ࢯࣈࣜ࢔࣮ࢻ࢝ࣉࢭࣝ 100mg

࡟㛵ࡍࡿ㈨ᩱ

ᮏ㈨ᩱ࡟グ㍕ࡉࢀࡓ᝟ሗ࡟ಀࡿᶒ฼ཬࡧෆᐜ࡟ࡘ࠸࡚ࡢ㈐௵ࡣࠊࣖࣥࢭࣥࣇ࢓࣮࣐ᰴᘧ ఍♫࡟ᖐᒓࡍࡿࡶࡢ࡛࠶ࡾࠊᙜヱ᝟ሗࢆᮏ⸆๣ࡢ㐺ṇ౑⏝௨እࡢႠ฼┠ⓗ࡟౑⏝ࡍࡿࡇ ࡜ࡣ࡛ࡁࡲࡏࢇ ࠋ

ࣖࣥࢭࣥࣇ࢓࣮࣐ᰴᘧ఍♫ TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

⋡ᰴ 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲ ...... 3 1.5.1 ⿠ේ෶ߪ⊒⷗ߩ⚻✲ ...... 3 1.5.2 ᧄ೷ߩኻ⽎∔ᖚ෸߮⥃ᐥ਄ߩ૏⟎ઃߌ ...... 3 1.5.2.1 C ဳᘟᕈ⢄Ἳߩ᭎ⷐ...... 3 1.5.2.2 C ဳᘟᕈ⢄Ἳߩᴦ≮ߩ⃻⁁ ...... 3 1.5.3 㐿⊒ߩ⚻✲ ...... 4 1.5.3.1 ຠ⾰ߦ㑐ߔࠆ⹜㛎ߩ᭎⇛ ...... 4 1.5.3.2 㕖⥃ᐥ⹜㛎ߩ᭎⇛ ...... 5 1.5.3.3 ⥃ᐥ㐿⊒ߩ᭎⇛ ...... 6 1.5.4 ᧄ೷ߩ੍ᗐߐࠇࠆᴦ≮਄ߩ૏⟎ઃߌ ...... 11

JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38

1 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

⇛ภ৻ⷩ⴫ ⇛ภ෶ߪ⇛⒓ ൻቇฬ෶ߪ৻⥸ฬ ᭴ㅧᑼ ↱᧪ Monosodium O CH3 (cyclopropylsulfonyl)[(2R,3aR,10Z,11aS, O S O CH 12aR,14aR)-2-({7-methoxy-8-methyl-2-[4- O NNa 3 O (1-methylethyl)-1,3-thiazol-2-yl]quinolin- H N N H TMC435 4-yl}oxy)-5-methyl-4,14-dioxo- CH ਥ⮎ H 3 H O N 1,2,3,3a,4,5,6,7,8,9,11a,12,12a,13,14,14a- H hexadecahydrocyclopenta[c]cyclopropa[g] S CH3

[1,6]diazacyclotetradecine-12a- N O carbonyl]azanide CH3

⇛ภ෶ߪ⇛⒓ ฬ⒓෸߮ౝኈ ALT alanine aminotransferase㧔ࠕ࡜࠾ࡦࠕࡒࡁ࠻࡜ࡦࠬࡈࠚ࡜࡯࠯㧕 AST aspartate aminotransferase㧔ࠕࠬࡄ࡜ࠡࡦ㉄ࠕࡒࡁ࠻࡜ࡦࠬࡈࠚ࡜࡯࠯㧕 BCOP bovine corneal opacity-permeability㧔࠙ࠪⷺ⤑ᷙỘ෸߮ㅘㆊᕈ㧕

CYP cytochrome P450㧔࠴࠻ࠢࡠ࡯ࡓ P450㧕 GCP Good Clinical Practice㧔ක⮎ຠߩ⥃ᐥ⹜㛎ߩታᣉߩၮḰ㧕 GLP Good Laboratory Practice㧔ක⮎ຠߩ቟ోᕈߦ㑐ߔࠆ㕖⥃ᐥ⹜㛎ߩታᣉߩၮḰ㧕 HCV hepatitis C virus㧔C ဳ⢄Ἳ࠙ࠗ࡞ࠬ㧕 HIV human immunodeficiency virus㧔ࡅ࠻఺∉ਇో࠙ࠗ࡞ࠬ㧕 The International Conference on Harmonisation of Technical Requirements for Registration ICH of Pharmaceuticals for Human Use㧔ᣣ☨ EU ක⮎ຠⷙ೙⺞๺࿖㓙ળ⼏㧕 IFN interferone㧔ࠗࡦ࠲࡯ࡈࠚࡠࡦ㧕 IL28B interleukin-28B㧔ࠗࡦ࠲࡯ࡠࠗࠠࡦ㧙28B㧕 LLNA local lymph node assay㧔ዪᚲ࡝ࡦࡄ▵⹜㛎㧕 PegIFN peginterferon㧔ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ㧕 PegIFNĮ-2a peginterferon alfa-2a㧔ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦࠕ࡞ࡈࠔ-2a㧕 PegIFNĮ-2b peginterferon alfa-2b㧔ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦࠕ࡞ࡈࠔ-2b㧕 P-gp P-glycoprotein㧔P-♧ߚࠎ⊕⾰㧕 time interval between the start of the Q wave and the end of the T wave in cardiac electrical QT cycle㧔ᔃ㔚࿑ QT㧕 JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 QTc QT interval corrected for heart rate㧔ᔃ㔚࿑ QT ⵬ᱜ୯㧕 RBV ribavirin㧔࡝ࡃࡆ࡝ࡦ㧕 RGT response-guided therapy RNA ribonucleic acid㧔࡝ࡏᩭ㉄㧕 SVR sustained virologic response㧔ᜬ⛯⊛࠙ࠗ࡞ࠬ㒶ᕈൻ㧕

㧨⥃ᐥ⹜㛎ߩ⹜㛎⇟ภߩᮡ⸥ߦߟ޿ߡ㧪 ⥃ᐥ⹜㛎ߩ⹜㛎⇟ภߪ㧘TMC435 ߩ㐿⊒ᤨᦼߦࠃߞߡᰴߩ 3 ㅢࠅߩᣇᴺߢઃਈߐࠇߚ㧔XXX ෸ ߮ XXXX ߪ㧘ߘࠇߙࠇ 3 ᩴ෸߮ 4 ᩴߩ࿕᦭ߩᢙሼ㧕ޕᧄ⾗ᢱߢߪ㧘ฦ⹜㛎⇟ภߪޟCXXXޠ෶ߪ ޟHPCXXXXޠߢ␜ߔޕ · TMC435350-TiDP16-CXXX㧔㐿⊒ೋᦼߩ⹜㛎ߦ૶↪㧕

· TMC435-TiDP16-CXXX

· TMC435HPCXXXX㧔ᦨㄭߩ⹜㛎ߦ૶↪㧕

2 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

1.5.1 ⿠ේ෶ߪ⊒⷗ߩ⚻✲ TMC435㧔ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ㧕ߪ㧘C ဳ⢄Ἳ࠙ࠗ࡞ࠬ㧔એਅ㧘HCV㧕ᗵᨴ∝ߦኻߔࠆᴦ ≮⮎ߣߒߡ㧘Medivir ␠෸߮ Tibotec Pharmaceuticals Ltd.㧔⃻ Janssen R&D Ireland㧕ߦࠃࠅ౒ห㐿 ⊒ߐࠇߚ╙ੑ਎ઍߩࡊࡠ࠹ࠕ࡯࠯㒖ኂ⮎ߢ޽ࠆޕTMC435 ߪᄢⅣ⁁᭴ㅧࠍ᦭ߒ㧘HCV ߩⶄ⵾ߦᔅ 㗇ߢ޽ࠆ NS3/4A ࠮࡝ࡦࡊࡠ࠹ࠕ࡯࠯ߣ㕖౒᦭⚿วߔࠆߎߣߦࠃࠅ․⇣⊛ߦߘߩᵴᕈࠍ㒖ኂߒߡ ᛫࠙ࠗ࡞ࠬ૞↪ࠍ␜ߔޕTMC435 ߩ᭴ㅧᑼࠍ࿑ 1.5-1 ߦ␜ߔޕ

O CH O S O 3 CH O NNa 3 O H N N H CH3 H N H O H S CH3

N O

CH3 ࿑ 1.5-1 TMC435 ߩ᭴ㅧᑼ

1.5.2 ᧄ೷ߩኻ⽎∔ᖚ෸߮⥃ᐥ਄ߩ૏⟎ઃߌ

1.5.2.1 C ဳᘟᕈ⢄Ἳߩ᭎ⷐ HCV ᗵᨴߪ㧘ో਎⇇ߢ⢄∔ᖚߩਥⷐߥේ࿃ߣߥߞߡ߅ࠅ㧘ߘߩᗵᨴ⠪ᢙߪ⚂ 1 ం 7000 ਁੱ㧘 ࿖ౝߢߪ 150 ਁੱએ਄ሽ࿷ߔࠆߣផቯߐࠇߡ޿ࠆ 1㧕ޕHCV ߦᗵᨴߔࠆߣኋਥ஥ߩ఺∉ᔕ╵ߦࠃ

JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 ࠅᕆᕈ⢄Ἳࠍ⊒∝ߒߚᓟ㧘ήᴦ≮ߩ႐ว 55㨪85%ߩᖚ⠪ߪ HCV ߇ឃ㒰ߐࠇߕᘟᕈ⢄Ἳ߳ߣ⒖ⴕ ߒ㧘⢄✢⛽ൻ߇✭ᓢߦㅴⴕߒ㧘20㨪25 ᐕߢ 5㨪20%ߩᖚ⠪ߪ⢄⎬ᄌߦ⥋ࠆޕ⢄⎬ᄌߪᦨ⚳⊛ߦ⢄ ਇో߿⢄⚦⢩≸ߦ⥋ࠆ㊀◊ߥォᏫࠍߚߤࠆ∔ᖚߢ޽ࠅ㧘⢄⎬ᄌ߆ࠄߩ⢄⚦⢩≸⊒∝₸ߪ᰷☨ߩᐕ 1㨪4%ߦᲧߒ࿖ౝߢߪᐕ 7%ߣ㜞޿ޕ߹ߚ㧘࿖ౝߢߩ⢄⚦⢩≸ߩᐕ㑆ᱫ੢⠪ߩ⚂ 80%߇ C ဳᘟᕈ ⢄Ἳ߆ࠄ⒖ⴕߒߚ߽ߩߣ⠨߃ࠄࠇߡ޿ࠆ 2㧕3㧕ޕC ဳᘟᕈ⢄Ἳߩ⥄ὼᴦ≹ߪᭂ߼ߡ⒘ߢ޽ࠅ㧘⢄ታ ⾰ౝߢߩ⢄⚦⢩ߩᄌᕈ෸߮უᱫᚲ⷗㧘ਗ߮ߦ㐷⣂ၞߦߪ࡝ࡦࡄ⃿ࠍਥ૕ߣߒߚἻ∝ᕈ⚦⢩ᶐẢߣ ✢⛽ൻ߇⃻ࠇ㧘ᜬ⛯⊛ߥ⢄ᯏ⢻⇣Ᏹࠍ๒ߔࠆޕ

1.5.2.2 C ဳᘟᕈ⢄Ἳߩᴦ≮ߩ⃻⁁ C ဳᘟᕈ⢄Ἳᴦ≮ߩਥߚࠆ⋡ᮡߪ㧘⢄Ἳߩᴉ㕒ൻߦࠃࠅ✢⛽ൻߩㅴⴕࠍᛥ߃㧘⢄⎬ᄌ෶ߪ⢄⚦ ⢩≸߳ߩㅴዷࠍ㒐ߋߎߣߢ޽ࠅ㧘ߘߩߚ߼ߦᦨ߽ലᨐ⊛ߥᴦ≮ߣߒߡ࠙ࠗ࡞ࠬឃ㒰߇㊀ⷐߣ⠨߃ ࠄࠇߡ߅ࠅ㧘․ߦ㧘㜞㦂⠪߿✢⛽ൻㅴዷ଀ࠍ฽߻㜞⊒߇ࠎ࡝ࠬࠢ⟲ߢߪ㧘ᣧᦼߦ᛫࠙ࠗ࡞ࠬ≮ᴺ ߇⠨ᘦߐࠇࠆߴ߈ߣߐࠇࠆ 1㧕ޕ ࿖ౝߦ߅޿ߡ㧘1992 ᐕߦࠗࡦ࠲࡯ࡈࠚࡠࡦ㧔એਅ㧘IFN㧕⵾೷߇࠙ࠗ࡞ࠬឃ㒰ࠍ⋡⊛ߣߒߚ C ဳᘟᕈ⢄Ἳߩᴦ≮⮎ߣߒߡ଻㒾ㆡ↪ߐࠇ㧘ߘߩᓟ࡝ࡃࡆ࡝ࡦ㧔એਅ㧘RBV㧕ߣߩ૬↪≮ᴺ߿ࡍࠣ

3 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

ࠗࡦ࠲࡯ࡈࠚࡠࡦ㧔એਅ㧘PegIFN㧕⵾೷߇㐿⊒ߐࠇ㧘HCV Genotype ߦᔕߓߡᛩਈᦼ㑆߇ᦨㆡൻ ߐࠇߚޕ ߎࠇ߹ߢ㧘PegIFN ෸߮ RBV ߩ 2 ೷≮ᴺߪ㧘㔍ᴦᕈߩ Genotype 1 ဳߢ㜞࠙ࠗ࡞ࠬ㊂ߩᖚ⠪ߦኻ ߔࠆᮡḰ≮ᴺߢ޽ߞߚ߽ߩߩ㧘SVR24 ₸㧔ᛩਈ⚳ੌᤨ෸߮ᛩਈ⚳ੌᓟ 24 ㅳߩⴊẏਛ HCV RNA ߇㒶ᕈൻߒߚⵍ㛎⠪ߩഀว㧕ߪ 50%⒟ᐲߢ޽ߞߚ 4㧕ޕ߹ߚ㧘ਥߥ᦭ኂ੐⽎ߪ㧘⊒ᾲ㧘ୱᕃᗵ㧘 㗡∩╬ߩࠗࡦࡈ࡞ࠛࡦࠩ᭽∝⁁ߢ޽ࠅ㧘᦭ኂ੐⽎߿⥃ᐥᬌᩏ୯⇣Ᏹߩߚ߼ߦᄙߊߩᖚ⠪߇ᷫ㊂෶ ߪભ⮎ߦ⥋ࠅ㧘12㨪16%ߩᖚ⠪߇ᴦ≮ࠍਛᱛߒߚ 4㧕ޕᦝߦ㧘ᴦ≮ᦼ㑆߇ 48 ㅳ㑆㧔ലᨐਇචಽߥ ႐วߪ 72 ㅳ㑆߹ߢᑧ㐳㧕ߣ㐳ߊ㧘ᖚ⠪ߩᔃり߳ߩ⽶ᜂߪᄢ߈߆ߞߚޕߘߩߚ߼㧘ᴦ≮ലᨐߩะ ਄㧘቟ోᕈ෸߮ᔋኈᕈߩᡷༀ㧘ਗ߮ߦᴦ≮ᦼ㑆ߩ⍴❗߇⺖㗴ߢ޽ߞߚޕ߹ߚ㧘PegIFN ෸߮ RBV ߩ 2 ೷≮ᴺߢౣΆ෶ߪήലߢ޽ߞߚᖚ⠪ߦኻߒߡ㧘ᛩਈᦼ㑆ߩᑧ㐳߽฽߼ߚ PegIFN ෸߮ RBV ߦ ࠃࠆౣᴦ≮ᤨߩ SVR24 ₸ߪ㧘೨ᴦ≮ౣΆ଀ߢ 50%㧘೨ᴦ≮ήല଀ߢߪ 14%⒟ᐲߣߐࠇ 5㧕6㧕㧘․ ߦ೨ᴦ≮ήല଀ߦኻߔࠆ᦭ലߥ᛫࠙ࠗ࡞ࠬ≮ᴺߪታ⾰ߥ߆ߞߚޕ

2011 ᐕߦ NS3/4A ࠮࡝ࡦࡊࡠ࠹ࠕ࡯࠯㒖ኂ೷ߢ޽ࠆ࠹࡜ࡊ࡟ࡆ࡞߇࿖ౝߢᛚ⹺ߐࠇ㧘PegIFNĮ- 2b ෸߮ RBV ߣߩ 3 ೷૬↪≮ᴺ߇ዉ౉ߐࠇߚޕ࠹࡜ࡊ࡟ࡆ࡞ࠍട߃ߚ 3 ೷૬↪≮ᴺߦࠃࠅ㧘ᴦ≮ ലᨐߪะ਄ߒ㧘✚ᴦ≮ᦼ㑆߇ 24 ㅳ㑆ߦ⍴❗ߐࠇ㧘C ဳᘟᕈ⢄Ἳߩᴦ≮ߪᄢ᏷ߦᡷༀߐࠇߚ 7㧕8㧕ޕ ߒ߆ߒߥ߇ࠄ㧘㊀◊ߥ⊹⤏㓚ኂ߿⽺ⴊ╬ߩ೽૞↪ߩߚ߼㧘቟ోᕈ਄ߩ ᔨߦࠃࠆಣᣇ೙㒢߿೽૞ ↪߳ߩኻᔕߥߤ㧘ᣂߚߥ⺖㗴߽಴ߡ߈ߡ޿ࠆޕ߹ߚ㧘࠹࡜ࡊ࡟ࡆ࡞ߩ࿖ౝ⥃ᐥ⹜㛎ߢߪ 65 ᱦࠍ ⿥߃ࠆᖚ⠪ߪኻ⽎ߣߐࠇߡ߅ࠄߕ㧘ᣣᧄ⢄⤳ቇળߦࠃࠆޟC ဳ⢄Ἳᴦ≮ࠟࠗ࠼࡜ࠗࡦޠ1㧕ߦ߅޿ ߡ㧘࠹࡜ࡊ࡟ࡆ࡞㧘PegIFNĮ-2b ෸߮ RBV ߩ 3 ೷૬↪≮ᴺߪ Genotype 1 ဳ㜞࠙ࠗ࡞ࠬ㊂ߩ C ဳᘟ ᕈ⢄Ἳᖚ⠪ߩ߁ߜ㕖㜞㦂⠪ࠍၮᧄߦㆡᱜߥᖚ⠪ࠍ⷗ᭂ߼ߚ਄ߢ૶↪ߔࠆߎߣ߇ផᅑߐࠇߡ߅ࠅ㧘 㕖㜞㦂⠪ߦ߅޿ߡ߽㧘IL28B ㆮવሶᄙဳ㧔SNP rs8099917㧕߇ࡑࠗ࠽࡯ࠕ࡟࡞㧔TG ෶ߪ GG㧕ߢ HCV ࠦࠕ㗔ၞ 70 ⇟ࠕࡒࡁ㉄߇ᄌ⇣ဳߩᖚ⠪ߦኻߒߡߪផᅑߐࠇߡ޿ߥ޿ޕ

1.5.3 㐿⊒ߩ⚻✲ JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 TMC435 ߩ㐿⊒ߩ⚻✲࿑ࠍ࿑ 1.5-2 ෸߮࿑ 1.5-3 ߦ␜ߔޕ

1.5.3.1 ຠ⾰ߦ㑐ߔࠆ⹜㛎ߩ᭎⇛

(1) ේ⮎ ේ⮎ߩ▤ℂߪࠪࡔࡊ࡟ࡆ࡞ߢⴕ߁ޕታ↢↥ߦ↪޿ࠆ⵾ㅧᣇᴺߢ⵾ㅧߒߚࠪࡔࡊ࡟ࡆ࡞ߪ㧘㐳ᦼ ଻ሽ⹜㛎㧔25°C/60%RH㧕෸߮ടㅦ⹜㛎㧔40°C/75%RH㧕ߦ߅޿ߡ㧘ߘࠇߙࠇ 18 ࠞ᦬㑆෸߮ 6 ࠞ ᦬㑆቟ቯߢ޽ߞߚޕ⧦㉃⹜㛎㧔50°C/3 ࠞ᦬㧕ߦ߅޿ߡࠪࡔࡊ࡟ࡆ࡞ߦ⚻ᤨ⊛ߥᄌൻߪ⹺߼ࠄࠇߥ ߆ߞߚ߽ߩߩ㧘⧦㉃⹜㛎㧔ᦑశ/ICH Q1B ߦḰ᜚㧕ߦ߅޿ߡᕈ⁁ߩᄌൻ㧘฽㊂ߩૐਅ෸߮ಽ⸃‛ ߩ↢ᚑ߇⹺߼ࠄࠇߚޕએ਄ߩ⚿ᨐߦၮߠ߈㧘ࠪࡔࡊ࡟ࡆ࡞ߩ࡝࠹ࠬ࠻ᦼ㑆ࠍ ࠞ᦬㧔ቶ᷷㧘ㆤ శ଻ሽ㧕ߦ⸳ቯߒߚޕ

4 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

(2) ⵾೷ ᧄ೷ߪ㧘1 ࠞࡊ࠮࡞ਛߦࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ 102.93 mg㧔ࠪࡔࡊ࡟ࡆ࡞ߣߒߡ 100 mg㧕ࠍ ฽᦭ߔࠆ⎬ࠞࡊ࠮࡞೷ߢ޽ࠆޕᧄ೷ߦᣂⷙᷝട೷ߪ૶↪ߒߡ޿ߥ޿ޕ ᧄ೷ߪ㧘㐳ᦼ଻ሽ⹜㛎㧔25°C/60%RH㧕෸߮ടㅦ⹜㛎㧔40°C/75%RH㧕ߦ߅޿ߡ㧘 ߩჇട߇ ⹺߼ࠄࠇߚ߽ߩߩ㧘ߘࠇߙࠇ 12 ࠞ᦬㑆෸߮ 6 ࠞ᦬㑆቟ቯߢ޽ߞߚޕ⧦㉃⹜㛎㧔50°C/3 ࠞ᦬㧕ߦ ߅޿ߡ⚻ᤨ⊛ߥᄌൻߪ⹺߼ࠄࠇߥ߆ߞߚޕ⧦㉃⹜㛎㧔ᦑశ/ICH Q1B ߦḰ᜚㧕ߢߪ㧘ή൮ⵝຠߦ ߅޿ߡಽ⸃‛ߩࠊߕ߆ߥჇട෸߮฽㊂ߩૐਅ߇⹺߼ࠄࠇߚ߇㧘৻ᰴ൮ⵝຠߢߪ቟ቯߢ޽ߞߚޕએ ਄ߩ⚿ᨐߦၮߠ߈㧘ᧄ೷ߩ᦭ലᦼ㑆ࠍ 24 ࠞ᦬㧔ቶ᷷㧘ㆤశ଻ሽ㧕ߦ⸳ቯߒߚޕ

1.5.3.2 㕖⥃ᐥ⹜㛎ߩ᭎⇛

1.5.3.2.1 ⮎ℂ⹜㛎

ലജࠍⵣઃߌࠆ⹜㛎ߣߒߡ㧘HCV NS3/4A ࡊࡠ࠹ࠕ࡯࠯ߦ⚿วߒߚࠪࡔࡊ࡟ࡆ࡞ߩ⚿᥏᭴ㅧࠍ ⸃ᨆߔࠆߣߣ߽ߦ㧘HCV NS3/4A ࡊࡠ࠹ࠕ࡯࠯ߦኻߔࠆ㉂⚛ቇ⊛㒖ኂ૞↪㧘࡟ࡊ࡝ࠦࡦ⚦⢩ࠍ↪ ޿ߚ᛫࠙ࠗ࡞ࠬ૞↪㧘ࡅ࠻෸߮േ‛⚦⢩ߦኻߔࠆ૞↪㧘HCV એᄖߩ࠙ࠗ࡞ࠬߦኻߔࠆ૞↪㧘 retinoic acid-inducible gene I ෸߮ toll-like receptor 3 ଐሽᕈ IFN ↥↢♽ߦኻߔࠆ૞↪㧘ઁߩ᛫ HCV ⮎෶ߪ᛫ࡅ࠻ ఺∉ਇో ࠙ࠗ࡞ࠬ㧔એਅ㧘HIV㧕⮎ߣߩ૬↪૞↪㧘ਗ߮ߦ⮎೷⠴ᕈߦ㑐ߔࠆᬌ⸛ ࠍⴕߞߚޕ೽ᰴ⊛⮎ℂ⹜㛎ߣߒߡ㧘ฦ⒳ฃኈ૕෸߮࠴ࡖࡀ࡞ߦኻߔࠆ in vitro ૞↪㧘ਗ߮ߦฦ⒳ ᯏ⢻෸߮⚵❱ߦኻߔࠆ in vitro ෸߮ in vivo ૞↪ࠍᬌ⸛ߒߚޕ቟ోᕈ⮎ℂ⹜㛎ߣߒߡ㧘ਛᨔ␹⚻♽㧘 ᔃⴊ▤♽㧘๭ๆ♽㧘⢗⣺▤♽㧘ⴊዊ᧼෸߮⿒ⴊ⃿ߦኻߔࠆ in vitro ෶ߪ in vivo ૞↪ࠍᬌ⸛ߒߚޕ

1.5.3.2.2 ⮎‛േᘒ⹜㛎 ๆ෼ߦ㑐ߔࠆ⹜㛎ߣߒߡ㧘⚦⢩⤑ㅘㆊᕈ㧘P-♧ߚࠎ⊕⾰㧔P-gp㧕ߦኻߔࠆᓇ㗀෸߮ⴊẏਛ⮎‛ JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 േᘒߦߟ޿ߡᬌ⸛ߒߚޕಽᏓߦ㑐ߔࠆ⹜㛎ߣߒߡ㧘⚵❱ౝỚᐲ㧘ߚࠎ⊕⚿ว㧘ⴊ⃿⒖ⴕ㧘ਗ߮ߦ ⢝ఽ෸߮੃ఽ⒖ⴕߦߟ޿ߡᬌ⸛ߒߚޕઍ⻢ߦ㑐ߔࠆ⹜㛎ߣߒߡ㧘⢄⚦⢩෸߮⢄⚦⢩↹ಽࠍ↪޿ߚ ઍ⻢቟ቯᕈ㧘ⴊẏ㧘♮෸߮⢙᳝ਛઍ⻢‛㧘ઍ⻢㉂⚛㧘ਗ߮ߦ⢄⮎‛ઍ⻢㉂⚛♽߳ߩᓇ㗀ߦߟ޿ߡ ᬌ⸛ߒߚޕឃᴭߦ㑐ߔࠆ⹜㛎ߣߒߡ㧘ࡑࠬࡃ࡜ࡦࠬ෸߮⢙᳝ਛឃᴭߦߟ޿ߡᬌ⸛ߒߚޕ⮎‛േᘒ ቇ⊛⮎‛⋧੕૞↪ߦ㑐ߔࠆ⹜㛎ߣߒߡ㧘ᧄ೷ߣ૬↪ߐࠇࠆน⢻ᕈߩ޽ࠆ⮎‛ߩઍ⻢ߦ෸߷ߔᓇ㗀 ߦߟ޿ߡᬌ⸛ߒߚޕ߹ߚ㧘ࠪࡔࡊ࡟ࡆ࡞ߩઍ⻢ߦ㑐ਈߔࠆਥߥ࠴࠻ࠢࡠ࡯ࡓ P450㧔એਅ㧘 CYP㧕ಽሶ⒳ߪ CYP3A ߢ޽ࠆߎߣ߇␜ߐࠇߚߎߣ߆ࠄ㧘ߎߩ㒖ኂ೷ߣߒߡ⍮ࠄࠇߡ޿ࠆ࡝࠻࠽ ࡆ࡞ࠍ↪޿㧘ࠪࡔࡊ࡟ࡆ࡞ߩⴊẏਛ⮎‛േᘒߦ෸߷ߔᓇ㗀ߦߟ޿ߡ߽ᬌ⸛ߒߚޕᦝߦ㧘ᧄ೷ߩ⥃ ᐥ⹜㛎ߦ߅޿ߡ⹺߼ࠄࠇߚⴊẏਛࡆ࡝࡞ࡆࡦỚᐲ਄᣹ߩ⊒⃻ᯏᐨࠍ᣿ࠄ߆ߦߔࠆߚ߼ߦ㧘ߘߩઁ ߩ⮎‛േᘒ⹜㛎ߣߒߡ㧘ࡆ࡝࡞ࡆࡦߩࠣ࡞ࠢࡠࡦ㉄ᛴว㧘ਗ߮ߦ⢄ขࠅㄟߺ෸߮⢙᳝ਛឃᴭ࠻࡜ ࡦࠬࡐ࡯࠲࡯ߦ㑐ߔࠆᓇ㗀ߦߟ޿ߡᬌ⸛ߒߚޕ

1.5.3.2.3 Ქᕈ⹜㛎 ᕆᕈᲥᕈߪࡑ࠙ࠬ㧔ዊᩭ⹜㛎ߢ⹏ଔ㧕㧘࡜࠶࠻㧘ࠗ࠿෸߮ࠨ࡞ࠍ↪޿ߡ⹏ଔߒߚޕ෻ᓳᛩਈᲥ ᕈߪ㧘ᒝ೙⚻ญᛩਈᲥᕈ⹜㛎ࠍࡑ࠙ࠬ㧔3 ࠞ᦬㑆߹ߢ㧕㧘࡜࠶࠻㧔6 ࠞ᦬㑆߹ߢ㧕㧘ࠗ࠿㧔9 ࠞ᦬

5 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

㑆߹ߢ㧕෸߮ࠨ࡞㧔1 ࠞ᦬㑆߹ߢ㧕ࠍ↪޿ߡᬌ⸛ߒ㧘ᷙ㙄ᛩਈᲥᕈ⹜㛎ࠍࡑ࠙ࠬ෸߮࡜࠶࠻㧔3 ࠞ᦬㑆߹ߢ㧕ࠍ↪޿ߡᬌ⸛ߒߚޕߔߴߡߩ⹜㛎ߢ࠻ࠠࠪࠦࠠࡀ࠹ࠖࠢࠬࠍ⹏ଔߒߚޕㆮવᲥᕈߪ㧘 in vitro ⹜㛎ߣߒߡ⚦⩶ࠍ↪޿ࠆᓳᏫ⓭ὼᄌ⇣⹜㛎෸߮ࡑ࠙ࠬ࡝ࡦࡈࠜ࡯ࡑ Tk ⹜㛎㧘in vivo ⹜㛎 ߣߒߡࡑ࠙ࠬዊᩭ⹜㛎ߢ⹏ଔߒߚޕ↢ᱺ⊒↢Ქᕈߪ㧘࡜࠶࠻ฃ⢝⢻෸߮⌕ᐥ߹ߢߩೋᦼ⢦⊒↢ߦ 㑐ߔࠆ⹜㛎㧘ࡑ࠙ࠬ෸߮࡜࠶࠻⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜㛎㧘࡜࠶࠻಴↢೨෸߮಴↢ᓟߩ⊒↢ਗ߮ ߦᲣ૕ߩᯏ⢻ߦ㑐ߔࠆ⹜㛎ߢ⹏ଔߒߚޕ߹ߚ㧘in vitro ߢ࠙ࠪⷺ⤑ᷙỘ෸߮ㅘㆊᕈ㧔BCOP㧕⹜㛎㧘 శᲥᕈ⹜㛎෸߮⚦⢩Ქᕈ⹜㛎㧘in vivo ߢࡑ࠙ࠬዪᚲ࡝ࡦࡄ▵⹜㛎㧔LLNA㧕㧘࠙ࠨࠡ⊹⤏৻ᰴೝ ỗᕈ⹜㛎෸߮࡜࠶࠻ߦ߅ߌࠆᛩਈน⢻ߥᦨᄢ㊂ߩᬌ⸛⹜㛎ࠍታᣉߒߚޕᦝߦ㧘5 ⒳㘃ߩਇ⚐‛ߦ ߟ޿ߡᲥᕈࠍ⹏ଔߒߚޕਥⷐߥ⹜㛎ߪ GLP ߦḰ᜚ߒߡታᣉߒߚޕ

1.5.3.3 ⥃ᐥ㐿⊒ߩ᭎⇛ C ဳᘟᕈ⢄Ἳߦኻߔࠆ TMC435 ߩ⥃ᐥ㐿⊒ߪ㧘ᶏᄖߢߪ Tibotec Pharmaceuticals Ltd.㧔⃻

Janssen R&D Ireland㧕߇ 20 ᐕࠃࠅ㐿ᆎߒߚޕ࿖ౝߢߪ㧘ࡗࡦ࠮ࡦࡈࠔ࡯ࡑᩣᑼળ␠߇ 20 ᐕ ࠃࠅ╙ II ⋧⹜㛎ࠍ㐿ᆎߒߚޕ⥃ᐥ㐿⊒ߩ᭎⇛ࠍએਅߦ␜ߔޕߥ߅㧘TMC435 ߩ↪㊂ߪࠪࡔࡊ࡟ࡆ ࡞ߣߒߡߩ↪㊂ߢ޽ࠆޕ ߹ߚ㧘޿ߕࠇߩ⥃ᐥ⹜㛎߽㧘ࡋ࡞ࠪࡦࠠት⸒ߩ୶ℂේೣ㧘ᣣ☨ EU ක⮎ຠⷙ೙⺞๺࿖㓙ળ⼏ 㧔ICH㧕ߢวᗧߐࠇߚޟක⮎ຠߩ⥃ᐥ⹜㛎ߩታᣉߩၮḰ㧔GCP㧕ޠ㧘ㆡ↪ߐࠇࠆⷙ೙ⷐઙ෸߮ߘ ࠇߙࠇߩᴦ㛎ታᣉ⸘↹ᦠߦೣߞߡታᣉ࡮ႎ๔ߒߚޕ

1.5.3.3.1 ╙ I ⋧⹜㛎 ᶏᄖߦ߅޿ߡ㧘ੱߢߩ቟ోᕈ෸߮ᔋኈᕈࠍᦨೋߦᬌ⸛ߔࠆ╙ I ⋧⹜㛎ߣߒߡ C101 ⹜㛎ࠍታᣉ ߒߚޕᧄ⹜㛎߆ࠄ㧘ஜᐽᚑੱߦኻߔࠆ TMC435 50㨪600 mg ߩන࿁ᛩਈ෸߮ 100㨪400 mg 1 ᣣ 1 ࿁

