0213-TAMI-01 30 45 75 ( ) Capsules 30 mg Capsules 45 mg Capsules 75 mg Powder for oral suspension Oseltamivir phosphate 1. 1.1 / 1.2 30 ROCHE 30 mg 45 ROCHE 45 mg 75 ROCHE 75 mg 1.3 1.4 / 1.5 : Oseltamivir phosphate 30 39.4 oseltamivir phosphate 30 oseltamivir 45 59.1 oseltamivir phosphate 45 oseltamivir 1
75 98.5 oseltamivir phosphate 75 oseltamivir 1.2% 12 oseltamivir 1.6 Oseltamivir carboxylate (cell culture assays)oseltamivir carboxylate50% 90% (EC 50 EC 90 ) 0.0008 μm >35 μm 0.004 μm >100 μm(1 μm=0.284 μg/ml) oseltamivir carboxylate oseltamivir carboxylate A oseltamivir carboxylate (neuraminidase)(hemagglutinin) A N1 I222T H274Y A N2 I222T R292K A N9 E119V R292K R305Q A H3N2 A28T R124M H1N9 H154Q 1 12 oseltamivir carboxylate 1.3% (4/301) 8.6% (9/105) A N1 H274Y N2 E119V R292K zanamivir oseltamivir oseltamivir zanamivir oseltamivir (E119V H274Y R292K) zanamivir (E119G/A/D R152K R292K) 2
2 2.1 75 13 30 45 1 2.2 3.2 13 75 2 5 13 75 2 5 40 75 2 30 45 2 ( ) 1 15 5 30 2 > 15-23 45 2 > 23-40 60 2 > 40 75 2 30 45 60 ( 4.2 ) 3
75 10 75 6 1 40 75 30 45 10 ( ) 1 10 15 30 > 15-23 45 > 23-40 60 > 40 75 30 45 60 ( 4.2 ) 2.2.1 (creatinine clearance) 60 / 30 60 / 30 5 10 30 / 30 5 30 30 CAPD (continuous ambulatory peritoneal dialysis) APD (automated peritoneal dialysis) oseltamivir carboxylate CAPD APD CAPD 3.2.5 2.4 ( < 10 /) oseltamivir 4
60 / 30 60 / 30 10-30 / 30 30 30 7 30 CAPD (continuous ambulatory peritoneal dialysis) APD (automated peritoneal dialysis) oseltamivir carboxylate CAPD APD CAPD 3.2.5 2.4 ( < 10 /) oseltamivir 3.2.5 3.2.5 1 3.2.5 1 ( 3.3 2.3 oseltamivir phosphate 2.4 ( 2.6.2 ) ( ) A B 2.2.1 ( 3.2.5 ) 5
30 25.713 sorbitol 45 oseltamivir 2.6 sorbitol sorbitol 1 ( 3.3 ) Neuropsychiatric Events 10 2.4.1 live attenuated influenza vaccine, LAIV 48 LAIV oseltamivir phosphate Oseltamivir phosphate esterases Oseltamivir oseltamivir phosphate P450 glucuronyl transferase ( 3.2 ) Cimetidine cytochrome P450 oseltamivir ( ) probenecid 2 probenecid 6
amoxicillin paracetamol oseltamivir paracetamol oseltamivir paracetamol cimetidine ( ) warfarin rimantadine amantadine oseltamivir ACE (enalapril captopril) thiazide (bendrofluazide) (penicillin cephalosporin azithromycin erythromycin doxycycline) H2 (ranitidine cimetidine) beta-(propranolol) xanthines (theophylline) (pseudoephedrine) opioids (codeine)(corticosteroids) (inhaled bronchodilators)(aspirin ibuprofen paracetamol) 2.5 2.5.1 oseltamivir 15-20% oseltamivir / ( 3.3 ) 2.5.2 oseltamivir oseltamivir oseltamivir oseltamivir oseltamivir oseltamivir 2.5.3 2.2.1 3.2.5 2.5.4 2.2.1 3.2.5 7
