± 3.5 250 (µg/ml) 81 ± 667 242 ± 72 65.3 ± 20.0 14.3 ± 11.9 3.56 ± 2.06 1.80 ± 0.24 < 0.3 (%) 59.7 ± 2.0.3 ± 2.3 3.1 ± 0.9 0.7 ± 0.3 0.4 ± 0.1 0.1 ± 0.0 0.0 74.5 ± 4.3 500 (µg/ml) 1698 ± 814 457 ± 146 164 ± 48 31.3 ±.1 7.92 ± 2.55 2.60 ± 0.72 < 0.3 (%) 62.3 ± 4.7 8.9 ± 0.4 2.3 ± 0.2 0.7 ± 0.1 0.2 ± 0.0 0.1 ± 0.0 0.0 74.5 ± 4.9 00 (µg/ml) 3035 ± 2058 722 ± 205 228 ± 93 58.9 ± 28.1 20.6 ± 5.9 7.37 ± 2.91 1.40 ± 0.54 (%) 60.4 ± 4.5 9.8 ± 0.9 3.4 ± 0.5 0.8 ± 0.2 0.3 ± 0.1 0.1 ± 0.0 0.1 ± 0.0 74.9 ± 4.5 (±n=6)
2.7.2-2 DRPM (Bioassay ) (mg) Cmax (µg/ml) AUC (µghr/ml) t 1/2 (β) (hr) 125 8.09±1.05 8.71±1.34 0.85±0.07 76.7±3.5 250 18.1±1.9 20.26±3.48 0.90±0.08 74.5±4.3 500 33.1±4.8 34.38±2.23 0.86±0.04 74.5±4.9 00 63.0±5.1 75.52±5.89 0.98±0.09 74.9±4.5 n=6auc 12 24 (%) 80 0 Cmax (µg/ml) 60 40 20 AUC (µg hr/ml) 80 60 40 20 0 250 500 750 00 0 250 500 750 00 投与量 (mg) 投与量 (mg) 2.7.2-3 Cmax () AUC () Cmax AUC 125 mg 00 mg ( 95% Cmax: -1.054.24AUC: -3.382.34)t 1/2 (β) Tukey 125 mg 00 mg (p=0.016) 500 mg 00 mg (p=0.036) 0.850.98 24 75% 125 mg 00 mg 75%DRPM DRPM-DC HPLC Cmax 4 AUC 24 2.7.2-3 HPLC DRPM
2.7.2-4 2.7.2-3 DRPM-DC (HPLC ) (mg) Cmax (µg/ml) AUC (µghr/ml) 125 0.242±0.023 0.116±0.079 12.7±1.3 250 0.479±0.064 0.816±0.149 12.1±2.1 500 0.932±0.137 2.163±0.255 15.5±1.7 00 2.437±0.502 5.181±0.550 17.2±2.4 n=6auc 4 24 (%) 2.7.2-4 DRPM (HPLC ) (mg) Cmax (µg/ml) AUC (µghr/ml) 125 8.33±0.87 8.96±1.38 76.9±4.1 250 16.1±1.5 18.71±2.15 75.4±1.0 500 30.7±5.0 32.36±2.57 76.1±2.3 00 60.4±4.2 70.97±5.44 73.3±3.4 n=6auc 12 24 (%) DRPM-DC AUC AUC 250 mg 4%500 mg 6%00 mg 7% 125 mg DRPM-DC DRPM-DC Cmax Cmax 250 mg 3% 500 mg 3% 00 mg 4%DRPM DRPM-DC 24 90%DRPM DRPM-DC 0.959 (DRPM-DCDRPM ) ( 5.3.3-Report 01) DRPM 2550125250500 mg ( n=2) 60 Cmax AUC 2- t 1/2 (β) 1 70%
2.7.2.2.1.1.2 6 (Bioassay ) 5.3.3-Report 0304 DRPM 500 mg 00 mg 1 2 6 (6 1 11 )30 2.7.2-4 Cmax 12 AUC 2- t 1/2 (β) 12 t 2.7.2-5 (µg/ml) 血漿中濃度 0 80 60 40 20 (500mg) 最終回投与 (500mg) 初回投与 (00mg) 最終回投与 (00mg) 0 2 4 6 8 12 時間 (hr) ( 平均値 ± 標準偏差,n=6) 2.7.2-4 DRPM 2.7.2-5 DRPM (mg) Cmax (µg/ml) AUC (µghr/ml) t 1/2 (β) (hr) 500 () 35.0±5.0 40.19±6.04 0.99±0.06 73.3±6.1 500 () 32.0±2.0 35.20±2.88 1.06±0.07 79.1±2.9 p=0.1285 p=0.0251* p=0.0141* p=0.0771 00 () 67.7±11.1 74.38±6.37 1.11±0.13 72.1±4.3 00 () 74.6±9.3 79.46±5.60 0.94±0.08 74.2±2.1 p=0.0514 p=0.0602 p=0.04* p=0.2141 n=6auc 12 12 p*p<0.05 (%)
Cmax 500 mg00 mg AUC 500 mg t 1/2 (β) 500 mg00 mg t 1/2 (β) 1 500 mg00 mg 500 mg00 mg 12 70% 500 mg00 mg 2- () 2.7.2-5 2.7.2-6 50 (µg/ml) 血漿中濃度 40 30 20 0 24 48 72 96 120 時間 (hr) ( 平均値 ± 標準偏差,n=6) 2.7.2-5 DRPM ( 1 500 mg)
0 血漿中濃度 (µg/ml) 80 60 40 20 0 0 24 48 72 96 120 時間 (hr) ( 平均値 ± 標準偏差,n=6) 2.7.2-6 DRPM ( 1 00 mg) 2.7.2-5 2.7.2-6 DRPM 2.7.2.2.1.1.3 1 3 (Bioassay ) 5.3.3-Report 05 DRPM 500 mg 1 3 (6 3 30 ) () () 2.7.2-7 Cmax 6 AUC 2- t 1/2 (β) 6 t 2.7.2-6