ߣ 200 mg 1 ᣣ 2 ࿁ߩ 5 ᣣ㑆෻ᓳᛩਈ㧘ਗ߮ߦ C ဳᘟᕈ⢄Ἳᖚ⠪ߦኻߔࠆ TMC435 200 mg 1 ᣣ 1 JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 ࿁ߩ 5 ᣣ㑆෻ᓳᛩਈߪ㧘߅߅߻ߨ቟ోߢ޽ࠅ㧘ᔋኈᕈߪ⦟ᅢߢ޽ࠆߎߣ߇⏕⹺ߐࠇߚޕ ࿖ౝߢߩ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߣߒߚ⥃ᐥ⹜㛎ታᣉߦవ┙ߜ㧘ᶏᄖ࿷૑ߩᣣᧄੱஜᐽᚑੱࠍ ኻ⽎ߣߒߡ╙ I ⋧⹜㛎㧔C109 ⹜㛎㧕ࠍ☨࿖ߢታᣉߒ㧘C101 ⹜㛎ᚑ❣ߣᲧセߒߚޕߘߩ⚿ᨐ㧘ᣣ ᧄੱஜᐽᚑੱߢߪᄖ࿖ੱஜᐽᚑੱߦᲧߴߡ TMC435 ߩหߓᛩਈ㊂ߦኻߒߡ߿߿㜞޿ᦑ㔺㊂߇ᓧࠄ ࠇࠆ௑ะ߇␜ߐࠇߚޕ ߘߩઁߩᣣᧄੱஜᐽᚑੱࠍኻ⽎ߣߒߚ╙ I ⋧⹜㛎ߣߒߡ㧘⋧ኻ⊛ࡃࠗࠝࠕࡌࠗ࡜ࡆ࡝࠹ࠖ⹜㛎 㧔HPC1003 ⹜㛎㧕෸߮㘩੐ߩᓇ㗀ࠍᬌ⸛ߔࠆ⹜㛎㧔HPC1007 ⹜㛎㧕ࠍታᣉߒߚޕ߹ߚᶏᄖߢ㧘 QT/QTc ߦኻߔࠆᓇ㗀ࠍᬌ⸛ߔࠆ⹜㛎㧔C117 ⹜㛎㧕ࠍታᣉߒ㧘ߘߩઁ㧘⋧ኻ⊛ࡃࠗࠝࠕࡌࠗ࡜ࡆ ࡝࠹ࠖ⹜㛎㧔3 ⹜㛎㧕㧘㘩੐ߩᓇ㗀ࠍᬌ⸛ߔࠆ⹜㛎㧔2 ⹜㛎㧕㧘ࡑࠬࡃ࡜ࡦࠬ⹜㛎㧔1 ⹜㛎㧕㧘․ ᱶᖚ⠪㧔⢄ᯏ⢻㓚ኂᖚ⠪෸߮⣢ᯏ⢻㓚ኂᖚ⠪㧕ߩ⮎‛േᘒࠍᬌ⸛ߔࠆ⹜㛎㧔ฦ 1 ⹜㛎㧕㧘⮎‛േ ᘒቇ⊛⮎‛⋧੕૞↪⹜㛎㧔12 ⹜㛎㧕෸߮శ቟ోᕈ⹜㛎㧔1 ⹜㛎㧕ࠍታᣉߒߚޕ

6 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

1.5.3.3.2 ╙ II ⋧⹜㛎 ᶏᄖߦ߅޿ߡ㧘Genotype 1 ဳ C ဳᘟᕈ⢄Ἳߩೋ࿁ᴦ≮ᖚ⠪෸߮ᣢᴦ≮ᖚ⠪ࠍኻ⽎ߦ㧘TMC435 න೷ᛩਈߒߚߣ߈ਗ߮ߦ PegIFNĮ-2a ෸߮ RBV ߣ૬↪ᛩਈߒߚߣ߈ߩ᛫࠙ࠗ࡞ࠬലᨐߦ߅ߌࠆ↪ ㊂ଐሽᕈ෸߮቟ోᕈࠍᬌ⸛ߔࠆ⋡⊛ߢ㧘Proof-of-Principle ⹜㛎㧔C201 ⹜㛎㧕ࠍ⸘↹ߒߚޕೋ࿁ᴦ ≮଀ߦኻߒ㧘TMC435 ࠍන೷ߢ 7 ᣣ㑆ᛩਈᓟ㧘PegIFNĮ-2a ෸߮ RBV ߣߩ 3 ೷૬↪ߢ 21 ᣣ㑆ᛩਈ ߔࠆߎߣߣߒߚޕ߹ߚ㧘ೋ࿁ᴦ≮଀෸߮ᣢᴦ≮଀ߦኻߒߡ㧘TMC435 ࠍ PegIFNĮ-2a ෸߮ RBV ߣ ߩ 3 ೷૬↪ߢ 28 ᣣ㑆ᛩਈߒߚޕߘߩ⚿ᨐ㧘ೋ࿁ᴦ≮଀ߦ߅ߌࠆ 3 ೷૬↪ᛩਈߢߪ㧘ᛩਈ 7 ᣣ⋡ ߩ HCV RNA ㊂ߩࡌ࡯ࠬ࡜ࠗࡦ߆ࠄߩᷫዋ㊂߇ TMC435 න೷ᛩਈࠃࠅᄢ߈ߊ㧘ᛩਈ 4 ㅳߩ HCV RNA ㊂ߩࡌ࡯ࠬ࡜ࠗࡦ߆ࠄߩᷫዋ㊂ߪ TMC435 75 mg ෸߮ 200 mg ᛩਈߢ߶߷ห⒟ᐲߢ޽ߞߚޕ ৻ᣇ㧘ᣢᴦ≮଀ߦ߅޿ߡ㧘ᛩਈ 4 ㅳߩ HCV RNA ㊂ߩࡌ࡯ࠬ࡜ࠗࡦ߆ࠄߩᷫዋ㊂ߪ㧘TMC435 150 mg ෸߮ 200 mg ᛩਈߦᲧߴߡ 75 mg ᛩਈߢዊߐ߆ߞߚޕ߹ߚ㧘TMC435 ߩ↪㊂෸߮ᦑ㔺㊂ߦ ଐሽߒߚⴊਛࡆ࡝࡞ࡆࡦ୯ߩ਄᣹߇ߺࠄࠇ㧘200 mg ᛩਈߢࠃࠅ㗼⪺ߢ޽ߞߚޕ

⛯޿ߡ㧘࿖ౝߦ߅ߌࠆᦨೋߩ⥃ᐥ⹜㛎ߣߒߡ㧘Genotype 1 ဳ㜞࠙ࠗ࡞ࠬ㊂ߩ C ဳᘟᕈ⢄Ἳߩೋ ࿁ᴦ≮ᖚ⠪ࠍኻ⽎ߦ㧘TMC435 ࠍ PegIFNĮ-2a ෸߮ RBV ߣ૬↪ߒߚߣ߈ߩ᦭ലᕈ෸߮቟ోᕈࠍᬌ ⸛ߔࠆ⋡⊛ߢ╙ II ⋧⹜㛎㧔C215 ⹜㛎㧕ࠍ㧘㕖⋤ᬌ⹜㛎ߣߒߡ⸘↹ߒߚޕTMC435 ߩ↪ᴺ࡮↪㊂ ߪ㧘C201 ⹜㛎⚿ᨐߦၮߠ߈ PegIFNĮ-2a ෸߮ RBV ߣߩ 3 ೷૬↪ᛩਈߣߒ㧘C109 ⹜㛎⚿ᨐࠍ〯߹ ߃㧘ᶏᄖᓟᦼ╙ II ⋧⹜㛎㧔C205 ⹜㛎㧕ߣห⒟ᐲߩᦑ㔺㊂߇ᓧࠄࠇࠆߣផቯߐࠇߚ 50 mg ෶ߪ 100 mg 1 ᣣ 1 ࿁ࠍ 12 ෶ߪ 24 ㅳ㑆ᛩਈߣߒߚޕߘߩ⚿ᨐ㧘TMC435 50 mg ෶ߪ 100 mg ࠍ 12 ෶ߪ 24 ㅳ㑆ᛩਈᓟߩ SVR24 ₸ߪ㧘ࠦࡦ࠻ࡠ࡯࡞⟲㧔PegIFNĮ-2a ෸߮ RBV ߩ 48 ㅳ㑆ᛩਈ㧕ߦᲧߴߡ ޿ߕࠇ߽㜞ߊ㧘߹ߚ㧘TMC435 ᛩਈߪ޿ߕࠇ߽߅߅߻ߨ቟ోߢ޽ࠅ㧘ᔋኈᕈߪ⦟ᅢߢ޽ߞߚޕ ᶏᄖߦ߅޿ߡߪ㧘TMC435 ߩⶄᢙߩᛩਈ㊂෸߮ᛩਈᦼ㑆ߢ PegIFNĮ-2a ෸߮ RBV ߣ૬↪ߒߚߣ ߈ߩ᦭ലᕈ෸߮቟ోᕈࠍᬌ⸛ߔࠆߚ߼㧘Genotype 1 ဳ C ဳᘟᕈ⢄Ἳߩೋ࿁ᴦ≮ᖚ⠪෸߮ᣢᴦ≮ᖚ ⠪ࠍኻ⽎ߦᓟᦼ╙ II ⋧⹜㛎 2 ⹜㛎㧔ߘࠇߙࠇ C205 ෸߮ C206 ⹜㛎㧕ࠍታᣉߒߚޕTMC435 ߩ↪

JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 ᴺ࡮↪㊂ߪ㧘C201 ⹜㛎⚿ᨐߦၮߠ߈㧘PegIFNĮ-2a ෸߮ RBV ߣߩ 3 ೷૬↪ᛩਈߣߒ㧘ೋ࿁ᴦ≮଀ ߦኻߒߡߪ 75 mg ෶ߪ 150 mg 1 ᣣ 1 ࿁ࠍ 12 ෶ߪ 24 ㅳ㑆ᛩਈ㧘ᣢᴦ≮଀ߦኻߒߡߪ 100 mg ෶ߪ 150 mg 1 ᣣ 1 ࿁ࠍ 12㧘24 ෶ߪ 48 ㅳ㑆ᛩਈߣߒߚޕߘߩ⚿ᨐ㧘ೋ࿁ᴦ≮଀㧘೨ᴦ≮ౣΆ଀㧘೨ᴦ ≮ㇱಽ෻ᔕ଀෸߮೨ᴦ≮ή෻ᔕ଀ߩ޿ߕࠇߦ߅޿ߡ߽㧘ฦ TMC435 ⟲ߩ SVR24 ₸ߪࡊ࡜࠮ࡏ⟲ 㧔ࡊ࡜࠮ࡏߣ PegIFNĮ-2a ෸߮ RBV ߩ 48 ㅳ㑆ᛩਈ㧕ߦᲧߴߡ㜞ߊ㧘TMC435 ᛩਈߪ߅߅߻ߨ቟ో ߢ޽ࠅ㧘ᔋኈᕈߪ⦟ᅢߢ޽ߞߚޕ

1.5.3.3.3 ╙ III ⋧⹜㛎 ⛯ߊ╙ III ⋧⹜㛎ߣߒߡ㧘Genotype 1 ဳ㜞࠙ࠗ࡞ࠬ㊂ߩ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߦ㧘PegIFNĮ- 2a ෸߮ RBV ߣߩ૬↪ߦࠃࠆ HPC3003㧘HPC3008 ෸߮ HPC3004 ⹜㛎㧔ߘࠇߙࠇೋ࿁ᴦ≮ᖚ⠪㧘 ೨ᴦ≮ౣΆᖚ⠪෸߮೨ᴦ≮ήലᖚ⠪߇ኻ⽎㧕ࠍ⸘↹ߒߚޕᦝߦ㧘PegIFNĮ-2b ෸߮ RBV ߣ૬↪ߒ ߚߣ߈ߩ᦭ലᕈ෸߮቟ోᕈࠍᬌ⸛ߔࠆ⋡⊛ߢ HPC3010 ⹜㛎㧔ߔߴߡߩᴦ≮ᱧߩᖚ⠪߇ኻ⽎㧕ࠍ ⸘↹ߒߚޕHPC3003 ⹜㛎ߪࡊ࡜࠮ࡏኻᾖੑ㊀⋤ᬌᲧセ⹜㛎㧘ߘߩઁߩ⹜㛎ߪ㕖ኻᾖ㕖⋤ᬌ⹜㛎ߣ ߒߚޕTMC435 ߩ↪ᴺ࡮↪㊂ߪ㧘╙ II ⋧⹜㛎⚿ᨐߦၮߠ߈㧘100 mg ࠍ 1 ᣣ 1 ࿁㧘12 ㅳ㑆ߣߒߚޕ ߚߛߒ㧘೨ᴦ≮ήല଀ߪ PegIFN ෸߮ RBV ߦኻߔࠆ෻ᔕᕈ߇ૐ޿ߎߣ߆ࠄ 6㧕㧘12 ㅳ㑆ᛩਈ⟲ߦ ട߃ߡ 24 ㅳ㑆ᛩਈ⟲ࠍ⸳ቯߒߚޕPegIFN ෸߮ RBV ߩᛩਈᦼ㑆ߪ㧘HPC3003 ⹜㛎ߩࡊ࡜࠮ࡏ⟲

7 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

෸߮ HPC3010 ⹜㛎ߩ೨ᴦ≮ήല଀ߢߪ 48 ㅳ㑆㧘ߘࠇએᄖߢߪ Response-guided Therapy㧔RGT㧕 ၮḰߦᓥߞߡ 24 ㅳ㑆෶ߪ 48 ㅳ㑆ߣߒߚޕ ਥⷐ⹏ଔ㗄⋡ߪ㧘HPC3003㧘HPC3008 ෸߮ HPC3004 ⹜㛎ߢ SVR24 ₸ߣߒߚޕߒ߆ߒ㧘ߘߩᓟ ߦᓧࠄࠇߚ⍮⷗ࠃࠅ㧘SVR24 ₸ߣ SVR12 ₸㧔ᛩਈ⚳ੌᤨ෸߮ᛩਈ⚳ੌᓟ 12 ㅳߩⴊẏਛ HCV RNA ߇㒶ᕈൻߒߚⵍ㛎⠪ߩഀว㧕ߦ৻⽾ᕈ߇␜ߐࠇߚߎߣ߆ࠄ㧘⁛┙ⴕ᡽ᴺੱක⮎ຠක≮ᯏེ ✚วᯏ᭴ߣක⮎ຠ↳⺧೨⋧⺣ࠍታᣉߒ㧘ਥⷐ⹏ଔ㗄⋡ࠍ SVR12 ₸ߦᄌᦝߒߚޕ ߘߩ⚿ᨐ㧘ೋ࿁ᴦ≮଀ߦ߅޿ߡ㧘TMC435 ⟲෸߮ࡊ࡜࠮ࡏ⟲ߩ SVR12 ₸ߪ 88.6%෸߮ 61.7%ߢ ޽ࠅ㧘ᐕ㦂෸߮ IL28B ㆮવሶᄙဳࠍጀ೎࿃ሶߣߒߡ⺞ᢛߒߚ⵬ᱜ୯ߩ⟲㑆Ꮕߪ⛔⸘ቇ⊛ߦ᦭ᗧߢ ޽ߞߚ㧔Cochran-Mantel-Haenszel ᬌቯ㧘p<0.0001㧕ޕ೨ᴦ≮ౣΆ଀෸߮೨ᴦ≮ήല଀ߦ߅޿ߡ߽㧘 TMC435 ⟲ߩ SVR12 ₸ߪ PegIFNĮ-2a ෸߮ RBV ߦࠃࠆౣᴦ≮ᤨߩ⥃ᐥᚑ❣ߣᲧセߒߡ޿ߕࠇ߽᦭ ᗧߦ㜞߆ߞߚޕPegIFNĮ-2b ෸߮ RBV ߣߩ૬↪ᤨߦ߅޿ߡ߽㧘ห᭽ߦ㜞޿᛫࠙ࠗ࡞ࠬലᨐ߇⹺߼ ࠄࠇߚޕ߹ߚ㧘޿ߕࠇߩ⹜㛎ߢ߽㧘TMC435 ᛩਈߪ߅߅߻ߨ቟ోߢ޽ࠅ㧘ᔋኈᕈߪ⦟ᅢߢ޽ߞߚޕ

ฦ⹜㛎ߢߩ቟ోᕈ⹏ଔߦട߃ߡ㧘࿖ౝ╙ II ⋧෸߮╙ III ⋧⹜㛎ߩ⸘ 5 ⹜㛎ߩ࠺࡯࠲ߦࠃࠆ૬ว ⸃ᨆࠍⴕߞߚޕߘߩ⚿ᨐ㧘C ဳᘟᕈ⢄Ἳᖚ⠪ߦ߅ߌࠆ TMC435 ᛩਈߩᔋኈᕈߪ⦟ᅢߢ޽ࠅ㧘 TMC435 ߩ PegIFN ෸߮ RBV ߣߩ૬↪ߪ PegIFN ෸߮ RBV ߩ 2 ೷≮ᴺߩ቟ోᕈࡊࡠࡈࠔࠗ࡞ߦᄢ ߈ߥᓇ㗀ࠍਈ߃ߥ޿ߣ⠨߃ࠄࠇߚޕTMC435 ᛩਈߦ㑐ㅪߒߚࡆ࡝࡞ࡆࡦ਄᣹߇⹺߼ࠄࠇߚ߽ߩߩ㧘 ৻ㆊᕈߢ޽ࠅ㧘߶ߣࠎߤ߇シᐲߢ㧘ALT ෶ߪ AST 㜞୯ࠍ઻ࠊߥ߆ߞߚޕࡆ࡝࡞ࡆࡦ਄᣹ߦࠃࠅ TMC435 ߩߺᛩਈਛᱛߦ⥋ߞߚⵍ㛎⠪ߩഀวߪૐߊ㧘ߔߴߡߩ⮎೷ߩᛩਈਛᱛߦ⥋ߞߚⵍ㛎⠪ߪ ޿ߥ߆ߞߚޕ ߹ߚ㧘TMC435 ߣ PegIFN ෸߮ RBV ߣߩ 3 ೷૬↪≮ᴺߩ᛫࠙ࠗ࡞ࠬലᨐߪ㧘ᬌ⸛ߒߚ޿ߕࠇߩ ㇱಽ㓸࿅ߢ߽㜞ߊ㧘ㇱಽ㓸࿅㑆ߦ᣿ࠄ߆ߥ⋧㆑ߪ⹺߼ࠄࠇߕ㧘㜞㦂⠪㧘✢⛽ൻㅴዷ଀㧘IL28B ㆮ વሶᄙဳࡑࠗ࠽࡯ࠕ࡟࡞ࠍ᦭ߔࠆᖚ⠪╬ߩ IFN ᴦ≮ᛶ᛫ᕈߩ㜞޿ᖚ⠪ߦኻߒߡ߽㧘TMC435 ࠍ฽ ߻ 3 ೷૬↪≮ᴺߩ㜞޿ᴦ≮ലᨐ߇␜ߐࠇߚޕᦝߦ㧘TMC435 ᛩਈߩᔋኈᕈ߇ᬌ⸛ߒߚߔߴߡߩㇱ

ಽ㓸࿅ߢ⹺߼ࠄࠇ㧘㜞㦂⠪߿✢⛽ൻㅴዷ଀ࠍ฽߼ߡ㧘TMC435 ߣ PegIFN ෸߮ RBV ߣߩ 3 ೷૬↪ JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 ≮ᴺߢ߽ PegIFN ෸߮ RBV ߩ 2 ೷≮ᴺߣห⒟ᐲߩᴦ≮ቢㆀ߇น⢻ߢ޽ࠆߣ⠨߃ࠄࠇߚޕ

1.5.3.3.4 ߘߩઁߩᶏᄖߢߩ⥃ᐥ㐿⊒⁁ᴫ ᶏᄖᓟᦼ╙ II ⋧⹜㛎ߩ⚿ᨐࠍ〯߹߃ߡ㧘TMC435 150 mg㧔ᛩਈᦼ㑆 12 ㅳ㑆㧕ߣ PegIFN ෸߮ RBV ߩ 3 ೷૬↪ߦࠃࠅ㧘Genotype 1 ဳ C ဳᘟᕈ⢄∔ᖚߩೋ࿁ᴦ≮ᖚ⠪ࠍኻ⽎ߣߒߚ╙ III ⋧⹜㛎 㧔C208 ෸߮ C216 ⹜㛎㧕෸߮೨ᴦ≮ౣΆᖚ⠪ࠍኻ⽎ߣߒߚ╙ III ⋧⹜㛎㧔HPC3007 ⹜㛎㧕ࠍታᣉ ߒߚޕ ߘߩઁ㧘ᶏᄖߢታᣉਛߩ Genotype 1 ဳ C ဳᘟᕈ⢄Ἳᖚ⠪ኻ⽎ߩ╙ III ⋧⹜㛎ߦߪ㧘೨ᴦ≮ήല ଀ࠍኻ⽎ߣߒߚ HPC3001 ⹜㛎㧘ਛ࿖㧘㖧࿖╬ߩೋ࿁ᴦ≮ᖚ⠪ࠍኻ⽎ߣߒߚ HPC3005 ⹜㛎㧘HIV ߣߩ㊀ⶄᗵᨴᖚ⠪ࠍኻ⽎ߣߒߚ C212 ⹜㛎㧘ᶏᄖ╙ II ⋧෸߮╙ III ⋧⹜㛎ߦ߅ߌࠆࡊ࡜࠮ࡏ⟲ߩᴦ ≮ᄬᢌ଀╬ࠍኻ⽎ߣߒߚ C213 ⹜㛎㧘ਗ߮ߦᶏᄖᓟᦼ╙ II ⋧෸߮╙ III ⋧⹜㛎ߢ TMC435 ᛩਈࠍ ฃߌߚⵍ㛎⠪ࠍኻ⽎ߦ 3 ᐕ㑆ߩㅊ〔ࠍⴕ߁ HPC3002 ⹜㛎߇޽ࠆޕ ߹ߚ㧘Genotype 1 ဳએᄖߩ Genotype㧔2㧘3㧘4㧘5㧘6㧕ߩ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߣߒߚ೨ᦼ ╙ II ⋧⹜㛎㧔C202 ⹜㛎㧕ࠍታᣉߒ㧘ߘߩ⚿ᨐߦၮߠ޿ߡ Genotype 4 ࠍኻ⽎ߣߒߚ╙ III ⋧⹜㛎 㧔HPC3011 ⹜㛎㧕ࠍታᣉਛߢ޽ࠆޕ

8 JEDI_DEV00 \ 0900fde980400983 \ 2.4 \ 2013-08-19 13:38

TMC435 1.5 9 ⹜㛎㗄⋡ 2005 2006 2007 2008 2009 2010 2011 2012 ً ᦬ً 6 ේ⮎ ⷙᩰ෸߮⹜㛎ᣇᴺ㧘ಽᨆࡃ࡝࠺࡯࡚ࠪࡦ 2013 ᐕ 1 ᦬ ຠ ⵾೷ 1᦬ً ً10 ᦬ ⾰ ේ⮎ 5 ᦬ ً⛮⛯ਛ ቟ቯᕈ ⵾೷ 3 ᦬ً ⛮⛯ਛ ലജࠍⵣઃߌࠆ⹜㛎 5᦬ ً ً 7 ᦬ ⮎ ೽ᰴ⊛⮎ℂ⹜㛎 1᦬ً ً 7 ᦬ ℂ ቟ోᕈ⮎ℂ⹜㛎 1᦬ً ً 11 ᦬ ๆ෼ 4᦬ ً ً 2 ᦬ ⮎ ಽᏓ 4᦬ ً ً 3 ᦬ ઍ⻢ 5᦬ ً ً 8 ᦬ ‛ േ ឃᴭ 8᦬ً ً 12 ᦬ ᘒ ⮎‛േᘒቇ⊛⮎‛⋧੕૞↪ 11 ᦬ً ً 3᦬ ߘߩઁߩ⮎‛േᘒ⹜㛎 6 ᦬ ً ً 9 ᦬ ᕆᕈᲥᕈ ࡜࠶࠻࡮ࠗ࠿࡮ࠨ࡞ 4᦬ ًً 8 ᦬ ࠞ᦬㧔ᒝ೙⚻ญ㧕 1᦬ً ً 10 ᦬ 3 ࡑ࠙ࠬ ࠞ᦬㧔ᷙ㙄㧕 11 ᦬ ًً11 ᦬ 3 1࡮6 ࠞ᦬㧔ᒝ೙⚻ญ㧕 1᦬ً ً 6᦬ ࡜࠶࠻ ࠞ᦬㧔ᷙ㙄㧕 4 ᦬ ًً 1 ᦬ 3 ෻ᓳᛩਈᲥᕈ 1 ࠞ᦬㧔ᒝ೙⚻ญ㧕 12 ᦬ ًً 8 ᦬ ࠗ࠿ 6ࠞ᦬㧔ᒝ೙⚻ญ㧕 9᦬ ً ً 11 ᦬ ࠞ᦬㧔ᒝ೙⚻ญ㧕 1 ᦬ً ً11 ᦬ 9 ࠨ࡞ 1ࠞ᦬㧔ᒝ೙⚻ญ㧕 7᦬ ًً 8 ᦬ Ქ ㆮવᲥᕈ In vitro & in vivo ⹜㛎 7᦬ ًً 3 ᦬ ᕈ ࡜࠶࠻ FEED 2 ᦬ً ً 8 ᦬ ᱺ⊒↢Ქᕈ ࡑ࠙ࠬ࡮࡜࠶࠻ EFD 1 ᦬ً ً 7 ᦬↢ ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲ ࡜࠶࠻ PPND 9 ᦬ ًً 8 ᦬ In vitro శᲥᕈ 5᦬ ًً 8 ᦬ 5 ᦬ ًً 8 ᦬ ዪᚲೝỗᕈ BCOP 8 ᦬ ًً10 ᦬ ࡑ࠙ࠬ LLNA㧘࠙ࠨࠡ⊹⤏৻ᰴೝỗ 3᦬ً ً6 ᦬ ਇ⚐‛ߩᲥᕈ 6 ᦬ ًً 3 ᦬ ߘߩઁߩᲥᕈ ࡜࠶࠻ᛩਈน⢻ᦨᄢ㊂ߩᬌ⸛ 1 ᦬ً ً9 ᦬ ⚦⢩Ქᕈ 5᦬ ًً10 ᦬ 2012 ᐕ 11 ᦬⃻࿷ 㧦ᶏᄖ⹜㛎㧔⹏ଔ⾗ᢱ㧕ً FEED㧦study of fertility and early embryonic development to implantation㧔ฃ⢝⢻෸߮⌕ᐥ߹ߢߩೋᦼ⢦⊒↢ߦ㑐ߔࠆ⹜㛎㧕㧘EFD㧦study for effects on embryo-fetal development㧔⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜ 㛎㧕㧘PPND㧦study for effects on pre- and postnatal development, including maternal function㧔಴↢೨෸߮಴↢ᓟߩ⊒↢ਗ߮ߦᲣ૕ߩᯏ⢻ߦ㑐ߔࠆ⹜㛎㧕㧘BCOP㧦bovine corneal opacity-permeability㧔࠙ࠪⷺ⤑ ᷙỘ෸߮ㅘㆊᕈ㧕㧘LLNA㧦local lymph node assay㧔ዪᚲ࡝ࡦࡄ▵⹜㛎㧕 ࿑ 1.5-2 㐿⊒ߩ⚻✲࿑㧔ຠ⾰ߦ㑐ߔࠆ⹜㛎෸߮㕖⥃ᐥ⹜㛎㧕

TMC435 1.5 10 ⹜㛎⇟ภ࡮⹜㛎㗄⋡ 2005 2006 2007 2008 2009 2010 2011 2012 C101㧔ᄖ࿖ੱߦ߅ߌࠆ⮎‛േᘒ㧕 1᦬ٌ ٌ 9 ᦬ C109㧔ᣣᧄੱߦ߅ߌࠆ⮎‛േᘒ㧕 8 ᦬ ًً11 ᦬ HPC1003㧔⋧ኻ⊛ࡃࠗࠝࠕࡌࠗ࡜ࡆ࡝࠹ࠖ㧕 4 ᦬٨٨6 ᦬ HPC1007㧔㘩੐ߩᓇ㗀㧕 6 ᦬٨٨7 ᦬ C117㧔QT/QTc 㑆㓒߳ߩᓇ㗀㧕 1 ᦬ً ً7 ᦬ ╙ ઁߩ⋧ኻ⊛ࡃࠗࠝࠕࡌࠗ࡜ࡆ࡝࠹ࠖ⹜㛎 I 7 ᦬ٌ ٌ8 ᦬ 㧦3 ⹜㛎 ⋧ ߩ㘩੐ߩᓇ㗀⹜㛎㧦2 ⹜㛎 1 ᦬ٌ ٌ6 ᦬ઁ ࡑࠬࡃ࡜ࡦࠬ⹜㛎㧦1 ⹜㛎 2᦬ٌ ٌ 4 ᦬ ᱶᖚ⠪ߩ⮎‛േᘒࠍᬌ⸛ߒߚ⹜㛎㧦2 ⹜㛎 2 ᦬ٌ ٌ 1 ᦬․ ⮎‛േᘒቇ⊛⮎‛⋧੕૞↪⹜㛎㧦12 ⹜㛎 11 ᦬ٌ ٌ8 ᦬ ⥃ శ቟ోᕈ⹜㛎㧦1 ⹜㛎 8 ᦬ٌ ٌ 4 ᦬ ᐥ C201㧔ೋ࿁ᴦ≮ᖚ⠪㧘ᣢᴦ≮ᖚ⠪㧕 12 ᦬ ٌ ٌ 4 ᦬ ╙ 4 ᦬ ٨ C215㧔ೋ࿁ᴦ≮ᖚ⠪㧕 7 ᦬٨ II C205㧔ೋ࿁ᴦ≮ᖚ⠪㧕 5 ᦬ ٌٌ 4 ᦬ ⋧ C206㧔ᣢᴦ≮ᖚ⠪㧕 9 ᦬ ٌ ٌ8 ᦬ ٨10 ᦬ HPC3003㧔ೋ࿁ᴦ≮ᖚ⠪㧕 1 ᦬٨ 8 ᦬ ٨٨ HPC3008㧔೨ᴦ≮ౣΆᖚ⠪㧕 12 ᦬ ٨9 ᦬ HPC3004㧔೨ᴦ≮ήലᖚ⠪㧕 1 ᦬٨ ╙ ٨11 ᦬ ٨ III HPC3010㧔PegIFNĮ-2b ૬↪㧕 4 ᦬ C208㧔ೋ࿁ᴦ≮ᖚ⠪㧕 1 ᦬ٌ ⛮⛯ਛ ⋦ C216㧔ೋ࿁ᴦ≮ᖚ⠪㧕 1 ᦬ٌ ⛮⛯ਛ HPC3007㧔೨ᴦ≮ౣΆᖚ⠪㧕 1 ᦬ٌ ⛮⛯ਛ 2012 ᐕ 11 ᦬⃻࿷ ٨㧦࿖ౝ⹜㛎㧔⹏ଔ⾗ᢱ㧕㧘ً㧦ᶏᄖ⹜㛎㧔⹏ଔ⾗ᢱ㧕㧘ٌ㧦ᶏᄖ⹜㛎㧔ෳ⠨⾗ᢱ㧕

࿑ 1.5-3 㐿⊒ߩ⚻✲࿑㧔⥃ᐥ⹜㛎㧕 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

JEDI_DEV00 \ 0900fde980400983 \ 2.4 \ 2013-08-19 13:38 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

1.5.4 ᧄ೷ߩ੍ᗐߐࠇࠆᴦ≮਄ߩ૏⟎ઃߌ TMC435 ߣ PegIFN ෸߮ RBV ߣߩ 3 ೷૬↪≮ᴺߪ PegIFN ෸߮ RBV ߩ 2 ೷≮ᴺࠍ਄࿁ࠆఝࠇߚ ᴦ≮ലᨐࠍ␜ߒ㧘TMC435 ૬↪ߦࠃࠅ⥃ᐥ⊛ߦ᣿ࠄ߆ߥ቟ోᕈ਄ߩᣂߚߥ໧㗴ߪ⹺߼ࠄࠇߥ߆ߞ ߚޕᦝߦ㧘ᣢሽߩᴦ≮ᴺߢߪ᦭ലߥᴦ≮ㆬᛯ⢇߇ߥ߆ߞߚ㜞㦂⠪㧘✢⛽ൻㅴዷ଀෸߮ IL28B ㆮવ ሶᄙဳࡑࠗ࠽࡯ࠕ࡟࡞ࠍ᦭ߔࠆᖚ⠪ߦ߽㧘ᣂߚߥᴦ≮ᯏળࠍឭଏߒᓧࠆߣ⠨߃ࠆޕട߃ߡ㧘✚ᴦ ≮ᦼ㑆ߩ⍴❗㧘◲ଢߥ᦯⮎ᣇᴺ㧘ਔ PegIFN ⵾೷㧔PegIFNĮ-2a ෸߮ PegIFNĮ-2b㧕ߣߩ૬↪╬ߦࠃ ࠆࡌࡀࡈࠖ࠶࠻߽ᦼᓙߢ߈ࠆޕߒߚ߇ߞߡ㧘TMC435 ૬↪ߦࠃࠅᦼᓙߐࠇࠆ⥃ᐥ਄ߩࡌࡀࡈࠖ࠶ ࠻ߪ㧘੍ᗐߐࠇࠆ࡝ࠬࠢࠍ਄࿁ࠆߣ್ᢿߒ㧘⵾ㅧ⽼ᄁᛚ⹺↳⺧ࠍⴕ߁ߎߣߣߒߚޕ ߹ߚ㧘TMC435 ߣ PegIFN ෸߮ RBV ߣߩ 3 ೷૬↪≮ᴺߪ㧘C ဳᘟᕈ⢄Ἳߦ߅ߌࠆᧂల⿷ක≮࠾ ࡯࠭ࠍḩߚߔᣂߚߥ╙৻ㆬᛯ⮎ߣߥࠅ㧘ක≮਄ߩ᦭↪ᕈߪᣢሽߩᴦ≮ᴺߦᲧߴߡ㜞޿ߣ⠨߃㧘 20 㧔ᐔᚑ 㧕ᐕ ᦬ ᣣઃߌߢఝవክᩏຠ⋡⹥ᒰᕈ⋧⺣↳⺧ࠍⴕߞߚޕ

JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38

11 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲

ෳ⠨ᢥ₂

1㧕 ᣣᧄ⢄⤳ቇળ ⢄Ἳ⸻≮ࠟࠗ࠼࡜ࠗࡦ૞ᚑᆔຬળ✬. C ဳ⢄Ἳᴦ≮ࠟࠗ࠼࡜ࠗࡦ㧔╙ 1 㧕. 2012.