2.5.5 2.2.1 3.2.5 2.5.6 2.2.1 3.2.5 2.6 2.6.1 2647 / 858 1945 / 148 / (ADRs) 1-2 / / ( 75 5 75 6 ) ( 1%) 1% / ( ) (75 6 ) () oseltamivir ( 1%)( 1%) a Oseltamivir (75 ) N=2647 N=1977 Oseltamivir (75 ) N=1945 N=1588 10% 6% 8% 4% 8% 3% 2% 1% 2% 1% 17% 16% 8
<1% <1% 4% 3% a oseltamivir ( 1/10) ( 1/100 < 1/10) (n=2647) (n=1945) oseltamivir 1% oseltamivir <1% ( ) - (6% 7%) (2% 3%) - (3% 4%)(2% 2%) (1% 1%) ( ) - (3% 4%) (1% 1%)(1% 1%) - (4% 4%) (3% 3%)(2% 3%) ( ) - ( 2% 3%) - (7% 7%) (2% 2%)(1% 2%) (1% 1%) (1% <1%) ( ) - (1% <1%) - (1% <1%) ( ) - (2% 2%)(1% 1%) - (7% 7%)(5% 5%) (5% 6%)(1% 1%) ( ) - (2% 3%)(1% 2%) (1% 1%) ( ) - (3% 3%) 942 ( 65 ) 475 ( 18 1-12 ) 12 238 9
1480 698 1 12 6 12 oseltamivir 858 oseltamivir oseltamivir 1 12 (n=858) 1% (n=622) 1% (oseltamivir 16% 8%) (n=99) 6 (n=49) 148 (oseltamivir 8% 2%) oseltamivir (n=858) 1% (n=148) 5%/ oseltamivir /<1% ( ) - (9% 9%) (4% 4%) (3% 3%) ( ) - (5% 8%) (2% 3%) (1% 3%) (1% 2%) ( ) - ( 3% 4%)(2% 2%) - (12% 26%)(11% 20%) ( ) - ( 1% 2%) ( ) - (1% <1%) ( ) - (1% <1%) ( ) - (<1% 1%), ( ) - (<1% 1%) 10
2.6.2 ( ) / Stevens-Johnson oseltamivir / ( ) 2.6.2.1 oseltamivir ( 2.6.2 ) 2.7 ( 2.6 ) 3. 3.1 3.1.1 Oseltamivir phosphate oseltamivir carboxylate OC OC A B (neuraminidase enzymes) (neuraminidase) Oseltamivir carboxylate A B 50%(IC 50 ) OC (nanomolar)oc 11
3.1.2 / (inactivated vaccine) 1997-1998 40 97% A 3% B 32 38% 50% (secondary endpoint) (AUC of viral titres) 75 2 5 13 / 1 2 4 (>100 F/37.8 C) ( ) 1 12 ( 5.3 ) 67% A 33% B 48 35.8 40% 2 12
334 6 12 53.6% oseltamivir 6 ( ) oseltamivir (FEV 1 ) 10.8% 4.7% (p=0.0148) A B 2 7 92% 18-65 76% 42 80% 92% 86% 42 1% 1-12 1-12 30-75 10 21% (15/70) 4% (2/47) 475 ( 18 1-12 ) RT-PCR >99.0 F/37.2 C ( )( 24 ) 13
3.0% (7/231) 0.4% (1/232) (neuraminidase) oseltamivir oseltamivir (%) * * 4/1245 (0.32%) 5/1245 (0.4%) (1-12 ) 19/464 (4.1%) 25/464 (5.4%) * (7 ) (10 ) (42 ) 12 oseltamivir A B oseltamivir 2008 2008 H1N1 >99% oseltamivir H275Y 2009 H1N1 ( ) oseltamivir oseltamivir oseltamivir H1N1 oseltamivir oseltamivir oseltamivir oseltamivir N1 N2 ( WHO ( ) ) 3.2 3.2.1 oseltamivir phosphate oseltamivir (esterase) 30 14
2-3 (prodrug) ( 20 ) 75% oseltamivir 5% ( 2) ( 2.2 ) 75oseltamivir oseltamivir carboxylate(cv%)(n=20) Oseltamivir Oseltamivir carboxylate (ng/ml) 65.2 (26) 348 (18) 0-12 (ng h/ml) 112 (25) 2719 (20) 3.2.2 oseltamivir phosphate (mean volume of distribution V ss ) 23 oseltamivir phosphate ( 3%) 42% 3.2.3 Oseltamivir phosphate (esterase) oseltamivir cytochrome P450 ( 2.4.1 3.2.4 oseltamivir ( 90%) 6-10 ( 99%)(18.8 /) (7.5 / 20% 3.2.5 100 2 5 oseltamivir oseltamivir carboxylate 3 15
