薬事分科会資料
Contents
1. 6 CYP3A CYP3A 2 3 4 52. CD 3 15mg 1 2
3. 15mg 1 1 i 10mg 1 1 3 15mg 1 2 15mg 1 1 B 1 1 J ROCKET AF 6 1 278 15mg CLcr 30 49mL min 10mg 1 1 QD
4. 2 7 8 SUE 4 400mg 2 600mg CK CPK AST GOT CRP
5. 2 75 1 3 eGFR 6 1 L2 0800900 50 5 55
6. E 2 BEA P 1 10 Sm RR a BE b c 1 p b 1t i tj 70 3 8 75mg 97 6 4
7. 2 L 5 3 2
8. 23 625mg 602 1088 x6 PTP 1 Van Giersbergen PLM et al J Clin Pharmacol 2005 45 42 47 2 3 4 5 Weber C et al Drug Metab Disp 1999 27 810 815 6 m vitroM 4E A ES GRO PRI 7 Van Giersbergen PLM et al J Clin Pharmacol 2003 43 15 22 8 Dingemanse J et al Int J Clin Pharmacol Ther 2002 40 310 316 9 Dingemanse J et al J Clin Pharmacol 2002 42 283 289 10 Binet I et al Kidney International 2000 57 224 231 11 Van Giersbergen PLM et al Clin Pharmacol Ther 2002 71 253 262 12 Weber C et al J Clin Pharmacol 1999 39 847 854 13 Van Giersbergen P
9. JU RAW AW ANS Ww v tA 4 241 48 9 9 7 2 9 6 2 5 2 1 4 1 7
10. 8 1
11. NPN GE amp EPESEXE BUB HEGSEREES o 000000 X000 TURA BERE CINRGI INO 01 02 9 4 5 6 21 7 14
12. CYP2C9 CYP344 Ca 1 1 gt 2 CYP3A4 Ca 4 90 Caf PUE OO ftr d if T UL 0o if vb E RE 234 b CYP3A4
13. 2 S3 5cL CYP2C9 CYP3A4 CYP3A4 CYP2C9 CYP3A4
14. AGBLE O DER Z ED KECURERERE CYP3A4 CYP3A4 CYP2C9 CYP2C9 CYP3A4 1 CYP3A4 Ca
15. 800 ppm 2013 8 CR ARR 2014 6 40 C 800ppm EI MR INOflo for inhalation 800ppm XE FID _ 22000AMI00004000 _1999 12 2018 8 5m
16. 2 ME c0 BE RURHIRS UTE NEN TH Tek s B TER MEE Dd Hn AST GOT ALT GPT ALEP y GT GTP ICE OSEE T dE RT 5 zem BEY X ACR Up Ue Bp 5 cpm S Im HE SEASUE XE E L7IBIPIAR CSS 2 5 1
17. 2 2 3 3 4 5 6 2 7 8 9 4 1 1 3 ALT GPT AST GOD
18. 0 3 15mg 1 2 0 PMERUBI ESEETED REED x 7 MOI A B 1 1 _ HoiivHB4 2
19. 3 30 co 7 2 18 8 10 20 HR ACH Exe XAXX TEZSUE TRBESEODREXAO SEE
20. 2 S48 Di B 1 2 Chi1d Pugh B C
21. 25mg 100mg 1 2 1 253mg 1 1 2 1 50mg 1 1 5 1 100mg 1 1 2 1 2 1 100mg JOH 5 1 100 200mg 1 1 2 1 1 100mg 1 400mg 1 1 2 2 2 1 25mg 2 1 25
22. 3 4 Child Pugh A B 2 2 5 6 3 OCHEQEUNER RES 500 mm
23. 2 4 48 3 SGLT2
24. 20 56 mg m Cd Vd 2011 003 PFS Vd Cd Vd Cd lt gt lt
25. 65 39 200mg 24 9 195 65 28 431 30855596 40 0 27 02 34 09 suate 1 32 n festa 1 24 2 95 19 16 842 6042 9662 13 12 923 6397 99811 6 5 833 3588
26. StageIVB 9 1 2011 T ESRB 25 000 2012 2012 1 H1 12 31 7 028 2010 10 737 2014 12 100
27. 6 Koo E 7 EUN 1 us Ol ON i PTP A A ER be E oth 2 PTP 2 7 3
28. ADH Be Ze HUPPERZE A
29. 0 1mg 1 1 0 5mg 1 1 1 i 1 r 2 12 6 3 6 6 1 IN BE 6
30. T D iB UR AIRNCE HORS B IK mu WEHRTMRTE FR fn X RUSSE BhUERDTDI 3EB CEU GE GA 5H R36 EHERUM ER SRBOAL d a b mE 9 NkTEU ALT GPT AST GOT ALP y GTP LDH
31. m 2 39 DOCA 3 2 39 6 ET ETa ET 1
32. 30mg250mg 30mg S00mg HbAlc 2 HbAlc NGSP mgydL 0 x 16 m HUS 29 57 0 98 0 10 13 02 4 95 115 0 83 0 06 hme 2 NEN V 50mg V M V M250 V MS00 V M250 50m g250mg V M500 50mg500mg 8 p lt 0 001 V M500 S Cn e 2 w
33. 8 cog uec 9 1 4 18 5 2 5 000 ppm
34. 9 2 099 ad 10 QSERUEDKCBR 2655 OO RR 72 KR 2 11 88b JR CR BH 12 COHUETRHOT CK CPK
35. 95 CD 2 44 1 57 3 80 p 0 0001 MDR TB C209 57 C208 C209 Grade 3 QT 2012 6 IL C208 C209 FDA Fast Track 2012 12
36. ER 6 2E 2 s
37. CYP3A4 40 26 65 0 8 20 0 7 17 5 3 7 5 3 7 5900 l2 50 2 50 2 50 2 5 0 2 5 0 2 5099 2 5 096 2 5 000 2 5 0 WHO IV II 328 172 52 496 49 14990 i amp h 2 799 25 76 23 7096 18 5 59 14 4 3 12 3 790 Hj 10 309 10 30 10 3 00600 10 30 WH
38. 0 1 4 3 ngmL 4 5 ngmL 2
39. 1 2 3 1 1 EMEN E 50mg 200mg 30 000 mg 200 000 mg
40. 2015 Cis Pac 10 Ponatinib INN JAN CML 13 Ph
41. 8 3 8 40 m
42. 2 AUCo 24 Cmax ss Pe CV 90 AX 72 2 5mg 20mg 112 669 20mg AUC 39 Vss 50L 10L h 429 4 C 10mg 2 3 1 3 11 15mg tmax AUC Cmax
43. HR 2 85 7171 J er MEER SRI TFI RIDES fF ipia E doc We Lp iila DB St John sWort 4 15mg
44. IE UL BORA ETI TE 9 PTP PTP PTP 10 0 2 104 1 000mg kg SOmgl H2 B H5 Coo t RakSES AUC 199
45. S ame si d EXE H8 do EU 8544c6248 CYP3A4 CYP3A4 P TURA ER L PUREIESMERI 72 EREIZ 0 7
46. 3 4 GuE B 1 2 3 5 BUD A BERE CK CPK 6 S amp TEBESE
47. 2 3 6 4 7 2 1 5 1 4 3 A 5 1 0 7 B
48. Ep d 1 2 2 2 3EZAGSCEL i BEZESL DES DESERESO QUA HUS E ARXEER UCLOSBRERER TO HWEHR S dBILIVCBVLEAJGg
49. SGLT2 2 GLP 1 4 B MAO cn 9573 25 XXI ggiz Kk 5 T Bp am wy Ao 392
50. 1 1 3 2 1 3 4 8 4 5
51. 9 1 2 12 15 mg 1 2 3 1 30mg 1 2 2 3 P450 3A4 2 2 CYP3A4 4 477 CT T bd 8 CYP2J2 BCRP 1 HIV CYP3A4 P P
52. SXHA MEUREEE y GTP ALT GPT AST GOT ALP Ug B 2 iu RR REN 2TEAE ZEJK A EE Ye BL 7k i A ago D 1 2 Bj Au PW PU I DD CRP CK CPK MB CK CPK 5
53. B e 15mg 1 1 10mg 1 1 e JRBDRBIKGD T E RO ib nde xcte hx 076 08 Rc C ESE HT S 3 15mg 1 2 _ 15mg 1 1 DRARSEOBERSSCUSSAMREPRUPA 0 30 49mL min 10mg 1 1 XOU TES 2 15 29mL min
54. E 2 1 7 3 3 1 5 Q 1
55. HL 215 74 py 34 490 13 B 7 0 9 4 296 8 3 7 8 3 7 HI 92 19 20 7 5 3 4 1 1 Toxic Epidermal Necrolysis TEN Stevens Johnson
56. ET 1 Ls 3 30 31 32 33 34 4 929 5 1 22
57. 0 1mg 30 10 Xx3 PTP 0 5Smg 30 10 3 PTP 1 Andriole GL et al N Engl J Med 362 1192 1202 2010 2 Theoret MR et al N Engl J Med 365 97 99 2011 3 Akaza H et al JpnJ Clin Oncol 41 417 423 2011 4 Gubelin HW et al J Am Acad Dermatol 70 489 98 2014 Norwod OT et al South Med 68 1359 1365 1975 6 Tian G et al Biochemistry 34 13433 13459 1995 T 151 8566 4 6 15 TEL 0120 S61 007 9 00 18 00 FAX 0120 561 047 24 4 6 15 http glaxosmithkline co p LD HD LD 1 50mg
58. ETA ETs 04030462 2015 8 9 2013 11 I 27UP i 62 5mo Tracleer 62 5 Lene B L 87219 21700AMY00170000 2005 6 2005 6 201 2015 ESH ET s sg w ERRAT rd 2001 11 y i d 2 1 1 a 3 32
59. 18 04 16 42 100 HR 1 11 9576CI 0 87 1 42 HR 2 0 MEN n 100 n 100 1 20 0 85 Tu EE 119 15 42 99 12 99 0 921 86 0 507 1 43 E 2 ROCKET AF 14 236 20mg CLcr 30 49mL min 15mg QD PT INR 20 3 0 23 572 2 579 9 6 95
60. n 32 o 125mg 1 2 6 WHO WHO MV n 213 125mg1 2 250mg 1 2 WHO
61. 33 1 B 0 3 212 2 0 9 gt 1 Add on 400mg 300mg X 150mglH XE UEBUS dE 150mg 300mg 1 2 p lt 0 001 Q2 Add on Smg kg
62. 8 2 2 A ELA y iere Ec HRT IIS NRN a bodedi edeiiebesiesi 3 C 3 MENTOR 05 AER CRORGIBARREE GO e 0 HESNOCHBECBOR EDRSES BEGgED ON d DS Me iut wen aieo 2 N 3
63. 30 50 mL min 1 6 mg kg 1 2 3 mg kg 5 5 AUC Cmax 4 8 7 Q 3 1 4049 1 60 541 No iris ioa 1501001 150 150 150 307 602 309 604 608 162 248 162 248 GEM T AA JV 3X IV AE Mt 8 27 39 67 119 d 69 294 56 394 Z BER Ze
64. th 2 CLUF 12 de 51 X zt Ca Co Tua tia AUC d Vd F pgmL ug mL h h jughumD Ck 0 61 3046 0 98 t141 109 003 20 10 1 13 0 97 1 00 X143 1226 30 04 10 09 1 71 152 40 96 x148 3371 30 05 30 18 2 UV y WELL 600mg 1 1 5 25mg t 5 13Lhr 141 5 25mg th 2 6L hr 23 8
65. m is iN BREF HH 1 2 4 65 20 30 8 10 15499 2 3 1200 2 3 19 2 3 1 20 74 35 099 5 25 096 1 5 0 1 5 0 E
66. 6 1 E U 7 8 AR
67. 2 DOCA 3 5 ETT ET ET 1 Bosentan Hydrate JAN 4 C1 1 Dimethylethy1 N 6 2 hydroxyethoxy 5 2 methoxyphenoxy 2 pyrimidin 2 yD pyrimidin 4 y1 benzenesulfonamide monohydrate 0 0 1 CH NH O u E gt CH JN HO N O A od