2㧕 ෘ↢ഭ௛⑼ቇ․೎⎇ⓥ੐ᬺޟC ဳ⢄Ἳߩ⸻≮ࠟࠗ࠼࡜ࠗࡦ╷ቯߦߟ޿ߡޠߦ㑐ߔࠆ⎇ⓥ ⃰✬. C ဳ⢄Ἳ⸻≮ࠟࠗ࠼࡜ࠗࡦ. කቇᦠ㒮, 2007.

3㧕 Yoshida H, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann Intern Med. 1999 Aug 3;131(3):174-81.

4㧕 Kuboki M, et al. Peginterferon alpha-2a (40 KD) plus ribavirin for the treatment of chronic hepatitis C in Japanese patients. J Gastroenterol Hepatol. 2007 May;22(5):645-52.

5㧕 Kaiser S, et al. High sustained virologic response rates in HCV genotype 1 relapser patients retreated with peginterferon alfa-2a (40KD) plus ribavirin for 72 weeks. Hepatology. 2008 Oct;48(Suppl S1):1140A.

6㧕 Jensen DM, et al. Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-Į2b: a randomized trial. Ann Intern Med. 2009 Apr 21;150(8):528-40.

7㧕 Kumada H, et al. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2012 Jan;56(1):78-84.

8㧕 Hayashi N, et al. Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C. J Viral Hepat. 2012 Feb;19(2):e134-42.

JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38

12 TMC435 1.6 ᄖ࿖ߦ߅ߌࠆ૶↪⁁ᴫ╬ߦ㑐ߔࠆ⾗ᢱ

1.6 ᄖ࿖ߦ߅ߌࠆ૶↪⁁ᴫ╬ߦ㑐ߔࠆ⾗ᢱ ⃻࿷㧘TMC435 ⵾೷ߩᛚ⹺ขᓧ࿖ߪߥ޿ޕ ෸߮ ߦ߅޿ߡ㧘TMC435 ⵾೷㧔150 mg ࠞࡊ࠮࡞㧕ࠍ 20 ᐕ ᦬㧘 ᦬ߦߘࠇߙࠇ↳⺧ ߒߚޕᧄ೷ߩડᬺਛᩭ࠺࡯࠲ࠪ࡯࠻㧔CCDS ේᢥ㧕ࠍᰴࡍ࡯ࠫએ㒠ߦ␜ߔޕ

JEDI_DEV00 \ 0900fde9803ffd17 2.2 2013-08-16 09:22

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JEDI_DEV00 \ 0900fde9803e8931 1.2 2013-05-22 09:38

1 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

1.7 ห⒳หലຠ৻ⷩ⴫ ⃻࿷࿖ౝߢ૶↪ߐࠇߡ޿ࠆਥߥห⒳หലຠ৻ⷩࠍએਅߦ␜ߔޕ

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04

1 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

ળ␠ฬ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑᩣᑼળ␠ ↰ㄝਃ⪉⵾⮎ᩣᑼળ␠ ਛᄖ⵾⮎ᩣᑼળ␠

ᛚ⹺ ̆ 2011 ᐕ 9 ᦬ 26 ᣣ 2003 ᐕ 10 ᦬ 16 ᣣ ᐕ᦬ ⷙ೙ ಣᣇߖࠎක⮎ຠ ഍⮎ ಣᣇߖࠎක⮎ຠ ഍⮎ ಣᣇߖࠎක⮎ຠ ඙ಽ O ᧄ⾰㧦ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a(ㆮવሶ⚵឵ CH3 ߃)ߩ࡝ࠫࡦᱷၮߩ 1 ▎ᚲߦޔ1 ಽሶߩಽᨑࡐ࡝ O S O ࠛ࠴࡟ࡦࠣ࡝ࠦ࡯࡞߇ޔࠕࡒ࠼⚿วࠍ੺ߒߡ౒ CH O NNa 3 ᦭⚿วߒߡ޿ࠆୃ㘼Ⱞ⊕⾰ O -2a( H ಽሶᑼ㧦ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ ㆮવሶ⚵ N ឵߃)㧦C H N O S N H 860 1349 227 255 9 CH ಽᨑࡐ࡝ࠛ࠴࡟ࡦࠣ࡝ࠦ࡯࡞㧦࡝ࠫࡦಽሶߩǩ ൻቇ H N 3 H O ෸߮ǭࠕࡒࡁၮߦࠞ࡞ࡏ࠾࡞ၮࠍ੺ߒߡಽሶ㊂ ᭴ㅧᑼ H S CH3 ⚂ 20, 000 ࠳࡞࠻ࡦߩࡕࡁࡔ࠻ࠠࠪࡐ࡝ࠛ࠴࡟ࡦ ࠣ࡝ࠦ࡯࡞㎮߇ 1 ᧄߕߟ⚿วߒߚ߽ߩ߆ࠄߥ N O ࠆޕ CH3 ಽሶ㊂㧦⚂ 60, 000 ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a(ㆮવሶ⚵឵߃)㧦 ಽሶ㊂ 19, 236. 87 ಽᨑࡐ࡝ࠛ࠴࡟ࡦࠣ࡝ࠦ࡯࡞㧦ಽሶ㊂⚂ 40, 000 ᯍ⦡ߩࠠࡖ࠶ࡊ࡮⊕⦡ߩࡏ࠺ࠖߩ  ภ⎬ࠞࡊ࠮ ⊕⦡࡮⚛㍤ ᵈ኿೷㧔ࡃࠗࠕ࡞㧕 ࡞ ࠹࡜ࡊ࡟ࡆ࡞ 250mg ࡍࠟࠪࠬ⊹ਅᵈ ࡍࠟࠪࠬ⊹ਅᵈ ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ 102.93mg㧔ࠪࡔࡊ࡟ࡆ 90Ǵg 180Ǵg

࡞ߣߒߡ 100mg㧕 ᚑಽ ᦭ലᚑಽ ࡍࠣࠗࡦ࠲࡯ࡈ ࡍࠣࠗࡦ࠲࡯ࡈ 㧔1 ࡃࠗࠕ࡞ ࡮฽᦭㊂ ࠚࡠࡦࠕ࡞ࡈࠔ ࠚࡠࡦࠕ࡞ࡈࠔ ೷ဳ㨯 㧔1.0mL㧕 -2a㧔ㆮવሶ⚵ -2a㧔ㆮવሶ⚵ ਛ㧕 ឵߃㧕 90Ǵg ឵߃㧕 180Ǵg ฽㊂ 㧔ࠗࡦ࠲࡯ࡈࠚ 㧔ࠗࡦ࠲࡯ࡈࠚ ࡠࡦ ࠕ࡞ࡈࠔ- ࡠࡦ ࠕ࡞ࡈࠔ- 2a㧔ㆮવሶ⚵឵ 2a㧔ㆮવሶ⚵឵ ߃㧕ߣߒߡ㧕 ߃㧕ߣߒߡ㧕

࠮ࡠࠣ࡞࡯ࡊ 1㧔ࠫࠚࡁ࠲ࠗࡊΣ㧔1a㧕෶ߪΤ ࠮ࡠࠣ࡞࡯ࡊ 1(ࠫࠚࡁ࠲ࠗࡊΣ(1a)෶ߪΤ(1b))ߩ 㧨ࡍࠟࠪࠬ⊹ਅᵈ 180Ǵg ߩ႐ว㧪 㧔1b㧕㧕ߩ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆᰴߩ޿ߕࠇ߆ߩ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆᰴߩ޿ߕࠇ߆ߩ࠙ࠗ࡞ࠬⴊ 1.C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ∝ߩᡷༀ 2.࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦࠃࠆએਅߩ޿ߕࠇ߆ߩ C 1㧕ⴊਛ HCV RNA ㊂߇㜞୯ߩᧂᴦ≮ᖚ⠪ ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ (1)ⴊਛ HCV RNA ㊂߇㜞୯ߩᧂᴦ≮ᖚ⠪ 2㧕ࠗࡦ࠲࡯ࡈࠚࡠࡦࠍ฽߻ᴦ≮ᴺߢήല෶ߪౣ (1)࠮ࡠࠣ࡞࡯ࡊ 1(ࠫࠚࡁ࠲ࠗࡊΣ(1a)෶ߪΤ(1b)) (2) Άߣߥߞߚᖚ⠪ ࠗࡦ࠲࡯ࡈࠚࡠࡦ⵾೷ߩන⁛≮ᴺ㧘෶ߪ࡝ࡃࡆ ߢ HCV-RNA ㊂߇㜞୯ߩᖚ⠪ <ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ> ࡝ࡦߣߩ૬↪≮ᴺߢήല෶ߪౣΆߣߥߞߚᖚ⠪ (2)ࠗࡦ࠲࡯ࡈࠚࡠࡦන⁛≮ᴺߢήല෶ߪࠗࡦ࠲ 1㧚ᧄ೷ߩ૶↪ߦ޽ߚߞߡߪޔⴊਛ HCV RNA ߇ <ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ> ࡯ࡈࠚࡠࡦන⁛≮ᴺᓟౣΆߒߚᖚ⠪ 㓁ᕈߢ޽ࠆߎߣޔ෸߮⚵❱௝෶ߪ⢄੍஻⢻ޔⴊ (1)ᧄ೷ߩ૶↪ߦ㓙ߒߡߪ㧘HCV RNA ߇㓁ᕈߢ 3.B ဳᘟᕈᵴേᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷ ዊ᧼ᢙ╬ߦࠃࠅޔᘟᕈ⢄Ἳߢ޽ࠆߎߣࠍ⏕⹺ߔ ޽ࠆߎߣࠍ⏕⹺ߔࠆߎߣ㧚 ༀ ࠆߎߣޕ (2)ⴊਛ HCV RNA ㊂߇㜞୯ߩᧂᴦ≮ᖚ⠪ߦ↪޿ 㧨ࡍࠟࠪࠬ⊹ਅᵈ 90Ǵg ߩ႐ว㧪 2㧚ᧂᴦ≮ᖚ⠪ߦ↪޿ࠆ႐วߪޔⴊਛ HCV RNA ࠆ႐วߪ㧘ⴊਛ HCV RNA ㊂߇ RT̃PCR ᴺߢ 5.0 1.C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ㊂߇ RT-PCR ᴺߢ 5.0 Log IU/mL એ਄ߦ⋧ᒰߔࠆ LogIU/mL એ਄ߦ⋧ᒰߔࠆߎߣࠍ⏕⹺ߔࠆߎߣ㧚 2.࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦࠃࠆએਅߩ޿ߕࠇ߆ߩ C (3)C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ߳ ߎߣࠍ⏕⹺ߔࠆߎߣޕ ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ߩᧄ೷ߩ૶↪ߦ޽ߚߞߡߪ㧘⥄Ꮖ఺∉ᕈ⢄Ἳ㧘 (1)࠮ࡠࠣ࡞࡯ࡊ 1(ࠫࠚࡁ࠲ࠗࡊΣ(1a)෶ߪΤ(1b)) 3㧚ࠗࡦ࠲࡯ࡈࠚࡠࡦࠍ฽߻ᴦ≮ᴺߩ߁ߜޔઁߩ ࠕ࡞ࠦ࡯࡞ᕈ⢄Ἳ╬ߘߩઁߩᘟᕈ⢄∔ᖚߢߥ޿ ߢ HCV-RNA ㊂߇㜞୯ߩᖚ⠪ ࡊࡠ࠹ࠕ࡯࠯㒖ኂ೷ߦࠃࠆᣢᴦ≮଀ߦኻߔࠆᛩ (2)ࠗࡦ࠲࡯ࡈࠚࡠࡦන⁛≮ᴺߢήല෶ߪࠗࡦ࠲ ߎߣ㧘⢄⎬ᄌࠍ઻߁ᘟᕈ⢄Ἳߢߥ޿ߎߣ෸߮⢄ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ല⢻㨯 ਈ⚻㛎ߪߥ޿ޕߎࠇࠄߩᖚ⠪ߦኻߒߡߪޔ࠙ࠗ ࡯ࡈࠚࡠࡦන⁛≮ᴺᓟౣΆߒߚᖚ⠪ ਇోࠍ઻ࠊߥ޿ߎߣࠍ⏕⹺ߔࠆ㧚߹ߚ㧘⚵❱௝ ലᨐ ࡞ࠬᕈ⢄∔ᖚߩᴦ≮ߦචಽߥ⍮⼂࡮⚻㛎ࠍᜬߟ 3.࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦࠃࠆ C ဳઍఘᕈ⢄⎬ᄌߦ ෶ߪ⢄੍஻⢻㧘ⴊዊ᧼ᢙ╬ߦࠃࠅᘟᕈ⢄Ἳߢ޽ කᏧ߇೨ᴦ≮ߩ⒳㘃ޔ೨ᴦ≮ߦኻߔࠆ෻ᔕᕈޔ ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ࠆߎߣࠍ⏕⹺ߔࠆߎߣ㧚 4.B ဳᘟᕈᵴേᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷ ⠴ᕈᄌ⇣ߩ᦭ήޔᖚ⠪ߩᔋኈᕈ╬ࠍ⠨ᘦߒߚ਄ ༀ ߢޔᧄ೷ᛩਈߩนุࠍ್ᢿߔࠆߎߣޕ <ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ> 1.C ဳᘟᕈ⢄Ἳ෶ߪ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ ࠗ࡞ࠬⴊ∝ߩᡷༀ߳ߩᧄ೷ߩ૶↪ߦ޽ߚߞߡ ߪޔHCV-RNA ߇㓁ᕈߢ޽ࠆߎߣޔ෸߮⚵❱௝ ෶ߪ⢄੍஻⢻ޔⴊዊ᧼ᢙ╬ߦࠃࠅޔᘟᕈ⢄Ἳ෶ ߪઍఘᕈ⢄⎬ᄌߢ޽ࠆߎߣࠍ⏕⹺ߔࠆߎߣޕ 2.B ဳᘟᕈᵴേᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷ ༀ߳ߩᧄ೷ߩ૶↪ߦ޽ߚߞߡߪޔHBV-DNA ㊂ ߩ᷹ቯ╬ߦࠃࠅ࠙ࠗ࡞ࠬߩჇᱺࠍ⏕⹺ߔࠆߎ ߣޔ෸߮⚵❱௝෶ߪ⢄੍஻⢻ޔⴊዊ᧼ᢙ╬ߦࠃ ࠅޔ⢄⎬ᄌࠍ઻ࠊߥ޿ᘟᕈᵴേᕈ⢄Ἳߢ޽ࠆߎ ߣࠍ⏕⹺ߔࠆߎߣޕ߹ߚޔࠟࠗ࠼࡜ࠗࡦ╬ޔᦨ ᣂߩᖱႎࠍෳᾖߒޔᧄ೷ߩ૶↪߇ㆡಾߣ್ᢿߐ ࠇࠆᖚ⠪ߦᛩਈߔࠆߎߣޕ ㅢᏱޔᚑੱߦߪࠪࡔࡊ࡟ࡆ࡞ߣߒߡ100mgࠍ1 ᣣ ㅢᏱ㧘ᚑੱߦߪ㧘࠹࡜ࡊ࡟ࡆ࡞ߣߒߡ 1 ࿁ 750mg 1. C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ 1 ࿁⚻ญᛩਈߒޔᛩਈᦼ㑆ߪ12ㅳ㑆ߣߔࠆޕᧄ೷ ࠍ 1 ᣣ 3 ࿁㘩ᓟ⚻ญᛩਈߒ㧘ᛩਈᦼ㑆ߪ 12 ㅳ㑆 ާࡍࠟࠪࠬ⊹ਅᵈ 90Ǵgޔࡍࠟࠪࠬ⊹ਅᵈ 180Ǵ ߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ ߣߔࠆ㧚ᧄ೷ߪ㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈ gި ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࠔ̃2b(ㆮવሶ⚵឵߃)෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߎ 2. ࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦࠃࠆએਅߩ޿ߕࠇ߆ߩ 㧔ㆮવሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߎ ߣ㧚 C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ߣޕ ާࡍࠟࠪࠬ⊹ਅᵈ 90Ǵgޔࡍࠟࠪࠬ⊹ਅᵈ 180Ǵ ↪ᴺ㨯 gި ↪㊂ Ԭ࠮ࡠࠣ࡞࡯ࡊ 1㧔ࠫࠚࡁ࠲ࠗࡊΣ㧔1a㧕෶ߪΤ 㧔1b㧕㧕ߢ HCV-RNA ㊂߇㜞୯ߩᖚ⠪

2 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪

ળ␠ฬ MSD ᩣᑼળ␠ ਛᄖ⵾⮎ᩣᑼળ␠ MSD ᩣᑼળ␠

ᛚ⹺ 2004 ᐕ 10 ᦬ 22 ᣣ 2007 ᐕ 1 ᦬ 26 ᣣ 2001 ᐕ 11 ᦬ 21 ᣣ ᐕ᦬ ⷙ೙ ഍⮎ ಣᣇߖࠎක⮎ຠ ഍⮎ ಣᣇߖࠎක⮎ຠ ഍⮎ ಣᣇߖࠎක⮎ຠ ඙ಽ

H3C-(O-CH2CH2)n-OCO-Interferon alfa-2b ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵

߃)(C860H1353N229O255S9㧧 ಽሶ㊂㧦19268.91) ߩࠕ ࡒࡁ㉄ᱷၮ(Cys1㧘His7㧘Lys31㧘His34㧘Lys49㧘 Lys83㧘Lys112㧘Lys121㧘Tyr129㧘Lys131㧘Lys133㧘 Lys134㧘Ser163 ෸߮ Lys164)ߩ 1 ▎ᚲߦ 1 ಽሶߩࡔ ൻቇ ࠻ࠠࠪࡐ࡝ࠛ࠴࡟ࡦࠣ࡝ࠦ࡯࡞(ᐔဋಽሶ㊂㧦⚂ ᭴ㅧᑼ 12,000)߇ࠞ࡞ࡏ࠾࡞ၮࠍ੺ߒߡ౒᦭⚿วߒߡ޿ ࠆୃ㘼࠲ࡦࡄࠢ⾰(ಽሶ㊂㧦⚂ 32,000)

ᵈ኿೷ ᷆⿒⦡ߩࡈࠖ࡞ࡓࠦ࡯࠹ࠖࡦࠣ㍤ ⎬ࠞࡊ࠮࡞೷ ⽼ᄁฬ ࡝ࡃࡆ࡝ࡦ 200mg ࡝ࡃࡆ࡝ࡦ 200mg ࡍࠣࠗࡦ࠻ࡠࡦ®

⊹ਅᵈ↪ ᚑಽฬ 50ȝg 100ȝg 150ȝg /0.5m /0.5m /0.5m ೷ᒻ࡮ L ↪ L ↪ L ↪ ฽㊂ ࡍࠣࠗࡦ࠲ 1 ࡃࠗࠕ࡞ਛߩ฽ 74ȝg 148ȝg 222ȝg ࡯ࡈࠚࡠࡦ ᦭㊂ ᦭ ࠕ࡞ࡈࠔ-2b ᣣᧄ⮎ዪᣇޟᵈ 50ȝg 100ȝg 150ȝg ല 㧔ㆮવሶ⚵ ኿↪᳓ޠ0.7mL ߦ ᚑ ឵߃㧕 ṁ⸃ߒߚṁᶧ ಽ 0.5mL ਛߦ฽߹ࠇ ࠆ㊂

1.࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦࠃࠆᰴߩ޿ߕࠇ߆ߩ C 1.ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a(ㆮવሶ⚵឵ 1.ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵ ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ߃)ߣߩ૬↪ߦࠃࠆએਅߩ޿ߕࠇ߆ߩ C ဳᘟᕈ⢄ ߃)ޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ (1)ⴊਛ HCV RNA ㊂߇㜞୯ߩᖚ⠪ Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ⚵឵߃)෶ߪࠗࡦ࠲࡯ࡈࠚࡠࡦ ࡌ࡯࠲ߣߩ૬↪ߦ (2)ࠗࡦ࠲࡯ࡈࠚࡠࡦ⵾೷න⁛≮ᴺߢήലߩᖚ⠪ (1)࠮ࡠࠣ࡞࡯ࡊ㧝(ࠫࠚࡁ࠲ࠗࡊΣ(1a)෶ߪΤ(1b)) ࠃࠆᰴߩ޿ߕࠇ߆ߩ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ ෶ߪࠗࡦ࠲࡯ࡈࠚࡠࡦ⵾೷න⁛≮ᴺᓟౣΆߒߚ ߢ HCV-RNA ㊂߇㜞୯ߩᖚ⠪ ࡞ࠬⴊ∝ߩᡷༀ ᖚ⠪ (2)ࠗࡦ࠲࡯ࡈࠚࡠࡦන⁛≮ᴺߢήല෶ߪࠗࡦ࠲࡯ (1)ⴊਛ HCV RNA ㊂߇㜞୯ߩᖚ⠪ 2.࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦࠃࠆ C ဳઍఘᕈ⢄⎬ᄌ ࡈࠚࡠࡦන⁛≮ᴺᓟౣΆߒߚᖚ⠪ (2)ࠗࡦ࠲࡯ࡈࠚࡠࡦ⵾೷න⁛≮ᴺߢήലߩᖚ⠪ ߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ 2.ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a(ㆮવሶ⚵឵ ෶ߪࠗࡦ࠲࡯ࡈࠚࡠࡦ⵾೷න⁛≮ᴺᓟౣΆߒߚ <ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ> ߃)ߣߩ૬↪ߦࠃࠆ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ ᖚ⠪ 1㧚ᧄ೷ߪ࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߎߣ(ޣ⥃ᐥᚑ ࠗ࡞ࠬⴊ∝ߩᡷༀ 2.ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵ ❣ޤߩ㗄ෳᾖ)ޕ ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ  ߃)ߣߩ૬↪ߦࠃࠆ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ 2㧚ᧄ೷ߩ૶↪ߦ㓙ߒߡߪޔHCV RNA ߇㓁ᕈߢ 1.ᧄ೷ߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a(ㆮ ࠗ࡞ࠬⴊ∝ߩᡷༀ ޽ࠆߎߣޔ෸߮⚵❱௝෶ߪ⢄੍஻⢻ޔⴊዊ᧼ᢙ વሶ⚵឵߃)ߣ૬↪ߔࠆߎߣޕC ဳᘟᕈ⢄Ἳ෶ߪ ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ  ╬ߦࠃࠅޔᘟᕈ⢄Ἳ෶ߪઍఘᕈ⢄⎬ᄌߢ޽ࠆߎ C ဳઍఘᕈ⢄⎬ᄌߦኻߔࠆᧄ೷ߩන⁛≮ᴺߪή 1㧚ᧄ೷ߪޔC ဳᘟᕈ⢄Ἳߦኻߒߡߪࠗࡦ࠲࡯ࡈ ߣࠍ⏕⹺ߔࠆߎߣޕߥ߅ޔⴊਛ HCV RNA ㊂߇ ലߢ޽ࠆޕ ࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵߃)ޔࡍࠣࠗࡦ࠲ 㜞୯ߩ C ဳᘟᕈ⢄Ἳߦᧄ೷ࠍ↪޿ࠆ႐วޔⴊਛ 2.C ဳᘟᕈ⢄Ἳ෶ߪ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ ࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵߃)෶ߪࠗࡦ HCV RNA ㊂߇ RT-PCR ᴺߢ 105IU/mL એ਄෶ߪ ࠗ࡞ࠬⴊ∝ߩᡷༀ߳ߩᧄ೷ߩ૬↪ߦ޽ߚߞߡ ࠲࡯ࡈࠚࡠࡦ ࡌ࡯࠲ߣޔC ဳઍఘᕈ⢄⎬ᄌߦኻ

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 b-DNA ᴺߢ 1Meq./mL એ਄ߢ޽ࠆߎߣࠍ⏕⹺ߔ ߪޔHCV-RNA ߇㓁ᕈߢ޽ࠆߎߣޔ෸߮⚵❱௝ ߒߡߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવ ല⢻࡮ ࠆߎߣޕ ෶ߪ⢄੍஻⢻ޔⴊዊ᧼ᢙߥߤߦࠃࠅޔᘟᕈ⢄Ἳ ሶ⚵឵߃)ߣ૬↪ߔࠆߎߣ(ޣ⥃ᐥᚑ❣ޤߩ㗄ෳ ലᨐ 3㧚ᧄ೷ߩන⁛ᛩਈᤨߩ࿖ౝߦ߅ߌࠆ᦭ലᕈ࡮቟ ෶ߪઍఘᕈ⢄⎬ᄌߢ޽ࠆߎߣࠍ⏕⹺ߔࠆߎߣޕ ᾖ)ޕC ဳᘟᕈ⢄Ἳ෶ߪ C ဳઍఘᕈ⢄⎬ᄌߦኻߔ

ోᕈߪ⏕┙ߒߡ޿ߥ޿ޕ ࠆᧄ೷ߩන⁛≮ᴺߪήലߢ޽ࠆޕ 2㧚C ဳᘟᕈ⢄Ἳ෶ߪ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀߦኻߔࠆᧄ೷ߩ૬↪ߦ޽ߚ ߞߡߪ HCV RNA ߇㓁ᕈߢ޽ࠆߎߣޔ෸߮⚵❱ ௝෶ߪ⢄੍஻⢻ޔⴊዊ᧼ᢙ╬ߦࠃࠅᘟᕈ⢄Ἳ෶

ߪઍఘᕈ⢄⎬ᄌߢ޽ࠆߎߣࠍ⏕⹺ߔࠆߎߣޕߥ

߅ޔⴊਛ HCV RNA ㊂߇㜞୯ߩ C ဳᘟᕈ⢄Ἳߦ ᧄ೷ࠍ↪޿ࠆ႐วޔⴊਛ HCV RNA ㊂߇ RT-PCR ᴺߢ 105IU/mL એ਄෶ߪ b-DNA ᴺߢ 1Meq./mL એ ਄ߢ޽ࠆߎߣࠍ⏕⹺ߔࠆߎߣޕ

1.࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦࠃࠆ C ဳᘟᕈ⢄Ἳߦ߅ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a(ㆮવሶ⚵឵ 1.C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀߩ႐ ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀߩ႐ว ߃)ߣ૬↪ߔࠆߎߣޕㅢᏱޔᚑੱߦߪޔਅ⸥ߩ↪ ว ࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߎߣޕㅢᏱޔᚑੱߦߪޔ ᴺ࡮↪㊂ߩ࡝ࡃࡆ࡝ࡦࠍ⚻ญᛩਈߔࠆޕᧄ೷ߩᛩ ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵߃)ޔ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵ ਈߦ㓙ߒߡߪޔᖚ⠪ߩ⁁ᘒࠍ⠨ᘦߒޔᷫ㊂ޔਛᱛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ 2b(ㆮવሶ⚵឵ ߃)ߣߒߡ 1 ࿁ 1.5Ǵg/kg ࠍㅳ 1 ࿁⊹ਅᛩਈߔࠆޕ ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ߃)෶ߪࠗࡦ࠲࡯ࡈࠚࡠࡦ ࡌ࡯࠲ߣ૬↪ߔࠆߎ ᧄ೷ߩᛩਈߦ㓙ߒߡߪޔᖚ⠪ߩ⁁ᘒࠍ⠨ᘦߒޔ ૕㊀ 㧝ᣣᛩਈ㊂ ᦺ㘩ᓟ ᄕ㘩ᓟ ߣޕ ↪ᴺ㨯 ᷫ㊂ޔਛᱛ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 60kg એਅ 600mg 200mg 400mg ㅢᏱޔᚑੱߦߪޔਅ⸥ߩ↪ᴺ࡮↪㊂ߩ࡝ࡃࡆ࡝ ↪㊂ 2.࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦࠃࠆ C ဳઍఘᕈ⢄⎬ᄌ 60kg ࠍ⿥߃ ࡦࠍ⚻ญᛩਈߔࠆޕ 800mg 400mg 400mg ߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀߩ႐ว 80kg એਅ ᧄ೷ߩᛩਈߦ㓙ߒߡߪޔᖚ⠪ߩ⁁ᘒࠍ⠨ᘦߒޔ

࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߎߣޕㅢᏱޔᚑੱߦߪޔ 80kg ࠍ⿥߃ ᷫ㊂ޔਛᱛ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ -2b( 1,000mg 400mg 600mg ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ ㆮવሶ⚵឵ ࠆ ߃)ߣߒߡ 1 ࿁ 1.0Ǵg/kg ࠍㅳ 1 ࿁⊹ਅᛩਈߔࠆޕ ᧄ೷ߩᛩਈߦ㓙ߒߡߪޔᖚ⠪ߩ⁁ᘒࠍ⠨ᘦߒޔ ᷫ㊂ޔਛᱛ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ

3 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

ԭࠗࡦ࠲࡯ࡈࠚࡠࡦන⁛≮ᴺߢήല෶ߪࠗࡦ࠲ ࡯ࡈࠚࡠࡦන⁛≮ᴺᓟౣΆߒߚᖚ⠪ ૶↪ߦ޽ߚߞߡߪޔHCV-RNA ߇㓁ᕈߢ޽ࠆߎߣ

ࠍ⏕⹺ߒߚ߁߃ߢⴕ߁ޕ

ㅢᏱޔᚑੱߦߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ- 2a㧔ㆮવሶ⚵឵߃㧕1 ࿁ 180Ǵg㧔ࠗࡦ࠲࡯ࡈࠚ ࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕ߣߒߡ㧕 ࠍㅳ 1 ࿁ޔ⊹ਅߦᛩਈߔࠆޕ ᧄ೷ߩᛩਈߦ㓙ߒߡߪޔᖚ⠪ߩ⁁ᘒࠍ⠨ᘦߒޔ ᷫ㊂ޔਛᱛ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 3.࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦࠃࠆ C ဳઍఘᕈ⢄⎬ᄌߦ

߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ާࡍࠟࠪࠬ⊹ਅᵈ 90

Ǵgި ૶↪ߦ޽ߚߞߡߪޔHCV-RNA ߇㓁ᕈߢ޽ࠆߎߣ ࠍ⏕⹺ߒߚ߁߃ߢⴕ߁ޕ ㅢᏱޔᚑੱߦߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ- 2a(ㆮવሶ⚵឵߃)1 ࿁ 90Ǵg(ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ ࡞ࡈࠔ-2a(ㆮવሶ⚵឵߃)ߣߒߡ)ࠍㅳ 1 ࿁ޔ⊹ਅ ߦᛩਈߔࠆޕᧄ೷ߩᛩਈߦ㓙ߒߡߪޔᖚ⠪ߩ⁁

ᘒࠍ⠨ᘦߒޔᷫ㊂ޔਛᱛ╬ߩㆡಾߥಣ⟎ࠍⴕ߁

ߎߣޕ 4.B ဳᘟᕈᵴേᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷ ༀ ާࡍࠟࠪࠬ⊹ਅᵈ 90Ǵgޔࡍࠟࠪࠬ⊹ਅᵈ 180Ǵ

gި ૶↪ߦ޽ߚߞߡߪޔHBV-DNA ㊂ߩ᷹ቯ╬ߦࠃࠅ ࠙ࠗ࡞ࠬߩჇᱺࠍ⏕⹺ߒߚ߁߃ߢⴕ߁ޕ

ㅢᏱޔᚑੱߦߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-

2a(ㆮવሶ⚵឵߃)1 ࿁ 90Ǵg(ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ ࡞ࡈࠔ-2a(ㆮવሶ⚵឵߃)ߣߒߡ)ࠍㅳ 1 ࿁ޔ⊹ਅ ߦᛩਈߔࠆޕߥ߅ޔᐕ㦂ޔHBV-DNA ㊂╬ߦᔕߓ ߡޔ1 ࿁ߩᛩਈ㊂ࠍ 180Ǵg ߣߔࠆߎߣ߇ߢ߈ ࠆޕ ᧄ೷ߩᛩਈߦ㓙ߒߡߪޔᖚ⠪ߩ⁁ᘒࠍ⠨ᘦߒޔ

