250 mg500 mg 2.7.5
2.7.5 2.7.5 2.7.2 1 Tanigawara Y, Nomura H, Kagimoto N, Okumura K, Hori R. Premarketing population pharmacokinetic study of levofloxacin in normal subjects and patients with infectious diseases. Biol. Pharm. Bull. 1995; 18: 315-320. 2 7 2005 11 19 3 -. 1998 26 5,180. Jpn J Antibiot. 2000; 53: 387-408. 4 -. 2000 37 8,474. Jpn J Antibiot. 2003; 56: 341-64. 5 -. 2002 52 11,475. Jpn J Antibiot. 2005; 58: 17-44. 6 -. 2004 77 18,639. Jpn J Antibiot. 2006; 59: 428-51 7 National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing; twelfth informational supplement, M100-S7. NCCLS, Wayne, PA, USA, 1997. 8 National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing; twelfth informational supplement, M100-S10. NCCLS, Wayne, PA, USA, 2000. 9 National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing; twelfth informational supplement, M100-S12. NCCLS, Wayne, PA, USA, 2002. 10 Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing: Fifteenth informational supplement, M100-S15. CLSI, Wayne, PA, USA, 2005. 2.7.35 1). 10 8 25 743 2. 1
2.7.5 3 4 5. 1997; 45: 762-78.. 2005 10 11 2004 10 1993 2.7.36 1. 10 8 25 743 2.UTI 4. 1997;45(4):203-47. 3 2004 10 4 1993 2.7.3 1). 10 8 25 743 2) World Health Organization. Background document: the diagnosis, treatment and prevention of typhoid fever. 2003. 3).. ; 2005; 129-33. 4),. Levofloxacin. Jpn. J. Antibiotics 1992; 45: 253-7. 5),,,,,. XXX VIILevofloxacin. Jpn. J. Antibiotics 1992; 45: 557-68. 6) Joshi S and Amarnath SK. Fluoroquinolone resistance in Salmonella typhi and S. paratyphi A in Bangalore, India. Transactions of the royal society of tropical medicine and hygiene 2007; 101: 308-10. 7) Pokharel BM, Koirala J, Dahal RK, Mishra SK, Khadga PK and Tuladhar NR. Multidrug-resistant and extended spectrum beta-lactamase (ESBL)-producing Salmonella enterica (serotypes Typhi and Paratyphi A) from blood isolates in Nepal: surveillance of resistance and a search for newer alternatives. Int J. of Infect. Dis. 2006; 10: 434-8. 2
2.7.5 2.7.4 1, 1991;39: 687-9. 2, 1995;43(11): 3 Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004; 350: 1013-22. 4 Hori S, Kizu J, Kawamura M. Effects of anti-inflammatory drugs on convulsant activity of quinolones: a comparative study of drug interaction between quinolones and anti-inflammatory drugs. J Infect Chemother. 2003; 9: 314-20 5 Park-Wyllie LY, Juurlink DN, Kopp A, Shah BR, Stukel TA, Stumpo C, et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med 2006; 354: 1352-61. 3
250 mg500 mg 2.7.6
2.7.6 2.7.6.1-1 I... 2 2.7.6.1-2 I 1 II III I... 5 2.7.6.1-3 I 2 3 I... 6 2.7.6.1-4 I... 7 2.7.6.1-5 I... 9 2.7.6.1-6 500 mg... 11 2.7.6.1-7 500 mg I... 12 2.7.6.1-8 500 mg 1 1 7 I... 13 2.7.6.1-9 500 mg 1 1 7 I... 14 2.7.6.1-10 500 mg I... 15 2.7.6.1-11 I... 17 2.7.6.1-12 QT/QTc I... 20 2.7.6.2-1 I... 22 2.7.6.2-2... 24 2.7.6.2-3... 24 2.7.6.2-4 I... 25 2.7.6.2-5 I... 27 2.7.6.2-6 500 mg 1 1 7 I... 30 2.7.6.2-7 500 mg 1 1 7 1 7 I... 30 2.7.6.2-8 I... 31 2.7.6.3-1 BE... 33 2.7.6.3-2 BE... 35 iv
2.7.6 2.7.6.3-3 500 mg 1 250 mg 2 BE... 37 2.7.6.3-4 BE... 38 2.7.6.4-1 PK... 40 2.7.6.4-2 PK... 41 2.7.6.4-3 500 mg PK... 45 2.7.6.4-4 500 mg PK... 47 2.7.6.4-5 500 mg PK... 49 2.7.6.4-6 7 PK... 51 2.7.6.4-7 PK... 54 2.7.6.5-1 DDI 1... 57 2.7.6.5-2 DDI 1... 57 2.7.6.5-3 DDI 1... 58 2.7.6.6-1 n = 12 DDI 1... 61 2.7.6.6-2 DDI 1... 62 2.7.6.7-1 DDI... 65 2.7.6.7-2 1 2... 67 2.7.6.7-3 1 2... 68 2.7.6.7-4 DDI... 70 2.7.6.7-5 DDI... 71 2.7.6.7-6 DDI... 74 2.7.6.9-1 DDI 2... 82 2.7.6.9-2 R- S- DDI 2... 83 2.7.6.9-3 DDI 2... 84 2.7.6.10-1 DDI 3... 89 2.7.6.10-2 C max C min t max t min DDI 3... 89 2.7.6.10-3 C max C min AUC 0-23h t max t min DDI 3... 90 2.7.6.11-1 III... 91 2.7.6.11-2 III... 95 v
2.7.6 2.7.6.11-3 PPS III... 97 2.7.6.11-4 III... 98 2.7.6.11-5 III... 99 2.7.6.11-6 III... 100 2.7.6.11-7 III... 102 2.7.6.11-8 III... 104 2.7.6.11-9 III... 105 2.7.6.11-10 MIC MIC 0.06>128 III... 107 2.7.6.11-11 MIC MIC 0.015>32 III... 108 2.7.6.11-12 MIC MIC 0.06>128 III... 109 2.7.6.11-13 MIC MIC 0.015>32 III... 110 2.7.6.11-14 III... 112 2.7.6.11-15 III... 113 2.7.6.11-16 III... 115 2.7.6.12-1 RTI III... 121 2.7.6.12-2 RTI III... 124 2.7.6.12-3 RTI III... 125 2.7.6.12-4 PPS RTI III... 128 2.7.6.12-5 PPS RTI III... 129 2.7.6.12-6 3 PPS RTI III... 130 2.7.6.12-7 PPS RTI III... 130 2.7.6.12-8 PPS RTI III... 130 2.7.6.12-9 PPS RTI III... 131 2.7.6.12-10 MIC PPS RTI III... 133 2.7.6.12-11 :PK / PD... 135 2.7.6.12-12 PK / PD :PK / PD... 136 2.7.6.12-13 PK / PD :PK / PD... 137 vi
2.7.6 2.7.6.12-14 RTI III... 138 2.7.6.12-15 RTI III... 139 2.7.6.13-1 UTI III... 147 2.7.6.13-2 UTI III... 149 2.7.6.13-3 UTI III... 151 2.7.6.13-4 PPS UTI III... 152 2.7.6.13-5 PPS UTI III... 153 2.7.6.13-6 PPS UTI III... 154 2.7.6.13-7 Clinical outcomepps UTI III... 154 2.7.6.13-8 Clinical outcomepps UTI III... 154 2.7.6.13-9 Microbiological outcomepps UTI III... 155 2.7.6.13-10 Microbiological outcomepps UTI III... 155 2.7.6.13-11 PPS UTI III... 156 2.7.6.13-12 PPS UTI III... 156 2.7.6.13-13 MIC PPS UTI III.. 158 2.7.6.13-14 Clinical outcomepps UTI III... 160 2.7.6.13-15 Microbiological outcomepps UTI III... 160 2.7.6.13-16 UTI III... 161 2.7.6.13-17 UTI III... 162 2.7.6.14-1 QT... 166 2.7.6.14-2 QT... 169 2.7.6.14-3 QT... 171 2.7.6.14-4 QT... 171 2.7.6.14-5 QT... 172 2.7.6.14-6 t max QT/QTc QT... 173 2.7.6.14-7 t max QTcF QT... 173 2.7.6.14-8 QT... 176 2.7.6.15-1 QT... 180 2.7.6.15-2... 183 vii
2.7.6 2.7.6.15-3 QT... 184 2.7.6.15-4 t max QTc Bazett QT... 185 2.7.6.15-5 t max QTc Fridericia QT... 185 2.7.6.16-1 QT... 188 2.7.6.16-2... 191 2.7.6.16-3 n = 47 QT... 193 2.7.6.16-4 t max QTc Bazett QT... 194 2.7.6.16-5 t max QTc Fridericia QT... 194 viii
2.7.6 ALP ALT AST AUC AUC 0-t AUC 0-inf AUC last BMI C 24h CI CKCPK CLcr CL nr /F CL r CLSI CL ss /F CL t /F C max COPD CPMP CRP CYP QTc QTc ELISA EMEA FAS FDA GOT GPT γ-gtp HBs HCV HIV HPLC LDH MIC MRT PK / PD PPS PT QTc t Body Mass Index 24 Non-renal Clearance Clinical Laboratory Standards Institute Committee for Proprietary Medicinal Products C P450 QTc QTc Enzyme Linked Immunosorbent Assay European Medicines Agency Full Analysis Set Food and Drug Administration B C Pharmacokinetics / Pharmacodynamics Per Protocol Set Corrected QT ix