68. 5 MDR TB MDR TB MDR TB 2005 1 10 2005 4E 8 26 MDR TB II C208 C209 24 C208 Cox B
69. t 9 3 09e amp T 9 4 100mg 300mg 100mg 3 AUC C 100mg 32 6 2 5 400mg 2mg 6 7 8 9 10 11 12 13 14 15 2mg 14 12 20
70. 88 1 15 7 INOT12 2 Clark R H et al New Eng J Med 2000 342 7 469 74 3 Davidson D et g Pediatrics 1998 101 3 325 34 IK 3001 CVS 301 5 Barst RJ et g Pediatr Cardiol 2010 Jul 31 5 598 606 6 Huang QW et g Biol Neonate 1999 76 6 374 82 7 Hedenstierna G et al Abstract A657 Anaesthesiology 1993 78 1 8 H gmanM e qg Acta Physiol Scand 1994 151 125 129 9 Radomski MW er al Proc Natl Acad Sci USA 1990 87 13 5193 7 10 CR 013402 11 1303 001 1032 12 1303 5 1052 13 TK 1303 002 1032 14 Wennmalm A et g Br J Pharmacol 1992 106 3 507 8 15 Westfelt UN et al Br J Pharmacol 1995 114 1621 4 16 Kouyoundjian C er al J Clin Invest 1994 94 578 84 17 Young JD et aj Br J Anaesth 1994 73 511 6 18 Romand JA et al J Appl Physiol 1994 76 1350 5 19 Jacob TD et al J A
71. 13 14 GLP 1 X GLP 1 3 23 X mm omm DERE XO SXLERY DU EGE SEA2M KTUL b 2 EE
72. 335 185 55 2299 oo 18 5969 51 15 296 26 7 896 21 6 396 18 5 490 FR 149 65 43 6 19 12 899 12 8 1 11 7 4 212 107 50 596 47 22 2 21 j 99 12 pij 5 796 11 5 299 92 36 Bi 39 196 14 15 2 18 5 5 499
73. CINRG1I TINO 01 02 224 85 19 8 5 15 6 7 4 amp 722 U 77 2 dnd 10 4 S 8 3 00 X amp 98 8f 3 6 8 3 699 7 3 1 12 BI 6 IK 3001 CVS 301 3 4 HH D
74. oin vitro CYP2C19 1 1 CYP3A4 JMKTL ARAUJRS2553 CYP3A4 CYP3A4
75. 4 ss gx p 0 006 Add on X 8 BOR BUS EOS GESE ls RE ec GUN RU SC UE jl FN E Fk 0 16 0 30 0 46 0 8 2 0 4 0 12 R 096 096 096 0 7 0 6 0976 5 3 95 2 82 5 177 2 496 2 896 28 31 33 35 3 2 0 43 4 635 4 678 en 0 0 696 0699 3 103 2 86 5 189 2 996 2 396 2 696 CBJIBDH ERO 0 EO BELHS FH EC 3 gt 1 T 1 1 200mg 2
76. PT INR 24 PT INR 5 3 24
77. Cx 2 2 AUC CYP2Cl9 CYP3A4 3 8 In vito HMG CoA 38 7c SE 3e DR SS CYP3A4 7 AUC CYP3A4 CYP2C19 Ca 1 2 AUC 1 5 CYP3A4 CYP2C9 fis LI DE 3 CYP2C9
78. 2011 10 14000 20 27 mg m CRd Rd PX 171 009 PFS Rd CRd PX 171 009 CRd ONO 7037 05 CRd
79. 2014 9 Lensing A et al 2014 10 Lensing A et al 2010 11 Lensing A et al 2012 12 Perzborn E et al J Thromb Haemost 3 514 2005 13 Biemond BJ et al Thromb Haemost 97 471 2007 14 Perzborn E et al 2005 B 530 0001 4 9 B 0120 106 398 530 0001 4 9 3
80. diis 0 6mg kg 0 3mgkg 0 15mg kg R 0 15mg kg B id 0 15mg kg B A 1 1 1 1 C P28EASIU aes LRIELXI 2 1 3 1 3 3 3 3 4 12mg kg B 0 6mg kg B Anco METRE IE BrEes LELEXIE2BIASILC 5 1 2 1 2 1 2 1 2 1 2 0 6mgkg 0 3mgkg X O 3mg kg H 3 L2mg kg H 2 5 0 3mg kg ONU OW 5 1 10mg kg 17 5mg kg HR 1 3mg kg 5 15mg kg 17 3mg kg H 200mg H 200mg H 200mg 400mg 200mg H 1 1 2 1 2 1 2 1 2 1 2 4 1 EEFEEEI lI
81. B 1 2mg kg 2 1 120mg 1 240mg 3 4 8 5 4 3 1 6
82. 2 M b un 3 2 ERES TNEENEE NOE IS CREER
83. 1 InS rp 1 BEBERLA LZ 3 IF BLE c 5 ROO fn 98 p a 6 100 200 300 400 mg AUC C Fi y Cua Tar AUC t 2 mg Lg ml ib Lag h mL th 10o 039 a L3 39 182 001 48 42 200 Q0 4l 160 RD 5123 1103 61 4l 3 1sr s 13 23 1LSS CAL SS 31 Ax 2S8 Bt 921 Ui 3101 C02 119 51 6 CV CYP2C19 CYP2C19 EM Extensive Metabolizer HEM Heterozygous Extensive Metabolizer PM Poor Metabolizer 1 200 mg 1 2 1 400 mg 1 2 EM HEM 2 PM 3
84. 800 ppm 999 200 ppm EEEEHIILETTITTTTTTITTTHIH ETETTTTHTTTETE THITLITEEEE THEHEFT SFSEFFFFFTFF it FI poxok H2 EUR 1 34 2 NG AN 3 VERSES UL CIEN gt E D 2
85. 4 0 190 5 OBERBEIR E A BB m0 w np Xt 2 0 599 o 5 1 5 6 amp m 242 D HE mim T om 5 Xd
86. 40C A ck c
87. DNS AST GOT T ALT GPT 2 gt 3 5xULN ASFT ALT 2 AST ALT gt 5 8xULN gt 8xULN ULN AST 4LT 3 2 2 AST ALT CB 2
88. ud 5 wx NO IND Le SS
89. St John s Wor AUC 3994 CYP3A4 4 100 80 80 0 25 0 24 090 y GTP 1 0 8 0 8 0 8 0 8 0 AST GOT 7 0 ALP 7 0 ALT GPT 6 0 0 S 0 5 099 F 5 009 2 53 6 149 278 7 6
90. 1 2 2 8 28 1600 mg zd cd FTP PTP PTP
91. 200msg 2018 F0 BH zx T CB GNOD 876179 nt 50mg 200mg VFEND Tablets W iW4x 2014 10 14 50 50mg 200mg 21700AMY00171 31700AMY00172 2005 6
92. tz FWTATv WR fX X CT BET BUSPBUBJV 2 NE 0 17 196 0 1 Ri Tg KE ey DNE TENA I BP3HI DE tn 8 D vid il NEED odi MORITZ RX sad cma NIU P ilu 24 NN LE E TS 7 77 3 ALT GPT EX AST y GTP LDH GOD A1 P
93. 1 CYP3A4 i NIS 2 200ANRUI 2 2 AK IO rm EE BLA WOeaPl dx cr d aep ISM Bi E CYP3A4 RU em se ueri 2 CYP3A4 dE Wu ccu Ac 2 2 2U0JAA0Im rp dit 2 2 s aM orto zs Bram pL RBPERJS OO Ef Bb o BB iT EIE OO BT RE TETE mE OTI ER
94. 2 6 PSA PSA 3 0 5mg 6 PSA 50 6 PSA 2 PSA 6 PSA 4 PSA huit m 5 freetotal PSA free PSA
95. 8 9 PTP PTP PTP 10 1 10 1 ffn38 HRS 1 D 10 62 5mg 125mg 3 4 C 500 2000 1 1500 INE
96. 7 A E Ik SERRA 2m SE hprpxk3b ULBAAE 4 fL lt 3 6 1 1 1 2000
97. s 10094 ZWyvABgBp 65 3 7 JE 30 099 46 60 67 119 85 174 162 248 76 794 56 394 48 995 65 394 2 95 1 1 180 e
98. 6 HIV 2 3 4 5 Im 20OO B m ime 20OO DO 15mL min 30mL min _
99. CGI S 9 HAM D17 9 YMRS 92 29 11 97 80 30 s5 2 6 4 4 3 8 7 5 1 7 3 0 20 52 i CS 1 1 7 1 CO amp e t ii d 1038 17x40 32 68 18508 10211 9 a b 17 c Y LZ PRSE BRE d LOCF Last Observation Carried Forward HAM D17 YMRS 91 t Lx H e 0 8 1 7 1 9 5 6 i 1 puff e 8 1 3 Q 4 6 7 dimethoxy 4 ethyl B carboline 3 carboxylate DMCM ILk0wvyALGAXsrmuss pEbrESEMgOB 5 7 9 99 9
100. CYP3A4 lcs degree e CYP3A4 m fin Ug S E ss cU p x es PM PDE5 pou E gd rchessnsx Jaco 2 CYP3A4 2
101. o8 1 IO 2 ES SGLT2 L DER
102. 30mgI H 2 S00mgl 2 30mg1 2 7 6 250mgl H 2 300mgl H 2 4 1 1 S0mg 2S0mg S0mg S00mg 1 2 lt gt 1
103. 2 7 9 1 7 H27 8 20 gt gt TEWUGE PET 2 1
104. AUC 1 2 Chi1d Pugh B 8 AUC 2 3 AUOC 2 6 Xa 2 6 PT 2 1 Child Pugh C 6 1 12 600mg 10mg AUC 2 5 fZ Cmax 1 6 f ERU 2 20 400mg 10mg AUC 2 6 Cmax 1 7 13 400mg 20mg AUC 1 4 Cmax 1 3 3
105. 13 X CT 14 15 SEE Ff EY 2 3 1 5
106. 7 OT Vt 400mg 1 2 5 25mg 5 25mg E 3 100mg 1 1 2g 1 2 6 100 400mg 10 30mg Cx AUC 10 24 In vitro RIRORIER TI OCT2 4r L7E B EGRE I US e BH E3 5 STREETS 1 gt 1
107. CYP3A4 CYP3A4 QT ZEE amp 4 x PESE RR lorsades de pomtes mop EE zivinEl Vt XfbmSetgiidi ditr CYP3A4 X CYP3A4
108. 50kg 1 200mg 1 2 1 300mg 1 2 40kg 2 12 12 SOkg ee CE cum um c RR c Rc M Lo am me qe RM Nike cue e e dm am eer Gud Re i m mir Rc zn m uu cm d RC RR a n c Rm 1 2 1
109. 8 5 9 3 2 1 1 3 4 D
110. 13 10 8 4294 1 SEHR JV PRHEAE DRE 72354 BEST AUR 1 BX 4xuidEmoocsbb6oivcwBWlEHU vcum 2 5 1 2 6
111. 0 5 4 Cmax 1 m 1 000 diXxSmyr nm vy AG g L 12 16 20 24 n n 8 AUC Cmax tmax tk bed L3 49 lOmg l 564 24 5 226 9 18 7 1 4 0 5 4 0 7 1 35 3 CV 90 n 8 1 1 40mg 3 051 21 3 329 4 26 1 2 36 10 15 20mg 1 1 7 E usgh D z g L b hb lOmg 1 H 1 443 21 0 232 6 18 7 3 0 1 074 0 5 7 18 2 1 533 14 9 246 9 10 6 7 7 41 2 15mg TH B 2 080 26 7 347 623 0 4 01 04 0 6 3 35 1 amp T6 9 20mg 1H 2 419 24 6 391 2 21 2 2 5 2 0 4 0 6 1 20 8 7H H 2 839 20 9 398 5 24 3 0 1 5 4 0 7 7 23 6 CV n 12 DVT PE
112. 31 D II Norwood Hamilton TLy IV V 3 917 200 AA 0 02 0 1 0 Smg 24 1mg 2 54cm 0 1 0 5mg 1mg 2 3 Norwood Hamilton 2 0 02 0 1 0 Smg 2 54cm 7 757 0 02mg n 181 n 185 0 1mg n 188 0 5mg n 184 4 9 17 1 63 0 89 6 56 5 7 87 8 12 7 74 7 67 148 141 67 9 94 4 614 p 0 001 p 0 001 p 0 001 99 165
