1.8.2 Page1 1.8.2 96% 2002 40 B 1 123 (1) in vitro 1) in vitro C. glabrata C. krusei 1 2 19951997 3 1999 2002 MIC MIC 2
1.8.2 Page2 1 19951997 MIC () MIC 50 / MIC 90 µg/ml Candida albicans (54) 0.016 / 0.063 Candida glabrata (25) 0.25 / 0.5 Candida guilliermondii a) (2) 0.125 Candida krusei a) (5) 0.25 1 Candida parapsilosis (13) 0.063 / 0.125 Candida tropicalis (12) 0.031 / 0.063 Aspergillus fumigatus (10) 0.25 / 0.5 Other Aspergillus spp. a) (8) 0.25 1 Cryptococcus neoformans (16) 0.125 / 0.25 Fusarium oxysporum a) (2) 4 >8 Fusarium solani a) (1) 2 Scedosporium apiospermum a) (4) 0.125 0.25 a) 10 MIC 99M109,496MIC1 Table12 23 MIC MICµg/mL 0.25 7 A. fumigatus 14 0.5 3 1 4 A. niger 1 0.5 1 0.0039 1 0.0078 3 C. albicans 11 0.016 2 0.031 3 0.063 1 0.125 1 0.063 1 C. glabrata 6 0.125 4 0.25 1 C. guilliermondii 1 0.063 1 C. krusei 1 0.25 1 C. parapsilosis 2 0.031 1 0.063 1 0.063 1 C. neoformans 4 0.125 2 0.25 1 Fusarium sp. 1 4 1 A1501001 Table 5.11.1 3 3.4 µg/ml SD=1.8 µg/ml 2.9 µg/ml 0.6 µg/ml8.4 µg/ml MIC
1.8.2 Page3 2) PK 4.6 L/kg 110 0.221.0 0.46 1000 ng/ml 1000 ng/g 3) 3 3 3 (1501001) 1/2 5/5 4/4 1/1 11/12 (91.7%) 10/16 3/5 14/18 1/1 28/40 (70.0%) () / 3 3 (150307/602) (150309/604) 11/21 23/38 1/2 1/1 36/62 (58.1%) 67/119 1/2 2/7 1/1 71/129 (55.0%) 40/86 4/12 5/9 4/7 53/114 (46.5%) 3 (150608) 162/248 162/248 (65.3%)
1.8.2 Page4 3 (1501001) 1/1 7/7 8/8 (100%) () / 3 3 (150307/602) (150309/604) 1/4 0/1 3/9 1/2 1/1 6/17 (35.3%) 1/2 1/1 2/4 0/1 4/8 (50.0%) 0/3 1/2 2/2 0/1 0/1 3/9 (33.3%) 47/60 (78.3%) 71/129 (55.0%) 102/210 (48.6%) 3 (150608) 162/248 (65.3%) (a) 1/2 5/5 4/4 1/1 11/1291.7% 28/4070.0% 8/8100% in vitro MIC=0.1250.25 µg/ml 3/933.3% 1 3 MIC 4 µg/ml
1.8.2 Page5 MIC 4/850.0% in vitro 4) (a) In vitro DI/022/0Scedosporium apiospermum B MIC0.391.5625 71 µg/ml 1 1995 1997 Scedosporium apiospermum 4 MIC 0.1250.25 µg/ml (b) In vivo in vivo DI/09/98 DI/002/98 2 Scedosporium apiospermum a) DI/09/98 S. apiospermum H76.03 2.510 mg/kg 1 2 10 4 10 mg/kg 1 2 10 1CTD 2.6.2.2 (1) 1) DI/022/0 2CTD 2.6.2.2 (2) 4) Scedosporium p3233
1.8.2 Page6 4 S. apiospermum H76.03 (mg/kg) log 10 CFU/g ± 1 2 1 2 10 11/11 <0.08 *** 0.65 ± 0.27 *** 1.44 ± 0.19 *** 0.33 ± 0.26 *** 2.62 ± 0.29 *** 5 11/11 <0.08 *** 0.92 ± 0.43 ** 1.58 ± 0.34 *** 0.50 ± 0.39 *** 2.88 ± 0.44 *** 2.5 3/11 <0.07 *** 1.71 ± 0.46 2.68 ± 0.58 1.32 ± 0.49 ** 3.64 ± 0.52 *** 10 1/10 1.02 ± 0.78 *** 1.63 ± 0.52 * 2.83 ± 0.87 1.78 ± 0.36 * 4.22 ± 0.46 *** 0 0/11 