2.7.6 λ z RTI t max t 1/2 TPEIA UTI Vd/F Vd z Vd z /F Respiratory Tract Infection Urinary Tract Infection Vd z A. baumannii Acinetobacter baumannii A. junii Acinetobacter junii A. johnsonii Acinetobacter johnsonii A. lwoffii Acinetobacter lwoffii B. cepacia Burkholderia cepacia BLNAR β-lactamase-negative ampicillin-resistant Haemophilus influenzae BLNAS β-lactamase-negative ampicillin-susceptible Haemophilus influenzae C. freundii Citrobacter freundii C. koseri Citrobacter koseri C. difficile Clostridium difficile C. freundii Citrobacter freundii CNS coagulase-negative staphylococci E. aerogenes Enterobacter aerogenes E. avium Enterococcus avium E. cloacae Enterobacter cloacae E. coli Escherichia coli E. faecalis Enterococcus faecalis E. faecium Enterococcus faecium G. morbillorum Gemella morbillorum H. influenzae Haemophilus influenzae H. parainfluenzae Haemophilus parainfluenzae K. oxytoca Klebsiella oxytoca K. ozaenae Klebsiella ozaenae K. pneumoniae Klebsiella pneumoniae M. (B.) catarrhalis Moraxella (Branhamella) catarrhalis M. morganii Morganella morganii MRSA Methicillin-resistant Staphylococcus aureus MSSA Methicillin-susceptible Staphylococcus aureus P. aeruginosa Pseudomonas aeruginosa P. agglomerans Pantoea agglomerans P. alcalifaciens Providencia alcalifaciens x
2.7.6 PISP Penicillin-intermediate Streptococcus pneumoniae P. mirabilis Proteus mirabilis P. rettgeri Providencia rettgeri PRSP Penicillin-resistant Streptococcus pneumoniae PSSP Penicillin-susceptible Streptococcus pneumoniae P. vulgaris Proteus vulgaris S. agalactiae Streptococcus agalactiae S. anginosus Streptococcus anginosus S. aureus Staphylococcus aureus S. capitis Staphylococcus capitis S. epidermidis Staphylococcus epidermidis S. haemolyticus Staphylococcus haemolyticus S. maltophilia Stenotrophomonas maltophilia S. marcescens Serratia marcescens S. mitis Streptococcus mitis S. pneumoniae Streptococcus pneumoniae S. salivarius Streptococcus salivarius S. sanguis Streptococcus sanguis S. saprophyticus Staphylococcus saprophyticus O (LVFX) ( )-(S)-9-fluoro-2,3-dihydro-3-methyl-10-( 4-methyl-1-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de][1,4]benzoxazine-6-carboxylic acid hemihydrate H 3 C N F N O N H COOH CH 3 CPFX MFLX xi
2.7.6 2.7.6.1-1 I 2/4 2. [] 1 2 3 4HIV HBs HCV TPEIA 5 6 90 mmhg 140 mmhg 40 mmhg 90 mmhg 40 /99 / 7 8 9 90 400 ml 100 ml 210 ml 1200 ml 10 6 11 12 13 [] 14 90 mmhg 140 mmhg 40 mmhg 90 mmhg 40 /99 / 15 14 16 I II III 1 2 3 750 mg 500 mg 1 500 mg 1 250 mg 500 mg 500 mg 1000 mg 1. 84 12 7 2. 84 12 7 63 9 7 84 12 7 250 mg S05009-1) 500 mg S05009-2 250 mg S05009-3 500 mg S05009-4 3
2.7.6 2.7.6.1-1 I 3/4 1 2 3 750 mg 500 mg 1 500 mg 1 250 mg 500 mg 500 mg 1000 mg 250 mg 1 500 mg 1 250 mg 1 500 mg 1 500 mg 1 500 mg 1 1 1 7 500 mg 1 500 mg 1 1 1 7 250 mg 1 250 mg 1 500 mg 1 500 mg 1 500 mg 1 500 mg 1 500 mg 2 500 mg 2 1. I 1 II III C maxt maxauc 0-24h AUC 0-72h AUC 0-infC 24ht 1/2CL t/ F Vd z/ FMRTλ zcl r 500 mg ) I 2 3 1 7 C maxc 24ht maxauc 0-24h CL r7 t 1/2 CL ss/ FVd z/ FMRTλ z 1 C max 7 C max 1 C 24h 7 C 24h 1 AUC 0-24h 7 AUC 0-24h 1 0-24h 7 0-24h 2. I 2 3. 2.7.6.1-2 2.7.6.1-3 1. C maxt maxauc 0-24h AUC 0-72h AUC 0-infC 24ht 1/2CL t/ FVd z/ FMRT λ zcl r 250 mg750 mg C max AUC 0-72h AUC 0-inft 1/2CL t/fvd Z/FMRTλ z Y X Log (Y) = Log (α) + β Log (X) + error β 95% 4
2.7.6 2.7.6.1-1 I 4/4 2. 95% 12 PR QRS QT RR QTc Bazett QTcB Fridericia QTcF QT OTc t max QTc 95% t max t max median QTc C max 2.7.6.1-2 I 1 II III I 28 2 1 1 2 3 4 8 BMI 12 a b,c d a 0.250.51.52348122436486072 b 123481224 c 500 mg d 240022448812122424484872 5
2.7.6 2.7.6.1-3 I 2 3 I 28 2 1 1 2 3 4 5 6 7 8 9 10 14 15 16 28 30 BMI 12 a b c a 1 0.250.511.5234812 26 1.5 7 0.250.511.5234812 8 2436 9 4860 10 72 b 1 240 1 0224488121224 7 0224488121224 c I 2 1 1.1.1 9 3 1.1.2 500 mg 2006 1 1 750 mg 23 500 mg 1 1 7 1 500 mg 1 250 mg 500 mg 1 500mg 6
2.7.6 1 1 500 mg 1000 mg 1000 mg 1 750 mg 1.2 84 2.7.6.1-4 2.7.6.1-4 I 1 750 mg 9 3 2 500 mg 9 3 3 500 mg 9 3 250 mg 9 3 500 mg 9 3 500 mg 9 3 1000 mg 9 3 1.3 63 84 1.4 I 1 II III 48 2037 51.081.0 kg 155.5185.5 cm 12 2439 67.590.9 kg 171.0192.1 cm I 2 3 12 2027 56.071.6 kg 159.8 177.5 cm 12 6774 50.682.6 kg 144.7172.3 cm 7
2.7.6 1.5 1.5.1 1.5.1.1 250 mg500 mg750 mg 1000 mg 2.7.6.1-1 2.7.6.1-5 t max 1.0 ± 0.51.4 ± 0.7 h C max 250 mg 500 mg750 mg 1000 mg 3.72 ± 0.937.35 ± 2.2110.53 ± 3.32 15.37 ± 2.63 µg/ml t 1/2 7.36 ± 1.709.63 ± 2.11 h mean ± SD 2.7.6.1-1 I 8
2.7.6 2.7.6.1-5 I C max (µg/ml) t max (h) AUC 0-72h (µgh/ml) AUC 0-inf (µgh/ml) a t 1/2 (h) CL t /F (L/h) Vd z /F (L) CL r (L/h) 250 mg mean 3.72 1.1 21.77 21.85 7.36 11.64 120.7 9.05 n = 9 SD 0.93 0.3 2.91 2.94 1.70 1.64 16.6 1.53 500 mg mean 7.35 1.4 57.86 58.02 9.63 8.81 123.6 7.40 n = 9 SD 2.21 0.7 9.70 9.68 2.11 1.30 36.0 1.14 750 mg mean 10.53 1.3 83.15 83.34 8.79 9.09 116.0 7.20 n = 9 SD 3.32 0.5 9.25 9.26 1.47 0.97 26.2 0.89 1000 mg mean 15.37 1.0 111.61 111.83 7.52 9.07 98.4 7.08 n = 9 SD 2.63 0.5 14.16 14.18 0.37 1.13 14.5 1.03 a 250750 mg C max 2.7.6.1-2 AUC 0-72h 2.7.6.1-3 C max AUC 0-72h Log (Y) = Log (α) + β Log (X) + error C max AUC 0-72h β C max 0.94495%CI = 0.712, 1.177AUC 0-72h 1.24295%CI = 1.114, 1.370C max 250750 mg AUC 0-72h 250 mg 750 mg 2.7.6.1-2 C max I 9
2.7.6 2.7.6.1-3 AUC 0-72h I 1.5.1.2 250 mg500 mg750 mg 1000 mg 2.7.6.1-4 500 mg 2.7.6.1-6 72 mean ± SD 77.5 ± 6.7%83.8 ± 3.4%78.9 ± 2.6%77.9 ± 4.4% 24 138.8877.7 µg/ml 10
2.7.6 2.7.6.1-7 500 mg I 1 2 3 4 8 12 24 (µg/ml) n = 7 / n = 7 3.77 ± 2.42 0.59 ± 0.35 5.26 ± 1.75 0.97 ± 0.17 3.92 ± 1.15 0.90 ± 0.17 3.36 ± 0.85 0.85 ± 0.18 1.95 ± 0.47 0.75 ± 0.15 1.25 ± 0.30 0.77 ± 0.17 0.37 ± 0.11 0.70 ± 0.15 mean ± SD 1.5.2 1.5.2.1 500 mg 1 1 7 2.7.6.1-5 2.7.6.1-8 2 7 1 7 C max C 24h t max AUC 0-24h t 1/2 mean ± SD 9.38 ± 2.92 h 500 mg t 1/2 9.63 ± 2.11 h 2 7 1 7 C max C 24h t max AUC 0-24h 1 7 C max C 24h AUC 0-24h t max 12
2.7.6 2.7.6.1-5 500 mg 1 1 7 I 2.7.6.1-8 500 mg 1 1 7 I n = 9 n = 9 1 7 1 7 a C max (µg/ml) C 24h (µg/ml) t max (h) AUC 0-24h (µgh/ml) t 1/2 a (h) CL ss /F (L/h) Vd z /F (L) CL r (L/h) mean 6.02 0.37 1.7 43.36 SD 1.04 0.08 0.8 3.76 mean 6.32 0.47 1.9 49.67 9.38 10.24 136.6 7.80 SD 1.15 0.15 0.9 6.68 2.92 1.51 36.4 0.89 mean 6.49 0.71 3.3 58.75 SD 0.90 0.20 0.7 8.91 mean 7.14 0.91 4.1 67.49 9.47 7.56 104.0 5.46 SD 2.09 0.30 2.5 10.70 1.85 1.13 28.6 1.10 13