ᷫ㊂ޔਛᱛ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ

<↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ> <↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ> <↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ> 1) ᧄ೷ࠍන⁛ᛩਈߒߚ㓙ߩ᦭ലᕈ෸߮቟ోᕈߪ (1)ᧄ೷න⁛ᛩਈߢߩ᦭ലᕈ෸߮቟ోᕈߪ⏕┙ߒ 1% ဳᘟᕈ⢄Ἳ ᧄ೷න⁛ ෶ߪ $ ဳᘟᕈᵴേᕈ ⏕┙ߒߡ޿ߥ޿ޕ ߡ޿ߥ޿㧚 ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ 2) ᧄ೷ߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a (2)ᧄ೷ߪ 12 ㅳ㑆ࠍ⿥߃ߡᛩਈߒߚ㓙ߩ᦭ലᕈ (1)C ဳᘟᕈ⢄Ἳߦ߅޿ߡޔᧄ೷න⁛ߩᛩਈᦼ㑆 ↪ᴺ㨯 㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ ෸߮቟ోᕈߪ⏕┙ߒߡ޿ߥ޿㧚(ޟ⥃ᐥᚑ❣ޠߩ ߪޔ⥃ᐥലᨐ෸߮೽૞↪ߩ⒟ᐲࠍ⠨ᘦߒߥ߇ࠄ ↪㊂ ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߣ 㗄ෳᾖ) ᘕ㊀ߦ᳿ቯߔࠆ߇ޔᛩਈ 12 ㅳߢലᨐ߇⹺߼ࠄ ૬↪ߔࠆ߇ޔᦨೋߩ12ㅳ㑆ߪ3೷૬↪ᛩਈߒޔ (3)ᧄ೷㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b(ㆮ ࠇߥ޿႐วߦߪᛩਈࠍਛᱛߔࠆߎߣޕ ⛯ߊ12ㅳ㑆ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ- વሶ⚵឵߃)෸߮࡝ࡃࡆ࡝ࡦࠍ૬↪ߔࠆ႐วߦ (2)B ဳᘟᕈᵴേᕈ⢄Ἳߦ߅޿ߡޔᧄ೷ߩᛩਈᦼ 2a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ߪ㧘3 ೷૬↪ᛩਈߢᴦ≮ࠍ㐿ᆎߒ㧘ᧄ೷ᛩਈ⚳ 㑆ߪޔ⥃ᐥലᨐ෸߮೽૞↪ߩ⒟ᐲࠍ⠨ᘦߒߥ߇ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦ ੌᓟ㧘ᒁ߈⛯߈ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ ࠄᘕ㊀ߦ᳿ቯߔࠆߎߣޕᧄ೷ߦࠃࠆᮡḰ⊛ߥᴦ ߦࠃࠆ2೷૬↪ᛩਈࠍታᣉߔࠆߎߣޕߥ߅ޔᖚ ̃2b(ㆮવሶ⚵឵߃)෸߮࡝ࡃࡆ࡝ࡦߦࠃࠆ 2 ೷૬ ≮ᦼ㑆ߪ 48 ㅳ㑆ߢ޽ࠆ(ޣ⥃ᐥᚑ❣ޤߩ㗄ෳ ⠪ߩᴦ≮ᱧ߿⢛᥊࿃ሶޔ෸߮ೋᦼߩᴦ≮ലᨐߦ ↪ࠍታᣉߔࠆ㧚ߥ߅㧘ᧄ೷ߣ૬↪ߔࠆࡍࠣࠗࡦ ᾖ)ޕ ᔕߓߡޔߎߩ2೷૬↪ᛩਈࠍᦝߦ24ㅳ㑆ᛩਈߔ ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b(ㆮવሶ⚵឵߃)෸߮ (3)B ဳᘟᕈᵴേᕈ⢄Ἳߦ߅޿ߡޔᧄ೷ߩᛩਈ㊂ ࠆߎߣࠍ⠨ᘦߔࠆޕߚߛߒޔᧄ೷ߣ૬↪ߔࠆ႐ ࡝ࡃࡆ࡝ࡦߪ 24 ㅳ㑆ࠍ⿥߃ߡᛩਈߒߚ႐วߩ ߣߒߡ 180Ǵg ࠍㆬᛯߔࠆ㓙ߦߪޔᖚ⠪ߩᐕ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 วޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવ ᦭ലᕈ෸߮቟ోᕈߪ⏕┙ߒߡ޿ߥ޿㧚(ޟ⥃ᐥᚑ 㦂ޔHBV-DNA ㊂ޔ⥃ᐥലᨐޔ೽૞↪ߩ⒟ᐲ╬ ሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ ❣ޠߩ㗄ෳᾖ) ࠍ⠨ᘦߒߥ߇ࠄᘕ㊀ߦ᳿ቯߔࠆߎߣޕ -2b㧔ㆮવሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߩ✚ᛩਈ (4)ᧄ೷ࠍⓨ⣻ᤨߦ᦯↪ߒߚ႐วߪ㧘චಽߥⴊਛ (4)ᧄ೷න⁛ߩᛩਈߪޔਅ⴫ߩ⥃ᐥᬌᩏ୯ࠍ⏕⹺ ᦼ㑆ߪ48ㅳࠍ⿥߃ߥ޿ߎߣޕ Ớᐲ߇ᓧࠄࠇߥ޿ߚ߼㧘ᔅߕ㘩ᓟߦ᦯↪ߔࠆࠃ ߒߡ߆ࠄ㐿ᆎߔࠆߎߣޕ 3) ᴦ≮ਛߩ᛫࠙ࠗ࡞ࠬലᨐ߇ਇචಽߥ႐วޔ⮎ ߁ߦᖚ⠪ߦᜰዉߔࠆߎߣ㧚߹ߚ㧘ᛩਈ㑆㓒╬ࠍ ᬌᩏ㗄⋡ ᛩਈ೨୯ ೷⠴ᕈ࠙ࠗ࡞ࠬ߇಴⃻ߒߡ޿ࠆߎߣ߇޽ࠆߚ ⺞▵ߔࠆࠃ߁㧘એਅߩౝኈ߽〯߹߃ߡᖚ⠪ߦᜰ ᅢਛ⃿ᢙ 1, 500/ǴL એ਄ ߼ޔᴦ≮ਛᱛࠍ⠨ᘦߔࠆߎߣޕ ዉߔࠆߎߣ㧚(ޟ⮎‛േᘒޠߩ㗄ෳᾖ) ⴊዊ᧼ᢙ 90, 000/ǴL એ਄ 4) ೽૞↪߿ᴦ≮ലᨐਇචಽ╬ߦࠃࠅᧄ೷ࠍਛᱛ 1)ૐ⢽⢌㘩ߩ㘩ᓟߦᧄ೷ࠍᛩਈߒߚ႐ว㧘㜞⢽ ࡋࡕࠣࡠࡆࡦ㊂ 10g/dL એ਄ ߒߚ႐วߦߪޔᧄ೷ߩᛩਈࠍౣ㐿ߒߥ޿ߎߣޕ ⢌㘩ߩ㘩ᓟߦᛩਈߒߚ႐วߦᲧߴߡⴊẏਛỚᐲ (5)ᧄ೷ߩᷫ㊂෶ߪਛᱛࠍᔅⷐߣߔࠆਛ╬ᐲ߆ࠄ 5) ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2 a㧔ㆮવሶ ߇ૐਅߔࠆߣߩႎ๔߇޽ࠆ㧚 ㊀ᐲߩ೽૞↪(⥃ᐥᬌᩏ୯⇣Ᏹࠍ฽߻)߇ႎ๔ߐ ⚵឵߃㧕ޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2 b 2)⥃ᐥ⹜㛎ߦ߅޿ߡᧄ೷ߩ᦭ലᕈ෸߮቟ోᕈߪ ࠇߡ޿ࠆߩߢޔ㊀ᐲߩ೽૞↪ࠍ⊒⃻ߔࠆน⢻ᕈ 㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩᛩਈ㊂ߪޔ 㘩ᓟߦߡ 8 ᤨ㑆㑆㓒ᛩਈߢᬌ⸛ߐࠇߡ޿ࠆ㧚 ߩ㜞޿ᖚ⠪෶ߪᛩਈ㐿ᆎ೨ߩ⥃ᐥᬌᩏ୯߇਄⸥ ฦ⵾ຠߩᷝઃᢥᦠߦቯ߼ࠄࠇߚ↪ᴺ࡮↪㊂ߦᓥ (5)ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b(ㆮવሶ⚵ ߩၮḰߦㄭ޿ᖚ⠪ߢߪޔᛩਈ㐿ᆎ߆ࠄ 2 ㅳ㑆ߪ ߁ߎߣޕ૬↪ߦ޽ߚߞߡߪޔᛩਈ㐿ᆎ೨ߦฦ⵾ ឵߃)ߪ㧘ㅢᏱ㧘ᚑੱߦߪ㧘1 ࿁ 1.5Ǵg/kg ࠍㅳ 1 ේೣ౉㒮ߐߖࠆߎߣ(ޟᘕ㊀ᛩਈޠߩ㗄ෳᾖ)ޕ ຠߩᷝઃᢥᦠߦቯ߼ࠄࠇߚ⥃ᐥᬌᩏ୯ၮḰࠍḩ ࿁⊹ਅᛩਈߔࠆ㧚 (6)ᧄ೷ᛩਈਛߪޔቯᦼ⊛ߦⴊᶧቇ⊛ᬌᩏࠍታᣉ ߚߒߡ޿ࠆߎߣࠍ⏕⹺ߔࠆߎߣޕ߹ߚޔᛩਈਛ (6)࡝ࡃࡆ࡝ࡦߪ㧘ㅢᏱ㧘ᚑੱߦߪ㧘ਅ⸥ߩ↪ ߒޔᅢਛ⃿ᢙޔⴊዊ᧼ᢙޔࡋࡕࠣࡠࡆࡦ㊂ߩᷫ ߦฦ⵾ຠߩ↪㊂⺞▵߿ᛩਈਛᱛࠍᔅⷐߣߔࠆ೽ ᴺ࡮↪㊂ߢ⚻ญᛩਈߔࠆ㧚 ዋ߇⊒⃻ߒߚ႐วߦߪޔਅ⴫ࠍෳ⠨ߦߒߡ↪㊂ ૞↪߇⊒⃻ߒߚ႐วߦߪޔฦ⵾ຠߩᷝઃᢥᦠࠍ ࡝ࡃࡆ࡝ࡦߩᛩਈ㊂ ࠍ⺞ᢛߔࠆߎߣ(ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄ෳ ෳᾖߔࠆߎߣޕ ᖚ⠪ߩ૕㊀ 1 ᣣᛩਈ㊂ ᦺ㘩ᓟ ᄕ㘩ᓟ ᾖ)ޕߚߛߒޔⴊዊ᧼ᢙ߇ 25,000/ǴL ᧂḩࠍ␜

60kg એਅ 600mg 200mg 400mg ߒߚ႐วߪޔᧄ೷ߦࠃࠆᴦ≮ߩਛᱛࠍ⠨ᘦߔࠆ 60kg ࠍ⿥߃ ߎߣޕ 800mg 400mg 400mg 80kg એਅ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ 80kg ࠍ⿥߃ࠆ 1,000mg 400mg 600mg ࡍࠣࠗࡦ࠲࡯ࡈࠚ ᬌᩏ㗄⋡ ᢙ୯ ࡠࡦ ࠕ࡞ࡈࠔ- ࡝ࡃࡆ࡝ࡦߩᛩਈߦ㓙ߒߡߪ㧘ᖚ⠪ߩ⁁ᘒࠍ⠨ 2a(ㆮવሶ⚵឵߃) ᘦߒ㧘ᷫ㊂㧘ਛᱛ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣ㧚 ᅢਛ⃿ᢙ 750/ǴL ᧂḩ 90Ǵg ߦᷫ㊂ ․ߦ㧘ᛩਈ㐿ᆎ೨ߩࡋࡕࠣࡠࡆࡦỚᐲ߇ 13g/dL 500/ǴL ᧂḩ ਛᱛ ᧂḩߩᖚ⠪ߦߪ㧘࡝ࡃࡆ࡝ࡦߩᛩਈ㊂ࠍ 200mg ⴊዊ᧼ᢙ 50, 000/ǴL ᧂ 90Ǵg ߦᷫ㊂ ᷫ㊂ߒ㧘ਅ⸥ߩ↪ᴺ࡮↪㊂ߢ⚻ญᛩਈߔࠆ㧚 ḩ 25, 000/ǴL ᧂ ਛᱛ ḩ ࡋࡕࠣࡠࡆࡦ 8. 5g/dL ᧂḩ ਛᱛ ㊂

4 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ ࡝ࡃࡆ࡝ࡦߩᛩਈ㊂ ᖚ⠪ߩ૕㊀ 㧝ᣣߩᛩਈ ᦺ㘩ᓟ ᄕ㘩ᓟ ㊂

60kg એਅ 600mg 200mg 400mg

60kg ࠍ⿥߃ 800mg 400mg 400mg 80kg એਅ 80kg ࠍ⿥߃ࠆ 1,000mg 400mg 600mg 2.C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ߩ႐ว ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵ ߃)ߣ૬↪ߔࠆߎߣޕ

ㅢᏱޔᚑੱߦߪޔਅ⸥ߩ↪ᴺ࡮↪㊂ߩ࡝ࡃࡆ࡝

ࡦࠍ⚻ญᛩਈߔࠆޕ ᧄ೷ߩᛩਈߦ㓙ߒߡߪޔᖚ⠪ߩ⁁ᘒࠍ⠨ᘦߒޔ ᷫ㊂ޔਛᱛ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ (1)ᛩਈ㐿ᆎ೨ߩࡋࡕࠣࡠࡆࡦỚᐲ߇ 14g/dL એ਄ ߩᖚ⠪ ࡝ࡃࡆ࡝ࡦߩᛩਈ㊂

ᖚ⠪ߩ૕㊀ 㧝ᣣߩᛩਈ ᦺ㘩ᓟ ᄕ㘩ᓟ ㊂

60kg એਅ 600mg 200mg 400mg 60kg ࠍ⿥߃ 800mg 400mg 400mg 80kg એਅ 80kg ࠍ⿥߃ 1,000mg 400mg 600mg

ࠆ (2)ᛩਈ㐿ᆎ೨ߩࡋࡕࠣࡠࡆࡦỚᐲ߇ 14g/dL ᧂḩ

ߩᖚ⠪

࡝ࡃࡆ࡝ࡦߩᛩਈ㊂ ᖚ⠪ߩ૕㊀ 㧝ᣣߩᛩ ᦺ㘩ᓟ ᄕ㘩ᓟ ਈ㊂ 60kg એਅ 400mg 200mg 200mg 60kg ࠍ⿥߃ 600mg 200mg 400mg 80kg એਅ

80kg ࠍ⿥߃ 800mg 400mg 400mg ࠆ

<↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ> <↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ> <↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ> 1㧚ᧄ೷ࠍᷝઃߩᣣᧄ⮎ዪᣇޟᵈ኿↪᳓ޠ0.7mL 1.ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a(ㆮવሶ⚵ 1㧚C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀߩ ߦṁ⸃ߒߚߣ߈ޔṁ⸃ᶧ 0.5mL ਛߦ⴫␜㊂ߩࡍ ឵߃)ߪޔC ဳᘟᕈ⢄Ἳߦ߅޿ߡߪޔㅢᏱޔᚑੱ ႐ว ࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵߃) ߦߪ㧝࿁ 180Ǵg ࠍޔC ဳઍఘᕈ⢄⎬ᄌߦ߅޿ߡ (1)ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵ ࠍ฽᦭ߔࠆޕ ߪޔㅢᏱޔᚑੱߦߪ㧝࿁ 90Ǵg ࠍㅳ㧝࿁ޔ⊹ਅ ߃)ߪޔㅢᏱޔᚑੱߦߪޔ1 ᣣ 1 ࿁ 600 ਁ㨪1,000 ↪ᴺ㨯 ᧄ೷ߩᛩਈߦ㓙ߒߡߪޔਅ⸥ࠍෳ⠨ߦޔᖚ⠪ߩ ߦᛩਈߔࠆޕ ਁ࿖㓙න૏ࠍㅳ 6 ࿁෶ߪㅳ 3 ࿁╭⡺ౝߦᛩਈߔ ↪㊂ ૕㊀ߦᔕߓߡᔅⷐ㊂ࠍ↪޿ࠆޕ 2.C ဳᘟᕈ⢄Ἳ෸߮ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ ࠆޕ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ߳ߩᧄ೷ߩᛩਈᦼ㑆ߪޔ⥃ (2)ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵ ૕㊀ ᛩਈ㊂ ૶↪ࡃࠗࠕ ᶧ㊂ ᐥലᨐ෸߮೽૞↪ߩ⒟ᐲࠍ⠨ᘦߒߥ߇ࠄᘕ㊀ߦ ឵߃)ߪޔㅢᏱޔᚑੱߦߪޔ1 ࿁ 1.5Ǵg/kg ࠍㅳ 1 (kg) (ȝg) ࡞ (mL) ᳿ቯߔࠆ߇ޔᛩਈ 24 ㅳߢലᨐ߇⹺߼ࠄࠇߥ޿ ࿁⊹ਅᛩਈߔࠆޕ 35㨪45 60 0.3 ႐วߦߪᛩਈߩਛᱛࠍ⠨ᘦߔࠆߎߣޕ (3)ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࡌ࡯࠲ߪޔㅢᏱޔᚑੱߪ 1 100ȝg/0.5mL ᣣ 600 ਁ࿖㓙න૏ߢᛩਈࠍ㐿ᆎߒޔᛩਈᓟ 4 ㅳ 46㨪60 80 0.4 3.⥃ᐥ⹜㛎ߩ⚿ᨐࠃࠅޔᛩਈਛᱛ଀ߢߪ᦭ല₸ ↪ 㑆߹ߢߪㅪᣣޔએᓟㅳ 3 ࿁㕒⣂ౝᛩਈ෶ߪὐṢ 61㨪75 100 0.5 ߇ૐਅߔࠆߚ߼ޔᷫ㊂࡮ભ⮎ߥߤߩಣ⟎ߦࠃ 㕒ᵈߔࠆޕ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 76㨪90 120 150ȝg/0.5mL 0.4 ࠅޔน⢻ߥ㒢ࠅ 48 ㅳ㑆ᛩਈߔࠆߎߣ߇ᦸ߹ߒ ޿ޕߚߛߒޔC ဳᘟᕈ⢄Ἳߦ߅޿ߡޔ࠮ࡠࠣ࡞ 2㧚C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷ 91㨪120 150 ↪ 0.5 ࡯ࡊ㧝(ࠫࠚࡁ࠲ࠗࡊΣ(1a)෶ߪΤ(1b))ߢ HCV- ༀߩ႐วޔㅢᏱޔᚑੱߦߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ RNA ㊂߇㜞୯ߩᖚ⠪એᄖߦኻߒߡߪޔᖚ⠪ߩ⁁ ࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵߃)1 ࿁ 1.0Ǵg/kg ૕㊀ ᛩਈ㊂ ૶↪ࡃࠗࠕ ᶧ㊂ ᘒ߿ᴦ≮߳ߩ෻ᔕᕈߦᔕߓߡ 24 ㅳ㑆ߢᛩਈ⚳ ࠍㅳ 1 ࿁⊹ਅᛩਈߔࠆޕ (kg) (ȝg) ࡞ (mL) ੌߔࠆߥߤᛩਈᦼ㑆ߩ⍴❗߽⠨ᘦߔࠆߎߣޕ 3㧚ᧄ೷ߩᛩਈᦼ㑆ߪޔ⥃ᐥലᨐ(HCV RNAޔ 35㨪45 40 50 g/0.5mL 0.4 ȝ 4.ᧄ೷ߩᛩਈߪޔਅ⴫ߩ⥃ᐥᬌᩏ୯ࠍ⏕⹺ߒߡ ALT ╬)෸߮೽૞↪ߩ⒟ᐲࠍ⠨ᘦߒߥ߇ࠄᘕ㊀ 50 ↪ 0.5 46㨪60 ߆ࠄ㐿ᆎߔࠆߎߣޕ ߦ᳿ቯߔࠆߎߣޕ․ߦᅢਛ⃿ᢙޔⴊዊ᧼ᢙޔࡋ 61㨪75 70 0.35 ࡕࠣࡠࡆࡦỚᐲߩផ⒖ߦᵈᗧߒޔᧄ೷ߩᷫ㊂޽ 100ȝg/0.5 C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ 76㨪90 80 0.4 ࠆ޿ߪਛᱛၮḰߦᓥ߁ߎߣޕ mL ↪ ᬌᩏ㗄⋡ ᛩਈ೨୯ 91㨪120 100 0.5 ⊕ⴊ⃿ᢙ 3,000/ǴL એ਄ (1)C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀߩ ႐ว 2 㧚ㅢᏱޔᚑੱߦߪޔਅ⸥ߩ↪ᴺ࡮↪㊂ߩ࡝ࡃ ᅢਛ⃿ᢙ 1,500/ǴL એ਄ 1)࠮ࡠࠣ࡞࡯ࡊ 1(ࠫࠚࡁ࠲ࠗࡊΣ(1a)෶ߪΤ ࡆ࡝ࡦࠍ⚻ญᛩਈߔࠆޕᧄ೷ߩᛩਈߦ㓙ߒߡ ⴊዊ᧼ᢙ 90,000/ǴL એ਄ ߪޔᖚ⠪ߩ⁁ᘒࠍ⠨ᘦߒޔᷫ㊂ޔਛᱛ╬ߩㆡಾ (1b))ߢⴊਛ HCV RNA ㊂߇㜞୯ߩᖚ⠪ߦ߅ߌࠆ ࡋࡕࠣࡠࡆࡦ㊂ 12g/dL એ਄ ߥಣ⟎ࠍⴕ߁ߎߣޕ ㅢᏱߩᛩਈᦼ㑆ߪ 48 ㅳ㑆ߢ޽ࠆޕࠗࡦ࠲࡯ࡈ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵߃)෶ߪࡍࠣࠗࡦ ᬌᩏ㗄⋡ ᛩਈ೨୯ ᖚ⠪ߩ૕㊀ ࡝ࡃࡆ࡝ࡦߩᛩਈ㊂ ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵߃)ߣߩ૬ ⊕ⴊ⃿ᢙ 3,000/ǴL એ਄ 㧝ᣣᛩਈ ᦺ㘩ᓟ ᄕ㘩ᓟ ↪ߩ႐วޔ⥃ᐥ⹜㛎ߩ⚿ᨐࠃࠅޔᛩਈਛᱛ଀ߢ ᅢਛ⃿ᢙ 1,500/ǴL એ਄ ㊂ ߪ᦭ലᕈ߇ૐਅߔࠆߚ߼ޔᷫ㊂࡮ભ⮎ߥߤߩಣ ⴊዊ᧼ᢙ 75,000/ǴL એ਄ 60kg એਅ 600mg 200mg 400mg ⟎ߦࠃࠅน⢻ߥ㒢ࠅ 48 ㅳ㑆ᛩਈߔࠆߎߣ߇ᦸ ࡋࡕࠣࡠࡆࡦ㊂ 12g/dL એ਄ 24 60kg ࠍ⿥߃ 800mg 400mg 400mg ߹ߒ޿ޕߥ߅ޔ ㅳ㑆એ਄ߩᛩਈߢലᨐ߇⹺߼

80kg એਅ ࠄࠇߥ޿႐วޔᛩਈߩਛᱛࠍ⠨ᘦߔࠆߎߣޕ (ޣ⥃ᐥᚑ❣ޤߩ㗄ෳᾖ) 80kg ࠍ⿥߃ࠆ 1,000mg 400mg 600mg 2)ߘࠇએᄖߩᖚ⠪ߦ߅ߌࠆㅢᏱߩᛩਈᦼ㑆ߪ 24

ㅳ㑆ߢ޽ࠆޕ(ޣ⥃ᐥᚑ❣ޤߩ㗄ෳᾖ)

(2)ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵ ឵߃)ߣߩ૬↪ߦࠃࠆ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌ ࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀߩ႐วޔㅢᏱߩᛩਈᦼ㑆 ߪ 48 ㅳ㑆ߢ޽ࠆޕߥ߅ޔ24 ㅳ㑆એ਄ߩᛩਈߢ ലᨐ߇⹺߼ࠄࠇߥ޿႐วޔᛩਈߩਛᱛࠍ⠨ᘦߔ ࠆߎߣޕ(ޣ⥃ᐥᚑ❣ޤߩ㗄ෳᾖ)

5 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

ᛩਈ㐿ᆎ೨ߩࡋࡕࠣࡠࡆࡦỚ B ဳᘟᕈᵴേᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ᐲ߇ 13g/dL ᧂḩߩᖚ⠪ߩ࡝ ࡍࠣࠗࡦ࠲࡯ࡈࠚ ᖚ⠪ߩ૕㊀ ࡃࡆ࡝ࡦߩᛩਈ㊂ ᬌᩏ㗄⋡ ᢙ୯ ࡠࡦ ࠕ࡞ࡈࠔ- 2a( ) 1 ᣣᛩਈ ㆮવሶ⚵឵߃ ᦺ㘩ᓟ ᄕ㘩ᓟ 750/ L ㊂ ᅢਛ⃿ᢙ Ǵ ᧂḩ ඨ㊂ߦᷫ㊂ 500/ L 60kg એਅ 400mg 200mg 200mg Ǵ ᧂḩ ਛᱛ 50,000/ L 60kg ࠍ⿥߃ ⴊዊ᧼ᢙ Ǵ ᧂ ඨ㊂ߦᷫ㊂ 600mg 200mg 400mg ḩ 80kg એਅ 25,000/ǴL ᧂ ਛᱛ 80kg 800mg 400mg 400mg ࠍ⿥߃ࠆ ḩ (7)ᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b(ㆮ ࡋࡕࠣࡠࡆࡦ 8.5g/dL ᧂḩ ਛᱛ વሶ⚵឵߃)෸߮࡝ࡃࡆ࡝ࡦࠍ૬↪ߔࠆߦ޽ߚߞ ㊂ ߡߪ㧘ࡋࡕࠣࡠࡆࡦỚᐲ߇ 12g/dL એ਄ߢ޽ࠆߎ 2࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦࠃࠆ C ဳᘟᕈ⢄Ἳ෶ߪ ߣ߇ᦸ߹ߒ޿㧚߹ߚ㧘ᛩਈਛߦࡋࡕࠣࡠࡆࡦỚ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ᐲߩૐਅ߇⹺߼ࠄࠇߚ႐วߦߪ㧘ਅ⸥ࠍෳ⠨ߦ (1)ᧄ೷ߩᛩਈᦼ㑆ߪޔ⥃ᐥലᨐ෸߮೽૞↪ߩ⒟ ࡝ࡃࡆ࡝ࡦߩ↪㊂ࠍ⺞▵㧘޽ࠆ޿ߪᧄ೷㧘ࡍࠣ ᐲࠍ⠨ᘦߒߥ߇ࠄᘕ㊀ߦ᳿ቯߔࠆ߇ޔᛩਈ 24 ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b(ㆮવሶ⚵឵߃)෸ ㅳߢലᨐ߇⹺߼ࠄࠇߥ޿႐วߦߪᛩਈߩਛᱛࠍ ߮࡝ࡃࡆ࡝ࡦߩᛩਈࠍਛᱛߔࠆߎߣ㧚ߥ߅㧘࡝ ⠨ᘦߔࠆߎߣޕ (2)⥃ᐥ⹜㛎ߩ⚿ᨐࠃࠅޔᛩਈਛᱛ଀ߢߪ᦭ല₸ ࡃࡆ࡝ࡦߩᦨૐ↪㊂ߪ 200mg/ᣣ߹ߢߣߔࠆ㧚 ߇ૐਅߔࠆߚ߼ޔᷫ㊂࡮ભ⮎╬ߩಣ⟎ߦࠃࠅޔ ࡍࠣࠗࡦ น⢻ߥ㒢ࠅ 48 ㅳ㑆ᛩਈߔࠆߎߣ߇ᦸ߹ߒ޿ޕ ࡋࡕࠣ ࠲࡯ࡈࠚ ࡝ࡃࡆ࡝ ࡠࡦ ࠕ࡞ ߚߛߒޔC ဳᘟᕈ⢄Ἳߦ߅޿ߡޔ࠮ࡠࠣ࡞࡯ࡊ ࡠࡆࡦ ᧄ೷ ࡦ ࡈࠔ̃ 1(ࠫࠚࡁ࠲ࠗࡊΣ(1a)෶ߪΤ(1b))ߢ HCV-RNA Ớᐲ 2b(ㆮવሶ ㊂߇㜞୯ߩᖚ⠪એᄖߦኻߒߡߪޔᖚ⠪ߩ⁁ᘒ߿ ⚵឵߃) ᴦ≮߳ߩ෻ᔕᕈߦᔕߓߡ 24 ㅳ㑆ߢᛩਈ⚳ੌߔ 200mg ࠆߥߤᛩਈᦼ㑆ߩ⍴❗߽⠨ᘦߔࠆߎߣޕ ᷫ㊂㧦 12g/dL 1,000mg/ᣣ (3)ㅢᏱޔᚑੱߦߪਅ⸥ߩ↪ᴺ࡮↪㊂ߩ࡝ࡃࡆ࡝ ᧂḩߦ ᛩਈߩ ࡦࠍ⚻ญᛩਈߔࠆߎߣޕ ᷫዋ ႐วߪ ૕㊀ 㧝ᣣᛩ ᦺ㘩ᓟ ᄕ㘩ᓟ 400mg ↪㊂ᄌᦝߥߒ ਈ㊂ ᷫ㊂ 10g/dL 60kg એ 600mg 200mg 400mg 200 mg ᧂḩߦ ਅ ᷫ㊂ ᷫዋ 60kg ࠍ 800mg 400mg 400mg 8.5g/dL ⿥߃ ᛩਈ ᛩਈ ᧂḩߦ ᛩਈਛᱛ 80kg એ ਛᱛ ਛᱛ ᷫዋ ਅ ਄⸥ߩၮḰߦട߃ߡ㧘ࡋࡕࠣࡠࡆࡦỚᐲ߇ 1 ㅳ 80kg ࠍ 1,000mg 400mg 600mg 㑆એౝߦ 1g/dL એ਄ᷫዋߒ㧘ߘߩ୯߇ 13g/dL ᧂ ⿥߃ࠆ ḩߩ႐วߪ㧘࡝ࡃࡆ࡝ࡦࠍᦝߦ 200mg ᷫ㊂ߔ (4)ᧄ೷ߣ࡝ࡃࡆ࡝ࡦߩ૬↪ᛩਈߪޔਅ⴫ߩ⥃ᐥ ࠆ㧚 ᬌᩏ୯ࠍ⏕⹺ߒߡ߆ࠄ㐿ᆎߔࠆߎߣޕ (8)ᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b(ㆮ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ વሶ⚵឵߃)෸߮࡝ࡃࡆ࡝ࡦࠍ૬↪ߔࠆߦ޽ߚߞ ᬌᩏ㗄⋡ ᛩਈ೨୯ ↪ᴺ㨯 3 ߡߪ㧘⊕ⴊ⃿ᢙ߇ 4,000/mm એ਄෶ߪᅢਛ⃿ᢙ ⊕ⴊ⃿ᢙ 3, 000/ǴL એ਄ ↪㊂ 3 3 ߇ 1,500/mm એ਄㧘ⴊዊ᧼ᢙ߇ 100,000/mm એ ᅢਛ⃿ᢙ 1, 500/ǴL એ਄ ਄ߢ޽ࠆߎߣ߇ᦸ߹ߒ޿㧚߹ߚ㧘ᛩਈਛߦ⊕ⴊ ⴊዊ᧼ᢙ 90, 000/ǴL એ਄ ⃿ᢙ㧘ᅢਛ⃿ᢙ෶ߪⴊዊ᧼ᢙߩૐਅ߇⹺߼ࠄࠇ ࡋࡕࠣࡠࡆࡦ㊂ 12g/dL એ਄ ߚ႐วߦߪ㧘ਅ⸥ࠍෳ⠨ߦࡍࠣࠗࡦ࠲࡯ࡈࠚࡠ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ࡦ ࠕ࡞ࡈࠔ̃2b(ㆮવሶ⚵឵߃)ߩ↪㊂ࠍ⺞▵㧘޽ ᬌᩏ㗄⋡ ᛩਈ೨୯ ࠆ޿ߪᧄ೷㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃ ⊕ⴊ⃿ᢙ 3, 000/ǴL એ਄ 2b(ㆮવሶ⚵឵߃)෸߮࡝ࡃࡆ࡝ࡦߩᛩਈࠍਛᱛ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ߔࠆߎߣ㧚 ᅢਛ⃿ᢙ 1, 500/ǴL એ਄ ࡍࠣࠗࡦ࠲ ⴊዊ᧼ᢙ 75, 000/ǴL એ਄ ࡝ࡃࡆ ࡯ࡈࠚࡠࡦ ࡋࡕࠣࡠࡆࡦ㊂ 12g/dL એ਄ ᬌᩏ㗄⋡ ᢙ୯ ࠕ࡞ࡈࠔ̃ ᧄ೷ (5)ᧄ೷ߩᷫ㊂෶ߪਛᱛࠍᔅⷐߣߔࠆਛ╬ᐲ߆ࠄ ࡝ࡦ 2b(ㆮવሶ⚵ ㊀ᐲߩ೽૞↪(⥃ᐥᬌᩏ୯⇣Ᏹࠍ฽߻)߇ႎ๔ߐ ឵߃) 1,500/mm3 ࠇߡ޿ࠆߩߢޔ㊀ᐲߩ೽૞↪ࠍ⊒⃻ߔࠆน⢻ᕈ ⊕ⴊ⃿ᢙ ߩ㜞޿ᖚ⠪෶ߪᛩਈ㐿ᆎ೨ߩ⥃ᐥᬌᩏ୯߇਄⸥ ᧂḩߦᷫዋ ↪㊂ ↪㊂ 750/mm3 ᧂ ඨ㊂ߦ ߩၮḰߦㄭ޿ᖚ⠪ߢߪޔᛩਈ㐿ᆎ߆ࠄ 2 ㅳ㑆ߪ ᅢਛ⃿ᢙ ᄌᦝ ᄌᦝ ḩߦᷫዋ ᷫ㊂ ේೣ౉㒮ߐߖࠆߎߣ(ޟᘕ㊀ᛩਈޠߩ㗄ෳᾖ)ޕ 80,000/mm3 ߥߒ ߥߒ ⴊዊ᧼ᢙ (6)ᧄ೷ߣ࡝ࡃࡆ࡝ࡦߩ૬↪ᛩਈਛߪޔቯᦼ⊛ߦ ᧂḩߦᷫዋ 1,000/mm3 ⴊᶧቇ⊛ᬌᩏࠍታᣉߒޔᅢਛ⃿ᢙޔⴊዊ᧼ᢙޔ ⊕ⴊ⃿ᢙ ᧂḩߦᷫዋ ࡋࡕࠣࡠࡆࡦ㊂ߩᷫዋ߇⊒⃻ߒߚ႐วߦߪޔਅ 500/mm3 ᧂ ᛩਈ ᛩਈ ⴫ࠍෳ⠨ߦߒߡ↪㊂ࠍ⺞ᢛߔࠆߎߣ(ޟ㊀ⷐߥ ᅢਛ⃿ᢙ ᛩਈਛᱛ ḩߦᷫዋ ਛᱛ ਛᱛ ၮᧄ⊛ᵈᗧޠߩ㗄ෳᾖ)ޕߥ߅ޔᛩਈࠍౣ㐿ߔ 50,000/mm3 ⴊዊ᧼ᢙ ࠆ႐วߦߪޔ⥃ᐥᬌᩏ୯߇ਅ⴫ߩਛᱛၮḰࠍ਄ ᧂḩߦᷫዋ ࿁ߞߚߎߣࠍ⏕⹺ߔࠆߎߣޕ (9) ᛩਈ㐿ᆎ೨ߩࡋࡕࠣࡠࡆࡦỚᐲ߇ 14g/dL ᧂ ߹ߚޔⴊዊ᧼ᢙߩᷫዋߦࠃࠆᛩਈਛᱛᓟߩᧄ೷ ḩ㧘ᅢਛ⃿ᢙ߇ 2,000/mm3 ᧂḩ޽ࠆ޿ߪⴊዊ᧼ ߩౣ㐿ߪޔਅ⴫ࠍෳ⠨ߦߔࠆߎߣޕ ᢙ߇ 120,000/mm3 ᧂḩߩᖚ⠪㧘㜞㦂⠪෸߮ᅚᕈ

ߢߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b(ㆮવሶ ⚵឵߃)෸߮࡝ࡃࡆ࡝ࡦߩᷫ㊂ࠍⷐߔࠆ㗫ᐲ߇㜞 ߊߥࠆ௑ะ߇⹺߼ࠄࠇࠆߩߢ㧘ᛩਈ㐿ᆎ߆ࠄ 2 ㅳ㑆ߪේೣ౉㒮ߐߖࠆߎߣ㧚

6 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷ 5.ᧄ೷ᛩਈਛߪޔቯᦼ⊛ߦⴊᶧቇ⊛ᬌᩏࠍታᣉ 4㧚ᧄ೷ߩ૶↪ߦ޽ߚߞߡߪޔਅ⴫ߩ⥃ᐥᬌᩏ ༀ ߒޔᅢਛ⃿ᢙޔⴊዊ᧼ᢙޔࡋࡕࠣࡠࡆࡦ㊂ߩᷫ ୯ࠍ⏕⹺ߔࠆߎߣ߇ᦸ߹ߒ޿ޕ࿖ౝ⥃ᐥ⹜㛎ߦ ᛩ⮎㐿 ᖚ⠪ߩ ࡝ࡃࡆ࡝ࡦߩᛩਈ㊂ ዋ߇⊒⃻ߒߚ႐วߦߪޔਅ⴫ࠍෳ⠨ߦߒߡ↪㊂ ߅޿ߡޔ࡝ࡃࡆ࡝ࡦߣߒߡ૕㊀޽ߚࠅ 1 ᣣ ᆎ೨ߩ ૕㊀ 㧝ᣣᛩ ᦺ㘩ᓟ ᄕ㘩ᓟ ࠍ⺞ᢛߔࠆߎߣޕ 13mg/kg ࠍ⿥߃ࠆ㊂ࠍᛩਈߒߚ႐วޔ⽺ⴊߩ⊒ ࡋࡕࠣ ਈ㊂ ߥ߅ޔᛩਈࠍౣ㐿ߔࠆ႐วߦߪޔ⥃ᐥᬌᩏ୯߇ ⃻㗫ᐲߩჇട߇⹺߼ࠄࠇߚޕߥ߅ޔ㧯ဳᘟᕈ⢄ ࡠࡆࡦ ਅ⴫ߩਛᱛၮḰࠍ਄࿁ߞߚߎߣࠍ⏕⹺ߔࠆߎ Ἳߦኻߒᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ Ớᐲ ߣޕ߹ߚޔⴊዊ᧼ᢙߩᷫዋߦࠃࠆᛩਈਛᱛᓟߩ -2b(ㆮવሶ⚵឵߃)ߩ૬↪ߦઁߩ᛫ HCV ೷ࠍ૬ 14g/dL 60kg એ 600mg 200mg 400mg ᧄ೷ߩౣ㐿ߪޔਅ⴫ࠍෳ⠨ߦߔࠆߎߣޕ ↪ߔࠆ႐วߦߪޔ᛫ HCV ೷ߩޛ↪ᴺ࡮↪㊂ߦ એ਄ ਅ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ 㑐ㅪߔࠆ૶↪਄ߩᵈᗧޜࠍ⏕⹺ߔࠆߎߣޕ 60kg ࠍ 800mg 400mg 400mg ᬌᩏ㗄 ᢙ୯ ࡝ࡃࡆ࡝ࡦ ࡍࠣࠗࡦ࠲ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ⿥߃ ⋡ ࡯ࡈࠚࡠࡦ ᬌᩏ㗄⋡ ᛩਈ೨୯ 80kg એ ࠕ࡞ࡈࠔ ⊕ⴊ⃿ᢙ 4,000/mm3 એ਄ 2a(ㆮવሶ⚵ ਅ ⴊዊ᧼ᢙ 100,000/mm3 એ਄ ߺ឵߃) 80kg ࠍ 1,000mg 400mg 600mg ࡋࡕࠣࡠࡆࡦỚᐲ 12g/dL એ਄ ᅢਛ⃿ 750/ǴL ᧂ ᄌᦝߥߒ 90Ǵg ߦᷫ ⿥߃ࠆ C ᢙ ḩ ㊂ ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷ 14g/dL 60kg એ 400mg 200mg 200mg ༀ 500/ǴL ᧂ ਛᱛ ਛᱛ ᧂḩ ਅ ᬌᩏ㗄⋡ ᛩਈ೨୯ ḩ 60kg ࠍ 600mg 200mg 400mg ᅢਛ⃿ᢙ 1,500/mm3 એ਄ ⴊዊ᧼ 50,000/ǴL ਛᱛ ਛᱛ ⿥߃ 3 ᢙ ᧂḩ (50,000/Ǵ ⴊዊ᧼ᢙ 70,000/mm એ਄ 80kg એ L એ਄ߦ࿁ ࡋࡕࠣࡠࡆࡦỚᐲ 12g/dL એ਄ ਅ ᓳᓟ 90Ǵg 5.ᧄ೷ߣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ 80kg ࠍ 800mg 400mg 400mg ߢౣ㐿น) ⚵឵߃)ޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮ ⿥߃ࠆ 25,000/ǴL ਛᱛ(ౣ㐿ਇ ਛᱛ(ౣ㐿 વሶ⚵឵߃)෶ߪࠗࡦ࠲࡯ࡈࠚࡠࡦ ࡌ࡯࠲ߩ૬ 3㧚ᧄ೷ߩᛩਈᦼ㑆ߪޔ⥃ᐥലᨐ(HCV RNAޔ ↪ᛩਈਛߪޔቯᦼ⊛ߦⴊᶧቇ⊛ᬌᩏࠍታᣉߒޔ

ᧂḩ น) ਇน) ALT ╬)෸߮೽૞↪ߩ⒟ᐲࠍ⠨ᘦߒߥ߇ࠄᘕ㊀ ࡋࡕࠣ 10g/dL ᧂ ᷫ㊂ 600mg/ ᄌᦝߥߒ ᅢਛ⃿ᢙޔⴊዊ᧼ᢙޔࡋࡕࠣࡠࡆࡦỚᐲߩૐਅ ߦ᳿ቯߔࠆߎߣޕ․ߦᅢਛ⃿ᢙޔⴊዊ᧼ᢙޔࡋ ࡠࡆࡦ ḩ ᣣψ400mg/ᣣ ߇⹺߼ࠄࠇߚ႐วߦߪޔਅ⴫ࠍෳ⠨ߦߒߡ↪㊂ ࡕࠣࡠࡆࡦỚᐲߩផ⒖ߦᵈᗧߒޔᧄ೷෶ߪ࡝ࡃ ㊂(ᔃ∔ 800mg/ᣣψ ࠍᄌᦝߔࠆߎߣޕ(ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄 ࡆ࡝ࡦߩᷫ㊂޽ࠆ޿ߪਛᱛၮḰߦᓥ߁ߎߣޕ ᖚ෶ߪ 600mg/ᣣ ෳᾖ)ߥ߅ޔC ဳᘟᕈ⢄Ἳߦኻߒᧄ೷ߣࡍࠣࠗࡦ (1)C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀߩ 1,000mg/ ߘߩᣢ ᣣψ ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b(ㆮવሶ⚵឵߃)ߩ૬↪ ႐ว 600mg/ᣣ ᓔߥߒ) ߦઁߩ᛫ HCV ೷ࠍ૬↪ߔࠆ႐วߦߪޔ᛫ HCV 1)࠮ࡠࠣ࡞࡯ࡊ 1(ࠫࠚࡁ࠲ࠗࡊΣ(1a)෶ߪΤ 8.5g/dL ᧂ ਛᱛ ਛᱛ ೷ߩޛ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧޜࠍ (1b))ߢⴊਛ HCV RNA ㊂߇㜞୯ߩᖚ⠪ߦ߅ߌࠆ ḩ ⏕⹺ߔࠆߎߣޕ ㅢᏱߩᛩਈᦼ㑆ߪ 48 ㅳ㑆ߢ޽ࠆޕ⥃ᐥ⹜㛎ߩ ࡋࡕࠣ 10g/dL ᧂ ᷫ㊂ ᄌᦝߥߒ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ⚿ᨐࠃࠅޔᛩਈਛᱛ଀ߢߪ᦭ലᕈ߇ૐਅߔࠆߚ ࡠࡆࡦ ḩޔ෶ߪ 600mg/ᣣψ ࠗࡦ࠲࡯ࡈ ߼ޔᷫ㊂࡮ભ⮎ߥߤߩಣ⟎ߦࠃࠅน⢻ߥ㒢ࠅ ㊂(ᔃ∔ ᛩਈਛޔ 400mg/ᣣ ࠚࡠࡦ ࠕ࡞ 48 ㅳ㑆ᛩਈߔࠆߎߣ߇ᦸ߹ߒ޿ޕߥ߅ޔ24 ㅳ ᖚ෶ߪ ᛩਈ೨୯ 800mg/ᣣψ ࡈࠔ-2b(ㆮ 600mg/ᣣ 㑆એ਄ߩᛩਈߢലᨐ߇⹺߼ࠄࠇߥ޿႐วߦߪᛩ ߘߩᣢ ߦᲧߴ㧞 વሶ⚵឵ 1,000mg/ᣣψ ਈߩਛᱛࠍ⠨ᘦߔࠆߎߣޕ(ޣ⥃ᐥᚑ❣ޤߩ㗄 ᓔ޽ࠅ) g/dL એ਄ ߃)ޔࡍࠣࠗ 600mg/ᣣ ࡦ࠲࡯ࡈࠚ ෳᾖ) ߩᷫዋ߇ ᬌᩏ㗄⋡ ᢙ୯ ᧄ೷ ࡠࡦ ࠕ࡞ࡈ 2)ߘࠇએᄖߩᖚ⠪ߦ߅ߌࠆㅢᏱߩᛩਈᦼ㑆ߪ 㧠ㅳ㑆ᜬ ࠔ-2b(ㆮવ 24 ㅳ㑆ߢ޽ࠆޕ(ޣ⥃ᐥᚑ❣ޤߩ㗄ෳᾖ) ⛯ ሶ⚵឵߃)෶ (2)C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷ ↪ᴺ㨯 8.5g/dL ᧂ ਛᱛ ਛᱛ ߪࠗࡦ࠲࡯ ↪㊂ ༀߩ႐วޔㅢᏱߩᛩਈᦼ㑆ߪ 48 ㅳ㑆ߢ޽ࠆޕ ḩޔ෶ߪ ࡈࠚࡠࡦ ࡌ ߥ߅ޔ24 ㅳ㑆એ਄ߩᛩਈߢലᨐ߇⹺߼ࠄࠇߥ޿ ᷫ㊂ᓟޔ ࡯࠲ ႐วߦߪᛩਈߩਛᱛࠍ⠨ᘦߔࠆߎߣޕ(ޣ⥃ᐥ 㧠ㅳ㑆⚻ 1,500/mm3 ඨ㊂ߦᷫ ᄌᦝߥߒ ᚑ❣ޤߩ㗄ෳᾖ) ㆊߒߡ߽ ᧂḩ ㊂ ⊕ⴊ⃿ᢙ 4 㧚ᧄ೷ߣ࡝ࡃࡆ࡝ࡦߩ૬↪ᛩਈߦ޽ߚߞߡ 12g/dL ᧂ 1,000/mm3 ਛᱛ ߪޔਅ⴫ߩ⥃ᐥᬌᩏ୯ࠍ⏕⹺ߔࠆߎߣ߇ᦸ߹ߒ ḩ ᧂḩ ޿ޕ 750/mm3 ඨ㊂ߦᷫ

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ᄌᦝߥߒ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ᧂḩ ㊂ ᅢਛ⃿ᢙ ᬌᩏ㗄⋡ ᛩਈ೨୯ 500/mm3 3 ਛᱛ ⊕ⴊ⃿ᢙ 4,000/mm એ਄ ᧂḩ 3 3 ᅢਛ⃿ᢙ 1,500/mm એ਄ 80,000/mm 3 ⴊዊ᧼ᢙ 100,000/mm એ਄ ᧂḩ(ࠗࡦ ࠲࡯ࡈࠚ ࡋࡕࠣࡠࡆࡦỚᐲ 12g/dL એ਄ ඨ㊂ߦᷫ ࡠࡦ ࡌ࡯ ᄌᦝߥߒ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷ ㊂ ༀ ࠲ߪ 3 ᬌᩏ㗄⋡ ᛩਈ೨୯ 50,000/mm ᧂḩ) ᅢਛ⃿ᢙ 1,500/mm3 એ਄ ⴊዊ᧼ᢙ 50,000/mm3 ⴊዊ᧼ᢙ 70,000/mm3 એ਄ ᧂḩ(ࠗࡦ

ࡋࡕࠣࡠࡆࡦỚᐲ 12g/dL એ਄ ࠲࡯ࡈࠚ 5㧚ᛩਈ㐿ᆎ೨ߩࡋࡕࠣࡠࡆࡦỚᐲ߇ 14g/dL ᧂ ࡠࡦ ࡌ࡯ ਛᱛ ḩޔᅢਛ⃿ᢙ 2,000/mm3 ᧂḩ޽ࠆ޿ߪⴊዊ᧼ᢙ ࠲ߪ 3 3 120,000/mm ᧂḩߩᖚ⠪ޔ㜞㦂⠪෸߮ᅚᕈߢߪ 25,000mm ᷫ㊂ࠍⷐߔࠆ㗫ᐲ߇㜞ߊߥࠆ௑ะ߇⹺߼ࠄࠇߡ ᧂḩ) ޿ࠆߩߢޔᛩਈ㐿ᆎ߆ࠄ 2 ㅳ㑆ߪේೣ౉㒮ߐߖ ᷫ㊂ 600mg/ ࠆߎߣޕ(ޟᘕ㊀ᛩਈޠߩ㗄ෳᾖ) ࡋࡕࠣࡠ ᣣψ400mg/ᣣ ࡆࡦỚᐲ 10g/dL 6㧚ᧄ೷ߣ࡝ࡃࡆ࡝ࡦߩ૬↪ᛩਈਛߪޔቯᦼ⊛ 800mg/ᣣψ ᄌᦝߥߒ ߦⴊᶧቇ⊛ᬌᩏࠍታᣉߒޔ⊕ⴊ⃿ᢙޔᅢਛ⃿ (ᔃ∔ᖚ ᧂḩ 600mg/ᣣ ᢙޔⴊዊ᧼ᢙ෶ߪࡋࡕࠣࡠࡆࡦỚᐲߩૐਅ߇⹺ ෶ߪߘߩ 1,000mg/ᣣψ 600mg/ᣣ ߼ࠄࠇߚ႐วߦߪޔਅ⴫ࠍෳ⠨ߦᧄ೷෶ߪ࡝ࡃ ᣢᓔߥ 8.5g/dL ( ߒ) ਛᱛ ࡆ࡝ࡦߩ↪㊂ࠍᄌᦝߔࠆߎߣޕ ޟ㊀ⷐߥၮᧄ ᧂḩ ⊛ᵈᗧޠߩ㗄ෳᾖ) 





    







7 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ᬌᩏ㗄 ᢙ୯ ࡝ࡃࡆ࡝ࡦ ࡍࠣࠗࡦ࠲࡯ ⋡ ࡈࠚࡠࡦ ࠕ࡞ ࡈࠔ-2a(ㆮવ ሶ⚵឵߃) ᅢਛ⃿ 750/ǴL ᧂḩ ᄌᦝߥߒ 90Ǵg ߦᷫ㊂ ᢙ 500/ǴL ᧂḩ ਛᱛ ਛᱛ ⴊዊ᧼ 50,000/ǴL ᧂ ਛᱛ ਛᱛ(50,000/ ᢙ ḩ ǴL એ਄ߦ࿁ ᓳᓟ 90Ǵg ߢ ౣ㐿น) 25,000/ǴL ᧂ ਛᱛ(ౣ㐿ਇน) ਛᱛ(ౣ㐿ਇ ḩ น) ࡋࡕࠣ 10g/dL ᧂḩ ᷫ㊂ ᄌᦝߥߒ ࡠࡆࡦ 600mg/ᣣψ ㊂(ᔃ∔ 400mg/ᣣ ᖚ෶ߪ 800mg/ᣣψ ߘߩᣢ 600mg/ᣣ ᓔߥߒ) 1,000mg/ᣣψ 600mg/ᣣ 8.5g/dL ᧂḩ ਛᱛ ਛᱛ ࡋࡕࠣ 10g/dL ᧂḩޔ ᷫ㊂ ᄌᦝߥߒ ࡠࡆࡦ ෶ߪᛩਈਛޔ 600mg/ᣣψ ㊂(ᔃ∔ ᛩਈ೨୯ߦᲧ 400mg/ᣣ ᖚ෶ߪ ߴ 2g/dL એ਄ 800mg/ᣣψ ߘߩᣢ ߩᷫዋ߇ 4 ㅳ 600mg/ᣣ ᓔ޽ࠅ) 㑆ᜬ⛯ 1, 000mg/ᣣψ 600mg/ᣣ

8.5g/dL ᧂḩޔ ਛᱛ ਛᱛ ෶ߪᷫ㊂ᓟޔ 4 ㅳ㑆⚻ㆊߒ ߡ߽ 12g/dL ᧂ ḩ

C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ᬌᩏ㗄 ᢙ୯ ࡝ࡃࡆ࡝ࡦ ࡍࠣࠗࡦ࠲࡯ ⋡ ࡈࠚࡠࡦ ࠕ࡞ ࡈࠔ-2a(ㆮવ ሶ⚵឵߃) ᅢਛ⃿ 1,000/ǴL ᧂ ᄌᦝߥߒ 45Ǵg ߦᷫ㊂ ᢙ ḩ 750/ǴL ᧂḩ ᄌᦝߥߒ 22.5Ǵg ߦᷫ ㊂ 500/ǴL ᧂḩ ਛᱛ ਛᱛ ⴊዊ᧼ 50,000/ǴL ਛᱛ ਛᱛ(50,000/ ᢙ ᧂḩ ǴL એ਄ߦ ࿁ᓳᓟ 45Ǵg ߢౣ㐿น) ↪ᴺ㨯 35, 000/ǴL ਛᱛ ਛᱛ(50,000/ ↪㊂ ᧂḩ ǴL એ਄ߦ ࿁ᓳᓟ 22.5 Ǵg ߢౣ㐿 น) 25, 000/ǴL ਛᱛ(ౣ㐿ਇ ਛᱛ ᧂḩ น) (ౣ㐿ਇน) ࡋࡕࠣ ᛩਈ㐿ᆎ 1㨪 ᷫ㊂ ᄌᦝߥߒ

ࡠࡆࡦ 4 ㅳᤨ 600mg/ᣣψ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ㊂(ᔃ∔ 11g/dL ᧂḩ 200mg/ᣣ ᖚ෶ߪ 800mg/ᣣψ ߘߩᣢ 400mg/ᣣ ᓔߥߒ) 1, 000mg/ᣣψ 400mg/ᣣ ᛩਈ㐿ᆎ 5㨪 ᷫ㊂ ᄌᦝߥߒ 48 ㅳᤨ 600mg/ᣣψ 10g/dL ᧂḩ 200mg/ᣣ 800mg/ᣣψ 400mg/ᣣ 1,000mg/ᣣψ 400mg/ᣣ 8.5g/dL ᧂḩ ਛᱛ ਛᱛ ࡋࡕࠣ ᛩਈ㐿ᆎ 1㨪 ᷫ㊂ ᄌᦝߥߒ ࡠࡆࡦ 4 ㅳᤨ 600mg/ᣣψ ㊂(ᔃ∔ 11g/dL ᧂ 200mg/ᣣ ᖚ෶ߪ ḩޔ෶ߪᛩ 800mg/ᣣψ ߘߩᣢ ਈਛޔᛩਈ 400mg/ᣣ ᓔ޽ࠅ) ೨୯ߦᲧߴ 1,000mg/ᣣψ 2g/dL એ਄ߩ 400mg/ᣣ ᷫዋ߇ 4 ㅳ 㑆ᜬ⛯ ᛩਈ㐿ᆎ 5㨪 ᷫ㊂ ᄌᦝߥߒ 48 ㅳᤨ 600mg/ᣣψ 10g/dL ᧂ 200mg/ᣣ ḩޔ෶ߪᛩ 800mg/ᣣψ ਈਛޔᛩਈ 400mg/ᣣ ೨୯ߦᲧߴ 1,000mg/ᣣψ 2g/dL એ਄ߩ 400mg/ᣣ ᷫዋ߇ 4 ㅳ 㑆ᜬ⛯ 8.5g/dL ᧂ ਛᱛ ਛᱛ ḩޔ෶ߪᷫ ㊂ᓟޔ4 ㅳ㑆 ⚻ㆊߒߡ߽ 12g/dL ᧂḩ

8 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷ ᬌᩏ㗄⋡ ᢙ୯ ᧄ೷ ࠗࡦ࠲࡯ࡈ ᬌᩏ㗄⋡ ᢙ୯ ࡝ࡃࡆ࡝ࡦ ᧄ೷ ༀ ࠚࡠࡦ ࠕ࡞ ⊕ⴊ⃿ᢙ 1,500/mm3 ᄌᦝߥߒ ඨ㊂ߦᷫ ᬌᩏ㗄 ᢙ୯ ࡝ࡃࡆ࡝ࡦ ࡍࠣࠗࡦ࠲ ࡈࠔ-2b( ㆮ ᧂḩ ㊂ ⋡ ࡯ࡈࠚࡠࡦ વሶ⚵឵ ߃)ޔࡍࠣࠗ 1,000/mm3 ਛᱛ ࠕ࡞ࡈࠔ ᧂḩ 2a(ㆮવሶ⚵ ࡦ࠲࡯ࡈࠚ 3 ࡠࡦ ࠕ࡞ࡈ ᅢਛ⃿ᢙ 750/mm ᄌᦝߥߒ ඨ㊂ߦᷫ ߺ឵߃) ᧂḩ ᅢਛ⃿ 1,000/ǴL ᄌᦝߥߒ 45Ǵg ߦᷫ ࠔ -2b( ㆮવ ㊂ ሶ⚵឵߃)෶ 3 ᢙ ᧂḩ ㊂ 500/mm ਛᱛ ߪࠗࡦ࠲࡯ ᧂḩ 750/ǴL ᧂ ᄌᦝߥߒ 22.5Ǵg ߦ ࡈࠚࡠࡦ ࡌ 80,000/mm3 ⴊዊ᧼ᢙ ᄌᦝߥߒ ඨ㊂ߦᷫ ḩ ᷫ㊂ ࡯࠲ ᧂḩ ㊂ 500/ǴL ᧂ ਛᱛ ਛᱛ 10g/dL ᧂ 3 50,000/mm ਛᱛ ḩ ḩޔ෶ߪ ᧂḩ ⴊዊ᧼ 50,000/ǴL ਛᱛ ਛᱛ ᷫ㊂ 600mg/ ᛩਈਛޔ ᣣψ400mg/ᣣ ࡋࡕࠣࡠ 10g/dL ᧂḩ ᷫ㊂ 600mg/ ᄌᦝߥߒ (50,000/ ᢙ ᧂḩ Ǵ ᛩਈ೨୯ 800mg/ᣣψ ࡆࡦỚᐲ ᣣψ400mg/ ᄌᦝߥߒ L એ਄ߦ࿁ 600mg/ᣣ ᣣ 800mg/ᣣ ߦᲧߴ (ᔃ∔ᖚ ᓳᓟ 45Ǵg ࡋࡕࠣࡠ 1,000mg/ᣣψ ψ600mg/ᣣ 2g/dL એ਄ ෶ߪߘߩ ߢౣ㐿น) ࡆࡦỚᐲ 600mg/ᣣ 1,000mg/ ߩᷫዋ߇ 4 ᣢᓔߥ ᣣ (ᔃ∔ᖚ ψ600mg/ᣣ 35,000/ǴL ਛᱛ ਛᱛ ㅳ㑆ᜬ⛯ ߒ) ෶ߪߘߩ 8.5g/dL ᧂḩ ਛᱛ ᧂḩ (50,000/Ǵ 8.5g/dL ᧂ L એ਄ߦ࿁ ᣢᓔ޽ ࡋࡕࠣࡠ 10g/dL ᧂ ᷫ㊂ ᄌᦝߥߒ ḩޔ෶ߪ ᓳᓟ 22.5 ࠅ) ࡆࡦỚᐲ ḩޔ෶ߪᛩ 600mg/ᣣψ ᷫ㊂ᓟޔ4 Ǵg ߢౣ㐿 (ᔃ∔ᖚ ਈਛޔᛩਈ 400mg/ᣣ ㅳ㑆⚻ㆊ ਛᱛ น) ෶ߪߘߩ ೨୯ߦᲧߴ 800mg/ᣣψ ߒߡ߽

2g/dL એ਄ߩ 600mg/ᣣ 25,000/ǴL ਛᱛ㧔ౣ㐿ਇ ਛᱛ(ౣ㐿 ᣢᓔ޽ࠅ 12g/dL ᧂ ᷫዋ߇ 4 ㅳ 1,000mg/ᣣ ᧂḩ น) ਇน) ḩ 㑆ᜬ⛯ ψ600mg/ᣣ ࡋࡕࠣ ᛩਈ㐿ᆎ㧝 ᷫ㊂ ᄌᦝߥߒ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ 8.5g/dL ᧂ ਛᱛ ࡠࡆࡦ 㨪4 ㅳᤨ 600mg/ᣣψ ᬌᩏ㗄⋡ ᢙ୯ ᧄ೷ ࡍࠣࠗࡦ ḩޔ෶ߪᷫ 200mg/ᣣ ㊂(ᔃ∔ 11g/dL ᧂḩ ࠲࡯ࡈࠚ ㊂ᓟޔ4 ㅳ㑆 800mg/ᣣψ ᖚ෶ߪ ࡠࡦ ࠕ࡞ ⚻ㆊߒߡ߽ 400mg/ᣣ ߘߩᣢ 12g/dL ᧂḩ 1,000mg/ᣣψ ࡈࠔ-2b(ㆮ ᓔߥߒ) C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ 400mg/ᣣ વሶ⚵ߺ ᬌᩏ㗄⋡ ᢙ୯ ࡝ࡃࡆ࡝ࡦ ᧄ೷ ᛩਈ㐿ᆎ 5 ᷫ㊂ ᄌᦝߥߒ ឵߃) 3 ᅢਛ⃿ᢙ 750/mm3 ᄌᦝߥߒ ඨ㊂ߦᷫ 㨪48 ㅳᤨ 600mg/ᣣψ ᅢਛ⃿ᢙ 750/mm ᄌᦝߥߒ ඨ㊂ߦᷫ ᧂḩ ㊂ 10g/dL ᧂḩ 200mg/ᣣ ᧂḩ ㊂ 3 3 800mg/ᣣψ 500/mm ਛᱛ 500/mm ਛᱛ ᧂḩ 400mg/ᣣ ᧂḩ 3 1,000mg/ᣣψ ⴊዊ᧼ᢙ 50,000/mm ᄌᦝߥߒ ඨ㊂ߦᷫ ⴊዊ᧼ᢙ 50,000/m ᄌᦝߥߒ ඨ㊂ߦᷫ 400mg/ᣣ 3 ᧂḩ ㊂ m ᧂḩ ㊂ 3 8.5g/dL ᧂ ਛᱛ ਛᱛ 35,000/mm ਛᱛ 35,000/m ਛᱛ ᧂḩ ḩ m3 ᧂḩ ᷫ㊂ ࡋࡕࠣࡠ 10g/dL ᧂḩ ᷫ㊂ 600mg/ ᄌᦝߥߒ ࡋࡕࠣ ᛩਈ㐿ᆎ 1 ᄌᦝߥߒ ࡋࡕࠣࡠ ᷫ㊂ ᄌᦝߥߒ ↪ᴺ㨯 600mg/ᣣψ ࡆࡦỚᐲ ᣣψ400mg/ ࡠࡆࡦ 㨪4 ㅳᤨ ࡆࡦỚᐲ 600mg/ᣣψ ↪㊂ 200mg/ᣣ ᵈ)(ᛩਈ㐿 ᣣ 800mg/ᣣ ㊂(ᔃ∔ 11g/dL ᧂ ᵈ)(ᛩਈ 10g/dL 400mg/ᣣ ψ600mg/ᣣ ᖚ෶ߪ ḩޔ෶ߪᛩ 800mg/ᣣψ 800mg/ᣣψ ᆎ೨ߩ Hb 400mg/ 㐿ᆎ೨ߩ ᧂḩ 1,000mg/ᣣψ ߘߩᣢ ਈਛޔᛩਈ ᣣ 600mg/ᣣ Ớᐲ߇ 1,000mg/ᣣψ Hb Ớᐲ 1,000mg/ᣣψ 600mg/ᣣ ᓔ޽ࠅ) ೨୯ߦᲧߴ 14g/dL એ 400mg/ ߇ 600mg/ᣣ 8.5g/dL ਛᱛ ᣣ 2g/dL એ਄ 14g/dL ਄) ᧂḩ 8.5g/dL ਛᱛ ߩᷫዋ߇㧠 એ਄) 10g/dL ᷫ㊂ 400mg/ ᧂḩ ࡋࡕࠣࡠ ᄌᦝߥߒ ㅳ㑆ᜬ⛯ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ࡆࡦỚᐲ ᧂḩ ᣣψ200mg/ ࡋࡕࠣࡠ ᷫ㊂ ᄌᦝߥߒ ᛩਈ㐿ᆎ 5 ᷫ㊂ ᄌᦝߥߒ ᵈ) ᣣ 600mg/ᣣ ࡆࡦỚᐲ 400mg/ᣣψ (ᛩਈ㐿 600mg/ᣣψ ψ400mg/ᣣ 㨪48 ㅳᤨ ᵈ)(ᛩਈ 10g/dL 200mg/ᣣ ᆎ೨ߩ Hb 200mg/ᣣ 600mg/ᣣψ 800mg/ᣣψ 10g/dL ᧂ 㐿ᆎ೨ߩ ᧂḩ Ớᐲ߇ 800mg/ᣣψ 400mg/ᣣ 400mg/ᣣ ḩޔ෶ߪᛩ Hb 14g/dL ᧂ 400mg/ᣣ Ớᐲ 800mg/ᣣψ 8.5g/dL ਛᱛ ਈਛޔᛩਈ ḩ) 1,000mg/ᣣψ ߇ 400mg/ᣣ ᧂḩ ೨୯ߦᲧߴ 400mg/ᣣ 14g/dL 8.5g/dL ਛᱛ ᵈ)ᔃ∔ᖚ෶ߪߘߩᣢᓔ߇޽ࠆᖚ⠪ߦᛩਈߔࠆ 㧞g/dL એ਄ ᧂḩ) ᧂḩ ႐วߦߪޔHb Ớᐲ߇ 10g/dL એ਄ߢ޽ߞߡ߽ᛩ ߩᷫዋ߇㧠 ᵈ)ᔃ∔ᖚ෶ߪߘߩᣢᓔ߇޽ࠆᖚ⠪ߦᛩਈߔࠆ ਈ೨ߦᲧߴ 2 g/dL એ਄ߩᷫዋ߇ 4 ㅳ㑆ᜬ⛯ߔࠆ ㅳ㑆ᜬ⛯ ႐วߦߪޔHb Ớᐲ߇ 10g/dL એ਄ߢ޽ߞߡ߽ᛩ ႐วߪ࡝ࡃࡆ࡝ࡦߩᷫ㊂ࠍޔHb Ớᐲ߇ 8.5g/dL 8.5g/dL ᧂ ਛᱛ ਛᱛ ਈ೨ߦᲧߴ 2g/dL એ਄ߩᷫዋ߇ 4 ㅳ㑆ᜬ⛯ߔࠆ એ਄ߢ޽ߞߡ߽ᷫ㊂ᓟ 4 ㅳ㑆⚻ㆊߒߡ߽ 12g/dL ḩޔ෶ߪᷫ ႐วߪᧄ೷ߩᷫ㊂ࠍޔHb Ớᐲ߇ 8.5g/dL એ਄ߢ ᧂḩߩ႐วߦߪᛩਈਛᱛࠍ⠨ᘦߔࠆߎߣޕ ㊂ᓟޔ㧠ㅳ ޽ߞߡ߽ᷫ㊂ᓟ 4 ㅳ㑆⚻ㆊߒߡ߽ 12g/dL ᧂḩ (ޟᘕ㊀ᛩਈޠߩ㗄ෳᾖ) 㑆⚻ㆊߒߡ ߩ႐วߦߪᛩਈਛᱛࠍ⠨ᘦߔࠆߎߣޕ(ޟᘕ㊀

߽ 12g/dL ᛩਈޠߩ㗄ෳᾖ)

ᧂḩ

9 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

ޣ⼊๔ޤ ޣ⼊๔ޤ ޣ⼊๔ޤ ᧄ೷ߪޔ࠙ࠗ࡞ࠬᕈ⢄∔ᖚߩᴦ≮ߦචಽߥ⍮ 㧔1㧕ᧄ೷ߪ㧘࠙ࠗ࡞ࠬᕈ⢄∔ᖚߩᴦ≮ߦචಽߥ ᧄ೷ߩᛩਈߦࠃࠅ㑆⾰ᕈ⢖Ἳޔ⥄Ვડ࿑߇޽ࠄ ⼂࡮⚻㛎ࠍᜬߟකᏧߩ߽ߣߢޔᧄ೷ߩᛩਈ߇ ⍮⼂࡮⚻㛎ࠍᜬߟකᏧߩ߽ߣߢ㧘ᧄ೷ߩᛩਈ߇ ࠊࠇࠆߎߣ߇޽ࠆߩߢޔޟ૶↪਄ߩᵈᗧޠߦච ㆡಾߣ್ᢿߐࠇࠆᖚ⠪ߦኻߒߡߩߺᛩਈߔࠆ ㆡಾߣ್ᢿߐࠇࠆᖚ⠪ߦኻߒߡߩߺᛩਈߔࠆߎ ಽ⇐ᗧߒޔᖚ⠪ߦኻߒ೽૞↪⊒⃻ߩน⢻ᕈߦߟ ߎߣޕ ߣ㧚 ޿ߡචಽ⺑᣿ߔࠆߎߣޕ

㧔2㧕ᧄ೷ߪ㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃ 2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣߩ૬↪ᛩ ਈߦࠃࠅ㧘ਛᲥᕈ⴫⊹უᱫⲢ⸃∝㧔Toxic Epidermal Necrolysis: TEN㧕㧘⊹⤏☼⤑⌒∝୥⟲