40 朝投与夕投与 (µg/ml) 血漿中濃度 30 20 0 1 2 3 4 5 6 時間 (hr) ( 平均値 ± 標準偏差,n=6) 2.7.2-71 3 DRPM ( 1 500 mg) 2.7.2-61 3 DRPM ( 1 500 mg) Cmax (µg/ml) AUC (µghr/ml) t 1/2 (β) (hr) 28.6±3.8 32.46±6.27 1.07±0.16 70.2±4.8 27.4±3.8 32.00±5.21 0.96±0.12 69.0±9.7 p=0.151 p=0.665 p=0.006* p=0.797 n=6auc 6 6 p*p<0.05 (%) t 1/2 (β) % CmaxAUC 6 70% 2.7.2-8 2- ()
50 (µg/ml) 血漿中濃度 40 30 20 0 4 8 12 16 20 24 時間 (hr) ( 平均値 ± 標準偏差,n=6) 2.7.2-8 1 3 ( 1 500 mg) 2.7.2-8 1 3 DRPM 2.7.2.2.1.2 5.3.3-Report 020304 ex vivo 2.7.2-7 2.7.2-7DRPM (HPLC ) (%) (mg) 0.5 2 125.30.6-250 5.840.92 5.651.90 500 7.890.86 7.920.39 00 8.760.54 7.281.04 n=6-:
2.52.8% 500 mg 1 2 6 ex vivo 2.7.2-8 t 2.7.2-8DRPM (500 mg HPLC ) (%) 0.5 2 8.332.71 9.792.03 8.642.26 8.991.54 p=0.6233 p=0.3150 n=6p ( 0.5 ) 2 3.5512.7% 9% 00 mg 1 2 6 ex vivo 2.7.2-9 t 2.7.2-9DRPM (00 mg Bioassay ) (%) 0.5 2 5.41.3 6.23.3 15.24.3 5.83.2 p=0.0040* p=0.8935 n=6p*p < 0.05 ( 0.5 ) 2 94.6% 84.8% %
1.523.8% 2.7.2.2.2 (Bioassay ) 5.3.3-Report 14 DRPM 250 mg (6669 ) 30 () 250 mg 2.7.2-9 Cmax 24 AUC 2- t 1/2 (β) 24 2.7.2-2.7.2- t 25 (µg/ml) 血漿中濃度 20 15 5 非高齢者高齢者 0 2 4 6 8 12 時間 (hr) ( 平均値 ± 標準偏差,n=6) 2.7.2-9 DRPM ( 250 mg)
2.7.2- ( 250 mg) Cmax (µg/ml) AUC (µghr/ml) t 1/2 (β) (hr) 17.5±2.5 25.72±4.62 1.43±0.19 78.2±9.7 18.1±1.9 20.26±3.48 0.90±0.08 74.5±4.3 p=0.648 p=0.0434* p=0.0004* p=0.421 n=6 AUC ( 24 12 ) 24 p*p<0.05 (%) Cmax AUC t 1/2 (β) 2.7.2-9 65.289.9% DRPM 2.7.2.2.3 (Bioassay HPLC ) 5.3.3-Report 15 DRPM 250 mg 30 250 mg 2.7.2-2.7.2-11 (CLcr) Group 1 (CLcr 30 ml/min )Group 2 (CLcr 30 ml/min 50 ml/min )Group 3 (CLcr 50 ml/min 70 ml/min ) 3 Cmax 24 AUC 2- t 1/2 (β) 24 2.7.2-11 2.7.2-11 t
(µg/ml) 30 20 Group 1 Group 2 Group 3 健康成人男性 (µg/ml) 0 Group 1 Group 2 Group 3 健康成人男性 血漿中濃度 血漿中濃度 1 0.1 0 6 12 18 24 時間 (hr) 0.01 0 6 12 18 24 時間 (hr) ( 平均値 ± 標準偏差,Group 1: n=2group 2: n=6group 3: n=4: n=6) 2.7.2- DRPM ( 250 mg) 0 累積尿中排泄率 (%) 80 60 40 20 健康成人男性 Group 3 Group 2 Group 1 0 6 12 18 24 時間 (hr) ( 平均値 ± 標準偏差,Group 1: n=2group 2: n=6group 3: n=4: n=6) 2.7.2-11 ( 250 mg)
2.7.2-11 ( 250 mg) (n=12) Cmax (µg/ml) 20.9±3.9 (13.5-29.0) AUC (µghr/ml) 48.34±12.67 (29.89-66.75) t 1/2 (β) (hr) 2.33±0.65 (1.58-3.71) (%) 64.6±11.5 (47.0-85.7) Group 1 (n=2) 17.9 64.31 3.56 58.2 Group 2 (n=6) 21.2±4.6 48.21±13.41 2.16±0.32 67.3±8.2 Group 3 (n=4) 21.9±1.3 40.55±5.89 1.98±0.38 63.9±17.6 (n=6) 18.1±1.9 (15.9-20.9) 20.26±3.48 (17.61-27.14) 0.90±0.08 (0.81-0.99) 74.5±4.3 (69.4-80.6) p=0.1234 p=0.0000* p=0.0000* p=0.0191* ( - ) 24 AUC ( 24 12 ) p ( (n=12) (n=6) )*p<0.05 2.7.2- CLcr 2.7.2-11 Cmax AUC t 1/2 (β) AUC 1.53.3 t 1/2 (β) 1.84.1 CmaxAUCt 1/2 (β) CLcr AUC t 1/2 (β) CLcr 2.7.2-12 2.7.2-12