oseltamivir carboxylate 75 75 150 < 10 / >10 <30 / (CAPD) 75 75 30 30 30 48 259* 348* 705* 766 850 1638 1175 655 39* 138* 288* 62 48 864 209 346 7476* 10876* 21864* 17381 12429 62636 21999 25054 * 48 (creatinine clearance) 60 / 30 60 / 30 5 10-30 / 30 5 30 30 CAPD (continuous ambulatory peritoneal dialysis) APD (automated peritoneal dialysis) oseltamivir carboxylate CAPD APD CAPD 2.2.1 2.4 ( < 10 /) oseltamivir 60 / 30 60 / 30 16
10~30 / 30 30 30 7 30 CAPD (continuous ambulatory peritoneal dialysis) APD (automated peritoneal dialysis) oseltamivir carboxylate CAPD APD CAPD 2.2.1 2.4 ( < 10 /) oseltamivir oseltamivir 2.2.1 ( 65-78 ) 25-35% 2.2.1 1 1-16 3 12 / 2.2 2 / ( 30 45 ) oseltamivir carboxylate 75 1 / Oseltamivir 12 3.3 3.3.1 ( oseltamivir Tg:AC ) oseltamivir phosphate 400/ 500/oseltamivir phosphate oseltamivir carboxylateauc 17
130 320 oseltamivir carboxylate 15 50 3.3.2 Oseltamivir Oseltamivir (Ames test) (human lymphocyte chromosome assay) (mouse micronucleus test)(syrian Hamster Embryo (SHE) cell transformation test)oseltamivir carboxylate L5178Y (L5178Y mouse lymphoma assay) 3.3.3 1500 // 6 oseltamivir 50 250 1500// oseltamivir oseltamivir carboxylate ( 0 24) 100 3.3.4 1500 // 500 // / 1500 // (500 // ) oseltamivir 480 44 15 20% 3.3.5 oseltamivir oseltamivir 0.01 0.3 (maximization test) oseltamivir 50% oseltamivir phosphate 7 657 18
500 ( 7 21 500 // ) 4. 4.1 25 C 4.2 / EXP ( ) 30-60 1. 75 2. 5 ( ) 3. * 15 30 2 > 15-23 45 3 > 23-40 0 4 4. 30 45 60 5. ( 1 )( ) 19
6. 75 1. 75 2. 5 ( ) 3. ( 1 )() 4. 5. 30 4-1000 45 4-1000 75 4-1000 1000 ( ) 30 45 024860 024861 : Roche S.p.A. : Via Morelli No. 2, 20090 Segrate (Milan, Italy) : F. Hoffmann-La Roche Ltd. : Wurmisweg, CH-4303 Kaiseraugst, Switzerland. 75 ( ) 025285 Cenexi SAS. : 52 Rue Marcel et Jacques Gaucher, 94120 Fontenay-sous-bois, France. F. Hoffmann-La Roche Ltd. : Wurmisweg, CH-4303, Kaiseraugst, Switzerland. F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland. 024056 : Rottendorf Pharma GmbH. 20
: Rottendorf Pharma GmbH, Ostenfelder Stresse 51-61 59320 Ennigerloh, Germany. : F. Hoffmann-La Roche Ltd. : Wurmisweg, CH-4303 Kaiseraugst, Switzerland. : F. Hoffmann-La Roche Ltd. Grenzacherstrasse 124, CH-4070 Basel, Switzerland. Ref: FE_CDS11.0 2011 10 12.11-TAM-3-B-03 : : 134 9 : (02)27153111 21