2.69 ± 0.51 2.23 ± 0.74 2.96 ± 0.24 2.11 ± 0.26 5.01 ± 0.44 * = P<0.05, ** = P<0.01, *** = P<0.001 t DI/09/98Table 2 b) DI/002/98 S. apiospermum H76.03 110 mg/kg 1 2 5 5 110 mg/kg 1 2 5 B 2.5 mg/kg 1 1 5 5 S. apiospermum H76.03 (mg/kg) log 10 CFU/g 1 2 1 2 B 1 1 10 11/11 <0.08 *** <0.63 * 2.20 ± 0.81 ** <0.84 ** 3.16 ± 0.70 ** 5 9/11 0.61 ± 0.39 ** 0.76 ± 0.56 * 2.42 ± 0.68 * 0.95 ± 0.55 ** 3.36 ± 0.69 ** 1 7/11 2.85 ± 1.36 1.47 ± 0.88 2.85 ± 0.72 2.06 ± 0.84 4.09 ± 0.95 10 4/11 <2.66 <1.30 2.62 ± 0.72 2.05 ± 0.91 3.66 ± 1.14 5 4/11 3.33 ± 1.05 1.26 ± 0.95 2.93 ± 0.77 2.15 ± 0.85 4.37 ± 0.59 1 1/6 3.53 ± 0.77 0.63 ± 0.30 * 2.43 ± 0.26 2.24 ± 0.51 3.80 ± 0.38 2.5 3/10 <2.09 1.53 ± 1.30 2.84 ± 1.01 1.67 ± 0.74 * 4.62 ± 0.90 0 5/11 3.60 ± 1.24 1.50 ± 0.89 3.07 ± 0.51 2.48 ± 0.73 4.34 ± 0.56 * = P<0.05, ** = P<0.01, *** = P<0.001 t DI/002/98Table 3
1.8.2 Page7 (c) 150309/604 10 10 6 6 150309/604 (MITT) ID MIC(µg/mL) 30901441181 58 S. apiospermum 0.25 30901441182 62 S. apiospermum 0.125 30902031130 27 ALL S. prolificans 4 30902031131 29 ALL S. prolificans 4 30902031132 70 AML Scedosporium sp. N/A 30902201701 27 S. apiospermum 0.25 30902251481 33 S. apiospermum 0.25 a) 60410056037 51 S. apiospermum N/A 60410406087 38 AML S. apiospermum 0.125 60410186026 46 CML Pseudallescheria boydii b) 0.125 CTD 2.5.4 p69 35 a) b) S. apiospermum 10 3 150307/602150309/604 1/24/12 1 A1501001150309/604 150608 1/211/21 23/31 2 a) 2 1CTD 1.8.2 (1) 3) 2CTD 1.8.2 (1) 3)
1.8.2 Page8 Thomas J. Walsh et al, Pediatric Infectious Disease Journal 2002; 21: 240248 CNS 5 1 2 60%3/5 Mark A. Nesky et al, Clinical Infectious Disease 2000; 31: 673677 Pseudallescheria boydiiscedosporium apiospermum 1 59 CT B 2 14 2 14 12 MRI Pseudallescheria boydii MIC B MIC >160.25 µg/ml b) 4 Thomas J. Walsh et al, Pediatric Infectious Disease Journal 2002; 21: 240248 1 1 Corrado Girmenia et al, Journal of Clinical Microbiology 1998; 36: 14361438 1 25 Scedosporium apiospermum CT Scedosporium apiospermum B 7
1.8.2 Page9 Scedosporium apiospermum B MIC 0.254 µg/ml Patricia Munoz et al, Clinical infectious Disease 2000; 31: 14991501 1 75 CT Scedosporium apiospermum 7 CT 40 63 8 Scedosporium apiospermum MIC 0.122 µg/ml B.P Howden et al, European Journal of Clinical Microbiology and Infectious Disease 2003; 22: 111113 1 nonmyeloablative BMT 53 MRI 3 Scedosporium prolificans Scedosporium prolificans 15 MRI Scedosporium prolificans MIC 24>16 µg/ml MIC 0.008 µg/ml 0.5 µg/ml