2.7.6 1.5.2.2 500 mg 1 1 7 2.7.6.1-9 1 7 24 69.6 ± 6.0 76.7 ± 7.7% 62.3 ± 10.6 72.4 ± 10.3% 2.7.6.1-9 500 mg 1 1 7 I 2 4 8 12 24 1 8.4 ± 3.7 21.5 ± 3.8 38.1 ± 7.6 50.9 ± 7.0 69.6 ± 6.0 n = 9 7 10.1 ± 4.5 23.9 ± 5.1 42.5 ± 5.7 56.9 ± 6.8 76.7 ± 7.7 1 2.4 ± 2.6 11.4 ± 6.0 29.6 ± 7.6 42.8 ± 8.4 62.3 ± 10.6 n = 9 7 4.3 ± 1.4 15.1 ± 5.1 33.2 ± 10.9 47.4 ± 9.7 72.4 ± 10.3 mean ± SD% of dose 1.5.3 1.5.3.1 500 mg 2.7.6.1-10 C max mean ± SD 7.35 ± 2.21 µg/ml4.61 ± 1.10 µg/mlauc 0-inf mean ± SD 58.02 ± 9.68 µgh/ml 47.21 ± 4.38 µgh/ml C max 1.59AUC 0-inf 1.23 C max 447.0 (µg/ml) kg 362.2 (µg/ml) kgauc 0-inf 3559.0 (µgh/ml) kg 3680.1 (µgh/ml) kg C max 1.23AUC 0-inf 0.97 14
2.7.6 2.7.6.1-10 500 mg I C max (µg/ml) t max (h) AUC 0-72h (µgh/ml) AUC 0-inf (µgh/ml) a t 1/2 (h) CL t /F (L/h) Vd z /F (L) CL r (L/h) n 9 9 9 9 9 9 9 9 mean 7.35 1.4 57.86 58.02 9.63 8.81 123.6 7.40 SD 2.21 0.7 9.70 9.68 2.11 1.30 36.0 1.14 n 9 9 9 9 9 9 9 9 mean 4.61 1.4 47.03 47.21 8.43 10.67 129.2 8.43 SD 1.10 0.5 4.30 4.38 0.57 1.01 6.9 0.76 a 1.5.3.2 500 mg 2.7.6.1-6 500 mg 72 83.8 ± 3.4%79.0 ± 6.8% 2.7.6.1-6 500 mg I 1.6 500 mg 1 1 7 2.7.6.1-7 15
2.7.6 14 7 28 21 C. difficile 2.7.6.1-7 500 mg 1 1 7 I 1.7 1.7.1 16
2.7.6 1.7.2 1.7.3 1.7.3.1 250 mg500 mg750 mg 1000 mg 500 mg 1 1 7 500 mg 500 mg 1 1 7 2.7.6.1-11 500 mg 3 1 500 mg 1 1 7 9 1 1 1 b 2.7.6.1-11 I 500 mg 500 mg 17 500 mg 500 mg/ 9 3 9 3 % 00.0 133.3 333.3 00.0 95% a 0.0, 33.6 0.8, 90.6 7.5, 70.1 0.0, 70.8 0 1 4 0 b af bmeddra/j V.8.1 % % 0 0.0 0 0 0.0 0 0.0 0 1 33.3 1 0 0.0 0 0.0 0 0 0.0 0 0.0 0 0 0.0 0 0.0 0 0 0.0 0 0 0 0 % % 1 11.1 1 0 0.0 0 0 0.0 1 11.1 1 0 0.0 1 11.1 1 0 0.0 1 11.1 1 0 0.0 0 0 0 0 0 17
2.7.6 1.7.3.2 500 mg 3 1 1.7.4 1.7.5 1.7.6 QT/QTc 2.7.6.1-12 t max QTc Fridericia C max 2.7.6.1-8 QT 450 msec 250 mg 1 500 mg 1 750 mg 1 QT 480 msec QTc Bazett Fridericia 450 msec QT 30 msec 250 mg 2 500 mg 1 750 mg 1 500 mg 1 500 mg 1 1 7 1 500 mg 1 1 7 1 250 mg 1 500 mg 1 750 mg 2 1000 mg 1 60 msec QTc Bazett 30 msec 1000 mg 2 500 mg 4 500 mg 1 1 7 1 500 mg 1 1 7 1 750 mg 2 500 mg 1 500 mg 1 1 7 1 60 msec QTc Fridericia 30 msec 18
2.7.6 750 mg 2 500 mg 1 1 7 1 60 msec t max QTc Fridericia t max QTc Fridericia C max 19
QT 2.7.6.1-12 QT/QTc I 250 mg > 450 msec > 480 msec 250 mg 500 mg 750 mg 1000 mg 500 mg 500 mg 750 mg 1000 mg 500 mg 500 mg 1 7 500 mg 1 500 mg 1 7 1 0 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 > 30 msec 2 1 1 1 1 2 0 1 1 0 1 0 1 0 c > 60 msec 0 0 0 0 0 0 0 0 0 0 0 0 0 0 500 mg 1 > 450 msec 0 0 0 0 0 0 0 0 0 0 0 0 0 0 > 480 QTcB a msec 0 0 0 0 0 0 0 0 0 0 0 0 0 0 > 30 msec 0 0 0 0 0 2 2 0 4 1 1 1 1 0 c > 60 msec 0 0 0 0 0 0 0 0 0 0 0 0 0 0 > 450 msec 0 0 0 0 0 0 0 0 0 0 0 0 0 0 > 480 QTcF b msec 0 0 0 0 0 0 0 0 0 0 0 0 0 0 > 30 msec 0 0 0 0 0 2 0 0 0 0 0 1 0 0 c > 60 msec 0 0 0 0 0 0 0 0 0 0 0 0 0 0 abazett bfridericia c 20
2.7.6 2.7.6.1-8 t max QTc Fridericia C max I 1.8 250 mg500 mg750 mg C max AUC 0-72h 1 1 500 mg 7 2 7 1 1 500 mg 7 7 C 24h AUC 0-24h 1 7 t max 500 mg C max AUC 0-inf C max 1.59AUC 0-inf 1.23 C max 1.23AUC 0-inf 0.97 1 2501000 mg 1 1 500 mg 7 3 4 2501000 mg QT/QTc 1 1 500 mg 7 QT/QTc 2501000 mg 500 mg 1 1 7 21
2.7.6 2.7.6.2-1 I 2/2 200 mg 500 mg 700 mg 500 mg 1 7 1. 27 9 9 2. 27 9 9 27 9 8 27 9 9 100 mg 0509A10 500 mg 0506G02 200 mg 100 mg 2 500 mg 500 mg 1 700 mg 100 mg 2 500 mg 1 500 mg 1500 mg 1 1 1 7 1. C maxt maxauc 0-72h AUC 0-inft 1/2CL t/fvd z/f CL r 1 7 C maxc 24ht maxauc 0-24h CL r7 t 1/2CL ss/fvd z/f 2. a 2.7.6.2-2 2.7.6.2-3 1. C maxt maxauc 0-72hAUC 0-inft 1/2CL t/fvd z/fcl r 200 mg700 mg C max AUC 0-72h Y X Log (Y) = Log (α) + β Log (X) + error β 95% AUC 0-inf t 1/2CL t/fvd z/fmrtλ z C maxc 24ht maxauc 0-24ht 1/2CL ss/fvd z/fcl r 2. 95% 12 PR QRS QT RR QTc Bazett a MedDRA/J V.9.0 23
2.7.6 2.7.6.2-2 2 1 1 2 3 4 7 BMI 12 a b a 0.250.51.52348122436486072 b 240022448812122424484872 2.7.6.2-3 2 1 1 2 3 4 5 6 7 8 9 10 14 BMI 12 a b a 1 0.250.511.5234812 26 1.5 7 0.250.511.5234812 8 2436 9 4860 10 72 b 1 240 1 0224488121224 7 0224488121224 24
2.7.6 2.1.1 6 9 2.1.2 500 mg 200 mg 700 mg 500 mg 1 1 2.2 36 27 9 2.7.6.2-4 2.7.6.2-4 I 200 mg 9 500 mg 9 700 mg 9 500 mg 1 9 2.3 27 200 mg500 mg700 mg 9 QTc>430 msec 1 8 27 200 mg500 mg700 mg 9 9 2.4 27 2029 55.073.0 kg 167.0183.0 cm CLcr mean ± SD 200 mg500 mg 700 mg 126.8 ± 20.8114.0 ± 17.7 112.8 ± 14.9 ml/min 9 2431 55.072.0 kg 161.0180.0 cm CLcr mean ± SD 110.5 ± 14.7 ml/min 25
2.7.6 2.5 2.5.1 2.5.1.1 200 mg500 mg 700 mg 2.7.6.2-1 2.7.6.2-5 t max 1.1 ± 0.51.5 ± 0.8 h 200 mg500 mg 700 mg C max 2.43 ± 0.637.02 ± 2.478.96 ± 1.95 µg/ml AUC 0-inf 17.07 ± 1.5254.76 ± 8.7484.54 ± 9.12 µgh/ml t 1/2 7.5 ± 1.79.4 ± 2.0 mean ± SD 2.7.6.2-1 I 26
2.7.6 2.7.6.2-5 I C max (µg/ml) t max (h) AUC 0-72h (µgh/ml) AUC 0-inf (µgh/ml) a t 1/2 (h) CL t /F (L/h) Vd z /F (L) CL r (L/h) 200 mg n 9 9 9 9 9 9 9 9 mean 2.43 1.1 17.00 17.07 7.53 11.80 126.9 10.35 SD 0.63 0.5 1.51 1.52 1.66 1.07 21.1 0.99 500 mg n 9 9 9 9 9 9 9 9 mean 7.02 1.4 54.52 54.76 9.36 9.38 124.3 7.84 SD 2.47 1.2 8.66 8.74 2.00 1.76 25.6 1.66 700 mg n 9 9 9 9 9 9 9 9 mean 8.96 1.5 85.32 84.54 8.39 8.27 100.2 7.09 SD 1.95 0.8 9.09 9.12 1.93 0.86 26.0 0.81 a 200700 mg C max 2.7.6.2-2 AUC 0-72h 2.7.6.2-3 C max AUC 0-72h t 1/2 CL t /FVd z /FMRTλ z Log (Y) = Log (α) + β Log (X) + error C max AUC 0-72h β C max 1.06295%CI = 0.864, 1.260AUC 0-72h 1.28195%CI = 1.188, 1.375C max 200700 mg AUC 0-72h 200700 mg 2.7.6.2-2 C max I 27
2.7.6 2.7.6.2-3 AUC 0-72h I 2.5.1.2 200 mg500 mg 700 mg 2.7.6.2-4 200500 700 mg mean ± SD 12 66.7 ± 2.6%55.5 ± 6.1% 57.3 ± 4.6% 48 86.4 ± 3.0%81.5 ± 5.1% 84.5 ± 2.2% 72 87.4 ± 3.1%83.0 ± 5.0% 85.6 ± 2.3% 2.7.6.2-4 I 28
2.7.6 2.5.2 2.5.2.1 500 mg 1 1 7 2.7.6.2-5 2.7.6.2-6 2 7 1 7 C max C 24h t max AUC 0-24h 2.7.6.2-5 500 mg 1 1 7 I 29
2.7.6 2.7.6.2-6 500 mg 1 1 7 I C max (µg/ml) C 24h (µg/ml) t max (h) AUC 0-24h (µgh/ml) t 1/2 a (h) CL ss /F (L/h) Vd z /F (L) CL r (L/h) 1 mean 5.41 0.46 1.6 43.9 8.77 n = 8 SD 1.06 0.14 0.8 4.5 1.30 7 mean 5.50 0.47 1.4 49.3 7.3 10.26 107.9 8.87 n = 8 SD 1.03 0.14 0.5 5.9 0.8 1.21 11.1 0.99 a 2.5.2.2 500 mg 1 1 7 1 7 2.7.6.2-7 1 7 24 mean ± SD 76.0 ± 4.7 86.6 ± 3.9% 2.7.6.2-7 500 mg 1 1 7 1 7 I 2 4 8 12 24 1 10.9 ± 3.9 24.0 ± 3.9 44.4 ± 4.0 58.9 ± 4.8 76.0 ± 4.7 7 12.5 ± 3.3 27.1 ± 3.0 49.5 ± 3.1 64.9 ± 3.6 86.6 ± 3.9 Mean ± SD% of dose 2.6 2.6.1 2.6.2 2.6.3 2.6.3.1 2.7.6.2-8 200 mg 9 500 mg 9 1 11.1% 2 700 mg 9 2 22.2% 2 500 mg 30