113. 2 7 1 8 amp 24250 C WWE m ZB CT 2 1o 7 5 7o 0 lt EN i i DRE 0
114. CYP2C9 CYP3A4 e CYP3A4 CYP2C9 CYP3A4 TE fET HMG CoA 58 CYP3A4 CYP2C9 Gr VASA CER OAM OO UE I R2 5 CYP3A4 CYP2C9
115. 3 CYP3A4 CYP3A4 EH 4E CYP3A4 4 II 557 fj 120 9 17 1 24 4 3 22 3 9 7 1 399 120 14 117 7 Di 5 896 6 5 099 2 17 120 20 16 7
116. 10 30 200858 2 1ppm 1 ppm 12 1 1 dei nT TE PT TT 1 1 ck 2 ECMO 3 Rape dq oc kk 4 NO NO PaO
117. gt 34 7 11 INOT12 20 ppm 4 4 PaO 260 mmHg SpO gt gt 92 5 ppm FiO gt 0 4 0 6 Pa0 70 mmHg 5 ppm NO FiO 0 1 BE 14 10 30 1 24 OD GE SD 21 3 37 0 19 7 37 9 27 2 33 0 NO 1
118. 1 25 200mg a heme Cas s CT ros ET i526 oso mot L5 s onssno asaa sor 122255 sss sae Lo s rasnon nain sons sosca poenas az C3 s EC 1se1o sc55 serena seneses ons GEHE Q 9 200mg 9 6ugmL 22ug mL
119. 10 ppm 20 ppm 20 ppm 40 ppm 1 18 55 18 mPAP 24 GEM 6 0 6 686 mmHg CVP 20 ppm MetHb 11 2 10 20 ppm MetHb 18 2 24 3 1 2 15 mmH Pao gt FiO gt 24
120. 6 e i 9 16 iP a s LLL i s AUCI i ies 9 AUC 2 OE e i t tem CN Meg ded 25 EM E LEE M20 7 AUC 27 49 92 Cmax 23 46 65 50mg 1 2 1 1 1 2 250 mg 1 2 500 mg 1 2 2 139 30 mg 1 2 12 HbAIc
121. 49mL min 3 4 2 1 PT INR aPTT n EE NE nos Rg 1
122. v ABS RI SE 1 NeALSEASIXESLL T IX 1 2 FSH LH
123. 0 2 50mg1 2 LD 1 1 2 2 2 3 2 3 4 4 5 6 7
124. 0 22 1 0 0 46 2 58 5 A35 37 In yyo CYP2C19 CYP2C9 CYP3A4 N 6 mE 96 2 7 1 1 200 mg 1 2 400 mg 1 2 Chxld Pugh AB 1 100 mg 1 2 1 200 mg 1 2 AUC 2 6
125. Die 180 dp 3 CYP2C19 2C9 3A4 CYP2C19 2C9 3A4 inviro CYP3A 1 MN SELL A Ec mp Jy NE BF BEAT OR 96 Ca 6994 AUC 78 Ca 3 0 AUC
126. gt 34 388 D EC AE 6 4 HELPS 0 8 Ae VOLES SIE TIE Bi res t FE 186 89 97 CINRGI 20 ppm 4 24 Pa002 60 mmHg pH 7 35 7 55 5 ppm FiO 0 7 96 7 Pa0 Z 60 mmHg FiO2 gt 0 8 NO 24 20 ppm 24 5 ppm NO FiO gt 1 0 PaO 60 mmHg MetHb gt 4 NO gt ppm NO ECMO 57 399 30 9 P 0 001 ECMO 0 001 Cochran Mantel
127. 8 196 8 1 HR 0 97 95 CI 0 76 1 22 0 8 1 2 HR 0 65 95 CI 0 33 1 28 PE 10 3 11 496 HR 0 90 9596CI 0 76 1 07 1 1 2 29 HR 0 49 9596 CI 0 31 0 79 J XH MER JN qv MEET 1 718 Fl m NE2 412 N 2 405 n 99 n 96 n 90 n 96 EXtER iE zdz E n 2 129 7 5 122 7 1 228 9 5 235 9 8 1 5 Ilmg kg 1 2 K acenocoumaro1 PT INR 2 0 3 0 2 3 15mg 1 2 15mg 1 1
128. 64mg gj wt PEU Aic pee E TEIRILL3200 RIFUE 43 4 d 0 4 E qne 3 M 5 v JR 1 385862 5mglz kl Y 2 Cudt A OAUCIEO T 39 fli ids I4 o j 082 087 AET0805 amp ome ME y rH o dC z 5 v AKI ese 5 Ro O0 TEA Klose NEL vy vKGDUEERIC OUU Iit ORRAUESDY Sg FF 32 ul R f lO0mm A 31mm E r 290mg Bie E TO gt m amp 1 m do PIE ee eA 1 AST GOT ALT GPT gt 3 1 2 0 3
129. S6c ET pAz 72 60 2 ET 1 ET ET ET 1 SS 3 UU B3 S T xui BK BUG OK Fx ou 4 1
130. 1 mn NM BB 1 2 1 1 2mg WS o 5 2mg 1 1 1mg 00031
131. 6 9 MDR TB 18 WHO Global Tuberculosis Report 2014 DS TB 2012 86 MDR TB MDR TB 55 97 MDR TB MDR TB Lb MDR TB MDR TB
132. 4 40 4 40 3 Bj 309 3 30 3 3090 1 1 13 AST GOT ALT GPT OG 2 A 3
133. Cis Cis Cis PFS OS Ci Cis ich egi A ues ad ga tiri Cis PFS idi Cis Cis Top Cis PFS OS Cis Pac Cis 2
134. 7 jc Qt 5 5 ppm TT i qa ym PESTT FJ qRT B2 REP rri g FF RT RE lt gt ORO DS DS SACK Q2 20 ppm 40 ppm NO 3
135. 1 6mgkg 1 B 2 2 1 4mgkg 1 2 2 12 12 0kg 12 50kg 23800mg 40kg 1 300mg 1 2 2 1 150mg 1 200mg 1 2 1 400mg 1 2 2 1 300mg 1 B 2 40kg 1 150mg I H2 2 1 100mg 1 2 2 1 150mg 1 2 2 12 12 50kg
136. 62 5mg 1 2 200mg1 1 5 5 AUCojs C 2 5 9 125mg 1 2 55 40mg 1 1 6 AUCojz 34 46 e o 0 9 1 125mg 1 2 6 5 1 600mg 1 1 6 6 AUC 589 7 BER
137. 9 1 PTP PTP PTP 2 10 1 199 2 0 4396 0 24 1000 19 95 0 6 3 9
138. HMGCoA ARx XHES Caf DL3E SELTECAEJE PDESIH 1 ATvOBSRASJRRS 5 CYP3A4 CYP2C9 1 2391 BE HC 0 Caf UE
139. gt 343 127 772 24 100mg BE 200mg 51 3 60 4 54 7 95 41 81 60 73 30 63 69 52 43 23 63 92 1 2 gt 1 Add on 150mg
140. 2 Time to withdrawal from study TWS p 0 010 MS 72538 de e iem Pe e P on vmm Lem poor m ue d bem P4 GER SENUSLO TESTE f e 1 4d 0 1 1 10 0C POTETPSES MM LL Q 1 1 Qiu 92i 0 28 56 4 112 140 168 196 S8 aS 32 28 25 20 16 iu TUENBUXLE 45 ag 31 32 3 26 23 0 2 II TWS Kaplan Meier 6 TWS 74 1 43 53 3 24 TWS 95 67 5 32 0 127 0 169 0 111 0 mc B TPTZHESEES seoo mc a 2 LL 32 3RHO EE TR EI
141. 3 5 2 1 Q PSA PSA PSA PSA 4 0ngtmL PSA
142. CORE 2mg 5mg 25mg 100mg Lamictai Tablets 20jx xx 201x xx 2014485 204 8 2mg 22000AMX02362 22000AMX02363 22000AMX02364 22000AMX02365 Smg 100mg 2008 12 2008 12 1990 11 85 Toxic Epidermal Necrolysis TEN Stevens Johnson
143. 10 62 5mg 1 2 200mgi 1 5 5 AUC j C 2 9 125mg 1 2 5 5 40mg 1 1 6 AUC j 34 46 6 9 1 125mg 1 2 6 5 1 600mg 1 1 6 6 AUC 58 7 19
144. 1000 2 4 2 1 5 1 1 6 25 200mg 1 7 2 5 WW cC XL tjj 31 38 Cx AUC 6 S0mg TI 2 10 6 lmD 4 lt a Pe 2 mg nes6 a S0mg nss6 m h JOO mg n 6 amp 200mg n 6 Y 2j amp zx ERE T A E E 2 1 25 200mg
145. 2005565 zh E B 2019 9 H XE EBESOAUISX Lo g325 r ER 2002 3 E 1 2
146. RE YXouohaliitvo 6 d6 k6l5HBcl dWY 2 Ax dI AST GOT ALT GPT lk dpi FESRDRAAG3U MpOGS c Lp ge yEATER E Loss Df R 3 EE V fifi oo UT lab es Ju Mp rid eo FREE OW ene CAE o KU ROUTImySrLyW Ls 2cc ce IL PRECES WERE RO HEIE ndis AST GOT ik EBEBERERR BOO SE Bic MO ALT GPT f amp x 3 5xULN 2 ELW E pz E 3 vr jpa Sap 42i XIULN d Br J x v M f amp 22 fe Ji QE RBS OC UC LIC v o nEETEO do dg A iBUCAST ALTIEE WE L 2 s ge LEER quu 3 T Exo xp pon ER RELOBEN RO S53 TUE T RUE Sw 5 gt 5 8xXULN O E URN Mi AR _ AST ALT 3j o SSXUN
147. Vildagliptin Ho LcN NAM UK N OH 25 1 3 Hydroxytricyclo 3 3 1 1 dec 1 yl amino acetyl pyrrolidine 2 carbonitrile APT CHzN3O gt 303 40 99 5 Bh 150 C 1 255 0 0042 1 0 1mol 0 035 JV pHA4 08 amp f amp rifz 0 25 1 pH6 8 dA RT IR Metformin Hydrochloride NH NH CHs HN N N HCI H CH 1 1 Dimethylbiguanide monohydrochloride CHriN HCI 165 62 1000 99 5 Bh 2212C
148. 1 03 ers GasD uo Ge ou 1 04 395 3 60 386 3 45 0 00 1 20 DVT PE DVT 15mg QD 25 1 4 0 PE PE 30 7 TT DVT MEER 3 13 6 2 8 0 1 8 3 BID 1 2 QD 1 1 1 5 PT INR 1 5 2 5 2 2 EINSTEIN DVT PE DVT 3 429 PE 4 817
149. 1 1 2 Child Pugh C 3 2 1 OS
150. D FDP HET 5 6 7 e 1 1 10 mgkg 100 mgkg 2
151. Sh xh D A D dr 35 8 an 3 En ln Sf S mS 8 I Hr 38 9 B 15mg 10mg 15mg A 4000 B e e 1
152. Bosentan Hydrate JAN 4 L1 Dimethylethyl N 6 2 hydroxyethoxy 5 2 methoxyphenoxy 2 pyrimidin 2 yl pyrimidin 4 yl benzenesulfonamide monohydrate rd mde OH C5 H29N35O S e H O 569 63 NN 99 5 WHO THE IMV
153. CYP3A4 O0 Cas 30 79 AUC 47 2 Cs AUC EO AUC Ca AUC CYP2C9 zB 5 7 18 CYP2C19 C 149 AUC 46 CYP3A4 Ca 36 AUC 61 Cag 15 AUC 53 9
154. NNRTT CYP3A4 CYP3A4 I wpp CYP3A4 7 C 1 1 CYP3A4 AUC 1 7 C 2 2 AUC 3 2 9 Zu 5wGv 1 9 CYP2C9 10
155. 4 10 3 01 12
156. 2012 8 EMA 2014 4E 3 WHO IX MDR TB WHO MDR TB IL TMC207TBC2001 100 mg 4 mL 400 mg 16 mL EE HPV HPV
157. CYP3A4 CYP3A4 1 1 2 PDE5 2 CYP3A4 3 HIV 4 Bi 8 TE Rit fH PDE5 CYP3A4
158. 15mg 1 1 10mg 1 1 3 15mg 1 2 15mg 1 1 AERE VEBDEFAKULEEAE As USt f Ee SERETE 0016750 CERE WSRIOCER GR Xa oo 9 L XE 20 2015 6 Xa 10mg 15mg Rm o Gk ERG Xarelto Tablets 10mg Xarelto Tablets 15mg m E