1.8.2 Page10 (d) 5) EU
1.8.2 Page11 1. 1.
1.8.2 Page12 (2) 40 kg 1 300 mg 1 2 2 1 150 mg 1 200 mg 1 2 1 400 mg 1 2 2 1 300 mg 1 2 40 kg 1 150 mg 1 2 2 1 100 mg 1 2 2 1 150 mg 1 2 1 6 mg/kg 1 2 2 1 3 mg/kg 1 4 mg/kg 1 2 12 23 4 40 kg 5 67 8
1.8.2 Page13 1) 2 (a) 3 A1501001 a) 3 c) 1 2 3 4 57 3 200 mg bid a) 300 mg bid 200 mg bid 200 mg bid 150 mg bid 4 mg/kg bid 4 mg/kg bid 4 mg/kg bid b) 6 mg/kg bid 3 mg/kg bid 3 mg/kg bid 3 mg/kg bid 3 mg/kg bid 2.5 µg/ml 2.5 µg/ml 2.5 µg/ml 2.5 µg/ml bid1 2 a) 40 kg 1 150 mg 1 2 2 100 mg 1 2 b) 3 3 2.5 µg/ml 200 mg 1 2 2.5 µg/ml 150 mg 1 2 c) 2 200 mg 1 2 4 mg/kg 1 2 3 200 mg 1 2 150 mg 1 2 100 mg 1 2 40 kg 4 mg/kg 1 2 3 mg/kg 1 2 57 4.5 µg/ml 84 300 mg 1 2 4 mg/kg 1 2 MIC 1 µg/ml 6 µg/ml 4.5 µg/ml 1 150230 6 µg/ml PK
1.8.2 Page14 CYP2C19 1 µg/ml 6 µg/ml 1 1 1 300 mg 1 2 40 kg 150 mg 1 2 1 6 mg/kg 1 2 3 57 CYP2C19 1 µg/ml 6 µg/ml 57 4.5 µg/ml 12 b) 3 40 kg 40 kg CYP2C19 100 CYP2C19 DRC DRC 2.7.3 40 kg 40 kg 86 2 57 1 3 57 1 7 1 8 57 3 150 mg 1 2 3 mg/kg 1 2 EM HEM PM
1.8.2 Page15 740 kg N=86 1 2 57 57 a) CYP2C19 EM HEM PM EM HEM PM 300 mg 0 0 0 0 0 1 0 0 0 1 250 mg 0 0 0 0 0 0 0 0 1 1 200 mg 16 23 10 5 54 3 13 1 1 18 150 mg 0 0 0 0 0 12 6 8 4 30 100 mg 1 0 0 0 1 1 2 1 0 4 4 mg/kg 5 5 1 5 16 2 1 0 0 3 3.5 mg/kg 0 0 0 0 0 0 1 0 0 1 3 mg/kg 5 4 4 2 15 6 6 3 5 20 2 mg/kg 0 0 0 0 0 0 1 1 1 3 27 32 15 12 86 25 30 14 12 81 2.7.3.(1)Table 5.1 a)86 5 57 840 kg 1 (N=81) EM HEM PM 28 a) 1.6 mg/kg 4.0 mg/kg 3.0 mg/kg 3.0 mg/kg 2.6 mg/kg 3.0 mg/kg 3.0 mg/kg 66 a) 57.7 mg 300.0 mg 150.0 mg 200.0 mg 108.9 mg 150.0 mg 150.0 mg 2.7.3.(1)Table 5.2 a) 27 12 54 1 40 kg 40 kg 14 2 57 1 3 57 1 9 1 10 100 mg 1 2 3 mg/kg 1 2 940 kg N=14 2 57 57 a) CYP2C19 EM HEM PM EM HEM PM 200 mg 0 1 0 0 1 0 0 0 0 0 150 mg 0 0 0 0 0 0 0 0 1 1 100 mg 0 4 1 2 7 1 3 0 1 5 50 mg 0 0 0 0 0 0 1 0 0 1 4 mg/kg 1 1 1 0 3 0 1 0 0 1 3 mg/kg 0 2 1 0 3 0 2 1 0 3 1 8 3 2 14 1 7 1 2 11 2.7.3.(1)Table 5.1 a) 14 3 57