80 5 AUC (µg hr/ml) 70 60 50 40 30 20 t 1/2 (β) (hr) 4 3 2 1 0 20 40 60 80 0 20 40 60 80 CLcr (ml/min) CLcr (ml/min) 2.7.2-12 AUC () t 1/2 (β) () CLcr Cmax CLcr AUC t 1/2 (β) CLcr (AUC: p=0.0262t 1/2 (β): p=0.0015) CLcr DRPM 2.7.2.2.4 (Bioassay ) 5.3.3-Report 16 DRPM 250 mg 30 2.7.2-13 Cmax 12 AUC 2- t 1/2 (β) 12 2.7.2-12 2.7.2-12
20 (µg/ml) 15 5 0 2 4 6 8 12 (hr) ( 平均値 ± 標準偏差,n=8) 2.7.2-13 DRPM ( 250 mg) 2.7.2-12 ( 250 mg) Cmax (µg/ml) AUC (µghr/ml) t 1/2 (β) (hr) 18.1±1.4 29.86±2. 1.44±0.11 65.8±8.6 DRPM 15.7±2.8 17.±2.56 0.94±0.16 80.4±8.0 p=0.0091* p=0.0000* p=0.0002* p=0.0017* n=8auc 12 12 p*p<0.05 (%) CmaxAUCt 1/2 (β) DRPM DRPM DRPM AUC 1.75 t 1/2 (β) 1.53 0.82 (5.52±0.71 L/hr) DRPM (12.00±2.21 L/hr) 50% DRPM DRPM
2.7.2.2.5 2.7.2.2.5.1 (Bioassay HPLC ) 5.3.3-Report DRPM 250 mg 30 3070 2.293.15 µg/g (7 ) 6.48 18.1 µg/ml ( ) 15.736.9% (7 ) 2.7.2-14 (µg/ml) or (µg/g) 0 1 0 30 60 90 (min) 2.7.2-14 (250 mg30 ) 2.7.2.2.5.2 (Bioassay ) 5.3.3-Report 08 DRPM 250 mg 30 45121 2.229.45 µg/ml (7 ) 58129 0.767.88 µg/g (9 ) 65143 0.253.42 µg/g (8 ) 67154 0.342.68 µg/g (4 ) 3.3315.6 µg/ml (9 ) 26.5% (1 ) 43.671.2% (5 ) 5.139.3% (5 ) 5.416.0% (3 ) 1 2.7.2-15
(µg/ml) or (µg/g) 0 1 0.1 0 60 120 180 (min) 2.7.2-15 (250 mg30 ) 2.7.2.2.5.3 (Bioassay ) 5.3.5-Report 05 DRPM 250 mg 60 0.140.40 µg/g (5 ) 7.9515.0 µg/ml (5 ) ( ) 1.14.9% (5 ) 2.7.2-16 (µg/ml) or (µg/g) 濃度 0 1 0.1 血清喀痰 0.01 0 2 4 6 8 時間 (hr) ( 平均値 ± 標準偏差,n=5) 2.7.2-16 (250 mg60 )
2.7.2.2.5.4 (Bioassay ) 5.3.3-Report 06 DRPM 250 mg 30 60 60160 0.76.3 µg/g (8 ) 2.42.2 µg/ml (8 ) 1 425.6% 15.072.4% (7 ) DRPM 500 mg 30 60 90130 1.044.51 µg/g (5 ) 5.5515.6 µg/ml (5 ) 18.749.9% (5 ) 2.7.2-17 0 (µg/ml) or (µg/g) 1 0.1 0 60 120 180 (min) 2.7.2-17 2.7.2.2.5.5 (Bioassay ) 5.3.5-Report 05 DRPM 250 mg 30 20215 1 6 0.2415.4 µg/ml (9 ) 0.231.87 µg/g (4 ) () 0.1846.6 µg/ml ( ) () 3.1611.1% (9 ) () 3.244.4% (4 ) () 2.7.2-18
(µg/ml) or (µg/g) 0 1 0.1 0 60 120 180 240 (min) 2.7.2-18 () (250 mg30 ) 2.7.2.2.5.6 (HPLC ) 5.3.3-Report 13 DRPM 250 mg 30 2.365.17 µg/ml (5 ) ( Cmax).524.4 µg/ml (5 ) ( ) 14.447.3% (5 ) 2.7.2-19 0 (µg/ml) 1 0.1 0 2 4 6 (hr) ( 平均値 ± 標準偏差,n=5) 2.7.2-19 (250 mg30 )
2.7.2.2.5.7 (Bioassay ) 5.3.5-Report 055.3.3-Report 07 DRPM 250 mg 30 40360 20 ( 16 12 ) 3 3 3 2 4 1 0.369.04 µg/g (17 ) 0.278.94 µg/g (17 ) 0.349.89 µg/g (17 ) 0.29 6.66 µg/g (14 ) 0.50.6 µg/g (16 ) 0.204.83 µg/g (11 ) () 0.1121.5 µg/ml (20 ) () 12.085.9% (17 ) 6.196.9% (17 ) 9.7122.8% (17 ).386.0% (14 ) 14.25.9% (16 ) 12.88.4% (11 ) () 1 µg/ml 0.21.3 µg/ml (20 ) () 72.1154.9% (20 ) 2.7.2-20 0 0 (µg/ml) 1 (µg/ml) 1 0.1 0 60 120 180 240 300 360 (min) 0.1 0 60 120 180 240 300 360 (min) 2.7.2-20 (250 mg30 )
0 0 (µg/g) 1 (µg/g) 1 0.1 0 60 120 180 240 300 360 (min) 0.1 0 60 120 180 240 300 360 (min) 0 0 (µg/g) 1 (µg/g) 1 0.1 0 60 120 180 240 300 360 (min) 0.1 0 60 120 180 240 300 360 (min) 0 0 (µg/g) 1 (µg/g) 1 0.1 0 60 120 180 240 300 360 (min) 0.1 0 60 120 180 240 300 360 (min) 2.7.2-20 (250 mg30 ) () DRPM 250 mg (6 ) 500 mg (4 ) 30 ( 2 ) 3.159.82 µg/ml9.5313.9 µg/ml (Cmax) 14.030.8 µg/ml26.2 50.7 µg/ml () 22.5