159. _ N 7 111 NF7 129 co n 100 n 10088 amp 848 07 LM 1 04 0 967 1 13 1 185 11 80 1 151 11 37 HE 15mg 1 1 t 10mg 1 1 2 D EINSTEIN DVT fE DVT 59 22 l 25 3 10mg 15mg 1 2 BID 15mg QD PE 37 il 30 3 15mg BID 15mg QD 5 a
160. 7 3 P450 CYP2C9 CYP3A4 CYP2C9 CYP3A4 CYP2C9 CYP3A4 gz uo CYP2C19 ee
161. 125mg DIE E S 4 SEI Czm piu uid 37 AUCo 5 6 16 125mg AUCo Crm 10 22 7 500mg 1 2 7 5 4L amp 5I Huc vo MH3EW MUS Z200 250ng mL 1 2 7 0 cci i Nu 30 3 4 n 8 AUCujs n 9
162. 2 INR INR 2 1 9 5 0 riRSI 5lc dose ME 2 1 E 2 1 1 3 2 1
163. 300mg 16 2 qm am E eo 3096 1496 5 9 zx d i 13 34 23 980 1596 059 3899 2696 G 9 ri mCSCDUBHOSO ovem hh Hr PE HEZCPIIEIIEEIEP Q Add on 1 Smg kg 1 3mg kg 5 1Smgkg ipe Sa Lt EEE VPIDIFSESESESESENIN 1476 3074 2176 Zi 1075 39 Apr 21 212 p 0 0009 UR
164. 59 EL lethargic 9 5 ED of amp DURESMERO ED p 2 Na 14947 3 4 5 6 Lamotrigine 3 5 Diamino 6 2 3 dichlorophenyl 1 2 4 triazine C H CLN 256 09 1 N CE ole Je NES logP 0 4 pH1 2 1 8 0 pH6 0 1 CP
165. bo 101 3 kPa 151 7C 241 1 F 1215 K 92 9 1352 9F 1803K 6 550 kPa 65 5 bar 949 4 psia 64 6 atm 21 1C 101 3 kPa 811 600 cm7kg 13 f Ib 1 mL 0 101 3 kPa 13 55 mL NO NO
166. esee La NEAR idest 2 3 3 2 10mg 1 1 EE EH 2373 23 b 72 5 IBEPEX ARE LI EcU PT INR ZA 3 0 2 AKA 4
167. 0 39 0 79 000 gt WHO HI n 19 kg 4 10 20 20 x40 1 31 25mg 1 2 1 625mg 1 2 1 625mg 1H2 1 125mg 1 2 31 25mg 62 5mg 1 ET 1 ET S6c ET pA 7 2 60 2 3209 ET 1 ET ET
168. 2mg Smg 25mg 100mg A B C 140 14 E X10 PTP 140 14 X10 PTP 140 14 X10 PTP 140 amp 14 X10 PTP 21 25mg 84 25mg 42 25mg 1 2 Newport DJ et al Pediatrics 122 e223 231 2008 3 WolfP et al J Epilepsy 5 73 79 1992 4 Yuen AW et al Br J Clin Pharmacol 33 511 513 1992 5 Binnie CD et al Epilepsia 27 248 254 1986 6 Jawad S et al Epilepsy Res 1 194 201 1987 7 Anderson GD et al Clin Pharmacol Ther 60 145 156 1996 8 Moris RG et al Br J Clin Pharmacol 46 547 551 1998 9 Yuen WC et al Br J Clin Pharmacol 26 242P 1988 10 Magdalou J et al J Pharmacol Exp Ther 260 1166 1173 1992 11 Green MD et al Drug Metab Dispos 23 299 1995 12 Fillastre JP et al Drugs Exp Clin Res 19 25 32 1993 13 Marcellin P et al Br J Clin Pharmacol 51 410 414 2001 14 Posn
169. Q HIV lb 510p XJ C 4996 69 7 AUC C 1 7 AUC 1 8 CYP3A4 CYP2C9 In py CYP3A4 po CYP3A4 mm vino
170. 2 6 HHV 6 3 8 8 Amxk 8
171. SLEEP pm z D LEE 2 F L2AO0HBHETE _ DARPECLO FETTE 7 4 V 4a Tov S Q CBBEIZISH BO RUP ICE Gm 2 IH RH lg RE CENE wx 5 cc Uff 68mm J X 60mm 3 XEPTLERGE 4 23228 DES 5 6 lt gt 1 2 3
172. 125mg1 2 6 2 WHO 15 6 21 n 18 n 21 6 125mg1 2 12 WHO WHO II 19 125mg1 2
173. GFin vj o L20050310069 131 8589 3 22 7 0120 664 467 FAX 03 3379 3053 3 22 7
174. 1 1 pH 2 ALT GPT AST GOT ALP Y GTP 2 3
175. AUC Cu 150 500mg Q00 400mg lR 33 9 34 9 GER 400mg AUC Cas Cual REB AIL 1000 4000mg 2 100 600mg H 200mg 1 3
176. 125mg 2500 2000 1500 O 125mg ng mL 1000 500 0 6 42 h 125mg Cna ng mLIAUCeptmgrymM tmsx tuz0 125mg 1748 6996 40 5 0 n 6 1287 2374 6193 7904 2 5 4 0 3 4 7 2 95 tmax LITE a O 18 24 2 WHO TV 13 62 5mg1 2 4 125mg1 2 4 62 5mg 125mg1 2 Cma ng mD AUCes ng h mL tmx 8 62 5mg 1187 6232 30 n 12 814 1560 4582 7881 1 0 4 0 125mg 2286 8912 2 3 6296 11531 1 0 6 0 n
177. 7 53 95 8 6 35 49 99 215 NO 5 40 ppm 8 7 512 ppm 7 1747 ppm 57 40 ppm in vivo U 46619 57 80 ppm 20 100 ppm 6 100 ppm NO EPS Nitric Oxide Nitric Oxide NO 30 01 ee Ns0
178. e 100 86 2 Fleiss 12 10 756 3 28 48 975 33 594 109 223 80 239 16 3 7 6 25 0 1 I vitro Q 7 3
179. gp d m 234835 C JUI M rA R00 MEE LOCA LZ DX MARO npEZ4EWUJgmeSNETEAZIE LLHES HE EC Bode 3 2 018 I0 xx j OJAZIIG 5 1 2 9 5 625mg 1 625mg 64 54mg Na Mg
180. 0 Smg n 33 1 0 Smg Cs pg mL AUCo hr pg mL Tasx hr 3288 541160 89 52316 9 20525 60 1 500 0 75 6 00 n 33 Tx 2 0 05 2 5mg 1 1 24 24 0 1 0 5mg 1 51 0 96 30 69 13 90ngmL 2 0 1 0 Smg 24 12 20 0 ing mL 0 5mg 1 1 6 6
181. AUC 20 GE 1 1 0 1 0 Smg 6 2 Smg AUCo 2573 2197ng hr mL GE 1 1 0 1 0 5mg 7 1 CYP3A4 CYP3A4 i vitro CYP3A4 2
182. PDESDH 5 amp 3 amp 0D ifn rp o HE 4 PDESPH E 4 amp 0 fri rbi s Rz 3 s 3 CYP3A4 dug Jb gt op QU eH Hs f 2 HIV CYP3A4 4 1 13 6 1 167 167 0 11 100 23 230
183. id tn 64 WHO 1 2 n 33 21 2 75 8 3 0 1 3 n 31 97 87 1 32 2 1 31 25mg 62 5mg 125mg 1 1 2 n 19 17 12 X 95 dyn sec m cm L min m 1 ET 1 ETA
184. 1 5 13 2 2 2 3 9 PTP PTP PTP E B 1 1 32 5 10 20 40mg
185. 125mg 1 2 Img 35gg 7 AUC 14 319 19 1 125mg 1 2 6 3 1 20mg 1 3 2 1 80mg 1 3 1 80mg 6 6 AUC Cmaxa 63 55 AUC Cm 50 42 1 1 1919 20 WHO WHO
186. CYP3A4 CYP2J2 Tv r7 o P P gp BCRP Bises ZA rcf RES S mVeSeBaBEYIL t RindEDESo 92 959 CLcr 50 79mL min CLcr 30 49mL min CLcr 15 29ml min 8 10mg AUC 1 4 1 5 1 6 Xa 1 5 1 9 2 0 PT 513 22 2 4 CLcr 15mL min Chi1d Pugh A 8 X 10mg
187. 48 350mg 1 1 14 AUCo2ap 1 40 1 71 2 00 Cmax 1 37 1 32 1 36 M20 7 AUC 4 1 66 3 20 7 30 Cmax 1 57 2 56 5 55 AUCo ap 1 3 2 69 7 23 Cmax 1 13 1 60 3 00 T em 18 30mg 1 2 1 ftstH XX CTHEBERCES E IEVEATU J 710 8 tH BEEELIE IRE OE T E09 x s 0 Lil qe 2 CX N3RUUPR VIR T 2 lt Cmax Tmax AUC Tis CLr 7 sia s TE idm x CH REB mmL b nghmL th L4 2
188. 3 5 eGFR Ut m 1 3mg dL 1 2mg dL eGFR
189. 1mgkg 1mgkg 350mg 50mg 1 350mg 1 2 1 200mg 1 2 1 300mg 1 2 40kg 2 12 12 30kg 12 30kg 200mg 1 6mg kg 1 2 2 1 3mgykg 1 4mgkg 1 2 1 9mgkg 1 2 2 1 8mg kg 1 2 Img kg mg kg
190. 3 2 2 1 50mg 1 1 2 1 100mg 1 2 1 200mg 1 2 6 1 300mg 1 2 7 1 300 400mg 1 2 1 1 100mg 1 400mg 1 2 3 i 3 lt gt LLL 3 3 1 3 i 3 1
191. 0 5mg 1 1 sa 1 872429 5 a X amp zc BER 1 2 e 0 1mg ee 0 5mg Zagalloe Capsules RT PTP BUTS El D 5o xS2cEESREB EAE CX Li uE 0o 2 3 4
192. 44 82 17 91ngtmL t 3 41 2 ng mL 1000 4 2 5mg 3h 0 5mg D 0 1mg BER Lll EPS s 0 05mg SH E Hd i amp 30 36 18 24 2 0 05 2 5mg 1 1 24 n 34 47 1 1 0 1 XH 0 5mg 2 MRP2 OATI OAT3 OATPIBI OATP1B3 IC 0 5 0 8 20puM 0 07pM 3 D CYP3A4 CYP3AS CYP1A2 2A6 2B6 2C8 2C9 2CI9 2D6 2E1 n vitro 2 CYP1A2 2C9 2D6 CYP2C19 3A4 1C50 50
193. 50mg 1 2 7 GLP 1 37 3 2 350mg 1 2 4 9 4 Inf amp E T I ERBIERUR TERERU ERI 1 2 1 1 10 HbAlc 0 6 1 2 2 2 350mg 1 2 7 Eb 74 B 9
194. 825 C rm 0000 8B 1 6 1mm 3 1mm 865mg WHO II IM gt Bb Bru IRURE eo LEE E E OE LZ E 2 BERE LIE RE DLP o M 8 Re P B RIUESELZ BU S FATE SCRVEGEE LC es 4 1 62 5mg 1 2 5 1 125mg 1 2 1 250mg gt 1 AST GOT ALT GPTT 3
195. 12 Ob 2 1 9529 n 122 62 5 125mg 1 2 16 1 6 23 10 30 3 8 10 Mann Whitney U Poisson D 00111 poisson X
196. p 00112 n 190 62 5 125m 1 2 24 19 22 10 2 7 3 3 14 p 00351 Pitman 0 909 9596 0 613 1 348 log rank p 0 6327 2 28 62 5 125mg 1 2 16
197. 2 2 6 D 7 c
198. 30 49mL min 10mg 1 1 639 326 51 096 88 13 896 50 7 896 40 6 396 24 3 896 23 3 696 18 2 8 17 2 7 15 2 396 z amp if 144590 2 296 12 1 9 11 1 796 9 1 496 7 1 196 7 1 1 7 1 196 7 1 196 20mg 30 49mL min 15mg 1 1 7 111 2 096 29 596 E 537 7 696 196 2 896 195 2 796 124 1 7 117 1 6 94 1 3 92 1 3 89 1 3 81 1 1 77 1 1