2.7.6 700 mg 500 mg 1 9 1 11.1% 1 b 2.7.6.2-8 I 200 mg 500 mg 700 mg 500 mg 1 9 9 9 9 % 0 111.1 222.2 111.1 95%CI a % 0.0, 33.6 0.3, 48.2 2.8, 60.0 0.3, 48.2 0 2 2 1 b af bmeddra/j V.9.0 % % % % 0 0 0 0 0 0 111.1 1 0 0 0 0 0 0 111.1 1 0 0 0 0 111.1 1 0 0 0 0 0 0 111.1 1 0 0 0 0 111.1 1 111.1 1 0 0 0 0 111.1 1 0 0 0 0 0 0 0 111.1 1 0 0 0 0 111.1 1 0 0 0 0 2.6.3.2 200 mg 500 mg 700 mg 9 1 11.1% 1 1 2.6.3.3 2.6.3.4 31
2.7.6 2.6.3.5 2.6.3.6 12 PR QRS QT RR QTc Bazett QTc Bazett 2.7 200 mg500 mg 700 mg C max AUC 0-72h 48 81.586.4% 500 mg 1 1 7 1 7 C max C 24h t max AUC 0-24h 200 mg 500 mg 9 1 2 700 mg 9 2 2 500 mg 1 1 7 9 1 1 12 200700 mg 500 mg 1 1 7 32
2.7.6 2.7.6.3-1 BE 2/2 2. (13) (14) 2003 (15) 1 (16) 1 7 (17) 1 14 (18) 2 2 1 2 A 500 mg 1 250 mg 2 7 B 250 mg 2 500 mg 1 1. 40 1 20 2. 41 A 21 B 20 40 A 20 B 20 41 A 21 B 20 500 mg S06002-1 250 mg S06002-3 1 2 500 mg 1 250 mg 2 7 1. C max AUC 0-72h t maxλ zauc 0-inf MRT 2. 2.7.6.3-2 1. C max AUC 0-72h 90% 90%0.801.25 500 mg 1 250 mg 2 0.901.11 500 mg 1 250 mg 2 AUC 0-inft maxmrt λ zt max 90% 2. 34
2.7.6 2.7.6.3-2 BE day a x 1 1 2 3 4 1 2 c x x x x x x x x x x x x x BMI x x d e x x x x x x x g f x x x x x x g x x x x x x g x x x x x x g HBsHCVHIVTPEIA x x x x x x x g h x i x x x x x b a 1 28 b 2 1 8 1 2 c 500 mg 1 250mg 2 d 1 e 5 f 5 g 2 2 h 2 i 0.250.50.7511.52348122436486072 3.1.1 I 500 mg 1 C max AUC 0-72h mean ± SD 7.35 ± 2.21 µg/ml57.86 ± 9.70 µgh/ml 250 mg 2 500 mg 1.0 0.311 0.160 AUC 0-72h C max α = 0.05 β = 0.2 1 18 36 AUC 0-72h 99 2 1 20 40 35
2.7.6 3.1.2 1 500 mg 3.2 41 A 21 B 20 A 1 2 2 40 3.3 41 A 21 B 20 2 1 A A 20 B 20 40 3.4 A 20 mean ± SD 25.7 ± 5.1 61.29 ± 5.40 kgbmi 20.81 ± 1.50 B 20 24.4 ± 3.4 63.16 ± 4.88 kgbmi 21.27 ± 1.41 3.5 500 mg 1 250 mg 2 2.7.6.3-3 C max 500 mg 1 7.8111 µg/ml 250 mg 2 8.0498 µg/ml 250 mg 2 500 mg 1 1.03190% = 0.9531.114 90% 0.801.25 AUC 0-72h 50.4613 µg h/ml50.6547 µg h/ml 1.00490% = 0.9901.017 90% 0.801.25 36
2.7.6 AUC 0-inf MRTλ z t max λ z 250 mg 2 P = 0.003 2.7.6.3-3 500 mg 1 250 mg 2 BE 500 mg 1 A 1 + B 2 n = 40 250 mg 2 A 2 + B 1 n = 40 90% a C max 7.8111 8.0498 1.031 (µg/ml) CV% 24.7 25.6 0.9531.114 AUC 0-72h 50.4613 50.6547 1.004 (µgh/ml) CV% 12.8 12.7 0.9901.017 AUC 0-inf 50.5650 50.7626 1.004 (µgh/ml) CV% 12.9 12.7 0.9901.018 MRT 9.108 9.201 1.010 (h) CV% 10.8 10.7 0.9941.027 λ z 0.08858 0.08283 0.935 (h -1 ) CV% 13.2 12.9 0.9020.969 t max 0.988 0.988 0.000 b (h) CV% 54.7 63.6 0.2080.208 b Compound symmetry a250 mg 2 500 mg 1 b250 mg 2 500 mg 1 500 mg 1 3.6 3.6.1 3.6.2 3.6.3 3.6.3.1 3.6.3.1.1 2.7.6.3-4 500 mg 1 1 2.4%95% = 0.1 12.9%250 mg 2 1 2.5%95% = 0.113.2% 37
2.7.6 500 mg 1 1 250 mg 2 1 2 6 10 1 72 60 IU/L49 IU/L 3 ALTGPTASTGOT 2 2.7.6.3-4 BE 500 mg 1 A 1 + B 2 250 mg 2 A 2 + B 1 41 40 % 12.4 12.5 95% a 0.112.9 0.113.2 1 2 b b % % af bmeddra / J V.9.1 12.4 1 00.0 0 12.4 1 00.0 0 00.0 0 12.5 2 00.0 0 12.5 1 00.0 0 12.5 1 3.6.3.1.2 250 mg 2 1 1 3.6.3.2 38
2.7.6 3.6.4 3.7 500 mg 1 250 mg 2 500 mg 1 250 mg 2 C max AUC 0-72h 250 mg 2 500 mg 1 90% 0.801.25 λ z 250 mg 2 500 mg 1 250 mg 2 3 39
2.7.6 2.7.6.4-1 PK 2/2 500 mg 1 1. 2. C maxt maxauc 0-72hAUC 0-inft 1/2CL t/fvd z/fmrt CL r 2.7.6.4-2 1. 2. Superposition C maxc minauc 0-24h 2.7.6.4-2 PK 1 4 1 2 3 4 8 24 0 1 2 3 4 5 6 8 12 24 48 72 1 1 8 a) a) a) 4 5 4 1 4 12 1 4 CLcr b) 2 4 7 24 0 1 2 3 4 5 6 8 12 24 48 72 a b24 CLcr 4.1.1 I CLcr 50 ml/min 10 II CLcr 50 ml/min 10 20 41
2.7.6 4.1.2 PK/PD 1 500 mg 500 mg 4.2 23 I 12 II 11 23 4.3 23 I 12 II 11 1 9:00 9:35 1 I I 11 II 11 22 4.4 I 11 mean ± SD 60.1 ± 8.8 65.15 ± 10.38 kgbmi 23.875 ± 2.670CLcrCockcroft 82.882 ± 26.482 ml/min II 11 73.4 ± 6.5 62.25 ± 9.62 kgbmi 23.905 ± 2.045CLcrCockcroft 26.489 ± 13.203 ml/min 4.5 4.5.1 500 mg CLcrCockcroft 50 ml/min I 50 ml/min II 2.7.6.4-1 CLcrCockcroft 2.7.6.4-2 2.7.6.4-3 I II CLcr CLcr I II t 1/2 AUC 0-72h CLcr CLcr t 1/2 AUC 0-72h 42
2.7.6 2.7.6.4-1 500 mg PK 43
2.7.6 2.7.6.4-2 500 mg CLcrCockcroft PK 44
2.7.6.4-3 500 mg PK CLcrmL/min a) C max t max AUC 0-72h AUC 0-inf t 1/2 CL t /F Vd z /F MRT µg/ml h µg h/ml µg h/ml h L/h L h I 80 n 5 5 5 5 5 5 5 5 Arithmetic mean 6.4694 1.600 62.9026 63.0998 8.314 8.236 98.40 11.046 Arithmetic SD 1.0227 0.894 13.7838 13.8481 0.525 1.799 19.99 1.549 50 80 n 6 6 6 6 6 6 6 6 Arithmetic mean 7.6538 1.167 97.4422 98.1845 9.875 5.120 72.60 13.803 Arithmetic SD 1.4354 0.408 7.8026 8.1354 1.310 0.396 8.44 2.273 n 11 11 11 11 11 11 11 11 Arithmetic mean 7.1155 1.364 81.7424 82.2369 9.165 6.536 84.33 12.550 Arithmetic SD 1.3532 0.674 20.7797 21.1071 1.278 2.005 19.42 2.370 II 20 50 n 7 7 7 7 7 7 7 7 Arithmetic mean 9.1680 1.286 150.9626 158.3686 15.883 3.204 72.30 22.041 Arithmetic SD 1.6815 0.488 18.0271 20.2582 3.793 0.452 14.52 5.472 20 n 4 4 4 4 4 4 4 4 Arithmetic mean 8.0330 1.750 250.6600 333.7683 33.693 1.665 72.35 47.915 Arithmetic SD 0.5904 0.957 58.3011 119.1624 14.568 0.641 11.79 20.343 n 11 11 11 11 11 11 11 11 Arithmetic mean 8.7553 1.455 187.2162 222.1503 22.359 2.645 72.32 31.450 Arithmetic SD 1.4591 0.688 61.1945 111.0731 12.371 0.921 12.97 17.678 acockcroft 45
2.7.6 AUC 0-72h C max CL t /F CLcrCockcroft 2.7.6.4-3 CLcr C max CLcr CL t /F AUC 0-72h 2.7.6.4-3 500 mg AUC 0-72h C max CL t /F CLcrCockcroft PK n = 22 46
2.7.6 4.5.2 500 mg CLcrCockcroft 50 ml/min I 50 ml/min II 2.7.6.4-4 2.7.6.4-4 CL r 2.7.6.4-5 I II 24 I II CLcr CLcr I II 0-48 hclcr CLcr 0-48 h 2.7.6.4-4 500 mg PK CLcr (h) ml/min a) 0-2 2-4 4-8 8-12 12-24 24-48 I 80 n 5 5 5 5 5 5 Arithmetic mean 361.9600 443.7800 260.5600 235.2760 193.9620 52.3320 Arithmetic SD 401.9104 319.8735 93.9977 162.2007 115.2266 49.4341 50 80 n 6 6 6 6 6 6 Arithmetic mean 184.6333 130.1517 158.6167 188.4667 124.6300 47.0667 Arithmetic SD 56.8434 54.2793 36.0688 71.0286 29.5085 18.1683 n 11 11 11 11 11 11 Arithmetic mean 265.2364 272.7100 204.9545 209.7436 156.1445 49.4600 Arithmetic SD 273.5036 263.1102 83.7795 116.8064 84.0073 33.9131 II 20 50 n 7 7 7 7 7 7 Arithmetic mean 173.1443 198.7614 142.8100 120.1629 112.8971 70.3171 Arithmetic SD 134.7783 132.3286 91.7731 61.0521 44.4159 32.7192 20 n 4 4 4 4 4 4 Arithmetic mean 35.8375 53.5025 50.2875 44.9975 40.2775 29.8750 Arithmetic SD 21.8956 14.9464 2.4197 5.8971 12.3279 4.3313 n 11 11 11 11 11 11 Arithmetic mean 123.2145 145.9400 109.1655 92.8300 86.4900 55.6109 Arithmetic SD 125.8647 126.2715 85.0538 60.7041 50.7113 32.6233 acockcroft µg/ml 47