1.8.2 Page16 10 40 kg 1 (N=11) EM HEM PM 4 a) 2.1 mg/kg 4.0 mg/kg 3.0 mg/kg 3.0 mg/kg 3.0 mg/kg 11 a) 50 mg 163.5 mg 142.5 mg 100.0 mg 100.0 mg 156.8 mg 100.0 mg 2.7.3.(1)Table 5.2 a) 4 3 3 1 150 mg 1 2 40 kg 100 mg 1 2 1 3 mg/kg 1 2 3 200 mg 1 2 4 mg/kg 1 2 18 4 CYP2C19 EM3 HEM13 PM1 1 EM2 HEM2 57 EM HEM PM 1 84 300 mg 1 2 4 mg/kg 1 2 7 5 EM2 HEM2 1 7 EM2 HEM3 PM1 1 40 kg 150 mg 1 2 7 3 EM1 HEM1 1 200 mg 1 2 7 1 57 150 mg 1 2 3 mg/kg 1 2 CYP2C19 3 2.5 µg/ml 1 PM 3 2.5 µg/ml 3 2.5 µg/ml PM 200 mg 1 2 1 4 mg/kg 1 2 3 CYP2C19 PM 200 mg 1 2 150 mg 1 2 4 mg/kg 1 2 3 mg/kg 1 2 EM HEM 2.5 µg/ml 200 mg 1 2 150 mg1 2 4 mg/kg 1 2 3 mg/kg 1 2 CYP2C19 2.5 µg/ml 150 mg 1 2 3
1.8.2 Page17 mg/kg 1 2 3 2.5 µg/ml CYP2C19 12 11 Plasma µ concentration of voriconazole (ug/ml) 10 9 8 7 6 5 4 3 2 1 0 EM HEM PM 1 CYP2C19 3 25%50%75% 25% 75% 1.5 3 3 8 3.4 µg/ml (SD=1.8 µg/ml) 2.9 µg/ml 0.6 µg/ml8.4 µg/ml c) 3 DRC PPS 65 76.9%50/65 91.7%11/12 68.3%28/41 100%8/8 PPS 65 57 1 64 57 11 PPS 57 1 1 200 mg 1 2 DRC 4 CYP2C19 HEM CYP2C19
1.8.2 Page18 11 PPS a) 1 (%) EM HEM PM 250 mg 0/0 0/0 0/0 1/1 1/1 200 mg 3/3 10/10(100%) 1/1 1/1 15/15(100%) 150 mg 7/8(87.5%) 4/4 6/7(85.7%) 0/2 17/21(81.0%) 100 mg 1/2 3/4 0/0 0/1 4/7(57.1%) 50 mg 0/0 0/1 0/0 0/0 0/1 4.0 mg/kg 0/0 1/1 0/0 0/0 1/1 3.5 mg/kg 0/0 1/1 0/0 0/0 1/1 3 mg/kg 2/4 4/6(66.7%) 1/1 2/3 9/14(64.3%) 2 mg/kg 0/0 1/1 0/1 0/1 1/3 13/17(76.5%) 24/28(85.7%) 8/10(80.0%) 4/9(44.4%) 49/64(76.6%) 2.7.3.(1)Table 4.7 a ) 1 d) 3 100 99 99.0% 78 78.0% 57 100 7 4 3 1 92 57 12 13 CYP2C19 PM EM/HEM 3 3 CYP2C19 1 14 AST, ALT, AlP, GTP, 2.7.3
1.8.2 Page19 12 (%) 1 EM HEM PM 300 mg 1/1(100%) 0 0 0 1/1(100%) 250 mg 0 0 0 1/1(100%) 1/1(100%) 200 mg 3/3(100%) 12/13(92.3%) 1/1(100%) 1/1(100%) 17/18(94.4%) 150 mg 10/12(83.3%) 6/6(100%) 7/8(87.5%) 5/5(100%) 28/31(90.3%) 100 mg a) 2/2(100%) 4/5(80.0%) 1/1(100%) 1/1(100%) 8/9(88.9%) 50 mg b) 0 1/1(100%) 0 0 1/1(100%) 4 mg/kg 2/2(100%) 2/2(100%) 0 0 4/4(100%) 3.5 mg/kg 0 1/1(100%) 0 0 1/1(100%) 3 mg/kg 6/6(100%) 8/8(100%) 4/4(100%) 5/5(100%) 23/23(100%) 2 mg/kg 0 1/1(100%) 1/1(100%) 1/1(100%) 3/3(100%) 24/26(92.3%) 35/37(94.6%) 14/15(93.3%) 14/14(100%) 87/92(94.6%) 2.7.3.