199. VIL AP24534 11 106 CML Ph ALL 3 62 5 mg 62 5 mg 64 54 mg 4 1 62 5 mg 1 2 5 1 125mg 1 2 1 220 mg WHO IL IV
200. 10mg 15mg 1 2 3 15mg 1 1 DVT 22 8 36 4 25 7 28 096 15mg 1 2 3 15mg 1 1 PE 30 15 50 096 77 30 39 096 8 10 496 6 7 896 4 5 2 15mg 1 2 3 20mg 1 1 DVT 1 718 AK OPER 2 412 401 23 3 776 32 2 4 130 1 177 28 5 240 5 896 101 f 2 496 81 2 096 77 1 9 76 1 8 75 1 896 66 1 6 60 1 596 56 1 4 0448 1 19 D
201. 2 HEM i PN VE Wi EUER TC ILE 2p U 21277 7 7 JE XERUTE 0rg ml 0 24 46 n 96 74H HEAR C 3 NR ERREIT SUE S I d EOD EH EU G 14 18 1 8 mg kg 1 2 1 9 mg kg 1 2 7 1 9 mgkg 1 2 7 C AUC 7 22 2 03 18 3 ngmL 43 8 10 0 136 gh m CYP2C19 gi Cmax AUC Taux ug mL ugeh mLy h EM 6 5 49 2 03 110 31 2 10 0 80 8 1 5 0 95 3 8 HEM 10 7 66 4 45 18 3 49 3 14 3 136 1 1 0 92 2 2 PM j 12 3 I16 130 99 1 840 117 1 0 0 95 1 1 18 722 2 03 18 3 43 8 10 0 156 1 0 0 92 3 8 1 2 12 15 30 kg 1 1 4 mg kg 1 2 1 6mgkg1 2 7 1 200 mg 1 2 7
202. 2 224 9 0 9555 1 224 9 0 4957 11 224 0 4 1 224 0 4 2 rue rio AR BR REI
203. uf 100mg m E S HE SA OSCAR BR 2 A lt ns ES E f X 5 x Y 1 Yr Ww E d Xogeg PB mL ihi mnghmL ih hib He p QU ET 2 07552 o au 25075428 2015050 n 0 9703 100 300 29072428 2012050 Las iiit Cop fs I P ERE HEU AEG OUR irs Fa amp 1 25 9 uu K 5 j yx mgdL nog 497 220 qo 29g 2076 514 492486 YY iii HJ A MX ve NEC dep EG B fu E REG E TUR S sipsi166 7100 2 740 308 159 zi e DIES n 6 O50 3 00 ETT E B 0 09 0 06 WEE dca 2404 p m 00 0 98 2 84 28 42 i 632 t 247 4322t14 2 240 5025 E n 4 100 4 4 1 07 0 06 0 09 30 59 4 05 YO E EE Se ruMEE Child Pugh A 2 5 6 Child Pugh X z1 T7909 EE Child Pugh A 2 7 10 12 1 06 0 09 M 2530ms 500mg
204. 3 40kg 5 1 62 5mg 1 2 1 1 AST GOT ALT GP id LBOS3ETEEAISI Bs 2 3 4 AAA 5 cZ4620C 4g PEE WEE INR INR 2 1 2
205. CYP2C19 EM CYP2C19 1 1 CYP2C19 1 17 HEM CYP2C19 1 2 CYP2C19 1 3 PM CYP2C19 2 2 CYP2C19 2 3 CYP2C19 3 3 2 96 100 3 37 1000 kcal 200 mg 1 2 7 C AUC 34 24 T 1 4 4 4 6 L kg 1 1 10
206. CYPIA2 2B6 2C8 2C9 2C19 2D6 2E1 3A4 CYP1A2 2C8 2B6 2C9 2C19 3A invitro 979 2 AD C 100mg 25 7 M20 7 55 594 9 5 8 1 M20 7 6 5 4 4 3 7 4 DPP 4 M20 7 S0mg 1 2 1 2 WEM 1 6 30mg
207. 1 2 Xi 3 253mg 100mg O Lennox Gastaut 2 mg mg Lennox Gastaut
208. 12 150mg Ta AUC 2 inse EA 53 17 56 296 in vitro HF ifnsit SE 1 JOug mL SB HR 6 C 240mg 15nCi 168 296 BK 94 N2 71 10 N5 3 1099 N2 0 14 4 10 11 UGT1A4 IR C
209. 1 1 1 B 25mg B 100mg B 50mg B 1 1 1 H 2 1 1 2 5 50mg H 200mg R 100mg H 1 1 2 1 2 1 1 2 6 100mg H 638 FH 300mg H 200mg H 200mg 7 300 400mg 400mg 1 1 2 400mg 1 1 2 2 1 100mg B 1 1 50mg H3 2 100mg HD 2
210. 4 1 1 SR ER 1 J 25mg 100mg 2mg 5mg 1 1 6c BUT 2mg 5mg 23mg dad E 2
211. PT INR 70 2 0 3 0 70 1 672 6 498 9 N 7 061 N 7 082 n 10084 amp 4E n 100 481 1 637 fic 11 637 22 1 26 2 61 100 HR 0 49 95 CI 0 24 1 00 per protocol 95 0 48 11 1 26 22 2 600 523 1 00 1 N 639 N 639 n 100 n 100 0 65 Bil TK URS 0 74 JErP pU PB EE 3E 0 99 my 2 96 1 2 3
212. 1 9mgykg 1 2 Img kg 1mgkg 350mg 50mg 1 350mg 1 2 12 50kg 1 200mg 1 2 1 300mg 1 2 50mg 200mg 2800mg
213. 1 650 ppm TK 4 23 mM 2 062 ppm 9 NO 9 73 5 9 MetHb NO NO NO MetHb NO MetHb gt 3 ECMO 51 89 30 97 57 394 30 994 ECMO 38 89 67 97 42 79 69 194
214. 800 ppm 7 4 20 ppm 4 20 ppm ppm 10 ppm 20 ppm 20 ppm 40 ppm 7 gos BER ERIC rx f nTI RBEA CER3SUO SERIE VC 5 ppm Hic 5 C of amp soitNL
215. 29 X 50 mg 30 PTP 200 mg 50 PTP 1 nifabntin L20050310037 2 nfabuun L20050310038 L20050310039 4 L20050310040 5 Purkins L et al Br J Clin Pharmacol 56 Suppl 1 37 2003 L20040707053 6 HIV P450 virro L20050310041 7 CYP3A4 P450 vitro L20050310042 3 8 Romero A J et al Clin Pharmacol Ther 71 4 226 2002 L20040707176 9 L20050310043 10 Purkins L et al Br J Clin Pharmacol 56 Suppl 1 24 2003 L20040707054 11
216. 6 4 3 1 7 3 P450 CYP2C9 CYP3A4 CYP2C9 CYP3A4 CYP2C9 CYP3A4
217. 7 96 96 7 17 72 14 10 7 MetHb NO MetHb NO gt 8 1 NO NO PaO MetHb 2 MetHb 1 12 24 1
218. 99 5 B e 10mg PTP 100 10 X10 140 14 E X10 500 g 10 S X 50 500 15mg PTP 100 10 X10 140 14 X10 500 amp 10 X50 500 B 1 Steinke W 2007 2 Langewische FW et al A XucdsU 5k BV RXE ELCBgd 2 xRPERAER 2004 3 Langewische FW et al 7 2006 4 Schwarz TH et al 2004 5 Ploeger B et al 2014 6 Berkowitz S et al 2011 7 Nesse1 C et al 2010 8 Lensing A et al
219. log rank p value 0 0132 Kaplan Meier OS 12 9 16 8 3 9 7 Am BU GOG 0240 Roche 2014 4 8 2014 6 2013 3 2014 22 GOG 0240
220. 1 0 0996 0 0896 0 07 0 25 0 0896 1 31 0 7896 0 54 0 38 0 2396 0 14 0 1790 0 01 T 2 ALT GPT AST GOD EXE 0 1 1 E 3
221. 3 NO 4 MetHb 2 5 C 5 NO 0 5 m 0 5 ppm ac Fi0 60 7 NO m ve
222. 4 UHufJ ES 5 ULN AST ALT 3 2 i M25 fi32mg ee T UOS 3 AST ALT WE DEDE AT I A p Zmg d HE 1 T4GE 41 4E i pur JERA DG HU MHNOCUDARR 4 v 7 vo Wbiak 3 Il y 7s i me wREKTUS Xp LOGA PUIASMAU RA 2 STEHT TATE Man TAUTA YXAXN vs 3 ges gt 1 TT Jg In T ra US n qp xs NON We xL 4 0 0 53 KHR RE I 11 FI HIE M pp e E p r Fr
223. BE BSUESTE X UB ii USEENGNORG 2 LD 50 mg 250 mg 4 S0mgl H 2 250mgl 2 2 QUE 50mel 2 fid ds 250mg1 2 5 3 HD 50 mg 500 mg 6
224. Ee EE mo LTG2 40 2mg 5 101 5mg ZU e Jv amp 25mg C i B3 GS L2 GS LS GS 100mg Lennox Gastaut O 871139 871179 Puis JuRGUN BE 2
225. o uera MHOLCAOHRH 3 AIL NE Nu 9 1 10 2 1 1 16 64mg 32mg 2 62 5mg Cjs 082 90 065 1 04 AUC 0 87 9096 078 097 90
226. p f 1 0 0167 2 24 99 165 8 35 GE 1 1 0 1 0 5mg 100 B T xi Va 3 i A oni E H T H LE tel 53 i H i 2 a i 45 MN 39 S ao 1 1 4 E Li n I 2 n p f 4 bud XY 10 P j e S 20 Em 2ABEI J 02czE 1ing 9 5mg Mug 1238 n7157 234 n 124 fJ238 u 151 1238 27145 1238 nz1515 2438 n 1333 272155 2333 n 1 5 2438 n 15D 2438 n 1 1 1mg 1 0 1 0 5mg 4 0 02 0 1 0 Smg 2 54cm 2 Norwood Hamilton 4338
227. 0 6mgkg 1 200mng 1 1 2 Q 2 1 0 15mgkg 1 1 2 1 0 3mgkg 1 1 1 2 1 0 3mg kg 1 1 5mgkg 1 1 3mg kg 1 2 1 200mg 3 34 2 1 0 6mgkg 1 2 2 1 1 2mg kg 1 2 1 2
228. 1 1 B 1 1 1 1 2 1 1 5 1 2 25 50mg 1 2 5 100mg H3 omid4 5 100mg H 3 38H 3 25 s n ID 1 1 2 1 2 100mg H3 5 100 200mg H 200 400mg H 100 200mg H 1 2 1 2 400mg 1 1 2 1 100mg H3 2 1 2 8
229. NOVARTIS CL 50mg T ERES DERI AI il a n 3 j 1 1 J m 3 E NVR CCC 142mm 7mm X 50mm Ex 73 1 2 S y ag EE ZUZTPZSmpRO Ai 1 VRRGERRIT AF COBRE ODE L AM E
230. 125mg 4 C C 37 AUCo Am 7 16 125mg AUC C 10 22 8 500mg 1 2 7 5 200 250ng mL 1 2 7 0 30 3 Af amp iz EX n 8
231. 3 1 2 1 50mg 1 1 2 1 100mg 1 2 1 2 1 100mg 1 200 400mg 1 2 3 Hi 3 23mg 100mg 2mg 2 Smg D 2 1 03m 1 i 2 1 6Gmg kg 1 1 2 1 2 1 0 6mgkg 1 1 10mg kg 1 1 2 158 1
232. 1 000mg kg 2 d 250mg kg H EA ESEO BE C fn 4 P3 RR OO XE AE p fc 3 13 30mg1 2 AEBEER AUC 3mg kg Smgkg 20mg kg 80mg kg ME OH LDH CK CPK ALT GPT AST GOT erus i E 8 amp
233. 3 2 3 UGT1A4 _
234. 2007 2009 15 425 MDR TB 154 MDR TB 1 0 Q6 000 A 10 830 AJ MDR TB 260 108 MDR TB MDR TB MDR TB 2 XDR TB MDR TB MDR TB
235. 3 2 10 11 1 50 75 8231 PSA 2 5 10 0ngfmL 4 57 Modified Gleason Score 87 10 0 5 1096 206 95 1 13 3 75 1 0 0 5mg 1 5 Cus 3288 5pg mL AUCo 32316 9hrpgmL 1 1 pg ml 4000 3000 1000 2000 t 0 12 24 36 48 60 72 hr 1