46.7%25.444.7% 2.7.2-21 (µg/ml) 0 1 0.1 0 1 2 3 4 5 6 7 (hr) ( 平均値 ± 標準偏差 ) 2.7.2-21 ( 2 ) 2 DRPM 250 mg 30 (3 ) 8.6352.47.90 µg/ml 1 (Cmax) 14.112.812.0 µg/ml 61.2409.465.8% 2 2.7.2-22 0 (µg/ml) 1 0.1 0 1 2 3 4 5 6 7 (hr) 2.7.2-22 ( 2 250 mg30 )
2.7.2.2.5.8 (Bioassay ) 5.3.3-Report 11 DRPM 250 mg 30 70115 0.160.87 µg/ml (5 ) 6.86 12.9 µg/ml (5 ) 2.3.5% (4 ) 2.7.2-23 0 (µg/ml) 1 0.1 0 30 60 90 120 (min) 2.7.2-23 (250 mg30 ) 2.7.2.2.5.9 (Bioassay HPLC ) 5.3.3-Report 095.3.5-Report 11 DRPM 250 mg 30 6090 0.266.09 µg/g (5) 5.05 14.2 µg/ml (6 ) 2.742.9% (5 ) 60155 0.272.58 µg/g (6 ) 1.957.77 µg/ml (6 ) 6.133.2% (6 ) 2.7.2-24
0 0 (µg/ml) or (µg/g) (µg/ml) or (µg/g) 1 1 0.1 0 60 120 180 0.1 0 60 120 180 (min) (min) 2.7.2-24 () () (250 mg30 ) DRPM 250 mg 30 60 75170 0.320.72 µg/ml (4 ) 1.9716.1 µg/ml (4 ) 4.218.8% (4 ) DRPM 500 mg 40 60 7087 0.827.44 µg/ml (3 ) 13.7 16.4 µg/ml (3 ) 5.048.6% (3 ) 2.7.2-25 0 (µg/ml) 1 0.1 0 60 120 180 (min) 2.7.2-25 2.7.2.2.5. (Bioassay ) 5.3.3-Report 12 DRPM 250 mg 30
705 0.342.19 µg/g (7 ) 2.555.60 µg/ml (6 ) 14.347.9% (6 ) 6075 0.361. µg/g (3 ) 4.085.15 µg/ml (3 ) 7.721.4% (3 ) 2.7.2-26 (µg/ml) or (µg/g) 1 (µg/ml) or (µg/g) 1 0.1 0 30 60 90 120 (min) 0.1 0 30 60 90 120 (min) 2.7.2-26 () () (250 mg30 ) 2.7.2.2.6 (Bioassay HPLC ) 5.3.3-Report 0206070809111213 5.3.5-Report 0511 2 3 DRPM 250 mg ( ) 500 mg () 30 (Bioassay ) 2.7.2-27 (250 mg) 2.7.2-28 (500 mg) 0 血漿 ( 血清 ) 中濃度 (µg/ml) 30 20 患者健康成人男性 血漿 ( 血清 ) 中濃度 (µg/ml) 1 0.1 患者健康成人男性 0 2 4 6 8 時間 (hr) 0.01 0 2 4 6 8 時間 (hr) 2.7.2-27 DRPM 250 mg (30 )
血漿中濃度 (µg/ml) 60 50 40 30 20 患者健康成人男性 血漿中濃度 (µg/ml) 0 1 0.1 患者健康成人男性 0 2 4 6 8 時間 (hr) 0.01 0 2 4 6 8 時間 (hr) 2.7.2-28 DRPM 500 mg (30 ) 2.7.2-27 2.7.2-28 1.19±0.34 hr ( 250 mghplc n=5) 2- t 1/2 (β) 0.88±0.16 hr ( 2 250 mgbioassay n=6)0.87±0.14 hr ( 2 250 mgbioassay n=3)0.89±0.22 hr ( 2 500 mgbioassay n=4) 1 0.90±0.08 hr ( 250 mgbioassay n=6)0.86±0.04 hr ( 500 mgbioassay n=6) Cmax 250 mg (30 ).530.8 µg/ml ( n=5 2 n=6 2 n=3) 500 mg (30 ) 26.250.7 µg/ml ( 2 n=4) 15.920.9 µg/ml ( 250 mgbioassay n=6)25.738.2 µg/ml ( 500 mgbioassay n=6) 2.7.2-13 2.7.2-16
2.7.2-13 / () ID/ / () R1411 () ( 2)/ ( 2) ( 2)/ ( 2) ( 2)/ ( 2) ( 2)/ ( 2) ( 2)/ ( 2) R1412 () ( 6)/ ( 6) ( 6)/ ( 6) ( 6)/ ( 6) ( 6)/ ( 6) HV: PT: HV/PT ( ) HV (37-40) HV (26-41) HV (25-35) HV (24-49) HV (28-30) HV (33.7, 26-45) HV (30.5, 27-43) HV (31.2, 28-41) HV (32.0, 26-42) DRPM 25 mg 60 DRPM 50 mg 60 DRPM 125 mg 60 DRPM 250 mg 60 DRPM 500 mg 60 DRPM 125 mg 30 DRPM 250 mg 30 DRPM 500 mg 30 DRPM 00 mg 30 () () Cmax (µg/ml) 1.22 1.03 AUC (µg hr/ml) 1.55 1.47 t 1/2 (β) (hr) - 0.93 (%) 79.3 63.5 2.48 2.44 3.42 3.52 0.98 1.17 62.7 65.4 5.34 7.78 8.16 11.61 0.90 0.86 62.9 62.4 13.7 13.5 20.09 18.38 1.16 0.93 69.3 65.5 22.3 23.1 30.74 35.31 0.83 1.31 71.9 68.7 8.09 (1.05) 8.71 (1.34) 0.85 (0.07) 76.7 (3.5) 18.1 (1.9) 20.26 (3.48) 0.90 (0.08) 74.5 (4.3) 33.1 (4.8) 34.38 (2.23) 0.86 (0.04) 74.5 (4.9) 63.0 (5.1) 75.52 (5.89) 0.98 (0.09) 74.9 (4.5) 5.3.3- Report01 5.3.3- Report02