(1)Table 6.1 a) 40 kg 5 40 kg 4 b) 40 kg 13 (%) 1 EM HEM PM 300 mg 1/1(100%) 0 0 0 1/1(100%) 250 mg 0 0 0 0/1(0%) 0/1(0%) 200 mg 2/3(66.7%) 6/13(46.2%) 1/1(100%) 1/1(100%) 10/18(55.6%) 150 mg 5/12(41.7%) 4/6(66.7%) 6/8(75.0%) 4/5(80.0%) 19/31(61.3%) 100 mg a) 1/2(50.0%) 3/5(60.0%) 1/1(100%) 1/1(100%) 6/9(66.7%) 50 mg b) 0 0/1(0%) 0 0 0/1(0%) 4 mg/kg 0/2(0%) 1/2(50.0%) 0 0 1/4(25.0%) 3.5 mg/kg 0 1/1(100%) 0 0 1/1(100%) 3 mg/kg 3/6(50.0%) 5/8(62.5%) 3/4(75.0%) 3/5(60.0%) 14/23(60.9%) 2 mg/kg 0 0/1(0%) 1/1(100%) 1/1(100%) 2/3(66.7%) 12/26(46.2%) 20/37(54.1%) 12/15(80.0%) 10/14(71.4%) 54/92(58.7%) 2.7.3.(1)Table 6.2 a) 40 kg 5 40 kg 4 b) 40 kg
1.8.2 Page20 ID 14 (kg) 0108 70 35.8 HEM 2102 51 64.2 PM 4001 70 54.1 HEM a mg 200 256 600 b) c) d) 2 3 42 3 20 e) 1 a) b) c) d) 1 e) e) 3 3 150 mg 200 mg 1 2 40 kg 100 mg 1 2 3 mg/kg 4 mg/kg 1 2 3 150 mg 1 2 40 kg 100 mg 1 2 3 mg/kg 1 2 57 PM HEM/EM CYP2C19 PM EM/HEM (b) 1 1 A1501022400 mg 1
1.8.2 Page21 2 1 2 200 mg 1 2 CYP2C19 300 mg 1 2 CYP2C19 HEM/EM 10 3 2 1 200300 mg 1 2 1 3 mg/kg 1 2 CYP2C19 4 mg/kg 1 2 CYP2C19 HEM/EM 1 3 mg/kg4 mg/kg 1 2 (c) CYP2C19 CYP2C19 CYP2C19 3 PK CYP2C19 2.7.2.3 CYP2C19 2.7.4.5.1 CYP2C19 3 3 EMHEM 2.5 µg/ml 1 µg/ml 6 µg/ml 1PM PM CYP2C19 EM HEM PM (d) 1 150 mg 1 200 mg 1 2 40 kg 100 mg 1 2 1 3 mg/kg 1 4 mg/kg 1 2
1.8.2 Page22 1 300 mg 1 2 1 4 mg/kg 1 2 5) 2) 1 A1501022 1 400 mg 1 2 200 mg 1 2 23 2 (ng/ml) 2 A1501022 1 VRCJP97501 1 6 mg/kg 1 2 3 mg/kg 4 mg/kg 1 2 24 3
1.8.2 Page23 (ng/ml) 3 VRCJP97501 3 A1501001 300 mg 1 2 6 mg/kg 1 2 1 1 1 300 mg 1 2 400 mg 1 2 6 mg/kg 1 2 5 3) PK 96%CV 13% 3 PK 100% ph