236. 2 1 253mg 1 1 1 0mg 1 1 2 6 1 100mg 1 1 2 1 1 S0mg 1 200mng 1 I 2 3 3 1 2 1 50mg 1 1 2 1 100mg 1 2 1 200mg 1 2 6 1 300mg 1 2 7 1 H 3007 400mg 1 2 1 1 100mg 1 400mg
237. B Xa Xa 2 2 v B D Y Y U Rivaroxaban JAN rivaroxaban INN 5 Chloro A 5S 2 oxo 3 4 3 oxomorpho lin 4 yl pheny1 1 3 oxazolidin 5 yl methyl thiophene 2 carboxamide H CisHaC1N 0 S 435 88
238. EDITI CORB i RUNDE BG AST GOT ALP ALT GPT y GT GTP EGER i1 1 2 5 6 1 7
239. Gf L20150615076 25 Qin wo L20050310046 26 fEP RUE AET OEIEXETERABR in vivo L20050310047 27 L20050310048 28 QTc L20050310049 29 1 L20050317019 30 I L20050317020 31 L20140815038 32 L20050310052 33 L20050310053 34 L20050310054 35 Lutsar Let al Cli
240. 2 4 CILUF 2 3 1 3 X 4 n 12 n 12 ss 5 ow qp om p ej 1 Child Pugh MEC M REN E KP TNUES re DR Cus 1 61 1 34 1 48 1 65 ug mL 1 14 2 53 0 99 1 81 1 22 2 26 1 12 1 84 1 e S 1 Eg AUC 69 07 ug hr mL 38 77 98 09 CL F 0 538 Ik 1 00 1 00 00 34 79 145 12 50 11 158 14 70 60 110 72 248 86 mL min kg 0 267 0 593 0 165 0 445 0 114 0 356 0 061 0 260 7 12 6 Ej 61mLmin 150mg Cu AUC t24 amp 0 CLF 2 35 0 40 ngmL 93 8 21 0 pg hr mL 31 2 5 4 0 396 0 063 mL min kg 9 150mg Car AUCo ee tp CL F 4245 0 18 sgmL 117 30
241. n 8 49 2 RY 12 125mg 1 2 95 6 10 4 5 25mg 1 2 Ci AUCojs 22 40 Cus AUCojz 24 29 32 12 500mg 1 2 10 6 26mg R S AUCe 38 29 14 1 INR INR 4 10
242. 0 5mg 3S2 23 26 18 24 23 30 2 52 90 24 2 2010ng
243. 2 voriconazole VRCZ QR 3S 2 2 4 difluorophenyl 3 5 fluoropyrimidin 4 y1 1 1 2 4 triazol 1 yl butan 2 ol Ci H 4E NO 349 31 99 5 V 1 mol L f Ie ARIS 2 logD 1 69 pH7 4 1
244. L20050310044 12 P450 zo L20050310045 13 Saari T Let al Eur J Clin Pharmacol 63 10 941 2007 L20071002034 14 Saari T Let al Br J Clin Pharmacol 63 1 116 2007 L20070313251 15 Hagelberg N M et al Eur J Clin Pharmacol 65 3 263 2009 L20090225001 16 Saari TLetal Eur J Clin Pharmacol 64 1 25 2008 L20080117022 17 Hynninen V V et al Antimicrob Agents Chemother 50 6 1967 2006 L20060606012 18 Hynninen V V et al Fundam Clin Pharmacol 21 6 651 2007 L20071203097 19 L20070115007 20 Rengelshausen J et al Clin Pharmacol Ther 78 1 25 2005 L20050812016 21 CE P 8 TIEEBRAURR L20041124004 22 HSCT FD L20150615074 23 SCT IFI GEZLSIDBO U L20150615075 24
245. ae A id 15 500mg 10mg AUC 1 5 Cmax 1 4 ERU 15 500mg 10mg AUC Cmax 1 3 4 18 150mg 600mg 20mg AUC 50 D 10 4 000IU 10mg Xa PT aPTT EAE oI7227t 0 13 500mg 100mg 15mg 7 11
246. 2010ng SmL 10099 amp v5 amp t amp SQkg S amp EOD 186 1 3 A BESEROM IAl 4 2 4 4325
247. 300mg 75mg 15mg 8 11 500mg 1 1 15mg 9 12 VKORCI 1639 A PT INR 2 0 3 0 15mg 1 1 aPTT Xa ETP PT PT INR 2 3 2 9 3
248. 36 22 7 9 83L h 164mL min We sina 2 4 C 100mg 168 85 15 23 5 50mg 1 2 1 3 P Am 0 5mM n vitro 9 2 3
249. CzHazNsOsS HO 56963 VM 995 23 32mg 28 14 2 x2 PTP 1 Gutierrez MM et al Int Clin Pharmacol Ther 2013 51 029 536 2 HAC Lp 8 BI DE Bri es TL RE Ron REL 7c BS 3 Weber C et al Drug Metab Disp 1999 27 810 815 4 In vitrol38 4 VAR Gr SS OO RS 5 Van
250. 0 5mg Smg 1 1 0 1 0 5mg 8 1 0 5mg 59 2 0 Smg 11 5 3 n vitre 99 8 gl 99 0 96 6 89 2 87 6 20 2000ng mL E EK BER 20 50 REOS EOD E VETERE RR EXER E LIE DRPRSETSI
251. 4 GOG 0204 GOG 0204 Cis Pac Cis Pac Cis Pac Car Pac II ICOG0S05 OS Car Pac Cis Pac Car Pac Cis Pac GOG 0240 Stage IVB 452 15 mg kg 3 2x2 II OS 0 74 95 CI 0 58 0 94 OS
252. gt 2011 26 000 25 2013 49 814 Ska 10 830 2014 47 845 MDR TB 2 WHO 2013 TB MDR TB MDR TB 110 100 2013 MDR TB 7 701 7 266 432 A MDR TB 64 0 8
253. 06mg kg H 3 1 2 8 iE3 8 25mg 100mg 1 2 1 25mg
254. 250mg HD 1 50mg 500mg 1 1 50mg 250mg S0mg 500mg 1 2 2 jay b oai ied 4 tx cuu s 2 2013 1 Do IURBODPP AREE C 77 7 46 E RGERE ER E 2 DERE Qo IXE MOS EE 5 BUT SLE LD HD EquMet Combination Tablets LD amp HD
255. 3 15mg BID 20mg QD 5 1mg kg BID K DUE PT INR 2 0 3 0 3 6 12 DVT 194 4 H XIHBXER I188 2H PE 216 9 214 9 48 DVT 1 731 1 264 1 718 1 213 PE 2 419 2 237 2 413 2 223 ITT 4 1 2 6
256. 7 V M V M250 V M500 Ix dh V M250 30mg 2530mg 70 20 100mg V M500 50mg 500mg AUC Cmax OES RUDS p lt 0 001 18 40 1 32 1 18 2 2 30mg 1 2 1 2 171 WA 50mg 250mg 50mg 500mg 30mg 1 2 14 HbAlc
257. CML 95 CML CP AP BP 3 AP 1 BP 2 3 2011 30 000 CML 11 000 ALL X ALL 30 Ph 2011 ALL 5 000 CML Ph ALL 5 CKD CML Ph ALL amp TKI TKI I AP24534 10 201
258. L CRM eos 40C us e 3 NO NO NO NO OSHA HE SOS Qs era
259. amp omw Il 2 mm Ri pm EN 3 6 Pfizer 30mg LUE EN VORS50 UL DK e MEE E ECEEES LE 15 5 I 7 EST Pfizer v ws 200mg VOR200 pa ha 40kg 0 500 mm n dh
260. 7 40mg 1 1 7 5mg 1 1 6 0 5mg 0 8395 8 PTP PITP PTP 9 1 18 52 27 23 52 24
261. ERPIG gc end s WLC ET 65 oo m M n2 E n M LIU LA A E 170 NER M TIL j ae co P OW UA A m om om um umo e 9m m m m m9 o 9m 9m 9e 9m m mo A A HO d SA Am Rs m m am 9A es 9m 99m 9m An RA e mom m9 m9 m mt 5 3 2 1 3 4 5 6 7 8
262. 1 BR 237 5 3v77 30g 150ug 300mg AUC 4 Ca 48 6199 C 35 0 E amp DESEE E 0D 7 2 AUCo S4 Ca 81 88 AUC 93 Ca EN 200mg 1 1 I5mg 1 1 6 AUC 4 Cg 76 80
263. 2 H QUOS CU EE V MEAT TRE 1 32 mg 4j 33 045 mg 2 1 120 mg 1 H 240 mg 1 2 mgkg 1 5 Hik H amp E OR ETA ETg 7 20154 1 27 P ioni 92mg 3E Wu SEDE du m Tracleer 32 mg dispersible tablets for pediatric ET 1 RIA 2001 11 z 4 gt KE Iu bak oe BE m fco riti m 1 1
264. N2 17 29 qe 1 ym 5 I 12 13mL mm 6 54umol L 100mg tj L6 22 AUC L8 4 20 6 P 12 24 100mg Cox Cu ERO Tau AUC t
265. P RR AUC js n 9 n 8 49 2 12 125mg 1 2 9 5 6 10 4 5 2 5mg 1 2 C AUC js 22 40 C AUCojs 24 29 3 12 500mg 1 2 10 6 26mg R S AUC 38 29 14 1 INR INR
266. 0 17 196 8k E ELE XU ME T7 vv3x dERUL HE Em EG DOSES shi EVE k B 1 2 DVI PE 4 DVT PE PBAEEAAKOO RE 3 DVT PE 55 12 49 100 804 5 75 75
267. LD 100 PTP 420 PTP 300 PTP 300 737 100 PTP 420 PTP 300 PTP 300 HD 1 Tuchmann Duplessis H et al Compt Rend 253 321 1961 EQMS00001 2 EQMU00002 3 EQMU00001 4 n vitro EQAU00005 5 Scheen A J Clin Pharmacokinet 30 5 359 1996 EQMS00002 6 CYP n vitro EQAU00006 7 CYP Gin vitro EQAU00007 8 CYP n vitro EQAU00008 9 HeH et al Drug Metab Dispos 37 3 536 2009 EQAM00264 10 EQAU00001 11 1 EQAU00010 12 2 LEQAU00011 13 3 EQAU00012 1 EQAU00013 15 Pentik inen P J et al Eur J Clin Pharmacol 16 195 1979 EQMS00003 16 Kimura N et al Drug Metab Pharmacokinet 20 5 379 2005 EQM
268. 08 125 1000 8 62 5 mg e 64 mg ng mL 12 48 h z amp OfnsERERESETE CIA2S SD n 16 WEBER A AZAR UG v o6 VOKRSUDG SEE Riv Ends ng mL 496 395 623 30 5 0 2524 3852 4 4 11 5 092 3404 3 453 774 B T 2809 4345 65 10 4 95 t ng h mL 2 5 1 2mg kg 1 2 12 800 600 400 20 ng mL 0051 2 3 75 12 h D SD n 5 E Cmar AUC 1 tmax IE ng mL ng h mL h 2mg kg 5 493 75 229974 2 00 2 1874 1301 1
269. 1 A 49 hi 48 50mg 250mg i uo by Bsp 4 Bun ipa MA 8 4 Kk 12 36 20 24 Tti OpUE thr 4 3 12 16 2 M T BRCRRD hn e Ajil50 250mg o 50mg 250 mg n 49 50mg 500mg mrt ne mE gt i erp imo 0 4 342 d6 20 24 6 353 8 Y Y 20 M FEAST hri itiRESRSS d e 30 500 mg o 50 mg 500 mg n 48 WEENUTAT 50mg 250mg n 49 Cmax ng mL 263 x 63 9 272 x 60 9 831 187 831 180 118042203 1 90