2.7.2-13 () / () R1414 () ID/ / () ( 6)/ ( 6) HV/PT ( ) HV (31.7, 24-38) () DRPM 500 mg 1 2 6 30 () DRPM 500 mg 1 2 6 30 () Cmax (µg/ml) 35.0 (5.0) 32.0 (2.0) AUC (µg hr/ml) 40.19 (6.04) 35.20 (2.88) t 1/2 (β) (hr) 0.99 (0.06) 1.06 (0.07) (%) ( 2)/( 2) HV (26-44) - - - - 73.3 (6.1) 79.1 (2.9) R1417 () ( 6)/ ( 6) HV (29.7, 25-41) DRPM 00 mg 1 2 6 30 () DRPM 00 mg 1 2 6 30 () 67.7 (11.1) 74.6 (9.3) 74.38 (6.37) 79.46 (5.60) ( 2)/( 2) HV (30-40) - - - - 1.11 (0.13) 0.94 (0.08) 72.1 (4.3) 74.2 (2.1) R1419 () HV: PT: (3 /) ( 6)/ ( 6) HV (22.5, 21-25) DRPM 500 mg 1 3 1 30 () DRPM 500 mg 1 3 1 30 () 28.6 (3.8) 27.4 (3.8) 32.46 (6.27) 32.00 (5.21) 1.07 (0.16) 0.96 (0.12) 70.2 (4.8) 69.0 (9.7) 5.3.3- Report03 5.3.3- Report04 5.3.3- Report05
2.7.2-14 / () R142A () ID/ R142G () R142H () HV: PT: / () ( 2/ 3)/ ( 2/ 3) ( 2)/ ( 0) ( 4/ 6)/ ( 4/ 6) ( 16)/ ( 16) ( 4)/ ( 4) ( 9)/ ( 8) ( 5)/ ( 5) ( 13)/ ( 13) HV/PT ( ) PT (58.8, 47-66) PT (74-74) PT (49.1, 24-61) PT (48.3, 35-69) PT (54.3, 35-67) PT (71.4, 64-75) PT (67.4, 61-72) PT (52.0, 37-69) DRPM 250 mg 60 DRPM 500 mg 30 DRPM 250 mg 30 DRPM 250 mg 30 DRPM 500 mg 30 DRPM 250 mg 30 60 DRPM 500 mg 30 60 DRPM 250 mg 30 0.140.40 µg/g <0.11.87 µg/g <0.1615.4 µg/ml <0.2.6 µg/g 0.8418.7 µg/ml 3.159.82 µg/ml 9.5313.9 µg/ml 0.76.3 µg/g 1.044.51 µg/g <0.25.12 µg/g 0.21.3 µg/ml 7.9052.4 µg/ml 5.3.5- Report05 5.3.3- Report06 5.3.3- Report07
2.7.2-14 () / () R143P () ID/ R143K () R143Q () R143S () R143T () R143V () R143W () HV: PT: / () ( 4/ 7)/ ( 4/ 6) HV/PT ( ) PT (64.7, 35-79) ( 1/ 3)/ ( 1/ 3) PT (54.5, 23-67) ( 3)/( 3) PT (57.3, 41-70) ( 7/ 5)/ ( 7/ 5) PT (42.1,21-64) ( 8/ 2)/ ( 8/ 2) PT (35.9, 22-70) ( 2/ 3)/ ( 2/ 3) PT (67.4, 52-78) ( 4/ 6)/ ( 4/ 6) PT (29.7,20-54) ( 4/ 1)/ ( 4/ 1) PT (59.4, 38-79) DRPM 250 mg 30 DRPM 250 mg 30 60 DRPM 500 mg 40 60 DRPM 250 mg 30 DRPM 250 mg 30 DRPM 250 mg 30 DRPM 250 mg 30 DRPM 250 mg 30 <0.207.88 µg/g 2.229.45 µg/ml 0.253.42 µg/g 0.342.68 µg/g 0.320.72 µg/ml 0.827.44 µg/ml 0.272.58 µg/g 0.266.09 µg/g 5.3.3- Report08 5.3.5- Report11 5.3.3- Report09 2.293.15 µg/g 5.3.3- Report 0.160.87 µg/ml 5.3.3- Report11 0.342.19 µg/g 0.361. µg/g 5.3.3- Report12 2.365.17 µg/ml 5.3.3- Report13