1.8.2 Page24 4) 40 kg 2 150303 44 kg 1 200 mg 1 2 10 µg/ml 40 kg 40 kg 40 kg PK 3 40 kg 40 kg 40 kg 150 mg 1 2 2 100 mg 1 2 3 3 61 3 15 15 3 µg/ml 25%75% 40 kg 8 2.6 1.4 3.4 0.6 5.2 40 kg 53 3.8 2.4 5.5 0.7 8.0 2.7.3.(1)Table 3.3 40 kg 40 kg 3 65 40 kg 76.8%43/56 40 kg 77.8%7/9 100 40 kg 80.2%69/86 40 kg 64.3%9/14 40 kg 150 mg 1 2 2 100 mg 1 2
1.8.2 Page25 5) Therapeutic Drug Monitoring (TDM) 3 3 4.5 µg/ml PK/PD 2/3 TDM (a) a) 1 2 5 2 1 4 A1501022AST, ALT,GTP 3 HEM1 300 mg 1 2 VRCJP96503 AST,ALT,GTP 2 PM 1 HEM 1 1 300 mg 1 2 5 5 3 4.5 µg/ml 4.5 µg/ml 4.5 µg/ml 1
1.8.2 Page26 血漿中ボリコナゾール濃度のトラフ値 (μg/ml) 12 10 8 6 4 2 0 EM / HEM 200 mg bid (A1501022) EM / HEM 300 mg bid (A1501022) PM 200 mg bid (A1501022) EM / HEM / PM 300 mg bid (VRCJP96503) 41 b) 3 3 3 57 84 8 8 5
1.8.2 Page27 12 11 Plasma µ concentration of voriconazole (ug/ml) 10 9 8 7 6 5 4 3 2 1 0 Present Absent 5 8 25%50%75% 25% 75% 1.5 3 3 PK PK PD PK PD PD 3 A1501001 100 MedDRA NOS NOS NOS NOS NOS
1.8.2 Page28 NOS PK 1 PK PK 6 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 6 A1501001 25%50%75% 25% 75% 1.5 3624 ng/ml 2049 ng/ml 3331 ng/ml 112710735 ng/ml 2821 ng/ml 1592 ng/ml 2421 ng/ml 5887260 ng/ml 3
1.8.2 Page29 c) 2/3 ASTALTAlP2.7.2.3 PK/PD ASTAlP Receiver Operating Characteristic CurvesROC 7 2/3 AST 12 10 10/101 (%) 8 6 4 2 0 6/86 8/140 13/261 2/50 19/434 3/76 12/601 6/173 9/499 01 12 23 34 45 56 67 78 89 9< µ 7 AST d)
1.8.2 Page30 (b) a) 3 3 3 57 84 8 3 8 8 Plasma µ concentration of voriconazole (ug/ml) 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 EFFECTIVE INEFFECTIVE 8 8 DRC PPS 25%50%75% 25% 75% 1.5 b) 2/3 2/3 2.7.2.3 9
1.8.2 Page31 % (µg/ml) 9 a) a) 2/3 95% 150303304309603604 608 n=280 2.7.2.3 c) Rex host factor TDM (c) 3 16 17 3 4401 AlP GTP 4401 AlP GTP 28
1.8.2 Page32 1 2102 2102 3.710 4 /µl 10.310 4 /µl ID a) () 16 b) * COSTART c 0001 EM 72 6mg/kg (1) 3mg/kg (25) 150mg (628) 634 0303 PM 55 300mg (1) 200mg (25) 100mg (642) 316 0503 53 300mg (1)200mg (24)150 mg (525) 100 mg (2639) 50mg (4060)100mg (6174) 3438 0601 PM 64 6mg/kg (1) 3mg/kg (25) 2mg/kg (510) 1.5mg/kg (10 22) 57 1402 PM 62 300mg (1) 