270. MetHb xk 5 Z PC eu 2 NO MetHb MetHb MetHb 3 INOT12 11
271. 3 8 2mg 5mg 25mg 100mg 1 2 1 0 3m 1 0 6mgkg 1 200mg 1 1 2 2 2 1 0 15mgkg LB 2 1 0 3mgkg 1 1 1 2 1 0 3mgkg 1 1 5m
272. 6 5 90 1877 5 8 5 0 3 0 1 1 2 Toxic Epidermal Necrolysis TEN 48 Stevens Johnson 3 5 000 TZE SUB BUR BER 1 2 4 QT
273. EE 62 5mg 125mg fr 38 cb amp ngimL h 10 62 5mg 125mg 2 cgaD A uM 62 5mg 772 4 3 n 10 619 964 182 24951 37 5 0 125mg 1922 3 6 n 10 1364 2710 6698 im 3 0 4 3 95 12 125mg 1 2 7 5 30 10 4 0 C 1212ng mL 959613 SRIX I 940 1564 AUC j 4640ng h mL 95 3641 5914 5 6 059048 SRIX TH 4 6 6 9 3 3 1 WHO II 6 1 125mg 1 2 2
274. 1 2 Jw
275. 886 9 59632 10 7 5 95 tsx 2 4 C 500mg 97 90 3 3 vitroiz 3384 A if 5E 4 F1 95 0 n 8 I5 0214 219ug mL O s EE 8B p C 40896 C do I5 4 Child Pugh A 8 125mg 5 Ne ta 15 30mL min 8
276. 1 1 2 1 350mg 1 1 2 1 100mg 1 2 6 1 200mg 1 1 2 1 1 100mg 1 400mg 1 1 2 2 2 1 25mg 2 1 25mg 1 1 1 S0mg 1 1 2 6 1 100mg 1 I 2 1 1 50mg 1 200mng 1 1 2 3
277. 12mg kg 381083 2 1 5 1Smgkg 1 2 1 400mg Qi 3 25mg 100mg D 2 1 25mg 1 1 2 1 50mg 1 1 2 1 100mg 1 1 2 6 1 200mg 1 1 2 1 1 100mg 1 400mg 1 1 2 Q 2 1 25mg
278. 4 3 Ca 61 779 AUC Ca 14 AUC 1 4 Ca 669 4 AUC 8299 b L7 C 939 AUC CYP3A4 2 CYP3A4 CYP3A4 H MEX CYP2CI9 amp QU CYP2C9 CYP3A4 CYP2C19 CYP2C9 mr nm mm mm TT am im im mm
279. 500mg 48 51 6 hOCT2 o 24 100mg AUC 2 01 1 31 2 33 1 42 Cmax 1 66 1 08 1 56 1 24 M20 7 AUC 44 L 7 2 6 6 1 6 7 Cmax 1 6 2 4 3 4 8 1 3 M20 7 50
280. L20050310060 47 vivo L20050310061 48 Candida Gn vivo L20050310062 49 Candida vive L20050310063 50 Candida non albicans GP Ein vivosAER L20050310064 51 Cryptococcus Qin vivo L20050310065 52 Cryptococcus yo L20050310066 53 yyo L20050310067 54 re L20050310068 55
281. 12 1 1 12 24 12 24 DVT 2 196 3 09 6 HR 0 68 9596CI 0 44 1 04 PE 2 1 1 89 HR 1 12 9596CI 0 75 1 68 DVT PE PP JN EPXVD XR 7 MES N 2 419 N22 413 n 96 n 99 RTT fuIBB SES prem ITT _ 1 5 l1mg kg 1 2 K acenocoumarol PT INR 2 0 3 0 2 DVT PE PE 3 PE PE DVT
282. 24 61 ug hr mL 31 2 6 4 0 313 0 087 mL min kg 8 D ik 425 lm peut DOE EI 2 1 S00mg 1 2 20mg 100mg 150mg 1 1
283. Haenszel O1 PaO gt A aDO aA PS0 001 gt 0 MetHb 80 ppm 36 13 36 MetHb 7 MetHb 7 10 sx 12 19 57 6 DD MetHb 10 5 9 IK 3001 CVS 301 ipe gt LVAD
284. MEAN EE ains p pue 125mg 1 2 lmg 35ug 7 OM UCU 14 31 8 19 1 l25mg 1 2 6 3 1 20mg 1 3 2 1 80mg 1 3 1 80mg 6 6 AUC C ax 63 55 AUC Czsx 50 42 5 1 e Kn Mu n 6 quu addc
285. amp 9958 2 2 4 12 20 16 12 10 2mgkg 400mg 12 HV EEG 20 7 95 HX 35 0 15 39 5922 9 12 HV EEG 7 6 95 85 7 42 13 99 64 1 1 10mgkg 200mg
286. m E Eno E nm ah d de iQ 1 300mg 1 2 2 1 150mg 1 200mg 1 2 1 400 mg 1 2 2 1 300mg 1 2 1 1S0mg 1 2 2 1 100mg 1 2 2 1 150mg 1 2 1 9 mg kg c 2 1 mgkg 1mgkg 350mg 50mg 1 350mg 1 2 eI 12
287. 0 24 83 6 90 996 40 n 39 GE 1 1 0 1 0 5mg 3 0 1 0 5mg 1 1 6 65 90 40 52 X Dutasteride N 2 5 Bis trifluoromethyl phenyl 3 oxo 4 aza Sa androst l ene 17f carboxamide CH5oFeNO gt 528 53 BR 5 242 250C logP 49 1
288. 1 0 1 mg 0 5 mg EDT X sy guum E d 2 DERE CS 193mm ES 6 6mm 193 mm 6 6 mm GS MUF D M
289. 1 0 83 QT torsades de pointes 5 3090 6 HZ 1 0 CEIESTE HX HIRAV 7 8
290. 11 1234 3337 95 tx 2 4 C 500mg 97 90 3 3 vitroizi3 2 dip Eoi n 8 0214 21 9 g mL 98 4 5 Child Pugh A 8 125mg 6 15 lt lt 30mL mm 8
291. 2 D MB 2 ODER 38 350mg 1 2 52 0 1 7 S8 1 HbAlc JDS 0 75 DPP 4 GLP 1 1 DPP 4 DPP 4 IC 2 7aM DPP 4 Ki 2 3nmM 9 2 GLP 1 2
292. 2 F RUCAZUBY V fc SEBOXA EX WORD C oiijg 100 1872 395 12 36 PP Qu 200 461 182 336 BE 7922299 190 37642 283 606 2 26 n 6 77 50 200 967 076 271 gt ozgo 7125 2451 380i 5984 2 24 n 6 0 50mg 1 2 0 2mg 1 3 amp HE 75 235 100 BR 3552 144i 3 3 n 6 ON OR Ce M Cmax AUCo n f ife E T o 15 26565 8054 cr m DPP 4 591 166 n 6 SPEM ERE doe o cbe Oso HEX CLcr S0 SOmL min CLcr 30 20mL min CLer 30mL min 3 50 150 300 532 625 2 2 CP d
293. 2194 53702936 53702797 ng h mL 2 50 2 50 2 50 2 50 zx Tmax b 0 7507 5 00 0 50 5 00 0 500 5 00 1 00 5 00 1 76 x 0 269 1 7 x 0 185 3 58 0 696 3 53 0 612 50mg 500mg n 48 Cmax ng mL 256 68 5 263 682 1 450 x 383 1 470 385 AUClast 1 180 224 1 190 212 9 370 2 2 020 9 380 1 980 ng h mL Tmax h 3 00 3 00 3 00 3 00 1 00 5 02 1 507 5 00 0 750 5 02 1 007 5 00 T1 2 b 1 892 0 317 1 88 0 207 3 96 0 777 4 09 0 781 gt S amp s S 2 24 50mg 500mg Cmax AUC 90 1 0 0 95 1 17 1 08 1 02 1 15 0 74 0 68 0 80 0 90 0 83 0 98 3 vitro A5 2 amp EA Gr 38 39 3996 X khv amp Rvrida mmBEeSgL usz wtrE 4 n 1 1 CYP2A6 2B6 2C8 2C9 2C19 2E1I 2J2 3A4
294. 3mg 1 1 1 2 1H EL LC25 50mg 1 100 200mg 1 2 3 3 2 1 50mg 1 1 2 1 100mg 1 2 12 1 100mg 3 0383 5 1 200 400mg L 2 3 i 3 1 gt 3 3 i 3 i 3 1 2 pd 2 UR RSEN in EI Ee
295. 4M nvitro 3 PXR CYP3A4 mm vitro 4 0 5mg 1 1 1 2 4 6 4 Wil 1 1 20mg 48 GE 1 1 0 1 0 5mg 2 0 Smg 1 1 6 S 42 0 1 5 247 87 Smg amp 50 69 70 t 49
296. 54 PL271 275 1994 39 Dalby NO et al Epilepsy Res 28 63 72 1997 40 Wheatley PL et al Epilepsia 30 34 40 1989 41 Otsuki K et al Epilepsy Res 31 101 112 1998 42 Stratton SC et al Epilepsy Res 53 95 106 2003 43 De Sarro G et al Neuropharmacology 35 153 158 1996 44 Smith SE et al Epilepsy Res 15 101 111 1993 45 Hosford DA et al Epilepsia 38 408 414 1997 46 Xie X et al Pfl gers Arch 430 437 446 1995 47 Leach MJ et al Epilepsia 27 490 497 1986 151 8366 4 6 15 TEL 0120 561 007 9 00 18 00 FAX 0120 561 047 24 4 6 15 http glaxosmithkline co jp 3 0 1img 0 5mg 0 1mg 1 0 1 mg 0 5mg 1 0 5 mg 0 1mg 1 1
297. 5445 8447 24 Richard V et al Circulation 1995 91 771 775 25 Chen SJ et al J Appl Physiol 1995 79 21222131 26 Karam H et al Cardiovascular Research 1996 31 287 295 oppo pcc 20 S E TT150 0012 1 1 39 olea qutt C LIA ECCE DI TEL 03 5774 4716 Jer eM 9 00 17 30 mk odo els Me A9 MM yocp Sy urge BERE M 1 1 39 3 253mg 100mg 1 dd AXZU 2mg 5mg 25mg 1 25mg 100mg 1 100mg 2mg 1 2mg Smg 1 5mg 253
298. 8 188 7 004 241 1 71 2 16_ 100 _ HR 0 79 9596CI 0 66 0 96 HR 1 46 per protoco1 95 0 79 189 1 70 243 Q 19 o aso gg 1 0 86 N 7 061 N 7 082 95 FTU n 100 iE gl ELE 0 26 0 0 44 0 P 93 ne 0 23 D 98 ioni 0 09 0 61 0 81 101 0 91 126 12 5 Gs 1 gg 0 89 170 1 53 193 1 71 0 73 1 10 1 1 ik 2 ik 3
299. Giersbergen PLM et al J Clin Pharmacol 2003 43 15 22 6 Dingemanse J et al Int J Clin Pharmacol Ther 2002 40 310 316 7 Dingemanse J et al J Clin Pharmacol 2002 42 283 289 8 Binet I et al Kidney International 2000 57 224 231 9 Van Giersbergen PLM et al Clin Pharmacol Ther 2002 11 253 202 10 Weber C et al J Clin Pharmacol 1999 39 847 854 11 Van Giersbergen PLM et al Br J Clin Pharmacol 2002 53 589 595 12 Dingemanse J et al Clin Pharmacokinet 2003 42 293 301 13 Van Giersbergen PLM et al Clin Pharmacol Ther 2007 8 414 419 14 Van Giersbergen PLM et al Int J Clin Pharmacol Ther 2006 44 113 118 15 Burgess G et al Eur J Clin Pharmacol 2008 64 43 50 16 Beghetti M et al Br Clin Pharmacol 2009 68 948 955 17 FUTURE 2 18 FUTURE 3 19 Barst RJ et al Clin Pharmacol Ther 2003 73 372 382 20 Clozel M et al J Pharmacol Exp Ther 1994 270 228 235 21 7 22 Park SH et al Am Respir Crit Care Med 1997 156 600 608 23 Wang QD et al J Cardiovasc Pharmacol 1995 26