2.7.6 2.7.6.4-4 500 mg PK 48
2.7.6 2.7.6.4-5 500 mg PK CLcrmL/min a) 0-48 h% CL r L/h I 80 n 5 5 Arithmetic mean 76.96 6.494 Arithmetic SD 8.25 1.821 50 80 n 6 6 Arithmetic mean 82.57 4.402 Arithmetic SD 1.51 0.305 n 11 11 Arithmetic mean 80.02 5.353 Arithmetic SD 6.08 1.602 II 20 50 n 7 7 Arithmetic mean 56.39 2.090 Arithmetic SD 13.51 0.628 20 n 4 4 Arithmetic mean 28.28 0.703 Arithmetic SD 11.83 0.322 n 11 11 Arithmetic mean 46.16 1.585 Arithmetic SD 18.78 0.871 acockcroft 4.5.3 2.7.6.4-5 2.7.6.4-7 2.7.6.4-6 500 mg 1 1 7 I 1 II 7 7 C max C min AUC 0-24h I II II CLcrCockcroft 20 50 ml/min 500 mg 250 mg 1 1 6 7 1 7 CLcr 20 ml/min 500 mg 250 mg 1 1 6 7 500 mg 250 mg 3 500 mg 125 mg 1 1 6 1 7 49
2.7.6 2.7.6.4-6 7 1/2 PK 500 mg 1 1 7 acockcroft I II CLcr 50 20 ml/min a) 80 80 50 20 C max n 5 6 11 7 4 11 µg/ml mean 7.1364 9.0872 8.2005 12.6467 17.5245 14.4205 SD 0.9505 1.1359 1.4298 1.3238 3.2011 3.1909 C min n 5 6 11 7 4 11 µg/ml mean 0.7154 1.4973 1.1419 3.6140 9.8000 5.8635 SD 0.3282 0.4263 0.5484 0.9089 3.8535 3.8329 AUC 0-24h n 5 6 11 7 4 11 µg h/ml mean 63.1056 98.1813 82.2378 158.4723 333.9290 222.2747 SD 13.8365 8.1533 21.1034 20.2749 119.4431 111.1883 51
2.7.6.4-6 7 2/2 PK CLcr ml/min a) 20 50 500 mg 1 1 7 250 mg 1 1 7 250 mg 4 20 20 50 20 20 50 20 C max n 7 4 11 7 4 11 7 4 11 µg/ml mean 12.6467 17.5245 14.4205 6.3234 8.7625 7.2104 5.0371 5.7933 5.3121 SD 1.3238 3.2011 3.1909 0.6620 1.6006 1.5956 0.7264 0.6445 0.7660 C min n 7 4 11 7 4 11 7 4 11 µg/ml mean 3.6140 9.8000 5.8635 1.8073 4.9000 2.9319 0.4704 1.8333 0.9660 SD 0.9089 3.8535 3.8329 0.4545 1.9266 1.9163 0.2034 0.9353 0.8718 AUC 0-24h n 7 4 11 7 4 11 7 4 11 µg h/ml b) mean 158.4723 333.9290 222.2747 79.2364 166.9645 111.1375 39.6181 83.4820 55.5686 SD 20.2749 119.4431 111.1883 10.1373 59.7214 55.5940 5.0689 29.8606 27.7969 acockcroft b AUC0-48h/2 500 mg 250 mg CLcr 1 1 6 ml/min a) 20 20 50 500 mg 250 mg 3 20 50 20 20 50 500 mg 125 mg 1 1 6 20 C max n 7 4 11 7 4 11 7 4 11 µg/ml mean 6.3317 8.9513 7.2843 5.0456 5.9820 5.3861 3.1743 4.6643 3.7161 SD 0.6592 1.7555 1.7123 0.7214 0.8057 0.8545 0.3269 1.0393 0.9764 C min n 7 4 11 7 4 11 7 4 11 µg/ml mean 1.8144 5.0950 3.0074 0.4791 2.0295 1.0429 0.9110 2.7118 1.5658 SD 0.4611 2.0972 2.0461 0.2112 1.1133 1.0052 0.2341 1.2182 1.1417 AUC 0-24h n 7 4 11 7 4 11 7 4 11 µg h/ml b) mean 79.2364 166.9645 111.1375 39.6181 83.4820 55.5686 39.6181 83.4820 55.5686 SD 10.1373 59.7214 55.5940 5.0689 29.8606 27.7969 5.0689 29.8606 27.7969 acockcroft b AUC0-48h/2 52
2.7.6 4.6 4.6.1 4.6.2 4.6.3 4.6.3.1 2.7.6.4-7 500 mg I 12 1 8.3%95%CI = 0.2%, 38.5%II 11 2 18.2%95%CI = 2.3%, 51.8% I 1 II 1 1 1 4.6.3.2 4.6.3.3 53
2.7.6 2.7.6.4-7 PK I 12 11 II % 18.3 218.2 95% a) 0.2, 38.5 2.3, 51.8 1 3 b) c) % af bmeddra/j V.9.1 System Organ Class ; SOC cmeddra/j V.9.1 Preferred Term ; PT % 18.3 1 218.2 3 00.0 0 19.1 1 00.0 0 19.1 1 18.3 1 00.0 0 00.0 0 19.1 1 4.6.4 4.7 CLcrCockcroft 50 ml/min 50 ml/min 500 mg CLcr 500 mg 1 1 7 7 500 mg 54
2.7.6 2 240 ml 1 g 3 1 8 15 12 48 10 5.8 1840 ±15% 24 12 12 5.9 5.9.1 C max t max AUC last t 1/2 AUC 0-inf 5.9.2 5.10 1 vs. 2 vs. C max t 1/2 AUC last AUC 0-inf t max t 1/2 t max C max AUC last AUC 0-inf P<0.05 Schuirmann 2 2 t 1/2 C max AUC 90% C max AUC 80~125%t 1/2 80~120% 56
2.7.6 5.11 5.11.1 24 12 12 24 24 16 1 2 5 2.7.6.5-1 2.7.6.5-1 DDI 1 lb in 12 23.3 1834 160 133210 70.0 6674 12 25.8 1836 133 92164 65.9 5974 24 24.5 1836 146 92210 68.0 5974 5.11.2 3 t max C max 2.7.6.5-2 DDI 1 mean SD mean SD a 90% a C max ng/ml 5930 1260 5090 880 0.86 (0.79, 0.94) t max h 1.0 b (0.8, 4.0) b 2.0 b (0.5, 4.0) b P = 0.0023 c AUC last ng h/ml 49400 7900 44400 6100 0.90 (0.87, 0.94) AUC 0-inf ng h/ml 50500 8100 45600 6100 0.91 (0.87, 0.94) t 1/2 h 6.22 1.56 6.45 1.93 1.04 (0.92, 1.15) C max AUC n=24 a 90%ANOVA 2 b c t max P 2 57
2.7.6 2.7.6.5-3 DDI 1 mean SD mean SD a 90% a C max ng/ml 5930 1260 6690 3220 1.06 (0.98, 1.15) t max h 1.0 b (0.8, 4.0) b 1.0 b (0.8, 2.0) b P = 0.0481 c AUC last ng h/ml 49400 7900 46900 8500 0.95 (0.91, 0.98) AUC 0-inf ng h/ml 50500 8100 47900 8400 0.95 (0.91, 0.98) t 1/2 h 6.22 1.56 6.06 1.39 0.97 (0.86, 1.09) C max AUC a 90%ANOVA 2 b c t max P AUC last AUC 0-inf t 1/2 t max C max ANOVA P 0.05 C max t 1/2 t max P<0.05 t max C max 3 7 6 C max t 1/2 133 vs. 160 AUC last AUC 0-inf 5.11.3 6 1 1 1 4 5.11.4 2 58
2.7.6 6.8 1860 Broca 15%+10% 12 6.9 6.9.1 72 24 6.9.2 6.10 HPLC 20 ng/ml 5 µg/ml 10 µg/ml 5 µg/ml C max t maxauc 0-72h AUC 0-inf 72 72 % doset 1/2 MRT CL t /FCL r apparent non-renal clearancecl nr /F 6.11 t max 90% 95%CI t max 90% 95%CI 6.12 6.12.1 13 1 60
2.7.6 12 2453 34.3 61.8100.2 kg76.7 kg 6.12.2 3 7 1 30 6.12.3 2.7.6.6-1 90% 95%CI 2.7.6.6-2 2.7.6.6-1 n=12 DDI 1 C max ng/ml t max h AUC 0-72h ng h/ml AUC 0-inf ng h/ml a mg 7265.1 ± 1779.8 4607.8-10696.0 1.10 ± 0.49 0.5-2.00 52785.0 ± 6053.7 42422.0-60007.1 53222.0 ± 5997.8 42832.5-60269.6 372.01 ± 43.71 285.14-424.95 + 6911.8 ± 1562.8 4058.9-9148.5 1.08 ± 0.50 0.5-2.00 66984.0 ± 7551.0 51010.9-78104.9 67611.0 ± 7581.6 51559.9-78565.6 358.48 ± 51.54 236.61-409.38 + 7103.2 ± 2144.0 5089.8-11286.0 1.04 ± 0.46 0.5-2.00 72635.0 ± 6969.2 61353.8-81864.9 73449.0 ± 7030.1 62386.3-83129.5 330.19 ± 29.89 275.57-367.22 a % dose 74.40 71.70 66.04 t 1/2 h MRTh CL r ml/min CL t /FmL/min CL nr /FmL/min mean ± SDmin - max a 72 8.32 ± 0.87 6.84-9.61 12.18 ± 1.33 10.10-15.38 119.16 ± 21.44 82.44-162.10 158.54 ± 18.98 138.27-194.56 39.38 ± 13.59 22.21-60.50 10.85 ± 1.16 9.25-13.54 14.79 ± 1.41 12.50-18.49 90.59 ± 17.80 55.44-111.34 124.84 ± 15.54 106.07-161.62 34.25 ± 13.59 22.27-60.62 10.96 ± 0.64 9.63-11.96 15.90 ± 1.12 14.19-18.15 76.78 ± 12.78 57.43-98.39 114.45 ± 11.34 100.24-133.58 37.67 ± 5.56 27.89-45.70 61