㧔Stevens̃Johnson ∝୥⟲㧕㧘⮎೷ᕈㆊᢅ∝∝୥

⟲㧔Drug̃induced hypersensitivity syndrome: DIHS㧕╬ߩోり∝⁁ࠍ઻߁㊀◊ߥ⊹⤏㓚ኂ߇⊒ ⃻ߔࠆ߅ߘࠇ߇޽ࠆߎߣ߆ࠄᰴߩ੐㗄ߦᵈᗧߔ ࠆߎߣ㧚ߥ߅㧘ᧄ೷ߪ⊹⤏⑼කߣㅪ៤ߒߡ૶↪ ߔࠆߎߣ㧚㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠ㧘ޟ㊀ᄢߥ ೽૞↪ޠߩ㗄ෳᾖ㧕

1㧕㊀◊ߥ⊹⤏㓚ኂߪᧄ೷ᛩਈᦼ㑆ਛߦ⊒⃻ߔࠆ

႐ว߇ᄙ޿ߩߢ㧘ᒰ⹥ᦼ㑆ਛߪ․ߦⷰኤࠍචಽ ߦⴕ߁ߎߣ㧚 2㧕㊀◊ߥ⊹⤏㓚ኂ㧘෶ߪએਅߩ∝⁁ࠍ઻߁⊒∐ ߇⊒⃻ߒߚ႐วߦߪ㧘ᛩਈࠍਛᱛߔࠆߥߤㆡಾ ߥಣ⟎ࠍⴕ߁ߎߣ㧚 ⊒ᾲ㧘᳓∊㧘⴫⊹೸㔌㧘☼⤑ߩ߮ࠄࠎ࡮ẩ≌㧘 ⚿⤑Ἳ╬ߩ⌒∛ᄌ㧘㗻㕙߿྾⢇╬ߩ⣲⣘㧘࡝ࡦ

ࡄ▵⣲⣘㧘෶ߪోりୱᕃᗵ

3㧕ᛩਈਛᱛᓟ߽∝⁁߇Ⴧᖡ෶ߪㆫᑧߔࠆ߅ߘࠇ ߇޽ࠆߩߢᖚ⠪ߩ⁁ᘒࠍචಽⷰኤߔࠆߎߣ㧚

ޣ⑌ᔊ㧔ᰴߩᖚ⠪ߦߪᛩਈߒߥ޿ߎߣ㧕ޤ ޣ⑌ᔊޤ㧔ᰴߩᖚ⠪ߦߪᛩਈߒߥ޿ߎߣ㧕 ޣ⑌ᔊ㧔ᰴߩᖚ⠪ߦߪᛩਈߒߥ޿ߎߣ㧕ޤ 1㧕ᧄ೷ߩᚑಽߦኻߒߡㆊᢅ∝ߩᣢᓔᱧߩ޽ࠆᖚ 㧔1㧕ᧄ೷ߩᚑಽߦኻߒㆊᢅ∝ߩᣢᓔᱧߩ޽ࠆᖚ 1.ዊᩊ⢫ḡࠍᛩਈਛߩᖚ⠪㧔ޟ⋧੕૞↪ޠߩ㗄 ⠪ ⠪ ෳᾖ㧕 2㧕ࠛࡈࠔࡆ࡟ࡦ࠷ޔ࡝ࡈࠔࡦࡇࠪࡦޔ࡝ࡈࠔࡉ 㧔2㧕ᧄ೷ߩ᦯↪ߦࠃࠅ㊀◊ߥ⊹⤏㓚ኂ߇⊒⃻ߒ 2.㑆⾰ᕈ⢖Ἳߩᣢᓔᱧߩ޽ࠆᖚ⠪㨇㑆⾰ᕈ⢖Ἳ ࠴ࡦࠍᛩਈਛߩᖚ⠪㨇ޟ⋧੕૞↪ޠߩ㗄ෳᾖ㨉 ߚߎߣߩ޽ࠆᖚ⠪ ߇Ⴧᖡ෶ߪౣ⊒ߔࠆߎߣ߇޽ࠆ㧔ޟ㊀ᄢߥ೽૞

㧔3㧕ࠦࡦ࠻ࡠ࡯࡞ߩ࿎㔍ߥᔃ∔ᖚ㧔ᔃ╭᪪Ⴇ㧘 ↪ޠߩ㗄ෳᾖ㧕ޕ㨉 ᔃਇో㧘ਇᢛ⣂╬㧕ߩ޽ࠆᖚ⠪ާ⽺ⴊ߇ේ࿃ߢ 3.⥄Ꮖ఺∉ᕈ⢄Ἳߩᖚ⠪㨇⢄Ἳ߇㊀∝ൻߔࠆߎ ᔃ∔ᖚ߇ᖡൻߔࠆߎߣ߇޽ࠆ㧚ި ߣ߇޽ࠆޕ㨉 㧔4㧕⇣Ᏹࡋࡕࠣࡠࡆࡦ∝㧔ࠨ࡜࠮ࡒࠕ㧘㎨⁁⿒ 4.ᧄ೷ߩᚑಽ෶ߪઁߩࠗࡦ࠲࡯ࡈࠚࡠࡦ⵾೷ߦ ⴊ⃿ᕈ⽺ⴊ╬㧕ߩᖚ⠪ާ⽺ⴊ߇ේ࿃ߢ⇣Ᏹࡋࡕ ኻߒㆊᢅ∝ߩᣢᓔᱧߩ޽ࠆᖚ⠪ ࠣࡠࡆࡦ∝߇ᖡൻߔࠆߎߣ߇޽ࠆ㧚ި 5.ૐ಴↢૕㊀ఽޔᣂ↢ఽޔ੃ఽޔ3 ᱦᧂḩߩᐜ 㧔5㧕ਅ⸥ߩ⮎೷ࠍ૶↪ਛߩᖚ⠪㧔ޟ⋧੕૞↪ޠ ఽ㧔ޟዊఽ╬߳ߩᛩਈޠߩ㗄ෳᾖ㧕 ߩ㗄ෳᾖ㧕 6.ࡢࠢ࠴ࡦ╬↢‛ቇ⊛⵾೷ߦኻߒㆊᢅ∝ߩᣢᓔ ૶↪਄ 1㧕᛫ਇᢛ⣂⮎ߩ߁ߜᰴߩ⮎೷ ᱧߩ޽ࠆᖚ⠪

ߩᵈᗧ ࠠ࠾ࠫࡦ⎫㉄Ⴎ᳓๺‛㧘ࡌࡊ࡝ࠫ࡞Ⴎ㉄Ⴎ᳓๺ ‛㧘ࡈ࡟ࠞࠗ࠾࠼㈶㉄Ⴎ㧘ࡊࡠࡄࡈࠚࡁࡦႮ㉄ Ⴎ㧘ࠕࡒࠝ࠳ࡠࡦႮ㉄Ⴎ 2㧕㤈ⷺࠕ࡞ࠞࡠࠗ࠼ ࠛ࡞ࠧ࠲ࡒࡦ㈬⍹㉄Ⴎ㧘ࠫࡅ࠼ࡠࠛ࡞ࠧ࠲ࡒࡦ ࡔࠪ࡞㉄Ⴎ㧘ࠛ࡞ࠧࡔ࠻࡝ࡦࡑ࡟ࠗࡦ㉄Ⴎ㧘ࡔ ࠴࡞ࠛ࡞ࠧࡔ࠻࡝ࡦࡑ࡟ࠗࡦ㉄Ⴎ

3㧕HMG̃CoA ㆶర㉂⚛㒖ኂ೷ߩ߁ߜᰴߩ⮎೷ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ࡠࡃࠬ࠲࠴ࡦ㧔࿖ౝᧂᛚ⹺㧕㧘ࠪࡦࡃࠬ࠲࠴ ࡦ㧘ࠕ࠻࡞ࡃࠬ࠲࠴ࡦࠞ࡞ࠪ࠙ࡓ᳓๺‛ 4㧕PDE5 㒖ኂ೷ߩ߁ߜᰴߩ⮎೷ ࡃ࡞࠺࠽ࡈࠖ࡞Ⴎ㉄Ⴎ᳓๺‛㧘ࠪ࡞࠺࠽ࡈࠖ࡞ ࠢࠛࡦ㉄Ⴎ㧔⢖㜞ⴊ࿶∝ࠍㆡᔕߣߔࠆ႐ว㧕㧘 ࠲࠳࡜ࡈࠖ࡞㧔⢖㜞ⴊ࿶∝ࠍㆡᔕߣߔࠆ႐ว㧕 5㧕ߘߩઁ ࡇࡕࠫ࠼㧘࠻࡝ࠕ࠱࡜ࡓ㧘ࠕ࡞ࡈ࠱ࠪࡦ㧔࿖ౝ ᧂᛚ⹺㧕㧘ࡉࡠ࠽ࡦ࠮࡝ࡦ㧘ࠦ࡞ࡅ࠴ࡦ㧔⢄⤳ ෶ߪ⣢⤳ߦ㓚ኂߩ޽ࠆᖚ⠪ߦ૶↪ߔࠆ႐ว㧕㧘 ࡝ࡈࠔࡦࡇࠪࡦ

1㧚ᘕ㊀ᛩਈ㧔ᰴߩᖚ⠪ߦߪᘕ㊀ߦᛩਈߔࠆߎ 1㧚ᘕ㊀ᛩਈ㧔ᰴߩᖚ⠪ߦߪᘕ㊀ߦᛩਈߔࠆߎ 1.ᘕ㊀ᛩਈ㧔ᰴߩᖚ⠪ߦߪᘕ㊀ߦᛩਈߔࠆߎߣ㧕 ߣ㧕 ߣ㧕 㧔1㧕ࠕ࡟࡞ࠡ࡯⚛࿃ߩ޽ࠆᖚ⠪ 1㧕ⴊਛ✚ࡆ࡝࡞ࡆࡦ߇㜞୯ߩᖚ⠪㨇ⴊਛ✚ࡆ࡝ 㧔1㧕ᧄ೷ߩ᦯↪ߦࠃࠅ⊹⤏㓚ኂ߇⊒⃻ߒߚߎߣ 㧔2㧕ᔃ∔ᖚߩ޽ࠆᖚ⠪෶ߪߘߩᣢᓔᱧߩ޽ࠆᖚ ࡞ࡆࡦ୯߇㜞޿ᖚ⠪ߦ߅ߌࠆ૶↪⚻㛎߇ߥ޿ޕ ߩ޽ࠆᖚ⠪ ⠪㨇ᔃᯏ⢻߇Ⴧᖡߔࠆߎߣ߇޽ࠆޕ㨉 ߹ߚޔᧄ೷ᛩਈᤨߦⴊਛࡆ࡝࡞ࡆࡦ୯ߩ਄᣹߇ 㧔2㧕ࠗࡦ࠲࡯ࡈࠚࡠࡦ⵾೷߿࡝ࡃࡆ࡝ࡦߩ૶↪ 㧔3㧕㊀ᐲߩ⢄ᯏ⢻㓚ኂߩ޽ࠆᖚ⠪㨇ࠃࠅ㊀◊ߥ ႎ๔ߐࠇߡ޿ࠆ㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄ෳ ߦࠃࠅ㧘㜞ᐲߩ೽૞↪㧔⊒∐╬㧕߇⊒⃻ߒߚߎߣ 㓚ኂߦ⥋ࠆߎߣ߇޽ࠆޕ㨉 ᾖ㧕ޕ㨉 ߩ޽ࠆᖚ⠪ާᧄ೷ࠍ૬↪ᛩਈߔࠆߎߣߦࠃࠅ೽૞ 㧔4㧕㊀ᐲߩ⣢ᯏ⢻㓚ኂߩ޽ࠆᖚ⠪㨇ࠃࠅ㊀◊ߥ 2㧕ਛ╬ᐲએ਄ߩ⢄ᯏ⢻㓚ኂᖚ⠪㨇Cmax ෸߮ ↪߇Ⴧᒝߔࠆน⢻ᕈ߇޽ࠆ㧚ި 㓚ኂߦ⥋ࠆߎߣ߇޽ࠆ㧔ޣ⮎‛േᘒޤߩ㗄ෳ AUC ߇਄᣹ߔࠆߎߣ߇ႎ๔ߐࠇߡ޿ࠆ㧔ޟ⮎‛ 㧔3㧕⣢ᯏ⢻㓚ኂߩ޽ࠆᖚ⠪ާ⣢ᯏ⢻㓚ኂߩᖡൻ ᾖ㧕ޕ㨉 േᘒޠߩ㗄ෳᾖ㧕ޕ㨉 ࠍ᧪ߔߎߣ߇޽ࠆ㧚ި 㧔5㧕㜞ⴊ࿶∝ߩᖚ⠪㨇⣖಴ⴊ߇޽ࠄࠊࠇࠆߎߣ 㧔4㧕㜞ⴊ࿶ߩ޽ࠆᖚ⠪ާ⣢ᯏ⢻㓚ኂߩ⊒⃻࡝ࠬ ߇޽ࠆޕ㨉 ࠢ߇㜞ߊߥࠆ߅ߘࠇ߇޽ࠆ㧚ި 㧔6㧕∨ᡨ⊒૞ߩ޽ࠆᖚ⠪㨇∝⁁߇Ⴧᖡߔࠆߎߣ 㧔5㧕♧ዩ∛ߩ޽ࠆᖚ⠪ާ⣢ᯏ⢻㓚ኂߩ⊒⃻࡝ࠬ ߇޽ࠆޕ㨉 ࠢ߇㜞ߊߥࠆ߅ߘࠇ߇޽ࠆ㧚ި 㧔7㧕ਛᨔ࡮♖␹␹⚻㓚ኂߩ޽ࠆᖚ⠪෶ߪߘߩᣢ 㧔6㧕ᛩਈ㐿ᆎ೨ߩࡋࡕࠣࡠࡆࡦỚᐲ߇ 14 g/dL ᧂ ᓔᱧߩ޽ࠆᖚ⠪㨇ਛᨔ࡮♖␹␹⚻㓚ኂ߇Ⴧᖡߔ ḩ㧘ᅢਛ⃿ᢙ߇ 2,000/mm3 ᧂḩ޽ࠆ޿ߪⴊዊ᧼ᢙ ࠆߎߣ߇޽ࠆޕ㨉 ߇ 120,000/mm3 ᧂḩߩᖚ⠪෸߮ᅚᕈާᛩਈਛᱛ޽ 㧔8㧕㛽㜑ᯏ⢻ᛥ೙ߩ޽ࠆᖚ⠪㨇㊀ᐲߩ⊕ⴊ⃿ᷫ ࠆ޿ߪᷫ㊂ࠍⷐߔࠆ㗫ᐲ߇㜞ߊߥࠆ௑ะ߇⹺߼ࠄ ዋޔⴊዊ᧼ᷫዋࠍ⿠ߎߔߎߣ߇޽ࠅޔᗵᨴ∝߿ ࠇߡ޿ࠆ㧚ި ಴ⴊ௑ะࠍว૬ߒ߿ߔ޿㧔ޟ㊀ᄢߥ೽૞↪ޠߩ 㧔7㧕ਛᨔ࡮♖␹␹⚻㓚ኂ෶ߪߘߩᣢᓔᱧߩ޽ࠆ 㗄ෳᾖ㧕ޕ㨉 ᖚ⠪ާਛᨔ࡮♖␹␹⚻∝⁁߇ᖡൻ෶ߪౣΆߔࠆߎ 㧔9㧕♧ዩ∛ߩᖚ⠪෶ߪߘߩᣢᓔᱧޔኅᣖᱧߩ޽ ߣ߇޽ࠆ㧚ި ࠆᖚ⠪ޔ⠴♧⢻㓚ኂߩ޽ࠆᖚ⠪㨇♧ዩ∛߇Ⴧᖡ ෶ߪ⊒∝ߒ߿ߔ޿ޕ㨉

10 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ ޣ⼊๔ޤ ޣ⼊๔ޤ ޣ⼊๔ޤ ᧄ೷ߩᛩਈߦࠃࠅ㑆⾰ᕈ⢖Ἳޔ⥄Ვડ࿑߇޽ࠄ 1.ᧄ೷ߢߪ௅ᄸᒻᕈ߇ႎ๔ߐࠇߡ޿ࠆߩߢޔᅧ 㧔1㧕ᧄ೷ߢߪ௅ᄸᒻᕈ߇ႎ๔ߐࠇߡ޿ࠆߩߢޔ ࠊࠇࠆߎߣ߇޽ࠆߩߢޔޣ૶↪਄ߩᵈᗧޤߦච ᇚ෶ߪᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚੱߦߪᛩਈ ᅧᇚ෶ߪᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚੱߦߪᛩ ಽ⇐ᗧߒޔᖚ⠪ߦኻߒ೽૞↪⊒⃻ߩน⢻ᕈߦߟ ߒߥ޿ߎߣ㧔ޣ⑌ᔊޤ෸߮ޟᅧᇚޔ↥ᇚޔ᝼੃ ਈߒߥ޿ߎߣ㧔ޣ⑌ᔊޤ෸߮ޟᅧᇚޔ↥ᇚޔ᝼ ޿ߡචಽ⺑᣿ߔࠆߎߣޕ ᇚ╬߳ߩᛩਈޠߩ㗄ෳᾖ㧕ޕ ੃ᇚ╬߳ߩᛩਈޠߩ㗄ෳᾖ㧕ޕ  2.ᧄ೷ߢߪ௅ᄸᒻᕈ෸߮♖Ꮍ࡮♖ሶߩᒻᘒᄌൻ 㧔2㧕ᧄ೷ߢߪ௅ᄸᒻᕈ෸߮♖Ꮍ࡮♖ሶߩᒻᘒᄌ  ╬߇ႎ๔ߐࠇߡ޿ࠆߩߢޔᅧᆼߔࠆน⢻ᕈߩ޽ ൻ╬߇ႎ๔ߐࠇߡ޿ࠆߩߢޔᅧᆼߔࠆน⢻ᕈߩ  ࠆᅚᕈᖚ⠪෸߮ࡄ࡯࠻࠽࡯߇ᅧᆼߔࠆน⢻ᕈߩ ޽ࠆᅚᕈᖚ⠪෸߮ࡄ࡯࠻࠽࡯߇ᅧᆼߔࠆน⢻ᕈ  ޽ࠆ↵ᕈᖚ⠪ߦᛩਈߔࠆ႐วߦߪޔㆱᅧࠍߐߖ ߩ޽ࠆ↵ᕈᖚ⠪ߦᛩਈߔࠆ႐วߦߪޔㆱᅧࠍߐ  ࠆߎߣ㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠ෸߮ޟᅧᇚޔ↥ ߖࠆߎߣ㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧ㧔4㧕ޠ෸߮ޟᅧ  ᇚޔ᝼੃ᇚ╬߳ߩᛩਈޠߩ㗄ෳᾖ㧕ޕ ᇚޔ↥ᇚޔ᝼੃ᇚ╬߳ߩᛩਈޠߩ㗄ෳᾖ㧕ޕ  3.ᧄ೷ߢߪ♖ᶧਛ߳ߩ⒖ⴕ߇ุቯߢ߈ߥ޿ߎߣ 㧔3㧕ᧄ೷ߢߪ♖ᶧਛ߳ߩ⒖ⴕ߇ุቯߢ߈ߥ޿  ߆ࠄޔࡄ࡯࠻࠽࡯߇ᅧᇚߩ↵ᕈᖚ⠪ߦᛩਈߔࠆ ߎߣ߆ࠄޔࡄ࡯࠻࠽࡯߇ᅧᇚߩ↵ᕈᖚ⠪ߦᛩਈ  ႐วߦߪޔޣ૶↪਄ߩᵈᗧޤࠍ෩቞ߔࠆߎߣ ߔࠆ႐วߦߪޔޣ૶↪਄ߩᵈᗧޤࠍ෩቞ߔࠆߎ  㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄ෳᾖ㧕ޕ ߣ㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧ㧔5㧕ޠߩ㗄ෳᾖ㧕ޕ   



    

 ޣ⑌ᔊ㧔ᰴߩᖚ⠪ߦߪᛩਈߒߥ޿ߎߣ㧕ޤ ޣ⑌ᔊ㧔ᰴߩᖚ⠪ߦߪᛩਈߒߥ޿ߎߣ㧕ޤ ޣ⑌ᔊ㧔ᰴߩᖚ⠪ߦߪᛩਈߒߥ޿ߎߣ㧕ޤ 㧔1㧕ᧄ೷෶ߪઁߩࠗࡦ࠲࡯ࡈࠚࡠࡦ⵾೷ߦኻ 1.ᅧᇚޔᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚੱ෶ߪ᝼ 㧔1㧕ᅧᇚޔᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚੱ෶ߪ ߒㆊᢅ∝ߩᣢᓔᱧߩ޽ࠆᖚ⠪ ੃ਛߩᇚੱ㨇േ‛ታ㛎ߢ௅ᄸᒻᕈ૞↪෸߮⢦࡮ ᝼੃ਛߩᇚੱ㨇േ‛ታ㛎ߢ௅ᄸᒻᕈ૞↪෸߮ 㧔2㧕ࡢࠢ࠴ࡦ╬↢‛ቇ⊛⵾೷ߦኻߒߡㆊᢅ∝ ⢝ఽ⥌ᱫ૞↪߇ႎ๔ߐࠇߡ޿ࠆޕ㨉 ⢦࡮⢝ఽ⥌ᱫ૞↪߇ႎ๔ߐࠇߡ޿ࠆޕ㨉 ߩᣢᓔᱧߩ޽ࠆᖚ⠪ 2.ᧄ೷ߩᚑಽ෶ߪઁߩ࠿ࠢ࡟ࠝࠪ࠼ࠕ࠽ࡠࠣ 㧔2㧕ᧄ೷ߩᚑಽ෶ߪઁߩ࠿ࠢ࡟ࠝࠪ࠼ࠕ࠽ࡠࠣ 㧔3㧕ዊᩊ⢫ḡࠍᛩਈਛߩᖚ⠪㧔ޟ⋧੕૞↪ޠ 㧔ࠕࠪࠢࡠࡆ࡞ޔࠟࡦࠪࠢࡠࡆ࡞ޔࡆ࠳࡜ࡆࡦ 㧔ࠕࠪࠢࡠࡆ࡞ޔࠟࡦࠪࠢࡠࡆ࡞ޔࡆ࠳࡜ࡆࡦ ߩ㗄ෳᾖ㧕 ╬㧕ߦኻߒㆊᢅ∝ߩᣢᓔᱧߩ޽ࠆᖚ⠪ ╬㧕ߦኻߒㆊᢅ∝ߩᣢᓔᱧߩ޽ࠆᖚ⠪ 㧔4㧕⥄Ꮖ఺∉ᕈ⢄Ἳߩᖚ⠪㨇⥄Ꮖ఺∉ᕈ⢄Ἳ 3.ࠦࡦ࠻ࡠ࡯࡞ߩ࿎㔍ߥᔃ∔ᖚ㧔ᔃ╭᪪Ⴇޔᔃ 㧔3㧕ࠦࡦ࠻ࡠ࡯࡞ߩ࿎㔍ߥᔃ∔ᖚ㧔ᔃ╭᪪Ⴇޔ ߇ᖡൻߔࠆߎߣ߇޽ࠆޕ㨉 ਇోޔਇᢛ⣂╬㧕ߩ޽ࠆᖚ⠪㨇⽺ⴊߦࠃࠅᔃ∔ ᔃਇోޔਇᢛ⣂╬㧕ߩ޽ࠆᖚ⠪㨇⽺ⴊ߇ේ࿃ߢ ᖚ߇ᖡൻߔࠆߎߣ߇޽ࠆޕ㨉 ᔃ∔ᖚ߇ᖡൻߔࠆߎߣ߇޽ࠆޕ㨉 4.⇣Ᏹࡋࡕࠣࡠࡆࡦ∝㧔ࠨ࡜࠮ࡒࠕޔ㎨⁁⿒ⴊ 㧔4㧕⇣Ᏹࡋࡕࠣࡠࡆࡦ∝㧔ࠨ࡜࠮ࡒࠕޔ㎨⁁⿒  ⃿ᕈ⽺ⴊ╬㧕ߩᖚ⠪㨇⽺ⴊߦࠃࠅ⇣Ᏹࡋࡕࠣࡠ ⴊ⃿ᕈ⽺ⴊ╬㧕ߩᖚ⠪㨇⽺ⴊ߇ේ࿃ߢ⇣Ᏹࡋࡕ  ࡆࡦ∝߇ᖡൻߔࠆߎߣ߇޽ࠆޕ㨉 ࠣࡠࡆࡦ∝߇ᖡൻߔࠆߎߣ߇޽ࠆޕ㨉  5.ᘟᕈ⣢ਇో෶ߪࠢ࡟ࠕ࠴࠾ࡦࠢ࡝ࠕ࡜ࡦࠬ߇ 㧔5㧕ᘟᕈ⣢ਇో෶ߪࠢ࡟ࠕ࠴࠾ࡦࠢ࡝ࠕ࡜ࡦࠬ  50mL/ಽએਅߩ⣢ᯏ⢻㓚ኂߩ޽ࠆᖚ⠪㨇ᧄ೷ߩ ߇ 50mL/ಽએਅߩ⣢ᯏ⢻㓚ኂߩ޽ࠆᖚ⠪㨇ᧄ೷  ⴊਛỚᐲ߇਄᣹ߒޔ㊀ᄢߥ೽૞↪߇↢ߓࠆߎߣ ߩⴊਛỚᐲ߇਄᣹ߒޔ㊀ᄢߥ೽૞↪߇↢ߓࠆߎ  ߇޽ࠆޕ㨉 ߣ߇޽ࠆޕ㨉㧔ޣ⮎‛േᘒޤߩ㗄ෳᾖ㧕 ૶↪਄  6.㊀ᐲߩ߁ߟ∛ޔ⥄Ვᔨᘦ෶ߪ⥄Ვડ࿑╬ߩ㊀ 㧔6㧕㊀ᐲߩ߁ߟ∛ޔ⥄Ვᔨᘦ෶ߪ⥄Ვડ࿑╬ߩ ߩᵈᗧ  ᐲߩ♖␹∛⁁ᘒߦ޽ࠆᖚ⠪෶ߪߘߩᣢᓔᱧߩ޽ ㊀ᐲߩ♖␹∛⁁ᘒߦ޽ࠆᖚ⠪෶ߪߘߩᣢᓔᱧߩ  ࠆᖚ⠪㨇߁ߟ∛߇ᖡൻ෶ߪౣΆߔࠆߎߣ߇޽ ޽ࠆᖚ⠪㨇߁ߟ∛߇ᖡൻ෶ߪౣΆߔࠆߎߣ߇޽  ࠆޕ㨉 ࠆޕ㨉  7.㊀ᐲߩ⢄ᯏ⢻㓚ኂߩ޽ࠆᖚ⠪㨇⢄੍஻⢻߇ૐ 㧔7㧕㊀◊ߥ⢄ᯏ⢻㓚ኂᖚ⠪㨇⢄੍஻⢻߇ૐਅߒ  ਅߒߡ޿ࠆน⢻ᕈ߇޽ࠅޔ㊀ᄢߥ೽૞↪߇↢ߓ ߡ޿ࠆน⢻ᕈ߇޽ࠅޔ㊀ᄢߥ೽૞↪߇↢ߓࠆߎ  ࠆߎߣ߇޽ࠆޕ㨉 ߣ߇޽ࠆޕ㨉  8.⥄Ꮖ఺∉ᕈ⢄Ἳߩᖚ⠪㨇⢄Ἳ߇㊀∝ൻߔࠆߎ 㧔8㧕⥄Ꮖ఺∉ᕈ⢄Ἳߩᖚ⠪㨇⥄Ꮖ఺∉ᕈ⢄Ἳ߇ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04  ߣ߇޽ࠆޕ㨉 ᖡൻߔࠆߎߣ߇޽ࠆޕ㨉     



  1.ᘕ㊀ᛩਈ㧔ᰴߩᖚ⠪ߦߪᘕ㊀ߦᛩਈߔࠆߎߣ㧕 1.ᘕ㊀ᛩਈ㧔ᰴߩᖚ⠪ߦߪᘕ㊀ߦᛩਈߔࠆߎߣ㧕 1.ᘕ㊀ᛩਈ㧔ᰴߩᖚ⠪ߦߪᘕ㊀ߦᛩਈߔࠆߎߣ㧕 㧔1㧕ᛩਈ㐿ᆎ೨ߩࡋࡕࠣࡠࡆࡦỚᐲ߇ 14g/dL 㧔1㧕ࠕ࡟࡞ࠡ࡯⚛࿃ߩ޽ࠆᖚ⠪ 㧔1㧕એਅߦ⹥ᒰߔࠆᖚ⠪㨇ᷫ㊂ࠍⷐߔࠆ㗫ᐲ߇ 3 ᧂḩޔᅢਛ⃿ᢙ 2,000/mm ᧂḩ޽ࠆ޿ߪⴊዊ᧼ᢙ 㧔2㧕ᔃ∔ᖚߩ޽ࠆᖚ⠪෶ߪߘߩᣢᓔᱧߩ޽ࠆᖚ 㜞ߊߥࠆ௑ะ߇⹺߼ࠄࠇߡ޿ࠆޕ㨉 3 120,000/mm ᧂḩߩᖚ⠪෸߮ᅚᕈ㨇ᷫ㊂ࠍⷐߔࠆ ⠪㨇⽺ⴊߦࠃࠅᔃ∔ᖚ߇ᖡൻߔࠆߎߣ߇޽ࠆޕ㨉 ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕 㗫ᐲ߇㜞ߊߥࠆ௑ะ߇⹺߼ࠄࠇߡ޿ࠆޕ㨉 㧔3㧕⣢ᯏ⢻㓚ኂߩ޽ࠆᖚ⠪㨇ࠃࠅ㊀◊ߥ㓚ኂߦ ૬↪ᤨ㧦ᛩਈ㐿ᆎ೨ߩࡋࡕࠣࡠࡆࡦỚᐲ߇ 14g/dL 㧔2㧕ਛᨔ࡮♖␹␹⚻㓚ኂ෶ߪߘߩᣢᓔᱧߩ޽ࠆ ⥋ࠆߎߣ߇޽ࠆޕ㨉 ᧂḩޔᅢਛ⃿ᢙ߇ 2,500/mm3 ᧂḩޔ޽ࠆ޿ߪⴊዊ ᖚ⠪㨇ਛᨔ࡮♖␹␹⚻∝⁁߇ᖡൻ෶ߪౣΆߔࠆ 㧔4㧕㜞ⴊ࿶∝ߩᖚ⠪㨇⣖಴ⴊ߇޽ࠄࠊࠇࠆߎߣ ᧼ᢙ 120,000/mm3 ᧂḩߩᖚ⠪෸߮ᅚᕈ ߎߣ߇޽ࠆޕ㨉 ߇޽ࠆޕ㨉 ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵ 㧔3㧕㜞ᐲߩ⊕ⴊ⃿ᷫዋޔᅢਛ⃿ᷫዋ෶ߪⴊዊ᧼ 㧔5㧕ਛᨔ࡮♖␹␹⚻㓚ኂߩ޽ࠆᖚ⠪෶ߪߘߩᣢ ߃㧕૬↪ᤨ㧦ᛩਈ㐿ᆎ೨ߩࡋࡕࠣࡠࡆࡦỚᐲ߇ ᷫዋߩ޽ࠆᖚ⠪㨇⊕ⴊ⃿ᷫዋޔᅢਛ⃿ᷫዋ෶ߪ ᓔᱧߩ޽ࠆᖚ⠪㨇ਛᨔ࡮♖␹␹⚻㓚ኂ߇Ⴧᖡߔࠆ 14g/dL ᧂḩޔᅢਛ⃿ᢙ߇ 2,000/mm3 ᧂḩޔ޽ࠆ޿ ⴊዊ᧼ᷫዋ߇ᦝߦᖡൻߔࠆߎߣ߇޽ࠅޔᗵᨴ∝ ߎߣ߇޽ࠆޕ㨉 ߪⴊዊ᧼ᢙ 120,000/mm3 ᧂḩߩᖚ⠪෸߮ᅚᕈ ෶ߪ಴ⴊ௑ะࠍ᧪ߒ߿ߔ޿ޕ㨉 㧔6㧕㛽㜑ᯏ⢻ᛥ೙ߩ޽ࠆᖚ⠪㨇㊀ᐲߩ⊕ⴊ⃿ᷫ ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࡌ࡯࠲૬↪ᤨ㧦ᛩਈ㐿ᆎ೨ߩ 㧔4㧕ᔃ∔ᖚ෶ߪߘߩᣢᓔᱧߩ޽ࠆᖚ⠪㨇ᔃ∔ᖚ ዋޔⴊዊ᧼ᷫዋࠍ⿠ߎߔߎߣ߇޽ࠅޔᗵᨴ∝߿಴ ࡋࡕࠣࡠࡆࡦỚᐲ߇ 14g/dL ᧂḩ޽ࠆ޿ߪᅢਛ⃿ ߇ᖡൻߔࠆߎߣ߇޽ࠆޕ㨉 ⴊ௑ะࠍว૬ߒ߿ߔ޿㧔ޟ㊀ᄢߥ೽૞↪ޠߩ㗄ෳ ᢙ߇ 2,000/mm3 ᧂḩߩᖚ⠪ 㧔5㧕㊀◊ߥ⢄㓚ኂߩ޽ࠆᖚ⠪㨇⢄㓚ኂ߇ᖡൻߔ ᾖ㧕ޕ㨉 㧔2㧕ᔃ∔ᖚ෶ߪߘߩᣢᓔᱧߩ޽ࠆᖚ⠪㨇⽺ⴊߦ ࠆ߅ߘࠇ߇޽ࠆޕ㨉 㧔7㧕♧ዩ∛ߩᖚ⠪෶ߪߘߩᣢᓔᱧޔኅᣖᱧߩ޽ ࠃࠅᔃᯏ⢻ߩ⇣Ᏹޔ౰⁁േ⣂∔ᖚ߇ᖡൻ෶ߪౣΆ 㧔6㧕ᘟᕈ⣢ਇో෶ߪࠢ࡟ࠕ࠴࠾ࡦࠢ࡝ࠕ࡜ࡦࠬ ࠆᖚ⠪ޔ⠴♧⢻㓚ኂߩ޽ࠆᖚ⠪㨇♧ዩ∛߇Ⴧᖡ෶ ߔࠆน⢻ᕈ߇޽ࠆޕ㨉 ߇ 50mL/ಽએਅߩ⣢ᯏ⢻㓚ኂߩ޽ࠆᖚ⠪㨇ᧄ೷ ߪ⊒∝ߒ߿ߔ޿ޕ㨉 㧔3㧕∩㘑෶ߪߘߩᣢᓔᱧߩ޽ࠆᖚ⠪㨇ⴊᷡዩ㉄ ߩⴊਛỚᐲ߇਄᣹ߔࠆߎߣ߇޽ࠆޕ㨉 㧔8㧕⥄Ꮖ఺∉∔ᖚߩᖚ⠪෶ߪߘߩ⚛࿃ߩ޽ࠆᖚ Ớᐲߩ਄᣹߇ႎ๔ߐࠇߡ޿ࠆޕ㨉 㧔7㧕⥄Ꮖ఺∉∔ᖚߩᖚ⠪෶ߪߘߩ⚛࿃ߩ޽ࠆᖚ ⠪㨇∔ᖚ߇Ⴧᖡ෶ߪ㗼ᕈൻߔࠆߎߣ߇޽ࠆ㧔ޟ㊀ 㧔4㧕ࠕ࡟࡞ࠡ࡯⚛࿃ߩ޽ࠆᖚ⠪ ⠪㨇∔ᖚ߇ᖡൻ෶ߪ㗼ᕈൻߔࠆߎߣ߇޽ࠆޕ㨉 ᄢߥ೽૞↪ޠߩ㗄ෳᾖ㧕ޕ㨉 㧔5㧕㜞ᐲߩ⊕ⴊ⃿ᷫዋ෶ߪⴊዊ᧼ᷫዋߩ޽ࠆᖚ 㧔8㧕↲⁁⣼ᯏ⢻⇣Ᏹ෶ߪߘߩᣢᓔᱧߩ޽ࠆᖚ⠪ 㧔9㧕㜞㦂⠪㧔ޟ㜞㦂⠪߳ߩᛩਈޠߩ㗄ෳᾖ㧕 ⠪㨇⊕ⴊ⃿ᷫዋ෶ߪⴊዊ᧼ᷫዋ߇ᦝߦᖡൻߔࠆߎ 㨇↲⁁⣼ᯏ⢻⇣Ᏹ߇ᖡൻߔࠆߎߣ߇޽ࠆޕ㨉 㧔10㧕૕㊀ 50kg ᧂḩߩᖚ⠪㨇ࡋࡕࠣࡠࡆࡦᷫዋ ߣ߇޽ࠅޔᗵᨴ∝෶ߪ಴ⴊ௑ะࠍ᧪ߒ߿ߔ޿ޕ㨉 㧔9㧕ࠕ࡟࡞ࠡ࡯⚛࿃ߩ޽ࠆᖚ⠪ ߿ⴊዊ᧼ᷫዋ╬ߩ೽૞↪߇⊒⃻ߒ߿ߔ޿ߩߢޔⷰ 㧔6㧕ਛᨔ࡮♖␹␹⚻㓚ኂ෶ߪߘߩᣢᓔᱧߩ޽ࠆ 㧔10㧕㜞ⴊ࿶∝ߩᖚ⠪㨇⣖ⴊ▤㓚ኂ߇⿠ߎࠆ߅ ኤࠍචಽߦⴕ߁ߎߣޕ㨉 ᖚ⠪㨇ਛᨔ࡮♖␹␹⚻∝⁁߇ᖡൻ෶ߪౣΆߔࠆߎ ߘࠇ߇޽ࠆޕ㨉 ߣ߇޽ࠆޕ㨉