200mg (24) 839 150mg (510)100mg (1184) 1011 1409 PM 55 1411 PM 49 2002 PM 53 2102 PM 51 2602 EM 72 3301 EM 67 4206 PM 67 4401 57 300mg (1) 200mg (26) 150mg (713)100mg (1484) 300mg (1) 200mg (24) 150mg (546)100mg (4684) 300mg (1) 200mg (26) 150mg (712)100mg (1285) 6mg/kg (12)3mg/kg (212) 2mg/kg (1235)150mg (3642) 6mg/kg (1) 4mg/kg (24) 3mg/kg (515)150mg (1624) 100mg (2584) 300mg (12) 200mg (25) 150mg (610)100mg (1184) 300mg (1) 200mg (210) 150mg (1127)100mg (2884) 300mg (12) 200mg (25) 150mg (56) 100mg (625) 150mg (2543)200mg (4353) 8113 12115 8114 AST 1222 ALT 1242 2243 GTP 950 1020 24113 AST 463 ALT 455 AlP 4 GTP 4 LDH 481 a) b) c) 1 Table 4.2.2.2 13 Table 6.21315
1.8.2 Page33 ID a) 17 () * () COSTART () b) c) 0001 EM 72 6mg/kg (1)3mg/kg (25) 150mg (628) 28 2835 0002 HEM 76 300mg (1)200mg (24) 4 4 4 () 0101 EM 56 300mg (1) 200mg (25) 150mg (58) 8 110 0102 HEM 68 6mg/kg (1)3mg/kg (213) 41 200mg (1441) 2266 0108 HEM 70 150mg (1)100mg (2) 2 35 0302 PM 51 6mg/kg (1)4mg/kg (24) 4 44 44 0501 PM 74 150mg (1)100mg (2) 2 12 1410 HEM 58 6mg/kg (12)4mg/kg (25) 3mg/kg (615) 15 1523 1901 PM 76 6mg/kg (1)3mg/kg (28) 8 817 2102 PM 51 6mg/kg (12)3mg/kg (212) 20 2mg/kg (1235) 150mg 42 (3642) 3660 2801 HEM 60 300mg (1) 200mg (29) 13 150mg (1013) 857 3701 HEM 74 150mg (1)100mg (210) 10 245 4201 51 150mg (1)100mg (229) 73 200mg (3073) 7395 4401 57 300mg (12)200mg (25) 150mg (56)100mg (625) 53 150mg (2543) 200mg 3985 (4353) a) b) 1 c) Table 4.2.1.24.2.3.2 6.9 13 Table 6.2 15 (d) 3 PK 3 PK PM EM/HEM 2.7.2.3 18 3 EM 28 HEM 40 PM 18 PK 1 200 mg 1 2 1 4 mg/kg 1 2 PM EM/HEM 1 200 mg 1 2 1 4 mg/kg 1 2 PM 1 150 mg 1 2 1 3 mg/kg 1 2 3 4.5 µg/ml EM/HEM PM
1.8.2 Page34 PM 20%PM 4.5 µg/ml PM EM/HEM 18 1 2 14 C min A1501001 2 150 mg 100 mg 150/100 mg 300 mg 150 mg 300/150 mg 300 mg 200 mg 300/200 mg 6 mg/kg 3 mg/kg 6/3 mg/kg 6 mg/kg 4 mg/kg 6/4 mg/kg < 40 kg n=1 CYP2C19 EM (n=28) HEM (n=40) PM (n=18) 40 kg < 40 kg 40 kg < 40 kg n=27 n=8 n=32 n=3 351 1726 (96.9) 3185 (100.6) 1887 (88.9) 3405 (94.6) 2319 (48.3) 2436 (72.1) 4726 (75.6) 2236 (86.1) 4071 (94.1) 3148 (84.6) 4670 (36.0) 9821 (36.7) 40 kg n=15 4108 (43.1) 8260 (50.2) ng/ml%cv (e) TDM 20% CYP2C19 PM 1 4.5 µg/ml 4 PK/PD 3 57 4.5 µg/ml