2.7.6 2.7.6.6-2 DDI 1 C max t max AUC 0-72h AUC 0-inf b t 1/2 MRT CL r CL t /F % 90%CI 95%CI h 90%CI a 95%CI a % 90%CI 95%CI % 90%CI 95%CI % 90%CI 95%CI % 90%CI 95%CI % 90%CI 95%CI % 90%CI 95%CI % 90%CI 95%CI % CL nr /F 90%CI 95%CI a CI b 72 95.3 83.7, 108.6 81.4, 111.6 0.0 0.25, 0.13 0.38, 0.25 127.0 123.0, 131.2 122.1, 132.1 126.9 122.7, 131.2 121.9, 132.2 96.4 92.0, 100.7 91.1, 101.6 130.5 123.1, 137.7 121.7, 139.3 121.5 118.1, 125.1 117.4, 125.8 76.0 70.9, 81.2 69.8, 82.2 78.7 75.5, 82.3 74.4, 83.1 87.0 74.3, 99.6 71.7, 102.3 96.9 85.1, 110.4 82.8, 113.4 0.06 0.38, 0.25 0.50, 0.25 138.2 133.8, 142.8 132.9, 143.8 137.9 133.3, 142.6 132.4, 143.6 88.8 84.4, 93.1 83.5, 94.0 131.8 124.6, 139.0 123.0, 140.6 130.9 127.2, 134.8 126.5, 135.6 64.4 59.3, 69.6 58.2, 70.6 72.2 68.6, 75.8 67.9, 76.5 95.7 83.0, 108.3 80.8, 110.6 C max 95%CI 95.381.4, 111.6%96.982.8, 113.4%t max 95%CI 0.0 0.38, 0.25h 0.06 0.50, 0.25h t 1/2 62
2.7.6 95%CI 130.5121.7, 139.3%131.8123.0, 140.6% AUC 0-72h 95%CI 127.0122.1, 132.1% 138.2132.9, 143.8% 74.4%71.70% 66.04% CL r 119 ml/min91 ml/min77 ml/min 95%CI 76.069.8, 82.2%64.458.2, 70.6% 6.12.4 9 16 possibly related4 1 + 24 1 5 1 + 38 2 1 2 +1 >200 5 1 1995 6 1995 12 11 1996 1 4 1996 7 3 possibly related extremely unlikely related 2 5 1 1 1 8 63
2.7.6 6.12.5 1 2 1 +2 6.13 500 mg C max t max t 1/2 30% AUC 0-72h 27% 38% 72 74.4%71.70% 66.04%CL r 119 ml/min91 ml/min77 ml/min CL r 64
1 日 2 回 ) を試験 1~3 日目まで 3 日間経口 1 日 4 回 を試験 1~5 日固まで 5 日間経
2.7.6 2.7.6.7-1 DDI 3/3 1. C maxt maxλ zauc 0-72hAUC 0-inft 1/2CL tvd zmrt CL r 2. a 2.7.6.7-2 2.7.6.7-3 1. C max AUC 0-72h 90% 2. a MedDRA/J V.9.1 2.7.6.7-2 1 2 a) 1 () 24 0800 1 7 8 9 10 11 12 30 00 30 00 30 00 30 00 30 30 23 4 () 1430 1630 2000 2030 0800 0830 2000 2030 0830 10 ( a ) ) 24.5 1.0 0.5 0 0.5 1.0 1.5 2.0 2.5 3.0 4.0 6.0 8.0 11.5 12 23.5 24 35.5 36 47.5 48 59.5 60 b) b) b) c) c) 72 d) e) f) g) h) LVFX i) c) j) k) l) m) a 1 28 911 b c 2 d 1 e24 f 1 2 g h i 5 j k 4872 l 72 m 2 67
2.7.6 2.7.6.7-3 1 2 1 a) () 12 3 45 7 8 9 10 11 24 0800 0730 0800 1300 1800 2300 1230 13001430 1630 1800 2030 2300 0800 0830 1300 1800 2030 2300 0830 30 00 30 00 30 00 30 00 30 / 72.5-49 -48.5-43.5-38.5-33.5 23.5 24 28.5 33.5 36 38.5-25 -24.5-19.5-14.5-9.5-10 -0.5 0 0.5 1.0 1.5 2.0 2.5 3.0 4.0 4.5 6.0 8.0 9.5 12 14.5 47.5 48 52.5 57.5 60 62.5 72 6 12 ( a) ( ) ) b) b) b) c) c) d) e) f) g) h) LVFX i) c) j) k) l) m) a 1 28 911 b c 4 d 1 e24 f1 2 g 1 h i 5 j k 4872 l 72 m 2 7.1.1 I 1 69 12 7.1.2 1 500 mg 1 4 1 400 mg 1 2 500 mg 1 1 t 1/2 4 t 1/2 612 68
2.7.6 4 2448 2 t 1/2 2 12 t max t max 60 t max 2 t max 15 30 60 60 7.2 24 AD 6 7.3 12 7.4 12 mean ± SD 26.3 ± 3.8 63.24 ± 6.38 kgbmi 22.38 ± 2.04 118.3 ± 13.7 ml/min 12 25.9 ± 5.4 65.38 ± 6.38 kgbmi 21.83 ± 1.45 112.3 ± 16.9 ml/min 7.5 7.5.1 2.7.6.7-1 2.7.6.7-4 C max 10.2576 µg/ml CV = 16.4% 10.3487 µg/ml CV = 69
2.7.6 13.6% 1.00990%CI = 0.960, 1.060 AUC 0-72h 48.2184 µgh/ml CV = 11.6% 61.0518 µgh/ml CV = 11.4% 1.26690%CI = 1.234, 1.299 2.7.6.7-1 DDI 2.7.6.7-4 DDI LVFX LVFX + C max AUC 0-72h AUC 0-inf t 1/2 CL t Vd z MRT CL r (µg/ml) (µg h/ml) (µg h/ml) (h) (L/h) (L) (h) (L/h) n 12 12 12 12 12 12 12 12 Geometric mean 10.2576 48.2184 48.2209 7.546 10.368 112.90 7.704 8.848 Geometric CV% 16.4 11.6 11.8 27.8 11.8 24.5 9.6 11.6 n 12 12 12 12 12 12 12 12 Geometric mean 10.3487 61.0518 61.4974 11.689 8.131 137.12 10.671 6.775 Geometric CV% 13.6 11.4 11.6 12.5 11.6 14.5 9.1 13.3 2.7.6.7-2 2.7.6.7-5 C max 9.5501 µg/ml CV = 15.3% 10.6039 µg/ml CV = 12.9% 1.11090%CI = 1.043, 70
2.7.6 1.182 AUC 0-72h 49.3008 µgh/ml CV = 7.1% 74.5861 µgh/ml CV = 12.0% 1.51390%CI = 1.477, 1.550 2.7.6.7-2 DDI 2.7.6.7-5 DDI LVFX LVFX + C max AUC 0-72h AUC 0-inf t 1/2 CL t Vd z MRT CL r (µg/ml) (µg h/ml) (µg h/ml) (h) (L/h) (L) (h) (L/h) n 12 12 12 12 12 12 12 12 Geometric mean 9.5501 49.3008 49.3405 7.561 10.133 110.51 8.228 8.156 Geometric CV% 15.3 7.1 7.1 19.2 7.1 20.2 13.0 11.5 n 12 12 12 12 12 12 12 12 Geometric mean 10.6039 74.5861 75.6489 12.409 6.610 118.34 13.551 5.157 Geometric CV% 12.9 12.0 12.1 9.5 12.1 14.8 10.8 19.5 71
2.7.6 7.5.2 2.7.6.7-3 0-72 h 85.32% CV = 5.5% 82.72% CV = 7.4% 0.97090%CI = 0.943, 0.996 CL r 8.848 L/h CV = 11.6% 6.775 L/h CV = 13.3% 2.7.6.7-4 0.76690%CI = 0.745, 0.787 2.7.6.7-3 DDI 2.7.6.7-4 0-72 h 80.41% CV = 12.2% 76.96% CV = 11.1% 0.95790%CI = 0.903, 72
2.7.6 1.015 CL r 8.156 L/h CV = 11.5% 5.157 L/h CV = 19.5% 2.7.6.7-5 0.63290%CI = 0.596, 0.671 2.7.6.7-4 DDI 7.6 7.6.1 7.6.2 7.6.3 7.6.3.1 2.7.6.7-6 8.3%1/12 95%CI = 0.2%, 38.5% 0%0/1295%CI = 0.0%, 26.5% 16.7%2/1295%CI = 2.1%, 48.4% 16.7%2/1295%CI = 2.1%, 48.4% 73
2.7.6 C 1 C 1 1 b 2.7.6.7-6 DDI LVFX LVFX + LVFX LVFX + 12 12 12 12 % 18.3 00.0 216.7 216.7 95% a 0.2, 38.5 0.0, 26.5 2.1, 48.4 2.1, 48.4 1 0 3 3 b af bmeddra/j V.9.1 % % % % 00.0 0 00.0 0 18.3 2 18.3 2 00.0 0 00.0 0 18.3 1 18.3 1 00.0 0 00.0 0 18.3 1 18.3 1 18.3 1 00.0 0 18.3 1 18.3 1 C- 18.3 1 00.0 0 18.3 1 00.0 0 00.0 0 00.0 0 00.0 0 18.3 1 7.6.3.2 8.3%1/12 95%CI = 0.2%, 38.5% 0%0/1295%CI = 0.0%, 26.5% 16.7%2/1295%CI = 2.1%, 48.4% 8.3%1/1295%CI = 0.2%, 38.5% 1 7.6.3.3 74
2.7.6 7.6.4 7.6.5 7.6.6 7.7 12 500 mg/100 ml C max AUC 75
1 掴年. 月. 日 ~II 月. 日
2.7.6 8.5.3 500 mg 500 mg 1 + 250 mg 1/2 + 2 125 mg 500 mg 1 + 250 mg 1/2 + 2 500 mg + 600 mg 500 mg 1 + 250 mg 1/2 + 2 125 mg + 600 mg 500 mg 1 + 250 mg 1/2 + 2 600 mg 500 mg 1 + 250 mg 1/2 + 2 500 mg 1 + 250 mg 1/2 + 2 8.6 6 6 1 8.7 2060 Broca 15%+10% 24 8.8 8.8.1 AUC HPLC LOQ 20 ng/ml 8.8.2 7.5-13.5 Hz 77
2.7.6 13.5-45.0 Hz1.5-4.5 Hz4.5-7.5 Hz1.5-7.5 Hz adaptive visual multiple choice reaction task Basle well-being scale 8.8.3 8.9 AUC Student t 2 Student t Wilcoxon 0.025 8.10 8.10.1 24 6 8.10.2 2949 39 65102 kg 79.3 kg 8.10.3 4 30 6 30 AUC 0-6.5h 125 mg + 600 mg 125 mg P<0.001 500 mg + 600 mg 500 mg P<0.03 78
2.7.6 8.10.4 125 mg 500 mg t 500 mg + 600 mg P 0.049 8.10.5 600 mg 1 125 mg 1 500 mg 2 125 mg + 600 mg 2 500 mg + 600 mg 1 1 1 11 3 possibly related 500 mg + 600 mg 1 AST21 U/L ALT33 U/LAST18 U/LALT 22 U/L AST ALT 1 17 µmol/l 26.1 µmol/l 1 79
2.7.6 8.11 125 mg 500 mg 600 mg 4 30 6 30 6 30 13% 80
2.7.6 9.7 144 HPLC R- S- 144 3 24 02 1 2 144 9.8 9.8.1 16 2340 150193 2.7.6.9-1 2.7.6.9-1 DDI 2 1 2 n = 8 1 2 n = 8 n = 16 2 3 5 3 5 8 3 0 3 SD 33.54.7 31.54.9 32.54.8 27-40 23-40 23-40 lb SD 175.912.9 170.413.7 173.213.2 162.0-193.0 150.0-190.0 150.0-193.0 in SD 69.32.4 71.42.8 70.32.7 66.0-73.0 68.0-76.5 66.0-76.5 9.8.2 / 15 1 82