2.7.2-15 / () R1415 () R1418 () ID/ / () ( 6)/ ( 6) ( / 2)/ ( / 2) HV/PT ( ) HV (67.2, 66-69) PT (68.4, 43-79) () DRPM 250 mg 30 DRPM 250 mg 30 Cmax (µg/ml) 17.5 (2.5) 20.9 (3.9) AUC (µg hr/ml) 25.72 (4.62) 48.34 (12.67) t 1/2 (β) (hr) 1.43 (0.19) 2.33 (0.65) (%) 78.2 (9.7) 64.6 (11.5) HV: PT: 2.7.2-16 / () R1416 () ID/ HV: PT: / () ( 8)/ ( 8) HV/PT ( ) HV (28.4, 20-38) () Cmax (µg/ml) DRPM 250 mg 30 DRPM 250 mg 30 1g 0.5g - 15.7 (2.8) 18.1 (1.4) AUC (µg hr/ml) 17. (2.56) 29.86 (2.) t 1/2 (β) (hr) 0.94 (0.16) 1.44 (0.11) (%) 80.4 (8.0) 65.8 (8.6) 5.3.3- Report14 5.3.3- Report15 5.3.3- Report16
2.7.2.3 500 mg 1 2 Cmax AUC 35.0±5.0 µg/ml40.19±6.04 µghr/ml (Cmax: 33.1±4.8 µg/mlauc: 34.38±2.23 µghr/ml) AUC Cmax 00 mg 1 2 Cmax AUC 67.7±11.1 µg/ml 74.38±6.37 µghr/ml (Cmax: 63.0±5.1 µg/mlauc: 75.52±5.89 µg hr/ml ) 500 mg 1 3 Cmax AUC 28.6±3.8 µg/ml32.46±6.27 µghr/ml (Cmax: 33.1±4.8 µg/mlauc: 34.38±2.23 µghr/ml ) Cmax AUC t 1/2 (β) 1 CmaxAUCt 1/2 (β) 1 1 2 6 ( 500 mg) DRPM Bioassay HPLC 2 2.7.2.4 2.7.2.5 2.7.2-17 in vitro DHP-I DHP-I COS1 E. coli 7347 band-culture in vitro 0 µg/ml 0.3300 µm DRPM DHP-I IPM MEPM CYP1A22A6, 2B6, 2C8, 2C9, 2C19, 2D62E1, 3A4/5 4A11 4.2.2.4- Report 04 4.2.2.4- Report 05
2.7.3 2.7.3.1 1) 250 mg 2 / 95% 500 mg 2 / MEPM MEPM () % MEPM 0.025 4 13 2.7.3.2 2.7.3-1 1)
2.7.3-1 R142R 30 R142U 32 R143R 56 R143U 42 19 19 83/80 19 19 83/90 20 20 219/220 20 20 205/180 250 mg 1 2 500 mg 1 2 250 mg 1 2 500 mg 1 2 250 mg 1 2 (MEPM)500 mg 1 2 250 mg 1 2 (MEPM)500 mg 1 2 44/36 39/34 43/38 40/32 112/96 7/97 97/76 8/79 () 14 45/25 67.5 (35-79) 5 41/29 67.0 (20-79) 7 125/68 67.0 (20-79) 5 111/44 69.0 (23-79) ( ) UTI UTI
2.7.3-1 () R142A 41 R142C 55 19 19 7/160 19 19 114/200 125 mg1 2 250 mg1 2 250 mg1 3 500 mg1 2 250 mg1 2 250 mg1 3 500 mg1 2 R142D 27 19 19 45/90 250 mg1 2 250 mg1 3 500 mg1 2 R142E 25 19 19 51/60 250 mg1 2 250 mg1 3 500 mg1 2 7/75 3 14 114/5 3 14 45/32 3 14 51/48 3 14 () 39/36 62.0 (20-69) 72/33 67.0 (23-79) 25/7 67.5 (23-79) 29/19 62.5 (23-77) ( )
2.7.3-1 () R142F 19 R143J 8 R143K 9 R143L 12 R143M 8 R143N 4 19 19 59/60 20 20 8/20 20 20 15/15 20 20 22/25 20 20 15/15 20 20 24/24 250 mg1 2 250 mg1 3 500 mg1 2 250 mg1 2 500 mg1 2 250 mg1 2 250 mg1 3 500 mg1 2 250 mg1 2 500 mg1 2 250 mg1 2 250 mg1 3 500 mg1 2 250 mg1 2 250 mg1 3 500 mg1 2 () 59/54 3 14 0/54 39.0 (23-78) 8/6 14 5/1 55.0 (28-74) 15/12 7 6/6 32.5 (23-70) 22/19 7 12/7 51.0 (25-71) 15/15 14 9/6 61.0 (23-77) 24/24 7 17/7 50.0 (21-77) ( ) ()
2.7.3-1 () R143E 7 R143A 13 20 20 15/20 20 20 11/15 250 mg1 2 250 mg1 3 500 mg1 2 500 mg1 2 500 mg1 3 R1431 14 20 20 18/20 500 mg1 2 500 mg1 3 00 mg1 2 () 15/15 14 9/6 58.0 (26-79) 11/11 14 ( 28 ) 5/6 67.0 (59-79) 18/15 14 /5 79.0 (44-95) ( )
2.7.3.2.1 5.3.5-Report02 2 2 2 4 (125 mg 2 / 250 mg 2 /250 mg 3 /500 mg 2 /) 90% (93.5%43/46 ) 250 mg 2 / 2 250 mg 2 / (0.0%7/7 ) 500 mg 2 / 2.7.3-2 () R142R R142U ( ) 250 mg 1 2 500 mg 1 2 250 mg 1 2 500 mg 1 2 95% 44/36 0.0% (36/36) 90.30.0% 39/34 88.2% (30/34) 72.596.7% 43/38 97.4% (37/38) 86.299.9% 40/32 96.9% (31/32) 83.899.9% 2.7.3.2.1.1 5.3.5-Report01 (L ) 250 mg 2 / (H ) 2 ( ) ( ) CRP () 2 79 79