11 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

㧔8㧕ᔃ∔ᖚ෶ߪߘߩᣢᓔᱧߩ޽ࠆᖚ⠪ާ⽺ⴊߦ 㧔10㧕⥄Ꮖ఺∉∔ᖚߩᖚ⠪෶ߪߘߩ⚛࿃ߩ޽ࠆ ࠃࠅᔃᯏ⢻ߩ⇣Ᏹ㧘౰⁁േ⣂∔ᖚ߇ᖡൻ෶ߪౣΆ ᖚ⠪㨇∔ᖚ߇Ⴧᖡ෶ߪ㗼ᕈൻߔࠆߎߣ߇޽ࠆ ߔࠆน⢻ᕈ߇޽ࠆ㧚ㆊ㊂ᛩਈߦࠃࠅ QT ᑧ㐳߇ႎ 㧔ޟ㊀ᄢߥ೽૞↪ޠߩ㗄ෳᾖ㧕ޕ㨉 ๔ߐࠇߡ޿ࠆ㧚㧔ޟㆊ㊂ᛩਈޠߩ㗄ෳᾖ㧕ި 㧔11㧕㜞㦂⠪㧔ޟ㜞㦂⠪߳ߩᛩਈޠߩ㗄ෳᾖ㧕 㧔9㧕∩㘑෶ߪߘߩᣢᓔᱧߩ޽ࠆᖚ⠪ާⴊਛዩ㉄ 㧔12㧕૕㊀ 50kg ᧂḩߩᖚ⠪㨇ࡋࡕࠣࡠࡆࡦᷫዋ ୯ߩ਄᣹߇ႎ๔ߐࠇߡ޿ࠆ㧚ި ߿ⴊዊ᧼ᷫዋ╬ߩ೽૞↪߇⊒⃻ߒ߿ߔ޿ߩߢޔ 㧔10㧕ࠕ࡟࡞ࠡ࡯⚛࿃ߩ޽ࠆᖚ⠪ ⷰኤࠍචಽߦⴕ߁ߎߣޕ㨉 㧔11㧕㜞㦂⠪㧔ޟ㜞㦂⠪߳ߩᛩਈޠߩ㗄ෳᾖ㧕

㧔12㧕ਛ╬ᐲߩ⢄ᯏ⢻㓚ኂᖚ⠪ާCmax ෸߮ AUC ߇ૐਅߔࠆߎߣ߇ႎ๔ߐࠇߡ޿ࠆ㧚㧔ޟ⮎‛േ ᘒޠߩ㗄ෳᾖ㧕ި 㧔13㧕ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔԟ2b㧔ㆮવ ሶ⚵឵߃㧕޽ࠆ޿ߪ࡝ࡃࡆ࡝ࡦߦ߅޿ߡᘕ㊀ᛩਈ ߣߐࠇߡ޿ࠆᖚ⠪ 2㧚㊀ⷐߥၮᧄ⊛ᵈᗧ 2㧚㊀ⷐߥၮᧄ⊛ᵈᗧ 2. ㊀ⷐߥၮᧄ⊛ᵈᗧ 1㧕ᧄ೷ߩᛩਈߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈ 㧔1㧕ᧄ೷ߪ㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃ 㧔1㧕ᧄ೷ࠍ࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆ႐วޔ࡝ࡃࡆ ࠔ-2 a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠ 2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߚ ࡝ࡦߩᷝઃᢥᦠߦ⸥タߐࠇߡ޿ࠆ⼊๔ޔ⑌ᔊޔ ࡦ ࠕ࡞ࡈࠔ-2 b㧔ㆮવሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ ߼㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b㧔ㆮવሶ ᘕ㊀ᛩਈޔ㊀ⷐߥၮᧄ⊛ᵈᗧޔ㊀ᄢߥ೽૞↪╬ ࡦߣ૬↪ᛩਈߔࠆߚ߼ޔฦ⵾ຠߩᷝઃᢥᦠߦ⸥ ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩᷝઃᢥᦠߦ⸥タߐࠇߡ ߩޣ૶↪਄ߩᵈᗧޤࠍᔅߕ⏕⹺ߔࠆߎߣޕ․ߦ タߐࠇߡ޿ࠆ⼊๔ޔ⑌ᔊޔ૬↪⑌ᔊޔᘕ㊀ᛩ ޿ࠆ⼊๔㧘⑌ᔊ㧘૬↪⑌ᔊ㧘ᘕ㊀ᛩਈ㧘㊀ⷐߥၮ ޣ⼊๔ޤߩㆱᅧߦ㑐ߔࠆᵈᗧߦߟ޿ߡߪޔߘߩ ਈޔ㊀ⷐߥၮᧄ⊛ᵈᗧޔ㊀ᄢߥ೽૞↪╬ߩޣ૶ ᧄ⊛ᵈᗧ㧘㊀ᄢߥ೽૞↪╬ߩޟ૶↪਄ߩᵈᗧޠࠍ ᜰ␜ࠍᔀᐩߔࠆߎߣޕ ↪਄ߩᵈᗧޤࠍᔅߕ⏕⹺ߔࠆߎߣޕ ᔅߕ⏕⹺ߔࠆߎߣ㧚 㧔2㧕C ဳઍఘᕈ⢄⎬ᄌᖚ⠪ߦኻߔࠆ࡝ࡃࡆ࡝ࡦ 2㧕శ✢ㆊᢅ∝߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߚ߼ޔᧄ 㧔2㧕ᧄ೷ߩ૶↪ߦ޽ߚߞߡߪ㧘ᖚ⠪ߦᧄ೷ߩ᦭ ߣߩ૬↪ߦࠃࠆᴦ≮ߪޔ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀࠍ ೷ޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2aޔ2b㧔ㆮ ലᕈ෸߮ෂ㒾ᕈ㧔ᧄ೷ߩᛩਈߦࠃࠅ⊒⃻ߔࠆน⢻ ⋡⊛ߣߒߚ߽ߩߢ޽ࠅޔᧄ૬↪≮ᴺߦࠃࠅ࠙ࠗ

વሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩ૬↪ਛߪޔㆊ೾ ᕈߩ޽ࠆ㊀ᄢߥ೽૞↪㧘ߘߩઁߩ೽૞↪ߩ⊒⃻㗫 ࡞ࠬቇ⊛ലᨐ߇ᓧࠄࠇߚ႐วߢ޽ߞߡ߽ޔ⢄⎬ ߥᄥ㓁శ✢߳ߩᦑ㔺ࠍㆱߌޔశᦑ㔺ߦኻߔࠆ㒐 ᐲ╬㧕ࠍචಽ⺑᣿ߒ㧘․ߦࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ᄌ߇ᴦ≹ߔࠆ߽ߩߢߪߥ޿ߚ߼ޔ⢄⎬ᄌߦኻߔ ⼔╷ࠍ⻠ߓࠆࠃ߁ᖚ⠪ߦኻߒᜰዉߔࠆߎߣޕ ࠕ࡞ࡈࠔ̃2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣ ࠆㆡಾߥಣ⟎ߪ⛮⛯ߔࠆߎߣޕ 㨇ޟߘߩઁߩᵈᗧޠߩ㗄ෳᾖ㨉 ߩ૬↪ߦࠃࠅ㜞㗫ᐲߦ⊹⤏∝⁁߇⊒⃻ߒ㧘ߣ߈ߦ 㧔3㧕ᅢਛ⃿ᷫዋޔⴊዊ᧼ᷫዋޔ⽺ⴊࠍ⿠ߎߔ߅ 3㧕ᧄ೷ᛩਈᤨߦⴊਛࡆ࡝࡞ࡆࡦ୯ߩ਄᣹߇ႎ๔ ㊀◊ߥ⊹⤏㓚ኂ߇⊒⃻ߔࠆߚ߼㧘⊹⤏߿☼⤑ߩ∝ ߘࠇ߇޽ࠆߩߢޔⴊᶧቇ⊛ᬌᩏࠍᧄ೷ߩᛩਈ㐿 ߐࠇߡ޿ࠆߩߢޔᧄ೷ᛩਈਛߪⴊਛࡆ࡝࡞ࡆࡦ ⁁㧔᳓∊㧘⴫⊹೸㔌㧘☼⤑ߩ߮ࠄࠎ࡮ẩ≌㧘⌒∛ ᆎᓟ 1 ㅳ㑆ߪㅳ 2 ࿁એ਄ޔએᓟޔᛩਈ㐿ᆎᓟ 8 ୯ޔ⢄ᯏ⢻ᬌᩏ୯ޔᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤ ᄌ㧘⊒∐ߦ㑐ㅪߒߚ⪺᣿ߥోり∝⁁╬㧕ߦᵈᗧ ㅳ㑆߹ߢߪᲤㅳޔߘߩᓟߪ 4 ㅳ㑆ߦ 1 ࿁એ਄ޔ ߒޔ⢄ᯏ⢻ߩᖡൻ߇⹺߼ࠄࠇߚ႐วߦߪㆡಾߥ ߒ㧘ߘߩࠃ߁ߥ∝⁁߇޽ࠄࠊࠇߚ႐วߦߪ㧘⋥ߜ ቯᦼ⊛ߦⴕ޿ޔᛩਈ⚳ੌᓟ߽ᬌᩏ୯߇࿁ᓳߔࠆ ಣ⟎ࠍⴕ߁ߎߣ ߦකᏧߩ⸻ኤࠍฃߌࠆࠃ߁ᜰዉߔࠆߎߣ㧚 ߹ߢቯᦼ⊛ߦⴕ߁ߎߣޕߥ߅ޔⴊ⃿ᷫዋ߇㗼⪺ 㧔3㧕ᧄ೷ߪ㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃ ߥ႐ว╬ߦߪޔ㗫࿁ߦᬌᩏ୯ߩ⏕⹺ࠍⴕ߁ߎ 2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦࠃ ߣޕ․ߦ C ဳઍఘᕈ⢄⎬ᄌߦ߅޿ߡߪޔC ဳᘟ ࠅ㧘ਛᲥᕈ⴫⊹უᱫⲢ⸃∝㧔Toxic Epidermal ᕈ⢄ἻߣᲧߴޔⴊ⃿♽ߩᷫዋ߇ᄙߊ⊒⃻ߔࠆ߅ Necrolysis: TEN㧕㧘⊹⤏☼⤑⌒∝୥⟲㧔Stevens̃ ߘࠇ߇޽ࠆߩߢޔචಽᵈᗧߔࠆߎߣޕ Johnson ∝୥⟲㧕㧘⮎೷ᕈㆊᢅ∝∝୥⟲㧔Drug̃ 㧔4㧕ᧄ೷ᛩਈਛߪޔᗵᨴ∝ޔ಴ⴊ∝⁁㧔ᱤ⡺಴ induced hypersensitivity syndrome :DIHS㧕╬ߩోり ⴊޔ㥦಴ⴊޔ⊹ਅ಴ⴊޔ⚡᢬╬㧕ޔ⽺ⴊߦ㑐ㅪ ∝⁁ࠍ઻߁㊀◊ߥ⊹⤏㓚ኂ߇⊒⃻ߔࠆ߅ߘࠇ߇޽ ߔࠆ∝⁁ߩ᦭ήࠍචಽ⏕⹺ߔࠆߎߣޕ⇣Ᏹ߇⹺ ࠆߎߣ߆ࠄᵈᗧߔࠆߎߣ㧚㊀◊ߥ⊹⤏㓚ኂ߇⹺߼ ߼ࠄࠇߚ႐วߦߪⴊᶧቇ⊛ᬌᩏࠍⴕ޿ޔᷫ㊂ޔ ࠄࠇߚ႐ว㧘෶ߪߎࠇࠄߩ∝⁁߇⇼ࠊࠇߚ႐ว ਛᱛ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ․ߦ C ဳઍఘ ૶↪਄ 㧔᳓∊㧘⴫⊹೸㔌㧘☼⤑ߩ߮ࠄࠎ࡮ẩ≌㧘⌒∛ ᕈ⢄⎬ᄌߦ߅޿ߡߪޔC ဳᘟᕈ⢄ἻߣᲧߴޔⴊ⃿ ߩᵈᗧ ᄌ㧘⊒∐ߦ㑐ㅪߒߚ⪺᣿ߥోり∝⁁ߩ⊒⃻╬㧕 ♽ߩᷫዋ߇ᄙߊ⊒⃻ߔࠆ߅ߘࠇ߇޽ࠆߩߢޔච ߪ㧘ᧄ೷㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b ಽᵈᗧߔࠆߎߣޕ 㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩᛩਈࠍ⋥ߜߦ 㧔5㧕⢄ᯏ⢻㓚ኂޔ⣢ᯏ⢻㓚ኂࠍ⿠ߎߔ߅ߘࠇ߇ ਛᱛߒ㧘⊹⤏⑼කߦฃ⸻ߐߖࠆߥߤㆡಾߥಣ⟎ࠍ ޽ࠆߩߢޔ↢ൻቇ⊛ᬌᩏߪ 4 ㅳߏߣߦቯᦼ⊛ߦ ⴕ߁ߎߣ㧚 ⴕ߁ߎߣޕ 㧔4㧕૕⴫㕙Ⓧߩ 50%ࠍ⿥߃ࠆోりᕈ⊒∐㧘⊒∐ 㧔6㧕ᧄ೷ߩᛩਈೋᦼߦ߅޿ߡޔࠗࡦࡈ࡞ࠛࡦࠩ

ߦ㑐ㅪߒߚోり∝⁁㧔⊒ᾲ㧘࡝ࡦࡄ▵⣲⣘╬㧕╬ ᭽∝⁁ߦ㑐ㅪߒߚ⊒ᾲ߇৻⥸ߦႎ๔ߐࠇߡ޿ࠆ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ߇⹺߼ࠄࠇߚ႐วߦߪ㧘ේೣߣߒߡᧄ೷ߩᛩਈࠍ ߇ޔ㜞ᾲࠍ๒ߔࠆ႐ว߽޽ࠆߩߢޔ⊒ᾲߦኻߒ ਛᱛߔࠆߣߣ߽ߦ㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ ߡ޽ࠄ߆ߓ߼චಽߦ㈩ᘦߔࠆߎߣޕߥ߅ޔᜬ⛯ ࡈࠔ̃2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩᷫ㊂ ߔࠆ⊒ᾲߪᗵᨴ∝ߦࠃࠆน⢻ᕈ߽޽ࠆߚ߼ޔ․ ෶ߪᛩਈਛᱛߦߟ޿ߡ߽ᘕ㊀ߦᬌ⸛ߔࠆߎߣ㧚․ ߦᅢਛ⃿ᢙ߇ૐਅߒߡ޿ࠆᖚ⠪ߢߪᵈᗧߔࠆߎ ߦ㧘㊀◊ߥ⊹⤏㓚ኂ߳ߩㅴⴕࠍ⇼߁႐วߦߪ㧘ᧄ ߣޕ ೷㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b㧔ㆮવሶ 㧔7㧕ᧄ೷ࠍ㐳ᦼᛩਈߔࠆ႐วߦߪޔ⥃ᐥലᨐ෸ ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩᛩਈࠍ⋥ߜߦਛᱛߒ㧘 ߮೽૞↪ߩ⒟ᐲࠍ⠨ᘦߒߡᛩਈࠍⴕ޿ޔലᨐ߇ ⊹⤏⑼කߦฃ⸻ߐߖࠆߥߤㆡಾߥಣ⟎ࠍⴕ߁ߎ ⹺߼ࠄࠇߥ޿႐วߦߪᛩਈࠍਛᱛߔࠆߎߣޕߥ ߣ㧚ߥ߅㧘ᧄ೷ߩߺࠍᛩਈਛᱛߒߚ႐วߦߪ㧘ᘕ ߅ޔ48 ㅳࠍ⿥߃ߡᧄ೷න⁛ᛩਈ෶ߪᧄ೷ߣ࡝ࡃ ㊀ߦ⚻ㆊⷰኤࠍⴕ߁ߣߣ߽ߦ㧘⊹⤏⑼කࠍฃ⸻ߐ ࡆ࡝ࡦߩ૬↪ᛩਈࠍߒߚ႐วߩ᦭ലᕈ࡮቟ోᕈ ߖࠆߥߤㆡಾߥಣ⟎ࠍⴕ߁ߎߣ㧚 ߪ⏕┙ߒߡ޿ߥ޿ޕ 㧔5㧕ࡋࡕࠣࡠࡆࡦỚᐲ㧘⊕ⴊ⃿ᢙ㧘ᅢਛ⃿ᢙ෸ 㧔8㧕ᛥ߁ߟޔ⥄Ვડ࿑߇޽ࠄࠊࠇࠆߎߣ߇޽ ߮ⴊዊ᧼ᢙߩᬌᩏߪ㧘ᛩਈ೨෸߮ᛩਈ㐿ᆎ 12 ㅳ ࠆޕ߹ߚޔば⁁ᘒޔ᡹᠄⊛ⴕേ߇޽ࠄࠊࠇޔઁ 㑆ߪዋߥߊߣ߽Ფㅳ㧘ߘߩᓟߪ 4 ㅳ㑆ߦ 1 ᐲታᣉ ኂⴕὑߦ⥋ࠆߎߣ߇޽ࠆޕᖚ⠪ߩ♖␹⁁ᘒߦච ߔࠆߎߣ㧚߹ߚ㧘ᤃᗵᨴᕈߣߥࠅ㧘ᗵᨴ∝෸߮ᗵ ಽᵈᗧߒޔਇ⌁ޔਇ቟ޔὶ῎ޔ⥝ᅗޔ᡹᠄ᕈޔ ᨴ∝ߩჇᖡࠍ⺃⊒ߔࠆߎߣ߇޽ࠆߩߢ㧘⊕ⴊ⃿ಽ ᤃೝỗᕈ╬߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߔ ↹෸߮ CRP ୯ߦߟ޿ߡ߽ห᭽ߦ᷹ቯߔࠆߎߣ㧚 ࠆߥߤޔᛩਈ⛮⛯ߩนุߦߟ޿ߡᘕ㊀ߦᬌ⸛ߔ 㧔6㧕ᕆᕈ⣢ਇో╬ߩ㊀◊ߥ⣢ᯏ⢻㓚ኂ෸߮㊀◊ ࠆߎߣޕ߹ߚޔߎࠇࠄߩ∝⁁߇⹺߼ࠄࠇߚ႐ว ߥ⢄ᯏ⢻㓚ኂߩᄙߊ߇ᛩਈ㐿ᆎ 1 ㅳ㑆એౝߦ⊒⃻ ߦߪޔᛩਈ⚳ੌᓟ߽ⷰኤࠍ⛮⛯ߔࠆߎߣ߇ᦸ߹ ߒߡ޿ࠆߩߢ㧘⣢ᯏ⢻ᬌᩏ㧔ࠢ࡟ࠕ࠴࠾ࡦ㧘ዩ⚛ ߒ޿ޕ ⓸⚛㧘ዩ㉄╬㧕㧘⢄ᯏ⢻ᬌᩏ෸߮㔚⸃⾰╬ߩ↢ൻ 㧔9㧕ᧄ೷ߩᛩਈߦ޽ߚߞߡߪޔᛥ߁ߟޔ⥄Ვડ ቇᬌᩏࠍ㧘ᛩਈ㐿ᆎᓟ 1 ㅳ㑆એౝߦዋߥߊߣ߽ 2 ࿑ࠍߪߓ߼ޔば⁁ᘒޔ᡹᠄⊛ⴕേޔਇ⌁ޔਇ ᐲታᣉߒ㧘ᦝߦᛩਈ㐿ᆎ 2 ㅳ㑆ᓟ෸߮ 4 ㅳ㑆ᓟߦ ቟ޔὶ῎ޔ⥝ᅗޔ᡹᠄ᕈޔᤃೝỗᕈ╬ߩ♖␹␹ 1 ᐲ㧘ߘߩᓟߪ 4 ㅳ㑆ߦ 1 ᐲታᣉߔࠆߎߣ㧚߹ ⚻∝⁁⊒⃻ߩน⢻ᕈߦߟ޿ߡᖚ⠪෸߮ߘߩኅᣖ ߚ㧘↲⁁⣼ᯏ⢻ᬌᩏߪ 12 ㅳ㑆ߦ 1 ᐲታᣉߔࠆߎ ߦචಽℂ⸃ߐߖޔߎࠇࠄߩ∝⁁߇޽ࠄࠊࠇߚ႐ ߣ㧚 วߦߪ⋥ߜߦㅪ⛊ߔࠆࠃ߁ᵈᗧࠍਈ߃ࠆߎߣޕ 㧔7㧕⽺ⴊࠍ⿠ߎߔน⢻ᕈ߇޽ࠆߎߣ߆ࠄ㧘ᖚ⠪ 㧔10㧕ㆊᢅ∝╬ߩ෻ᔕࠍ੍᷹ߔࠆߚ߼චಽߥ໧ ߦኻߒ⽺ⴊߦ㑐ㅪߔࠆ೽૞↪㧔߼߹޿╬㧕ߩ⊒⃻ ⸻ࠍⴕ߁ߣߣ߽ߦޔ޽ࠄ߆ߓ߼ᧄ೷ߦࠃࠆࡊ࡝ ߩน⢻ᕈߦߟ޿ߡචಽ⺑᣿ߔࠆߎߣ㧚߹ߚ㧘ቯᦼ ࠶ࠢ⹜㛎෶ߪ⊹ౝ෻ᔕ⹜㛎ࠍⴕ߁ߎߣ߇ᦸ߹ߒ ⊛ߦ⥃ᐥᬌᩏࠍⴕ߁ߥߤᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤ ޿ޕ ߒ㧘⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪㆡಾߥಣ⟎ࠍⴕ߁ 㧔11㧕ᧄ೷ᛩਈਛߦⷞജ෶ߪⷞ㊁ߩᄌൻޔ޽ࠆ ߎߣ㧚 ޿ߪઁߩ⌒∝⁁ࠍ⸷߃ߚ႐วߦߪޔㅦ߿߆ߦ⌒ ⑼කߩ⸻ኤࠍฃߌࠆࠃ߁ᖚ⠪ࠍᜰዉߔࠆߎߣޕ