1.8.2 Page35 3 PK 1 200 mg 1 2 1 4 mg/kg 1 2 PM PM 4.5 µg/ml 18 3 PPS 65 50 2.8 µg/ml 4.5 µg/ml 3 4.5 µg/ml 6) 3 MITT 19 12
1.8.2 Page36 19 6 6313 4 8712 4 22369 1 84 20 74285 5 401085 22 84286 1 84 1 85 1 26 7 845686 1 84 1 41 1 13 1 61 Pithomyces Bipolaris 1 6 77 71286 2.7.3.(1)Table 2.2 1 N=1821 91 400 181 106 366 39 3 12
1.8.2 Page37 7) 37 1000kcal 200mg 1 2 7 C max AUC 34% 24%T max 1.4 8) 2003 5 41 20 20 a) 40 kg 40 kg 1 6 mg/kg 1 2 1 400 mg 1 2 1 200 mg 1 2 1 2 1 4 mg/kg 1 2 1 200 mg 1 2 1 100 mg 1 2 a) CPMP Summary of Product Characteristic 40 kg 1 300 mg 1 2 40 kg 1 150 mg 1 2
1.8.2 Page38 (3) 9 4 25 606 607 21 21 (1) (2) [4.1] (3) [4.2 ] (1) 1 (2) (3) 1 () <30mL/min [ SBECD ]
1.8.2 Page39 1. () () 1. (1) (2)Child Pugh C (3) (2)(1)
1.8.2 Page40 () (4) 30mL/min50 ml/min[ SBECD [ 6.(3)]] 2. (1) (2) (3) (4) () (5) SBECD 1 3mg/kg 3. CYP 2C192C9 3A4 CYP 2C192C9 3A4 (1) R R R C max 93 AUC 96 CYP3A4 C max 69AUC 78 C max 3.0AUC4.3 CYP3A4 CYP3A4
1.8.2 Page41 C max 61AUC 77 R R R R R R R R R R C max 1.4 AUC 1.4 C max 66AUC 82 CYP2C19 CYP2C9 CYP3A4 CYP2C19 CYP2C9 CYP3A4 QT CYP3A4 torsades de pointes CYP3A4 (2) C max 49AUC 69 C max 1.7AUC 1.8 CYP3A4 CYP2C9
1.8.2 Page42 HIV NNRTI HMGCoA C max 1.1AUC 1.7 C max 2.2AUC 3.2 1.9 C max 2.2 AUC 3.8 In vitro CYP3A4 In vitro CYP3A4 In vitro CYP3A4 CYP3A4 In vitro CYP3A4 CYP3A4 CYP2C9 CYP2C19 CYP3A4 In vitro CYP3A4 CYP2C9 CYP3A4
1.8.2 Page43 100 78 78.0 25.024.0γGTP 11.0 8.08.08.08.0 ASTGOT7.0ALP 7.0ALTGPT 6.05.05.05.0 5.0 (1) 1
1.8.2 Page44 10) 11 (2) 5% 15% * ADH /
1.8.2 Page45 5% 15% * ALT GPT AST GOT ALP γgtp LDH D FDP * BUN 5. 6. (1) 10mg/kg 100mg/kg (2)
1.8.2 Page46 7. 8. 1600mg 9. () PTP PTP PTP 9 4 25 607 () 10. 4.5g/mL 4.5/mL