() L ( ) 95% Clopper-Pearson 2 14 L H () 3 ()7 () [ ()] L 85% 40 85% 85% H L 40 85% 95% (70.294.3%) 83 L 0.0% (36/36 ) 95% 90.30.0% 85% 95% (70.294.3%) 95% 95% 1 250 1 2 1 H 88.2% (30/34 ) 95% 72.596.7% L H (p=0.0506) 4 H H L 4 H 3 3 7 2 (p 0.19380.65951.0000) L H 85% L 0.0%H DRPM 1 250 mg 1 2
2.7.3.2.1.2 5.3.5-Report02 (L ) 250 mg 2 / (H ) UTI ( 3 ) 2) () 2 79 79 UTI L () 95% Clopper-Pearson UTI UTI ( 3 ) 2) 5 L H () [ ()] [ ()] [ ()] () L 90% 45 90% 90% H L 45 90% 95% (78.698.3%) 83 L 97.4% (37/38 ) 95% 86.2 99.9% 90% 95% (78.698.3%) 95% 95% 1 250 mg 1 2 1 H UTI 96.9% (31/32 ) 95% 83.899.9%UTI L H (p=near1) L 60.5% (23/38 )H 75.0% (24/32 ) 2 (p=0.2153) L 94.7% (36/38 )H 84.4% (27/32 ) 2 (p=0.2338)h L L 95.7% (45/47 )H 97.7% (42/43 ) 2 (p=near1)h 4
H L L 94.7% (36/38 )H 84.4% (27/32 ) 2 (p=0.2338)h L H L H 90% L 97.4%H DRPM 1 250 mg 1 2
2.7.3.2.2 5.3.5-Report0304 DRPM 250 mg 2 / DHP-I MEPM 2.7.3-3 () R143R 250 mg 1 2 (MEPM)500 mg 1 2 R143U 250 mg 1 2 (MEPM)500 mg 1 2 a) p (%) 95% 112/96 92.7% (89/96) 85.697.0% 7/97 90.7% (88/97) 83.195.7% 97/76 96.1% (73/76) 88.999.2% 8/79 88.6% (70/79) 79.594.7% p a) ( 95% ) 0.0033 (-5.89.8%) 0.0003 (-0.815.7%) 2.7.3.2.2.1 5.3.5-Report03 MEPM () MEPM 1) () DRPM 250 mg 2 /MEPM 500 mg 2 / 250 mg 2 /500 mg 2 / 3) ( ) 1) 2 79
500 mg 2 / 500 mg 2 / % DRPM MEPM 7 () [ ()] DRPM MEPM Fisher's exact test (2 tailed) DRPM 90%MEPM 87%DRPM MEPM ( ) DRPM MEPM () % 2.5% 80% 4) 1 95 1 220 219 DRPM 92.7% (89/96 )MEPM 90.7% (88/97 ) DRPM MEPM (p=0.0033 95% -5.89.8%) DRPM 86.0% (37/43 )MEPM 95.8% (46/48 )2 (250 mg 2 /) MEPM (500 mg 2 /) 2.7.3.2.2.2 5.3.5-Report04 MEPM UTI () MEPM UTI ( 3 ) 2) DRPM 250 mg 2 /MEPM 500 mg 2 / UTI ( 3 ) 2) 1) 2
79 UTI %DRPM MEPM UTI UTI ( 3 ) 2) 5 () [ ()] [ ()] [ ()] () DRPM MEPM DRPM 90%MEPM 85%DRPM MEPM ( ) DRPM MEPM () % 2.5% 80% 4) 1 77 90 180 205 DRPM 96.1% (73/76 )MEPM 88.6% (70/79 ) DRPM MEPM (p=0.0003 95% -0.815.7%) DRPM MEPM (250 mg 2 /) MEPM (500 mg 2 /)
2.7.3.2.3 ( ) 2 3 13 2.7.3-4 () 95% R142A 7/75 96.0% (72/75) 88.899.2% R142C 114/5 87.6% (92/5) 79.893.2% R142D () 45/32 84.4% (27/32) 67.294.7% R142E 51/48 89.6% (43/48) 77.396.5% R142F 59/54 88.9% (48/54) 77.495.8% R143J 8/6 0.0% (6/6) 54.10.0% R143K 15/12 91.7% (11/12) 61.599.8% R143L 22/19 0.0% (19/19) 82.40.0% R143M ( 15/15 0.0% (15/15) 78.20.0% ) R143N 24/24 0.0% (24/24) 85.80.0% R143E 15/15 0.0% (15/15) 78.20.0% R143A () 11/11 0.0% (11/11) 71.50.0% R1431 18/15 93.3% (14/15) 68.199.8% 5.3.5-Report05 2 () () 20 70 41 34 () 96.0% (72/75 ) 2 2
4 5.3.5-Report06 () ( ) ( ) 2 29 61 8 4 1 () 87.6% (92/5 ) 5.3.5-Report07 [ () ] () 11 6 5 () 84.4% (27/32 ) 5.3.5-Report08 () () () 22 6 5 4 4 7 () 89.6% (43/48 ) 5.3.5-Report09 ( ) () 9 () 18 14 3 () 88.9% (48/54 ) 3 2 8 5.3.5-Report ()