300. H 250mg 15mgkg 750mg Pe vr 98 3e m 7 p lt 0 01 3 Lennox Gastaut 3 25 Add on 0D 5mg kg H 200mg 1Smgkg 400mg 0 p lt 0 05 255 nx Add on 2 212 3mg kg 200mg 12 200mg 2 12 12mgkg 400mg 12 400mg
301. Iiy IV V 3 120 0 5mg 32 52 2 54cm 68 1 1 2 5e 1 Sc 9 In vitro 1 2 Sc 2 0 1 0 5mg 1 1 24 24 836 90 9 3 0 1 05 mg 12 4586 912
302. LM et al Br J Clin Pharmacol 2002 53 589 595 14 Dingemanse J et al Clin Pharmacokinet 2003 42 293 301 15 Van Giersbergen PLM et al Clin Pharmacol Ther 2007 81 414 4 9 16 Van Giersbergen PLM et al Int J Clin Pharmacol Ther 2006 44 113 118 17 Burgess G et al Eur J Clin Pharmacol 2008 64 43 50 18 Channick R et al Lancet 2001 358 1119 1123 19 Rubin LJ et al N Engl J Med 2002 346 896 903 20 Galie N et al Lancet 2008 371 2093 2100 21 Sasayama S et al Circ J 2005 69 131 137 22 Hatano M et al Heart Vessels 2014 Jul 16 23 EE TIER EZ ELS CE 3 A ELTE SIRO T EN 24 Matucci Cerinic M et al Ann Rheum Dis 2011 70 32 38 25 HR A E Hr PESE RELZ TE D ETRIER URINE 5c JV 25 Wl Hox ER 26 Barst RJ et al Clin Pharmacol Ther 2003 73 372 382 27 Clozel M et al J Pharmacol Exp Ther 1994 270 228 235 28 29 Park SH et al Am J Respir Crit Care Med 1997 156 600 608 30 Wang QD et al J Cardiovasc Pharmacol 1995 26 5445 8447 31 Richard V et al Circulation 1995 91 771 775 32 Porter KE et al Vasc Surg 1998 28 695 701 33 Verma S et al Cardiovasc Res 2001 49 146 151 34 Dumont A
303. O IV IT 28 17 60 7 40 7 Pl 25 0 3 10 7 175 68 38990 14 80 10 57 1 D 1 396597 AST GOT ALT GPT
304. PTT 1 5 2 5 PT INR 1 5 2 5 3 6 12 DVT 10mg BID 15mg QD 191 8 15mg BID 15mg QD 186 8 192 1 PE 204 7 213 0 ik 48 DVT 10mg BID 15mg QD REO 23 13 Dil 15mg BID 15mg QD 25 15 12 pir 7 PE B CH 30 28 7 6 OTT 4 12 24
305. QAU00031 33 DPP 2 EQAU00032 34 DPP 4 EQAUO00033 35 Ahr n Bo Best Pract Res Clin Endocrinol Metab 21 4 517 2007 EQAS00056 36 DPP 4 EQAU00034 37 He Y L et al Int J Clin Pharmacol Ther 48 9 582 2010 EQAF00039 38 Azuma K et al J Clin Endocrinol Metab 93 2 459 2008 EQAMO00196 39 2 HbAlc EQAU00036 40 Lee A J Pharmacotherapy 16 3 327 1996 EQMS00006 WO T105 6333 1 23 1 JROPAEKTIS DIRECT Ui 20 003 293 H amp 8 00 17 30 M RSERUMRHEE www hovartis to jb 01 1 23 1 50mg 200mg 200mg 1 x 2800mg 1 S0
306. S et al J Neurosurg 2001 94 281 286 35 Sato S et al 23 x 36 Akamata K et al Arthritis Res Ther 2014 16 R86 37 Chen SJ et al J Appl Physiol 1995 79 2122 2131 38 Karam H et al Cardiovascular Research 1996 31 287 295 T 150 0012 1 139 DI TEL 03 5774 4716 9 00 17 30 1 1 39 S RCTELION 300005G15H0901 3 lane 15 7L
307. S T 22 20 n ais 21 27 24 n TT Led PR uses ew bere pr ppp waws ree CCI el ls 3 1 10 4 18 173 Ge 6 6 um spp 2 9 3 102 ow AIL IBRU RR Xd 3 e Wu LIISPEEERUR 2 BP ER PREKRERI L1S0 2 BLESS S BR AE d RE Stevens Johnson II 347 3 0 5 Stevens Johnson
308. S00004 17 EQAUO0014 18 He Y L et al Int J Clin Pharmacol Ther 51 9 693 2013 EQOAF00126 19 He Y L et al Eur J Clin Pharmacol 63 7 677 2007 EQAM00145 20 He Y L et al Br J Clin Pharmacol 65 3 338 2008 EQAM00202 21 He Y L et al J Clin Pharmacol 48 1 85 2008 EQAM00186 22 Ayalasomayajula S P et al Curr Med Res Opin 23 12 2913 2007 EQAM00184 23 He Y L et al Curr Med Res Opin 23 5 1131 2007 EQAM00141 24 He Y L et al J Clin Pharmacol 47 8 998 2007 EQAMO00151 25 Serra D et al Int J Clin Pharmacol Ther 46 7 349 2008 EQAMO00219 26 He Y L et al Curr Med Res Opin 25 5 1265 2009 EQAM00280 27 Yamaguchi M et al Int J Clin Pharmacol Ther 51 8 641 2013 EQAM00798 28 Somogyi A etal Br J Clin Pharmacol 23 5 545 1987 EQMS00005 29 2 LMF237A1301 EQMUO00003 30 2 LMF237A1303 EQMUO00004 31 61 12 2593 2012 EQAJ00369 32 DPP 1 E
309. er J et al J Pharm Med 1 121 128 1991 15 Ebert U et al Eur J Clin Pharmacol 56 299 304 2000 16 van der Lee MJ et al Clin Pharmacol Ther 80 159 168 2006 17 Burger DM et al Clin Pharmacol Ther 84 698 703 2008 18 Levy RH et al Ther Drug Monit 27 193 198 2005 19 Weintraub D et al Arch Neurol 62 1432 1436 2005 20 DooseDR et al Epilepsia 44 917 922 2003 21 Gidal BE et al Epilepsy Res 64 1 11 2005 22 Perucca E et al Epilepsy Res 53 47 56 2003 23 Brodie MI et al Epilepsia 46 1407 1413 2005 24 Schieber FC et al Hum Psychopharmacol 24 145 152 2009 25 Reunanen M et al Epilepsy Res 23 149 155 1996 26 11 117 134 2008 27 25 425 440 2008 28 Messenheimer J et al Epilepsia 35 113 121 1994 29 Schapel GJ et al J Neurol Neurosurg Psychiatry 56 448 453 1993 30 Duchowny M et al Neurology 53 1724 1731 1999 31 Motte 7 et al N Engl J Med 337 1807 1812 19977 32 Biton V et al Neurology 65 1737 1743 2005 33 Matsuo F et al Neurology 43 2284 2291 1993 34 Schachter SC et al J Epilepsy 8 201 209 1995 35 Sander JW et al Epilepsy Res 6 221 226 1990 36 40 369 383 Q011 37 Miller AA et al Epilepsia 27 483 489 1986 38 Cramer CL et al Life Sci
310. g kg 1 1 3mg kg EL 2 1 200mg 3 2 2 1 0 6mgkg 1 2 2 1 12mg kg 1 2 1 2 1 1 2mgkg 1 15mgkg 1 2 1 400mg 3 i 3 3 gt 3
311. gt 1 FiO3 1 0 2 4 Pa0 gt 60 mmHg SpO gt 92 5 ppm 3 FiO FiO 0 4 0 6 PaO 2 70 mmHg 5 ppm 4 FIO 0 1 5 1ppm 1 ppm FiO gt 0 5 ppm 12 24 E dug MG ook gt OXCK 1 5 20
312. gt pOXOKR D FT e 7 4 20 ppm 4 20 ppm ppm 10 ppm 20 ppm 20 ppm 40ppm ES E
313. mg 100mg D 2 1 253mg 1 1 2 1 30mg 1 1 S 1 100mg 1 1 2 1 2 1 100mg 1 100 200mg 1 1 2 1 1 100mg 1 400mg 1 B 1 2 Q 2 1 25mg 2 1 2smg 1 1 1 2 1 25 50mg 1 100 200mg 1 2 3
314. mg 200mg 4 Q 1 200mg 1 2800mg 50mg 200mg 40kg 1 300mg 1 2 2 1 150mg 1 200mg 1 2 1 400mg 1 2 2 1 300mg 1 2 1 150mg 1 2 2 1 100mg 1 2 2 1 150mg 1 2 1 9mgkg 1 2
315. n Infect Dis 37 5 728 2003 L20040707110 36 Roffey S J et al Drug Metab Dispos 31 6 731 2003 120040707072 37 Hyland R etal Drug Metab Dispos 31 5 540 2003 120040707074 38 L20050310055 39 L20050310056 40 L20050310057 41 Herbrecht R et al N Engl J Med 347 6 408 2002 L20020909323 42 Perfect J R et al Clin Infect Dis 36 9 1122 2003 L20040707126 43 GB L20050310058 44 ypyo m o L20041124003 45 yyo L20030310039 46 yo
316. ppl Physiol 1994 76 1794 801 20 Frostell C et al Circulation 1991 83 2038 47 21 Katayama Y et al Respir Physiol 1994 97 301 7 22 Zayek M et al J Pediatr 1993 122 743 50 23 Berger JI et a Am Rev Respir Dis 1993 147 1080 6 24 Ogura H et al Surgery 1994 116 313 21 25 Phillips ML et al Pediatrics 1999 104 5 1095 100 105 0001 18 19 TEL 03 3578 7812 FAX 03 3578 7819 uh 18 19 Wd Bk Therapeutics I A 346 1 3S 15mg 1 15mg 10mg 1 10mg
317. rd 4 258 6dyn sec m cm 375 12 4 7 10 9mmHg 0 40 0 71 L min m 12 WHO Hn E EE UU 2 1 1 1 2mg kg 4mg kg 1 2 n 36 5 23 WHO n 28 393 536 7 1 2 2 1 RI 1 2mg kg 1 2 3 24
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