2.7.6 9.8.3 2 R- S- 2.7.6.9-2 2.7.6.9-2 R- S- DDI 2 R- A B % a ANOVA b 90%CI e C max µg/ml 1.59 ± 0.23 1.64 ± 0.28 3.0 NS EQ t max h 1.33 ± 0.49 1.47 ± 0.83 9.5 NS d --- AUC 0-t µgh/ml 75.9 ± 17.0 75.0 ± 17.4 +1.2 NS EQ AUC 0-inf µgh/ml 87.0 ± 24.1 86.1 ± 23.9 +1.0 NS EQ CL t /FmL/min 2.89 ± 0.88 2.93 ± 0.92 1.4 NS --- t 1/2 h 46.0 ± 11.2 46.3 ± 10.0 0.6 NS --- S- C max µg/ml 1.64 ± 0.21 1.70 ± 0.25 3.5 NS EQ t max h 1.27 ± 0.46 1.33 ± 0.49 4.5 NS d --- AUC 0-t µgh/ml 51.1 ± 11.9 49.3 ± 10.1 +3.7 NS EQ AUC 0-inf µgh/ml 54.2 ± 14.8 52.1 ± 11.8 +4.0 NS EQ CL t /FmL/min 4.58 ± 1.17 4.72 ± 1.23 3.0 NS --- t 1/2 h 31.9 ± 7.5 31.7 ± 6.4 +0.6 NS --- mean ± SDn=15 a BA B/B 100 b ANOVA c C max AUC 0-t AUC 0-90% d t max NS EQ90% 80125% R- R- 1.5 R- C max mean ± SD 1.64 ± 0.28 µg/ml 1.59 ± 0.23 µg/mlcl t /F 2.93 ± 0.92 ml/min 2.89 ± 0.88 ml/min t 1/2 46 R- 2 R- C max AUC 0-t AUC 0-inf 90%80 125% 83
2.7.6 S- S- 1.3 S- C max mean ± SD 1.70 ± 0.25 µg/ml 1.64 ± 0.21 µg/mlcl t /F 4.72 ± 1.23 ml/min 4.58 ± 1.17 ml/min t 1/2 32 S- 2 S- C max AUC 0-t AUC 0-90%80 125% 2 PT 2.7.6.9-3 2.7.6.9-3 DDI 2 PT a A B % b ANOVA c 90%CI d PT max e sec 3.5 ± 1.5 3.7 ± 2.1-5.4 NS EQ t max, PT f h 43.2 ± 21.7 35.2 ± 7.1 +22.7 NS g --- AUC 0-t PT h sech 186 ± 84 209 ± 102-11.0 NS EQ mean ± SD a PT b BA B/B 100 c ANOVA d PT max AUC 0-tPT 90% e PT f PT max g ANOVA t max, PT h PT0 - t NS EQ 90% 80125% PT 36 PT max 15 2 PT max t max, PT AUC 0-t PT Pt max AUC 0-t PT 90%80125% 84
2.7.6 9.8.4 16 6 15 5 3 2 2 1 AST ALT remotely related 1 6 9.9 500 mg 1 2 9 85
2.7.6 C max C min t max t min C max C min t max t min 10.11.3 10.12 10.12.1 ++ C max AUC 0-inf AUC 0-11h t 1/2 MRT 90%C max AUC 0-inf AUC 0-11h MRT t max 90%95%Wilcoxon 10.12.2 ++ C max t max C min t min - C max t max C min t min 90% 10.12.3 10.13 10.13.1 24 19.046.0 31.1 64.094.4 kg 78.1 kg 10.13.2 2.7.6.10-1 88
2.7.6 2.7.6.10-1 DDI 3 C max (ng/ml) AUC 0-t (ng h/ml) AUC 0-inf (ng h/ml) AUC 0-11h (ng h/ml) t 1/2 (h) MRT (h) t max (h) + (CV) * 226.2 (22.38) 162.0-325.0 826.16 (33.05) 564.20-1948.40 862.48 (33.78) 593.00-2073.70 809.85 (25.29) 567.94-1547.03 2.50 (32.47) 1.72-5.95 3.95 (23.11) 3.19-7.82 2.00 1.00-2.50 * t max + (CV) * 240.7 (23.21) 154.0-410.0 826.46 (30.45) 469.2-1790.90 860.51 (31.41) 488.80-1903.10 826.00 (30.49) 469.23-1790.92 2.47 (37.73) 1.23-6.12 3.80 (28.17) 2.19-7.87 2.50 1.00-2.50 + + (%) (90%) 106.2 (99.7, 113.3) 100.1 (95.8, 104.7) 99.8 (95.6, 104.1) 101.0 (96.6, 106.5) 97.0 (87.4, 107.6) 94.9 (89.7, 100.3) 111.8 (100, 111.8) 10.13.3 C max C min t max t min 2.7.6.10-2 C max C min AUC 0-23h t max t min 2.7.6.10-3 2.7.6.10-2 C max C min t max t min DDI 3 C max (mmol/l) C min (mmol/l) t max (h) + (CV) * 6.7 (9.44) 5.8-8.5 2.3 (16.92) 1.9-3.3 5.00 2.50-23.00 + (CV) * 6.5 (8.81) 5.4-7.9 2.7 (14.42) 1.8-3.1 4.75 2.50-10.00 + + (%) (90%) 98.1 (92.7, 102.1) 105.4 (99.0, 113.2) 100.0 (70.7, 100.0) t min (h) 1.50 1.25-3.50 1.50 1.25-7.00 100.0 (86.6, 115.5) * t max t min 89
2.7.6 2.7.6.10-3 C max C min AUC 0-23h t max t min DDI 3 C max (µiu/ml) C min (µiu/ml) AUC 0-23h (µiu h/ml) t max (h) t min (h) + (CV) * 94.6 (49.18) 35.6-208.0 ND (55.56) ND - 10.3 486.2 (38.80) 173.00-783.52 5.00 2.50-6.00 0.38 0.25-23.00 + (CV) * 82.7 (43.46) 21.7-154.0 ND (47.02) ND - 9.7 489.57 (42.77) 220.27-1087.70 5.00 2.50-6.00 0.25 0.25-4.00 + + (%) (90%) 90.1 (79.6, 104.5) 100.0 (100.0, 105.4) 100.0 (93.9, 128.4) 71.5 (41.7, 100.0) 101.3 (91.4, 117.5) * t max t min ND: 5 µiu/ml C- 10% 10.13.4 24 21 58 13 24 14 18 9 10.13.5 90
(4) 妊娠可能な年齢の女性は投与前の尿妊娠検査が陰性であり かつ投与開始から治療後 7~14
2.7.6 2.7.6.11-1 III 2/4 1.2 1 18 70 2 3 4 714 5 3 3 6 7 1 2 10 WBC/mm 3 25 WBC/µL 5 WBC/HPF 3 4 1 37 C 37.5 C 38 C 2 10 WBC/mm 3 25 WBC/µL 5 WBC/HPF 3 1 6 2 1 3 2 10 WBC/mm3 25 WBC/µL 5 WBC/HPF 3 1 1 2 2 10 WBC/mm 3 25 WBC/µL 5 WBC/HPF 3 1 2 >100 ml 2. 2.1 2.2 1 2 ASTGOT ALTGPT 3 2 3 <50 ml/min ) 92
2.7.6 2.7.6.11-1 III 3/4 4 5 QT 6 7 8 9 60 10 30 11 3 12 13 2.1 1 2 WBC<4.0 10 9 /L <2.0 10 9 1 20 mg 2 3 2.2 1 2 WBC<4.0 10 9 /L <2.010 9 1 20 mg 2 1. 1200 900 300 2. 1266 FAS 1245 883 362 PPS 1082 775 307 1245 883 362 164 164 500 mg 0510G05 1 500 mg1 1 714 710 35 1014 714 93
2.7.6 2.7.6.11-1 III 4/4 1. 1.1 Visit 4 2.7.6.11-2 1.2 1 Visit 3 Visit 4 Visit 3 Visit 4 2 Visit 4 Visit 3 Visit 2* Visit 4 Visit 3 MIC Visit 4 * : Visit 2 3 Visit 4 Visit 3 4 Visit 4 Visit 3 MIC 2. C maxc 24hAUC 0-24h 3. 1. 95% PPS 2. I 500 mg I 500 mg 1 1 7 C maxc 24hAUC 0-24h 3. 95% 94
2.7.6 2.7.6.11-2 III Visit 1 Visit 2 Visit 3 Visit 4 / / / 35 2 714 X a X c b b b ) e d f avisit 3 Visit 4 bvisit 1 c d e Visit 3 Visit 3 f 11.1.1 0.3% 95% 1 998 1,200 900 300 11.1.2 PK/PD C max / MIC 500 mg 1 1 C max MIC 1 µg/ml C max / MIC 500 mg 1 1 95
2.7.6 11.2 1266 899 367 785 114 35 28 19 16 18 317 50 4 10 7 12 15 11.3 1245 883 362 21 FAS 1245 883 362 21 PPS 1,082 775 307 105 51 24 3 21 5 883 1 164 99 65 I 500 mg 18 182 11.4 11.4.1 PPS 2.7.6.11-3 2.7.6.11-4 PPS 775 359 416 PPS 307 89 84 107 27 PPS 775 454 58.6% mean ± SD 47 ± 16 mean ± SD 62.5 ± 11.3 kg 694 89. %5 84 10.8% 382 49.3% 96
2.7.6 14 135 17.4% PPS 307 21 6.8% mean ± SD 40 ± 14 mean ± SD 57.7 ± 9.4 kg 294 95.8% 55 17.9% 60 19.5% 14 21 6.8% 775 S. aureus 21 2.7% S. pneumoniae 32 4.1% K. pneumoniae 69 8.9% H. influenzae 42 5.4%H. parainfluenzae 85 11.0% 307 E. coli 100 32.6% K. pneumoniae 14 4.6%P. mirabilis 13 4.2% 2.7.6.11-3 PPS III PPS 1082 1245 775 883 359 423 416 460 307 362 89 108 84 91 107 130 27 33 97
2.7.6 2.7.6.11-4 III PPS n = 775 n = 307 n = 883 n = 362 n = 1245 45458.6 216.8 51157.9 298.0 54043.4 32141.4 28693.2 37242.1 33392.0 70556.6 Mean ± SD 47 ± 16 40 ± 14 47 ± 16 40 ± 14 45 ± 16 kgmean ± SD 62.5 ± 11.3 57.7 ± 9.4 62.3 ± 11.2 57.9 ± 9.3 56.6 ± 12.3 69489.5 29495.8 79189.6 34595.3 113691.2 8110.5 134.2 9210.4 174.7 1098.8 69189.2 25282.1 77988.2 29581.6 107486.3 8410.8 5517.9 10411.8 6718.5 17113.7 39350.7 24780.5 45251.2 29380.9 74559.8 38249.3 6019.5 43148.8 6919.1 50040.2 14 64082.6 28693.2 72882.4 33592.5 106385.4 13517.4 216.8 15517.6 277.5 18214.6 % 11.4.2 182 164 18 121 66.5% 61 33.5% 164 103 62.8% 61 37.2% mean ± SD 61.1 ± 10.7 kg 60.9 ± 11.1 kg 63.3 ± 4.9 42 ± 17 43 ± 17 25 ± 2 CLcr 100.2 ± 28.4 ml/min 98.9 ± 29.2 ml/min 112.2 ± 15.5 ml/min 1052 630 422 N.D. 10 1 3.8 23.4 11.5 11.5.1 2.7.6.11-5 89.3%617/69195% = 87.0% 91.6% 87.8%245/27995% = 84.0%91.7% 98