3 3 ( ) 0.0% (6/6 ) 5.3.5-Report11 () ( ) 6 6 ( ) 91.7% (11/12 ) 5.3.5-Report12 () 3 3 1 2 () 0.0% (19/19 ) 5.3.5-Report13 [ ()] 4 () 1 () 0.0% (15/15 ) 5.3.5-Report14 () 13 11 ( ) 0.0% (24/24 ) 5.3.5-Report15 () () 6 2 7 ( ) 0.0% (15/15 ) 5.3.5-Report16 () 3 9 2 ( ) 0.0% (11/11 )
5.3.5-Report17 1) 18 15 14
2.7.3.3 2.7.3.3.1 DRPM 2 17 2 2 13 878 743 2.5.4.1 2.7.3.3.2 95% 2.7.3-24 p 90% 2.7.3.3.3 2.7.3-5 90% 90%
2.7.3-5 () (%) (%) (%) (%) 86 83 96.5 124 117 94.4 238 217 91.2 448 417 93.1 54 51 94.4 48 45 93.8 193 180 93.3 295 276 93.6 20 30 3 3 4 4 45 44 97.8 52 51 98.1 30 40 4 4 9 9 0.0 39 37 94.9 52 50 96.2 40 50 12 12 0.0 4 4 50 46 92.0 66 62 93.9 50 60 18 17 94.4 32 29 90.6 72 67 93.1 122 113 92.6 60 70 45 45 0.0 53 50 94.3 123 112 91.1 221 207 93.7 70 80 58 53 91.4 70 66 94.3 95 85 89.5 223 204 91.5 80 - - - - - - 7 6 85.7 7 6 85.7 40 kg 17 16 94.1 13 76.9 26 21 80.8 56 47 83.9 40 kg 50 kg 32 31 96.9 41 40 97.6 111 2 91.9 184 173 94.0 50 kg 60 kg 45 43 95.6 54 50 92.6 135 127 94.1 234 220 94.0 60 kg 70 kg 31 31 0.0 32 32 0.0 93 84 90.3 156 147 94.2 70 kg 80 kg 5 5 14 14 0.0 31 29 93.5 50 48 96.0 80 kg 7 6 85.7 12 12 0.0 19 18 94.7 8 80.0 11 90.9 23 22 95.7 44 40 90.9 3 3 - - - 34 32 94.1 37 35 94.6 66 62 93.9 96 89 92.7 209 192 91.9 371 343 92.5 1 1 - - - 127 118 92.9 128 119 93.0 70 68 97.1 76 73 96.1 61 55 90.2 207 196 94.7 8 8 0.0 0.0 6 98 92.5 124 116 93.5 132 126 95.5 162 152 93.8 325 299 92.0 619 577 93.2 111 8 97.3 121 115 95.0 254 236 92.9 486 459 94.4 27 24 88.9 50 46 92.0 173 157 90.8 250 227 90.8 2 2 1 1 4 4 7 7 0.0 140 134 95.7 172 162 94.2 431 397 92.1 743 693 93.3-2.7.3-6 94.3% (66/70 33/35 66/70 ) 90%
2.7.3-6 () (%) (%) (%) - - - - - - 11 11 0.0 - - - - - - 11 11 0.0 - - - - - - 19 19 0.0 15 15 0.0 - - - - - - 4 4 - - - - - - 22 20 90.9 - - - - - - 22 20 90.9 - - - - - - 6 6 0.0 - - - - - - 3 3 - - - - - - 3 3 70 66 94.3 96 89 92.7 166 150 90.4 () - - - - - - 8 8 0.0 - - - 61 56 91.8 88 76 86.4 - - - 61 56 91.8 76 68 89.5 - - - - - - 12 8 66.7 70 66 94.3 35 33 94.3 70 66 94.3 18 18 0.0 5 5 18 18 0.0 - - - - - - 3 2 20 17 85.0 11 9 81.8 21 19 90.5 11 90.9 6 6 0.0 6 6 0.0 3 3 1 1 5 5 5 5 1 1 4 4 13 13 0.0 11 11 0.0 13 12 92.3 70 68 97.1 76 73 96.1 66 60 90.9 47 46 97.9 39 37 94.9 29 27 93.1 23 22 95.7 37 36 97.3 26 25 96.2 () - - - - - - 6 3 50.0 () - - - - - - 5 5 - - - - - - 35 33 94.3 - - - - - - 21 20 95.2 - - - - - - 14 13 92.9 - - - - - - 24 22 91.7 - - - - - - 13 13 0.0 - - - - - - 5 5 - - - - - - 6 4 66.7 - - - - - - 37 32 86.5 - - - - - - 37 32 86.5 - - - - - - 9 9 0.0 - - - - - - 9 90.0 - - - - - - 18 14 77.8 - - - - - - 15 15 0.0 - - - - - - 4 4 () - - - - - - 0.0 () - - - - - - 1 1 - - - - - - 6 5 83.3 - - - - - - 6 5 83.3 - - - - - - 24 24 0.0 - - - - - - 11 11 0.0 - - - - - - 13 13 0.0 140 134 95.7 172 162 94.2 431 397 92.1 -