2.7.6 2.7.6.11-5 III %a b 95% 42060.819728.5446.4 304.3 691 89.387.0, 91.6 21066.77925.1 144.4 123.8 315 91.788.7, 94.8 21055.911831.4308.0 184.8 376 87.283.9, 90.6 20974.93612.9 186.5 165.7 279 87.884.0, 91.7 6381.8 911.7 22.6 33.9 77 93.588.0, 99.0 6380.8 79.0 45.1 45.1 78 89.783.0, 96.5 7172.4 1414.3 77.1 66.1 98 86.780.0, 93.5 1246.2 623.1 519.2 311.5 26 69.251.5, 87.0 % a + b 11.5.2 11.5.2.1 11.5.2.1.1 2.7.6.11-6 74.5%546/73395%CI = 71.3%, 77.6% 86.1%253/29495%CI = 82.1%, 90.0% 99
2.7.6 2.7.6.11-6 III 24333.230341.315521.1324.4 733 %a b 95% 74.571.3, 77.6 11032.113840.28023.3 154.4 343 72.367.6, 77.0 13334.116542.37519.2 174.4 390 76.472.2, 80.6 17760.27625.9 299.9 124.1 294 86.182.1, 90.0 5361.6 2326.7 78.1 33.5 86 88.481.6, 95.1 5266.7 1823.1 67.7 22.6 78 89.783.0, 96.5 6258.5 2927.4 98.5 65.7 106 85.879.2, 92.5 1041.7 625.0 729.2 14.2 24 66.747.8, 85.5 % a + b 11.5.2.1.2 Visit 3 Visit 4 75.8%47/62 87.7%50/57 69.2%175/253 89.3%208/233 H. parainfluenzae 69.2%54/78 88.6%62/70 K. pneumoniae 76.9%50/65 93.3% 56/60 H. influenzae 70.0%28/40 91.9%34/37 S. pneumoniae 79.3% 23/29 81.5%22/27 76.0%19/25 82.6%19/23 88.6%109/123 86.2%100/116 E. coli 84.9%79/93 85.2%75/88 P. mirabilis 100%13/13 84.6%11/13 K. pneumoniae 100%13/13 90.9%10/11 11.5.2.1.3 Visit 4 100%2/2 100%47/47 100%3/3 + 100%1/1 100
2.7.6 11.5.2.2 11.5.2.2.1 Visit 3 Visit 4 2.7.6.11-7 Visit 3 Visit 4 97.3%747/768 96.4%666/691 97.5% 348/357 96.8%306/316 97.1%399/411 96.0%360/375 Visit 3 Visit 4 96.0%290/302 95.7%267/279 94.2%81/86 93.7%74/79 98.8%81/82 98.7%76/77 94.4%101/107 94.9%93/98 100%27/27 96.0%24/25 101
2.7.6 2.7.6.11-7 III %a b 95% 27035.247762.1212.7 768 97.396.1,98.4 11331.723565.892.5 357 97.595.9,99.1 15738.224258.9122.9 411 97.195.5,98.7 23878.85217.2124.0 302 96.093.8,98.2 6879.1 1315.1 55.8 86 94.289.2,99.1 6882.9 1315.9 11.2 82 98.896.4,100.0 8579.4 1615.0 65.6 107 94.490.0,98.8 1763.0 1037.0 00.0 27 100 100,100 45766.120930.2253.6 691 96.495.0,97.8 21367.49329.4103.2 316 96.894.9,98.8 24465.111630.9154.0 375 96.094.0,98.0 24086.0279.7 124.3 279 95.793.3,98.1 7291.1 22.5 56.3 79 93.788.3,99.0 7090.9 67.8 11.3 77 98.796.2,100.0 8081.6 1313.3 55.1 98 94.990.5,99.3 1872.0 624.0 14.0 25 % a + b 96.088.3,100.0 11.5.2.2.2 97.9%462/472 96.2% 575/598 18 40 97.2%385/396 40 60 96.5%415/430 60 97.1%237/244 40 kg 60 kg 96.5%467/484 60 kg 80 kg 97.3%504/518 80 kg 97.0%65/67 102
2.7.6 11.5.2.2.3 Visit 3 Visit 4 96.9%63/65 94.7%54/57 97.7% 260/266 97.0%226/233 H. parainfluenzae 98.8%84/85 97.1%68/70 K. pneumoniae 98.5%67/68 96.7%59/61H. influenzae 95.1%39/41 94.6%35/37S. pneumoniae 96.9%31/32 92.6%25/27 92.0%23/25 91.3%21/23 96.9% 125/129 94.9%111/117 E. coli 95.9%93/97 93.3%83/89 K. pneumoniae 100%14/14 100%11/11 P. mirabilis 100%13/13 100%13/13 11.5.2.2.4 Visit 4 100%47/47 100%3/3 100%2/2 + 100%1/1 11.5.2.3 11.5.2.3.1 Visit 3 Visit 4 Visit 3 Visit 4 92.6%276/298 96.6%256/265 Visit 3 Visit 4 94.6%139/147 93.3%126/135 11.5.2.4 11.5.2.4.1 Visit 3 Visit 4 Visit 3 Visit 4 93.0%291/313 97.1%264/272 Visit 3 Visit 4 94.0% 140/149 95.5%126/132 11.5.2.4.2 Visit 3 2.7.6.11-8 2.7.6.11-9 103
2.7.6 S. aureus 100% 21/21 S. pneumoniae 96.6%28/29 K. pneumoniae 98.5%64/65 H. influenzae 97.4%37/38H. parainfluenzae 90.5%67/74 E. coli 91.5%86/94 K. pneumoniae 100%13/13P. mirabilis 100%13/13 2.7.6.11-8 III % a b 95% 58 3 61 95.189.7, 100 S. aureus 21 0 21 100100, 100 S. agalactiae 1 0 1 S. pneumoniae 28 1 29 96.689.9, 100 S. mitis 1 0 1 β-hemolytic treptococcus 7 1 8 87.564.6, 100 E. faecium 0 1 1 0.00.0, 0.0 233 19 252 92.589.2, 95.7 Neisseria spp. 2 0 2 100100, 100 M.(B.) catarrhalis 7 0 7 100100, 100 A. baumannii 13 1 14 92.979.4, 100 A. lwoffii 3 0 3 100100, 100 A. junii 2 0 2 100100, 100 E. coli 5 1 6 83.353.5, 100 C. freundii 1 0 1 K. pneumoniae 64 1 65 98.595.5, 100 K. ozaenae 2 0 2 100100, 100 K. oxytoca 3 0 3 100100, 100 P. agglomerans 1 0 1 E. cloacae 1 2 3 33.30.0, 86.7 E. aerogenes 1 0 1 S. marcescens 3 0 3 100100, 100 P. mirabilis 5 0 5 100100, 100 P. vulgaris 2 0 2 100100, 100 P. rettgeri 1 0 1 Haemophilus spp. 2 0 2 100100, 100 H. influenzae 37 1 38 97.492.3, 100 H. parainfluenzae 67 7 74 90.583.9, 97.2 P. aeruginosa 9 6 15 60.035.2, 84.8 S. maltophilia 2 0 2 100100, 100 % a b 104
2.7.6 2.7.6.11-9 III % a b 95% 24 1 25 96.088.3, 100 CNS 1 0 1 S. aureus 4 0 4 100100, 100 S. epidermidis 4 0 4 100100, 100 S. haemolyticus 1 0 1 S. saprophyticus 5 0 5 100100, 100 S. agalactiae 1 0 1 S. anginosus 2 0 2 100100, 100 S. mitis 1 0 1 S. sanguis 1 0 1 E. faecalis 2 0 2 100100, 100 E. faecium 0 1 1 0.00.0, 0.0 Leuconostoc spp. 1 0 1 G. morbillorum 1 0 1 116 8 124 93.589.2, 97.9 E. coli 86 8 94 91.585.8, 97.1 K. pneumoniae 13 0 13 100100, 100 K. oxytoca 1 0 1 E. aerogenes 2 0 2 100100, 100 P. mirabilis 13 0 13 100100, 100 A. johnsonii 1 0 1 % a b 11.5.2.4.3 Visit 3 MIC MIC 2.7.6.11-10 2.7.6.11-13 MIC 0.06 µg/ml 169 0.125 µg/ml 26 0.25 µg/ml 57 0.5 µg/ml 62 1 µg/ml 31 2 µg/ml 18 4 µg/ml 9 8 µg/ml 16 16 µg/ml 26 32 µg/ml 3 32 µg/ml 9 MIC 0.5 µg/ml 95.9%301/314 1 µg/ml 93.5%29/31 2 µg/ml 94.4%17/18 4 µg/ml 66.7%6/9 8 µg/ml 87.5%14/1616 µg/ml 76.9%20/26 32 µg/ml 3 3 32 µg/ml 66.7%6/9 MIC 0.5µg/mL 314 13 H. influenzae 1 H. parainfluenzae 5 K. pneumoniae 1 E. cloacae 2 P. aeruginosa 1 β-hemolytic Streptococcus 1 E. coli 1 P. aeruginosa 1 1 µg/ml 31 2 105
2.7.6 H. parainfluenzae 1 E. faecium 1 2 µg/m 18 1 S. pneumoniae 1 4 µg/ml 9 3 P. aeruginosa 3 8 µg/ml 16 2 A. baumannii 1 E. coli 1 16 µg/ml 26 6 E. coli 4 P. aeruginosa 1 E. faecium 1 32 µg/ml 9 3 E. coli 3 106
2.7.6.11-10 MIC MIC 0.06~>128 III Pathogen MIC(µg/mL) <=0.06 0.125 0.25 0.5 1 2 4 8 16 32 64 128 >128 Total Eradication rate (%) a) 2/2 16/16 1/1 0/1 1/1 20/21 95.2 S. aureus 2/2 16/16 1/1 1/1 20/20 100.0 E. faecium 0/1 0/1 0.0 74/78 13/13 7/7 10/11 2/2 1/4 1/2 0/2 1/1 1/1 110/121 90.9 A. baumannii 3/3 8/8 2/2 0/1 13/14 92.9 A. lwoffii 1/1 1/1 1/1 3/3 100.0 A. junii 2/2 2/2 100.0 E. coli 3/3 2/2 0/1 5/6 83.3 C. freundii 1/1 1/1 100.0 K. pneumoniae 52/53 1/1 1/1 1/1 1/1 1/1 57/58 98.3 K. ozaenae 1/1 1/1 2/2 100.0 K. oxytoca 3/3 3/3 100.0 P. agglomerans 1/1 1/1 100.0 E. cloacae 1/3 1/3 33.3 E. aerogenes 1/1 1/1 100.0 S. marcescens 3/3 3/3 100.0 P. mirabilis 4/4 1/1 5/5 100.0 P. vulgaris 1/1 1/1 2/2 100.0 P. rettgeri 1/1 1/1 100.0 P. aeruginosa 0/1 1/1 1/1 4/5 1/4 0/1 1/1 8/14 57.1 S. maltophilia 1/1 1/1 2/2 100.0 Total 74/78 15/15 23/23 11/12 2/3 1/4 2/3 0/2 1/1 1/1 130/142 91.5 Response rate (%) a) 94.9 100.0 100.0 91.7 66.7-25.0 66.7 0.0 100.0-100.0-91.5 a 107