12 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 㧔11㧕♧ዩ∛෶ߪߘߩᣢᓔᱧޔኅᣖᱧߩ޽ࠆᖚ  㧔7㧕⥄Ꮖ఺∉∔ᖚߩᖚ⠪෶ߪߘߩ⚛࿃ߩ޽ࠆᖚ ⠪ޔ⠴♧⢻㓚ኂߩ޽ࠆᖚ⠪㨇♧ዩ∛߇ᖡൻ෶ߪ  ⠪㨇∔ᖚ߇ᖡൻ෶ߪ㗼ᕈൻߔࠆߎߣ߇޽ࠆޕ㨉 ⊒∝ߔࠆ߅ߘࠇ߇޽ࠆޕ㨉  㧔8㧕シᐲ෶ߪਛ╬ᐲߩ⣢ᯏ⢻㓚ኂߩ޽ࠆᖚ⠪ 㧔12㧕㜞㦂⠪㨇ޟ㜞㦂⠪߳ߩᛩਈޠߩ㗄ෳᾖ㨉  㨇ᧄ೷ߩⴊਛỚᐲ߇਄᣹ߒޔ㊀ᄢߥ೽૞↪߇↢ߓ 㧔13㧕∨ᡨ⊒૞ߩ޽ࠆᖚ⠪㨇ઁߩࠗࡦ࠲࡯ࡈࠚ  ࠆߎߣ߇޽ࠆޕ㨉㧔ޣ⮎‛േᘒޤߩ㗄ෳᾖ㧕 ࡠࡦ⵾೷ߢޔ∝⁁߇ᖡൻߔࠆߎߣ߇ႎ๔ߐࠇߡ  㧔9㧕㜞ⴊ࿶∝ߩᖚ⠪㨇⣖಴ⴊࠍ฽߻⣖ⴊ▤㓚ኂ ޿ࠆޕ㨉  ߇↢ߓߚߣߩႎ๔߇޽ࠆޕ㨉 㧔14㧕㑆⾰ᕈ⢖Ἳߩᣢᓔᱧߩ޽ࠆᖚ⠪㨇㑆⾰ᕈ  㧔10㧕♧ዩ∛෶ߪߘߩᣢᓔᱧޔኅᣖᱧߩ޽ࠆᖚ ⢖Ἳ߇Ⴧᖡ෶ߪౣ⊒ߔࠆߎߣ߇޽ࠆ㧔ޟ㊀ⷐߥ  ⠪ޔ⠴♧⢻㓚ኂߩ޽ࠆᖚ⠪㨇♧ዩ∛߇Ⴧᖡ෶ߪ⊒ ၮᧄ⊛ᵈᗧޠޔޟ㊀ᄢߥ೽૞↪ޠߩ㗄ෳ  ∝ߒ߿ߔ޿ޕ㨉 ᾖ㧕ޕ㨉  㧔11㧕㜞㦂⠪㧔ޟ㜞㦂⠪߳ߩᛩਈޠߩ㗄ෳᾖ㧕      2.㊀ⷐߥၮᧄ⊛ᵈᗧ 2.㊀ⷐߥၮᧄ⊛ᵈᗧ 2.㊀ⷐߥၮᧄ⊛ᵈᗧ 㧔1㧕ࡋࡕࠣࡠࡆࡦỚᐲޔ⊕ⴊ⃿ᢙޔᅢਛ⃿ᢙ෸ 㧔1㧕ᧄ೷ߩᛩਈߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ 㧔1㧕ᧄ೷ߩᛩਈߪޔࠗࡦ࠲࡯ࡈࠚࡠࡦࠕ࡞ࡈࠔ ߮ⴊዊ᧼ᢙߩᬌᩏߪᛩਈ೨෸߮ᛩਈ㐿ᆎᓟ 8 ㅳ ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕ߣߩ૬↪ߢ޽ࠆߚ߼ޔ -2b㧔ㆮવሶ⚵឵߃㧕ޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ 㑆ߪᲤㅳޔߘߩᓟߪ 4 ㅳ㑆ߦ 1 ᐲታᣉߔࠆߎ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵ ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕෶ߪࠗࡦ࠲࡯ࡈࠚࡠ ߣޕ߹ߚޔ↢ൻቇ⊛ᬌᩏߪ 4 ㅳ㑆ߦ 1 ᐲޔ↲⁁ ߃㧕ߩᷝઃᢥᦠߦ⸥タߐࠇߡ޿ࠆ⼊๔ޔ⑌ᔊޔ૬ ࡦ ࡌ࡯࠲ߣߩ૬↪ߩߚ߼ޔߘࠇߙࠇߩᷝઃᢥᦠ ⣼ᯏ⢻ᬌᩏߪ 12 ㅳ㑆ߦ 1 ᐲታᣉߔࠆߎߣޕ․ߦ ↪⑌ᔊޔᘕ㊀ᛩਈޔ㊀ⷐߥၮᧄ⊛ᵈᗧޔ㊀ᄢߥ೽ ߦ⸥タߐࠇߡ޿ࠆ⼊๔ޔ⑌ᔊޔ૬↪⑌ᔊޔᘕ㊀ C ဳઍఘᕈ⢄⎬ᄌߦ߅޿ߡߪޔC ဳᘟᕈ⢄ἻߣᲧ ૞↪╬ߩޣ૶↪਄ߩᵈᗧޤࠍᔅߕ⏕⹺ߔࠆߎߣޕ ᛩਈޔ㊀ⷐߥၮᧄ⊛ᵈᗧޔ㊀ᄢߥ೽૞↪╬ߩ ߴޔⴊ⃿♽ߩૐਅ߇ᄙߊ⹺߼ࠄࠇࠆ߅ߘࠇ߇޽ 㧔2㧕C ဳᘟᕈ⢄Ἳ෶ߪ % ဳઍఘᕈ⢄⎬ᄌߦኻߔ ޣ૶↪਄ߩᵈᗧޤࠍᔅߕ⏕⹺ߔࠆߎߣޕߥ߅ޔ ࠆߩߢޔචಽᵈᗧߔࠆߎߣޕ ࠆᧄ೷ߩන⁛≮ᴺߪήലߢ޽ࠆߚ߼ޔᧄ೷ߪࡍࠣ ᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવ 㧔2㧕ᧄ೷ߩᛩਈߪޔ࡝ࡃࡆ࡝ࡦߣߩ૬↪ߩߚ ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕 ሶ⚵឵߃㧕ߩ૬↪ߦઁߩ᛫ *%8 ೷ࠍ૬↪ߔࠆ႐ ߼ޔ࡝ࡃࡆ࡝ࡦߩᷝઃᢥᦠߦ⸥タߐࠇߡ޿ࠆ⼊ ߣ૬↪ߔࠆߎߣޕ วߦߪޔ᛫ *%8 ೷ߩᷝઃᢥᦠߩޣ૶↪਄ߩᵈ ๔ޔ⑌ᔊޔᘕ㊀ᛩਈޔ㊀ⷐߥၮᧄ⊛ᵈᗧޔ㊀ᄢ 㧔3㧕C ဳઍఘᕈ⢄⎬ᄌᖚ⠪ߦኻߔࠆࡍࠣࠗࡦ࠲ ᗧޤࠍᔅߕ⏕⹺ߔࠆߎߣޕ ߥ೽૞↪╬ߩޣ૶↪਄ߩᵈᗧޤࠍᔅߕ⏕⹺ߔࠆ ࡯ࡈࠚࡠࡦࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕ߣߩ૬ 㧔2㧕C ဳᘟᕈ⢄Ἳ෶ߪ C ဳઍఘᕈ⢄⎬ᄌߦኻߔ ߎߣޕ․ߦ⼊๔ߩㆱᅧߦ㑐ㅪߔࠆᵈᗧߦߟ޿ߡ ↪ߦࠃࠆᴦ≮ߪޔ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀࠍ⋡⊛ߣߒ ࠆᧄ೷ߩන⁛≮ᴺߪήലߢ޽ࠆޕᧄ೷ߪޔC ဳᘟ ߪޔߘߩᜰ␜ࠍᔀᐩߔࠆߎߣޕߥ߅ޔᧄ೷ߣ࡝ ߚ߽ߩߢ޽ࠅޔᧄ૬↪≮ᴺߦࠃࠅ࠙ࠗ࡞ࠬቇ⊛ല ᕈ⢄Ἳߦኻߒߡߪࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡃࡆ࡝ࡦߩ૬↪ߦઁߩ᛫ HCV ೷ࠍ૬↪ߔࠆ႐ว ᨐ߇ᓧࠄࠇߚ႐วߢ޽ߞߡ߽ޔ⢄⎬ᄌ߇ᴦ≹ߔࠆ 㧔ㆮવሶ⚵឵߃㧕ޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ ߦߪᇬ᛫ *%8 ೷ߩᷝઃᢥᦠߩޣ૶↪਄ߩᵈᗧޤ ߽ߩߢߪߥ޿ߚ߼ޔ⢄⎬ᄌߦኻߔࠆㆡಾߥಣ⟎ߪ ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕෶ߪࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠍᔅߕ⏕⹺ߔࠆߎߣޕ ⛮⛯ߔࠆߎߣޕ߹ߚޔC ဳઍఘᕈ⢄⎬ᄌߦ߅޿ߡ ࡌ࡯࠲ߣޔC ဳઍఘᕈ⢄⎬ᄌߦኻߒߡߪࡍࠣࠗࡦ 㧔3㧕ᧄ೷ࠍ 48 ㅳࠍ⿥߃ߡᛩਈߒߚ႐วߩ቟ో ߪޔC ဳᘟᕈ⢄ἻߣᲧߴޔⴊ⃿♽ߩᷫዋ߇ᄙߊ⊒ ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ߣ૬ ᕈ࡮᦭ലᕈߪ⏕┙ߒߡ޿ߥ޿ޕ ⃻ߔࠆ߅ߘࠇ߇޽ࠆߩߢޔචಽᵈᗧߔࠆߎߣޕ ↪ߔࠆߎߣޕ 㧔4㧕C ဳઍఘᕈ⢄⎬ᄌᖚ⠪ߦኻߔࠆ࡝ࡃࡆ࡝ࡦ 㧔4㧕ᅧᆼߔࠆน⢻ᕈߩ޽ࠆᅚᕈᖚ⠪෸߮ࡄ࡯࠻ 㧔3㧕C ဳઍఘᕈ⢄⎬ᄌᖚ⠪ߦኻߔࠆࡍࠣࠗࡦ࠲ ߣߩ૬↪ߦࠃࠆᴦ≮ߪޔ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀࠍ ࠽࡯߇ᅧᆼߔࠆน⢻ᕈߩ޽ࠆ↵ᕈᖚ⠪ߪޔᛩਈਛ ࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ߣߩ૬ ⋡⊛ߣߒߚ߽ߩߢ޽ࠅޔ⢄⎬ᄌࠍᴦ≮ߔࠆ߽ߩ ෸߮ᛩਈ⚳ੌᓟ㧢ࠞ᦬㑆ߪା㗬ߢ߈ࠆㆱᅧᴺࠍ↪ ↪ߦࠃࠆᴦ≮ߪޔ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀࠍ⋡⊛ߣ ߢߪߥ޿ߚ߼ޔᧄ૬↪≮ᴺߦࠃࠅ࠙ࠗ࡞ࠬቇ⊛ ޿ࠆߥߤߒߡᅧᆼࠍㆱߌࠆߎߣޕ߹ߚޔᛩਈ⋥೨ ߒߚ߽ߩߢ޽ࠅޔᧄ૬↪≮ᴺߦࠃࠅ࠙ࠗ࡞ࠬቇ ലᨐ߇ᓧࠄࠇߚ႐วߢ޽ߞߡ߽ޔ⢄⎬ᄌߦኻߔ ߩᅧᆼᬌᩏ⚿ᨐ߇㒶ᕈߢ޽ࠆߎߣࠍ⏕⹺ᓟߦᛩਈ ⊛ലᨐ߇ᓧࠄࠇߚ႐วߢ޽ߞߡ߽ޔ⢄⎬ᄌ߇ᴦ ࠆㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ࠍ㐿ᆎߔࠆߎߣޕߥ߅ޔᅧᆼߒߡ޿ߥ޿ߎߣࠍ⏕ ≹ߔࠆ߽ߩߢߪߥ޿ߚ߼ޔ⢄⎬ᄌߦኻߔࠆㆡಾ 㧔5㧕ᧄ೷ߩᛩਈೋᦼߦ߅޿ߡޔ৻⥸ߦ⊒ᾲ߇ߺ ⹺ߔࠆߚ߼ߦޔᅧᆼᬌᩏࠍᲤ᦬㧝࿁ታᣉߔࠆߎߣ ߥಣ⟎ߪ⛮⛯ߔࠆߎߣޕ ࠄࠇࠆޕߘߩ⒟ᐲߪ୘ੱᏅ߇⪺ߒ޿߇ޔ㜞ᾲࠍ 㧔ޣ⼊๔ޤ෸߮ޣ⑌ᔊޤߩ㗄ෳᾖ㧕ޕ 㧔4㧕ᅧᆼߔࠆน⢻ᕈߩ޽ࠆᅚᕈᖚ⠪෸߮ࡄ࡯࠻ ๒ߔࠆ႐ว߽޽ࠆߩߢޔ㔚⸃⾰ࠍ฽߻᳓ಽ⵬⛎ 㧔5㧕♖ᶧਛ߳ߩᧄ೷ߩ⒖ⴕ߇ุቯߢ߈ߥ޿ߎߣ ࠽࡯߇ᅧᆼߔࠆน⢻ᕈߩ޽ࠆ↵ᕈᖚ⠪ߪᛩਈਛ ૶↪਄ ╬ޔ⊒ᾲߦኻߒߡ޽ࠄ߆ߓ߼චಽ㈩ᘦߔࠆߎ ߆ࠄޔࡄ࡯࠻࠽࡯߇ᅧᆼߒߡ޿ࠆ↵ᕈᖚ⠪ߦߪޔ ෸߮ᛩਈ⚳ੌᓟ 6 ࡨ᦬㑆ߪା㗬ߢ߈ࠆㆱᅧᴺࠍ ߩᵈᗧ ߣޕ ߘߩෂ㒾ᕈࠍᖚ⠪ߦචಽℂ⸃ߐߖޔᛩਈਛ෸߮ᛩ ↪޿ࠆߥߤߒߡᅧᆼࠍㆱߌࠆߎߣޕ߹ߚޔᛩਈ 㧔6㧕㛽㜑ᯏ⢻ᛥ೙ޔ⢄ᯏ⢻㓚ኂ╬߇޽ࠄࠊࠇࠆ ਈ⚳ੌᓟ㧢ࠞ᦬㑆ߪᧄ೷߇ሶችౝ߳⒖ⴕߒߥ޿ࠃ ⋥೨ߩᅧᆼᬌᩏ⚿ᨐ߇㒶ᕈߢ޽ࠆߎߣࠍ⏕⹺ᓟ ߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦ⥃ᐥᬌᩏࠍⴕ߁ߥߤ ߁ߦࠦࡦ࠼࡯ࡓࠍ૶↪ߔࠆࠃ߁ᜰዉߔࠆߎߣ ߦᛩਈࠍ㐿ᆎߔࠆߎߣޕߥ߅ޔᅧᆼߒߡ޿ߥ޿ ᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤߒޔ⇣Ᏹ߇⹺߼ࠄࠇߚ 㧔ޣ⼊๔ޤ෸߮ޟߘߩઁߩᵈᗧޠߩ㗄ෳᾖ㧕ޕ ߎߣࠍ⏕⹺ߔࠆߚ߼ߦޔᅧᆼᬌᩏࠍᲤ᦬ 1 ࿁ታ 㧔6㧕ᧄ೷ࠍ㐳ᦼᛩਈߔࠆ႐วߦߪޔ⥃ᐥലᨐ෸ ᣉߔࠆߎߣ㧔ޣ⼊๔ޤ෸߮ޣ⑌ᔊޤߩ㗄ෳ ႐วߦߪᇬᷫ㊂ޔભ⮎ޔਛᱛ╬ߩㆡಾߥಣ⟎ࠍ ߮೽૞↪ߩ⒟ᐲࠍ⠨ᘦߒߡᛩਈࠍⴕ޿ޔലᨐ߇⹺ ᾖ㧕ޕ ⴕ߁ߎߣޕ ߼ࠄࠇߥ޿႐วߦߪᛩਈࠍਛᱛߔࠆߎߣޕߥ߅ޔ 㧔5㧕♖ᶧਛ߳ߩᧄ೷ߩ⒖ⴕ߇ุቯߢ߈ߥ޿ߎߣ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 㧔7㧕ᧄ೷ߪㅳ 1 ࿁ᛩਈߢ޽ࠅᜬ⛯⊛ߥ૕ౝേᘒ 48 ㅳࠍ⿥߃ߡᧄ೷ࠍᛩਈߒߚ႐วߩ᦭ലᕈ࡮቟ ߆ࠄޔࡄ࡯࠻࠽࡯߇ᅧᆼߒߡ޿ࠆ↵ᕈᖚ⠪ߦ ࠍ␜ߔߚ߼ޔ㊀ᄢߥ೽૞↪ߩ㗄ߦ⸥タߒߚ∝⁁ ోᕈߪ⏕┙ߒߡ޿ߥ޿ޕ ߪޔߘߩෂ㒾ᕈࠍᖚ⠪ߦචಽℂ⸃ߐߖޔᛩਈਛ ߇޽ࠄࠊࠇߚ႐วߦߪޔ⋥ߜߦㅪ⛊ߔࠆࠃ߁ᖚ 㧔7㧕ᧄ೷ߩᛩਈߦࠃࠅޔ⽺ⴊ㧔ṁⴊᕈ⽺ⴊ╬㧕 ෸߮ᛩਈ⚳ੌᓟ 6 ࡨ᦬㑆ߪᧄ೷߇ሶችౝ߳⒖ⴕ ⠪ߦᜰዉߔࠆߎߣޕ ࠍ⿠ߎߔน⢻ᕈ߇޽ࠆߎߣ߆ࠄޔᖚ⠪ߦኻߒ⽺ⴊ ߒߥ޿ࠃ߁ߦࠦࡦ࠼࡯ࡓࠍ૶↪ߔࠆࠃ߁ᜰዉߔ 㧔8㧕ㆊᢅ∝╬ߩ෻ᔕࠍ੍᷹ߔࠆߚ߼චಽߥ໧⸻ ߦ㑐ㅪߔࠆ೽૞↪㧔߼߹޿╬㧕ߩ⊒⃻ߩน⢻ᕈߦ ࠆߎߣ㧔ޣ⼊๔ޤߩ㗄ෳᾖ㧕ޕ ࠍⴕ߁ߣߣ߽ߦޔ޽ࠄ߆ߓ߼ᧄ೷ߦࠃࠆࡊ࡝࠶ ߟ޿ߡචಽ⺑᣿ߔࠆߎߣޕ߹ߚޔቯᦼ⊛ߦ⥃ᐥᬌ 㧔6㧕ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ ࠢ⹜㛎෶ߪ⊹ౝ෻ᔕ⹜㛎ࠍⴕ߁ߎߣ߇ᦸ߹ߒ ᩏࠍⴕ߁ߥߤᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤߒޔ⇣Ᏹ߇ ⚵឵߃㧕ߣߩ૬↪ߩ႐วߦߪޔࡋࡕࠣࡠࡆࡦỚ ޿ޕ ⹺߼ࠄࠇߚ႐วߦߪᷫ㊂ޔભ⮎╬ߩㆡಾߥಣ⟎ࠍ ᐲޔ⊕ⴊ⃿ᢙޔᅢਛ⃿ᢙ෸߮ⴊዊ᧼ᢙߩᬌᩏ 㧔9㧕߼߹޿ޔ㍲ੂޔ௑⌁ޔ∋ഭࠍ⊒⃻ߔࠆߎߣ ⴕ߁ߎߣޕ ߪޔᛩਈ೨෸߮ᛩਈ㐿ᆎᓟ 8 ㅳ㑆ߪᲤㅳޔߘߩ ߇޽ࠆߩߢޔᧄ೷ᛩਈਛߩᖚ⠪ߦߪޔ⥄േゞߩ 㧔8㧕ᛥ߁ߟޔ⥄Ვડ࿑߇޽ࠄࠊࠇࠆߎߣ߇޽ ᓟߪ 4 ㅳ㑆ߦ 1 ᐲታᣉߔࠆߎߣޕ߹ߚޔ↢ൻቇ ㆇォޔᯏ᪾ߩᠲ૞ߦߥࠆߴߊᓥ੐ߐߖߥ޿ࠃ߁ ࠆޕ߹ߚޔば⁁ᘒޔ᡹᠄⊛ⴕേ߇޽ࠄࠊࠇޔઁኂ ⊛ᬌᩏߪ 4 ㅳ㑆ߦ 1 ᐲታᣉߔࠆߎߣޕ․ߦ C ဳ ᵈᗧߔࠆߎߣޕ ⴕὑߦ⥋ࠆߎߣ߇޽ࠆޕᖚ⠪ߩ♖␹⁁ᘒߦචಽᵈ ઍఘᕈ⢄⎬ᄌߦ߅޿ߡߪޔC ဳᘟᕈ⢄ἻߣᲧߴޔ 㧔10㧕㑆⾰ᕈ⢖Ἳ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩ ᗧߒޔਇ⌁ޔਇ቟ޔὶ῎ޔ⥝ᅗޔ᡹᠄ᕈޔᤃೝỗ ⴊ⃿♽ߩૐਅ߇ᄙߊ⹺߼ࠄࠇࠆ߅ߘࠇ߇޽ࠆߩ ߢޔ⊒ᾲޔຕ༿ޔ๭ๆ࿎㔍╬ߩ๭ๆེ∝⁁ߦච ᕈ╬߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤޔ ߢޔචಽᵈᗧߔࠆߎߣޕ ಽߦᵈᗧߒޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪޔㅦ߿ ᛩਈ⛮⛯ߩนุߦߟ޿ߡᘕ㊀ߦᬌ⸛ߔࠆߎߣޕ߹ ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕 ߆ߦ⢷ㇱ X ✢╬ߩᬌᩏࠍታᣉߔࠆߎߣޕ․ߦޔ ߚޔߎࠇࠄߩ∝⁁߇⹺߼ࠄࠇߚ႐วߦߪޔᛩਈ⚳ ߣߩ૬↪ߩ႐วߦߪޔࡋࡕࠣࡠࡆࡦỚᐲޔ⊕ⴊ 㑆⾰ᕈ⢖Ἳߩᣢᓔᱧߩ޽ࠆᖚ⠪ߦ૶↪ߔࠆߦ޽ ੌᓟ߽ⷰኤࠍ⛮⛯ߔࠆߎߣ߇ᦸ߹ߒ޿ޕ ⃿ᢙޔᅢਛ⃿ᢙ෸߮ⴊዊ᧼ᢙߩᬌᩏߪޔᛩਈ೨ ߚߞߡߪޔቯᦼ⊛ߦ⡬⸻ޔ⢷ㇱ X ✢╬ߩᬌᩏࠍ 㧔9㧕ᛥ߁ߟޔ⥄Ვડ࿑ࠍߪߓ߼ޔば⁁ᘒޔ᡹᠄ ෸߮ᛩਈ㐿ᆎᓟ 4 ㅳ㑆ߪᲤㅳޔߘߩᓟߪ 4 ㅳ㑆 ⴕ߁ߥߤޔචಽߦᵈᗧߔࠆߎߣޕ ⊛ⴕേޔਇ⌁ޔਇ቟ޔὶ῎ޔ⥝ᅗޔ᡹᠄ᕈޔᤃೝ ߦ 1 ᐲታᣉߔࠆߎߣޕࠗࡦ࠲࡯ࡈࠚࡠࡦ ࡌ࡯࠲ 㧔11㧕ᛥ߁ߟޔ⥄Ვડ࿑߇޽ࠄࠊࠇࠆߎߣ߇޽ ỗᕈ╬ߩ♖␹␹⚻∝⁁⊒⃻ߩน⢻ᕈߦߟ޿ߡᖚ⠪ ߣߩ૬↪ߩ႐วߦߪޔࡋࡕࠣࡠࡆࡦỚᐲޔ⊕ⴊ ࠆޕ߹ߚޔば⁁ᘒޔ᡹᠄⊛ⴕേ߇޽ࠄࠊࠇޔઁ ෸߮ߘߩኅᣖߦචಽℂ⸃ߐߖޔߎࠇࠄߩ∝⁁߇޽ ⃿ᢙޔᅢਛ⃿ᢙ෸߮ⴊዊ᧼ᢙߩᬌᩏߪޔᛩਈ㐿 ኂⴕὑߦ⥋ࠆߎߣ߇޽ࠆޕᖚ⠪ߩ♖␹⁁ᘒߦච ࠄࠊࠇߚ႐วߦߪ⋥ߜߦㅪ⛊ߔࠆࠃ߁ᵈᗧࠍਈ߃ ᆎᓟ 1 ㅳ㑆ߪ 2㨪3 ᣣߦ 1 ࿁ޔએᓟᛩਈ㐿ᆎᓟ 4 ಽᵈᗧߒޔਇ⌁ޔਇ቟ޔὶ῎ޔ⥝ᅗޔ᡹᠄ᕈޔ ࠆߎߣޕ ㅳ㑆߹ߢߪᲤㅳޔߘߩᓟߪ 4 ㅳ㑆ߦ 1 ࿁⒟ᐲታ ᤃೝỗᕈ╬߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߔ 㧔10㧕㜞ⴊ࿶∝෸߮♧ዩ∛ߩਔ∔ᖚࠍว૬ߔࠆᖚ ᣉߔࠆߎߣޕ ࠆߥߤޔᛩਈ⛮⛯ߩนุߦߟ޿ߡᘕ㊀ߦᬌ⸛ߔ ⠪ߢߪ⣖಴ⴊ߇↢ߓࠆ࡝ࠬࠢ߇㜞޿ߩߢᵈᗧߔࠆ ߹ߚޔᧄ೷ߩᛩਈߦ޽ߚߞߡߪޔ↲⁁⣼ᯏ⢻ᬌᩏ ࠆߎߣޕ߹ߚޔߎࠇࠄߩ∝⁁߇⹺߼ࠄࠇߚ႐ว ߎߣޕ ߪ 12 ㅳ㑆ߦ 1 ᐲታᣉߔࠆߎߣޕ ߦߪޔᛩਈ⚳ੌᓟ߽ⷰኤࠍ⛮⛯ߔࠆߎߣ߇ᦸ߹ 㧔7㧕ᧄ೷ߩᛩਈߦࠃࠅޔ⽺ⴊ㧔ṁⴊᕈ⽺ⴊ╬㧕 ߒ޿ޕ ࠍ⿠ߎߔน⢻ᕈ߇޽ࠆߎߣ߆ࠄޔᖚ⠪ߦኻߒ⽺ 㧔12㧕ᧄ೷ߩᛩਈߦ޽ߚߞߡߪޔᛥ߁ߟޔ⥄Ვ ⴊߦ㑐ㅪߔࠆ೽૞↪㧔߼߹޿╬㧕ߩ⊒⃻ߩน⢻ ડ࿑ࠍߪߓ߼ޔば⁁ᘒޔ᡹᠄⊛ⴕേޔਇ⌁ޔਇ ᕈߦߟ޿ߡචಽ⺑᣿ߔࠆߎߣޕ߹ߚޔቯᦼ⊛ߦ ቟ޔὶ῎ޔ⥝ᅗޔ᡹᠄ᕈޔᤃೝỗᕈ╬ߩ♖␹␹ ⥃ᐥᬌᩏࠍⴕ߁ߥߤᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤ ⚻∝⁁⊒⃻ߩน⢻ᕈߦߟ޿ߡᖚ⠪෸߮ߘߩኅᣖ ߒޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᷫ㊂ޔભ⮎╬ߩ ߦචಽℂ⸃ߐߖޔߎࠇࠄߩ∝⁁߇޽ࠄࠊࠇߚ႐ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ วߦߪ⋥ߜߦㅪ⛊ߔࠆࠃ߁ᵈᗧࠍਈ߃ࠆߎߣޕ

13 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

㧔8㧕ᛥ߁ߟ㧘⥄Ვડ࿑߇޽ࠄࠊࠇࠆߎߣ߇޽ 㧔12㧕߼߹޿ޔ㍲ੂޔ௑⌁ޔ∋ഭࠍ⊒⃻ߔࠆߎ ࠆ㧚߹ߚ㧘ば⁁ᘒ㧘᡹᠄⊛ⴕേ߇޽ࠄࠊࠇ㧘ઁኂ ߣ߇޽ࠆߩߢޔᧄ೷ᛩਈਛߩᖚ⠪ߦߪޔ⥄േゞ ⴕὑߦ⥋ࠆߎߣ߇޽ࠆ㧚ᖚ⠪ߩ♖␹⁁ᘒߦචಽߦ ߩㆇォޔᯏ᪾ߩᠲ૞ߦߥࠆߴߊᓥ੐ߐߖߥ޿ࠃ ᵈᗧߒ㧘ਇ⌁㧘ਇ቟㧘ὶ῎㧘⥝ᅗ㧘᡹᠄ᕈ㧘ᤃೝ ߁ᵈᗧߔࠆߎߣޕ ỗᕈ╬߇޽ࠄࠊࠇߚ႐วߦߪᧄ೷ᛩਈࠍਛᱛߔࠆ 㧔13㧕B ဳᘟᕈᵴേᕈ⢄Ἳߦ߅޿ߡߪޔᛩਈ⚳ੌ ߥߤ㧘ᴦ≮⛮⛯ߩนุߦߟ޿ߡᘕ㊀ߦᬌ⸛ߔࠆߎ ᓟߦ⪺ߒ޿࠻࡜ࡦࠬࠕࡒ࠽࡯࠯਄᣹㨇ALT ߣ㧚߹ߚ㧘ߎࠇࠄߩ∝⁁߇⹺߼ࠄࠇߚ႐วߦߪ㧘 㧔GPT㧕҈500IU/L㨉߇޽ࠄࠊࠇࠆ߅ߘࠇ߇޽ࠆ ᛩਈ⚳ੌᓟ߽ⷰኤࠍ⛮⛯ߔࠆߎߣ߇ᦸ߹ߒ޿㧚 ߩߢޔᛩਈ⚳ੌᓟ߽ቯᦼ⊛ߦ⢄ᯏ⢻ᬌᩏࠍⴕ 㧔9㧕ᛥ߁ߟ㧘⥄Ვડ࿑ࠍߪߓ߼㧘ば⁁ᘒ㧘᡹᠄ ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪㆡಾߥಣ⟎ࠍⴕ ⊛ⴕേ㧘ਇ⌁㧘ਇ቟㧘ὶ῎㧘⥝ᅗ㧘᡹᠄ᕈ㧘ᤃೝ ߁ߎߣޕ ỗᕈ╬ߩ♖␹␹⚻∝⁁⊒⃻ߩน⢻ᕈߦߟ޿ߡ㧘ᖚ ⠪෸߮ߘߩኅᣖߦචಽ⺑᣿ߒ㧘ߎࠇࠄߩ∝⁁߇޽ ࠄࠊࠇߚ႐วߦߪ⋥ߜߦㅪ⛊ߔࠆࠃ߁ᵈᗧࠍਈ߃ ࠆߎߣ㧚

3㧚⋧੕૞↪ 3㧚⋧੕૞↪ 3. ⋧੕૞↪ ࠪࡔࡊ࡟ࡆ࡞ߪਥߦ CYP3A ߦࠃࠅઍ⻢ߐࠇࠆޕ ᧄ೷ߪઍ⻢㉂⚛࠴࠻ࠢࡠ࡯ࡓ P450 3A4/5 ࠪࡔࡊ࡟ࡆ࡞ߪ࠻࡜ࡦࠬࡐ࡯࠲࡯㨇P ♧Ⱞ⊕㧔P- 㧔CYP3A4/5㧕㒖ኂ૞↪ࠍ᦭ߔࠆߎߣ߆ࠄ㧘 gp㧕ޔOATP1B1㨉ߩၮ⾰ߢ޽ࠅޔ߹ߚޔ CYP3A4/5 ߦࠃࠅઍ⻢ߐࠇࠆ⮎೷ߣ૬↪ߒߚߣ CYP3AޔP-gp ෸߮ OATP1B1 ࠍ㒖ኂߔࠆޕ ߈㧘૬↪⮎೷ߩⴊਛỚᐲࠍ਄᣹ߐߖࠆ߅ߘࠇ߇޽

㨇ޟ⮎‛േᘒޠߩ㗄ෳᾖ㨉 ࠆ㧚߹ߚ㧘ᧄ೷ߪ CYP3A4 ߦࠃߞߡઍ⻢ߐࠇࠆߎ ߣ߆ࠄ㧘CYP3A4 ࠍ⺃ዉߔࠆ⮎೷ߣ૬↪ߒߚߣ߈ ᧄ೷ߩⴊਛỚᐲ߇ૐਅߒ㧘CYP3A4 ࠍ㒖ኂߔࠆ⮎ ೷ߣ૬↪ߒߚߣ߈ᧄ೷ߩⴊਛỚᐲ߇਄᣹ߔࠆ߅ߘ ࠇ߇޽ࠆ㧚

૶↪਄ ߩᵈᗧ

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04

14 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 㧔8㧕㜞ⴊ࿶∝෸߮♧ዩ∛ߩਔ∔ᖚࠍว૬ߔࠆᖚ   ⠪ߢߪ⣖಴ⴊ߇↢ߓࠆ࡝ࠬࠢ߇㜞޿ߩߢᵈᗧߔ   ࠆߎߣޕ㧔ޟᘕ㊀ᛩਈޠ෸߮ޟ㊀ᄢߥ೽૞↪ޠ   ߩ㗄ෳᾖ㧕   㧔9㧕ᛥ߁ߟޔ⥄Ვડ࿑߇޽ࠄࠊࠇࠆߎߣ߇޽   ࠆޕ߹ߚޔば⁁ᘒޔ᡹᠄⊛ⴕേ߇޽ࠄࠊࠇޔઁ   ኂⴕὑߦ⥋ࠆߎߣ߇޽ࠆޕᖚ⠪ߩ♖␹⁁ᘒߦච   ಽᵈᗧߒޔਇ⌁ޔਇ቟ޔὶ῎ޔ⥝ᅗޔ᡹᠄ᕈޔ   ᤃೝỗᕈ╬߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߔ   ࠆߥߤޔᛩਈ⛮⛯ߩนุߦߟ޿ߡᘕ㊀ߦᬌ⸛ߔ   ࠆߎߣޕ߹ߚޔߎࠇࠄߩ∝⁁߇⹺߼ࠄࠇߚ႐ว   ߦߪޔᛩਈ⚳ੌᓟ߽ⷰኤࠍ⛮⛯ߔࠆߎߣ߇ᦸ߹   ߒ޿ޕ   㧔10㧕ᛥ߁ߟޔ⥄Ვડ࿑ࠍߪߓ߼ޔば⁁ᘒޔ᡹᠄   ⊛ⴕേޔਇ⌁ޔਇ቟ޔὶ῎ޔ⥝ᅗޔ᡹᠄ᕈޔᤃ   ೝỗᕈ╬ߩ♖␹␹⚻∝⁁⊒⃻ߩน⢻ᕈߦߟ޿ߡ   ᖚ⠪෸߮ߘߩኅᣖߦචಽℂ⸃ߐߖޔߎࠇࠄߩ∝   ⁁߇޽ࠄࠊࠇߚ႐วߦߪ⋥ߜߦㅪ⛊ߔࠆࠃ߁ᵈ   ᗧࠍਈ߃ࠆߎߣޕ    3.⋧੕૞↪ 3.⋧੕૞↪ 3.⋧੕૞↪

૶↪਄ ߩᵈᗧ

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04

15 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

1㧕૬↪⑌ᔊ㧔૬↪ߒߥ޿ߎߣ㧕 㧔1㧕૬↪⑌ᔊ㧔૬↪ߒߥ޿ߎߣ㧕 㧔1㧕૬↪⑌ᔊ㧔૬↪ߒߥ޿ߎߣ㧕 ⥃ᐥ∝⁁࡮ភ⟎ ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇ ᯏᐨ࡮ෂ㒾࿃ሶ ⮎೷ฬ╬ ᯏᐨ࡮ෂ㒾࿃ሶ ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ ᯏᐨ࡮ෂ㒾࿃ ᣇᴺ ᴺ ភ⟎ᣇᴺ ሶ ࠛࡈࠔࡆ࡟ࡦ࠷ ᧄ೷ߩⴊẏਛỚ ߎࠇࠄߩ⮎೷ߩ ࠠ࠾ࠫࡦ⎫㉄Ⴎ᳓ ߎࠇࠄ⮎೷ߦࠃࠆ ᧄ೷ߩ࠴࠻ࠢࡠ ዊᩊ⢫ḡ 㑆⾰ᕈ⢖Ἳ ᯏᐨߪਇ᣿ߢ ࠬ࠻࠶ࠢ࡝ࡦ ᐲ߇⪺ߒߊૐਅ ᒝ޿ %;2#  ⺃ ๺‛ ㊀◊ߥ෶ߪ↢๮ߦ ࡯ࡓ P450 ߦኻ ࡝ࡈࠔࡦࡇࠪࡦ ߒޔᧄ೷ߩലᨐ ዉ૞↪ߦࠃࠅޔ 㧔⎫㉄ࠠ࠾ࠫࡦ㧕 ෂ㒾ࠍ෸߷ߔࠃ߁ ߔࠆ㒖ኂ૞↪ߦ 㧔࠷ࡓ࡜ዊᩊ⢫ḡ ߇޽ࠄࠊࠇ ޽ࠆ߇ޔ㑆⾰ ࡝ࡈࠔࠫࡦ╬ ߇ᷫᒙߔࠆޕ ᧄ೷ߩઍ⻢߇ଦ ࡌࡊ࡝ࠫ࡞Ⴎ㉄Ⴎ ߥ੐⽎㧔ਇᢛ⣂㧘 ࠃࠅ㧘ߎࠇࠄߩ ࠛࠠࠬޔࠢ࡜ࠪࠛ ࠆߎߣ߇޽ ᕈ⢖Ἳߩ⊒⃻ ࡝ࡈࠔࡉ࠴ࡦ ㅴߐࠇࠆޕ ᳓๺‛ ⴊᶧ㓚ኂ㧘ⴊ▤ᡨ ⮎೷ߩઍ⻢߇㒖 ዊᩊ⢫ḡࠛࠠࠬޔ ࠆޕ ଀ߦߪዊᩊ⢫ ࡒࠦࡉ࠹ࠖࡦ 㧔ࡌࡊ࡝ࠦ࡯࡞㧕 ❗╬㧕߇⿠ߎࠆ߅ ኂߐࠇⴊਛỚᐲ ࠹ࠗࠦࠢዊᩊ⢫ḡ ḡߣߩ૬↪଀ ࡈ࡟ࠞࠗ࠾࠼㈶㉄ ߘࠇ߇޽ࠆ㧚 ߇਄᣹ߒ㧘૞↪ ࠛࠠࠬ ╬㧕 ߇ᄙ޿ޕ Ⴎ ߩჇᒝ߿⋧ട⊛ 㧔࠲ࡦࡏࠦ࡯࡞㧕 ߥ QT ᑧ㐳ࠍ⿠ ࡊࡠࡄࡈࠚࡁࡦႮ ߎߔ߅ߘࠇ߇޽ ㉄Ⴎ ࠆ㧚 㧔ࡊࡠࡁࡦ╬㧕 ࠕࡒࠝ࠳ࡠࡦႮ㉄ Ⴎ㧔ࠕࡦࠞࡠࡦ㧕 ࡇࡕࠫ࠼ 㧔ࠝ࡯࡜࠶ࡊ㧕 ࠛ࡞ࠧ࠲ࡒࡦ㈬⍹ ߎࠇࠄ⮎೷ߩⴊਛ ᧄ೷ߩ ㉄Ⴎ Ớᐲ߇਄᣹ߒ㧘ᧃ CYP3A4/5 ߦኻ 㧔ࠢ࡝ࠕࡒࡦ㧕 ᪳ⴊ▤ᡨ❗㧘⯯ⴊ ߔࠆ㒖ኂ૞↪ߦ ࠫࡅ࠼ࡠࠛ࡞ࠧ࠲ ╬ߩ㊀◊ߥ෶ߪ↢ ࠃࠅ㧘ߎࠇࠄߩ ࡒࡦࡔࠪ࡞㉄Ⴎ ๮ߦෂ㒾ࠍ෸߷ߔ ⮎೷ߩઍ⻢߇㒖 㧔ࠫࡅ࠺࡞ࠧ࠶࠻ ࠃ߁ߥ੐⽎߇⿠ߎ ኂߐࠇࠆ㧚 ╬㧕 ࠆ߅ߘࠇ߇޽ࠆ㧚

ࠛ࡞ࠧࡔ࠻࡝ࡦࡑ ࡟ࠗࡦ㉄Ⴎ 㧔ࠛ࡞ࠧࡔ࠻࡝ࡦ ࡑ࡟ࠗࡦ㉄Ⴎ㧕 ࡔ࠴࡞ࠛ࡞ࠧࡔ࠻ ࡝ࡦࡑ࡟ࠗࡦ㉄Ⴎ 㧔ࡔ࠹࡞ࠡࡦ╬㧕 ࠻࡝ࠕ࠱࡜ࡓ ࠻࡝ࠕ࠱࡜ࡓߩઍ 㧔ࡂ࡞ࠪࠝࡦ╬㧕 ⻢߇ᛥ೙ߐࠇ㧘ㆊ ᐲߩ㎾㕒߿๭ๆᛥ ೙╬߇⿠ߎࠆ߅ߘ ࠇ߇޽ࠆ㧚 ࡠࡃࠬ࠲࠴ࡦ㧔࿖ ᧄ೷ 750mg 1 ᣣ 3 ࿁ ౝᧂᛚ⹺㧕 ࠍ 6 ᣣ㑆᦯↪ᓟ㧘 ࠪࡦࡃࠬ࠲࠴ࡦ ࠕ࠻࡞ࡃࠬ࠲࠴ࡦ 㧔࡝ࡐࡃࠬ╬㧕 ࠞ࡞ࠪ࠙ࡓ᳓๺‛ ࠕ࠻࡞ࡃࠬ࠲࠴ࡦ 20mg 1 ᣣ 1 ࿁ࠍ૬ ࠞ࡞ࠪ࠙ࡓ᳓๺‛ ↪ߒߚߣ߈㧘ࠕ࠻ 㧔࡝ࡇ࠻࡯࡞㧘ࠞ ࡞ࡃࠬ࠲࠴ࡦߩ

࠺ࡘࠛ࠶࠻㧕 AUC ߇ 7.9 ୚ߦ਄ ᣹ߒߚ㧚ߎࠇࠄߩ ⮎೷ߩⴊਛỚᐲ߇ ਄᣹ߒ㧘㊀◊ߥ෶ ߪ↢๮ߦෂ㒾ࠍ෸ ૶↪਄ ߷ߔࠃ߁ߥ੐⽎ ߩᵈᗧ 㧔ᮮ⚉╭Ⲣ⸃∝ࠍ ฽߻ࡒࠝࡄࠪ࡯ ╬㧕߇⿠ߎࠆ߅ߘ ࠇ߇޽ࠆ㧚 ࠕ࡞ࡈ࠱ࠪࡦ㧔࿖ ߎࠇࠄ⮎೷ߩⴊਛ ౝᧂᛚ⹺㧕 Ớᐲ߇਄᣹ߒ㧘ૐ ࡃ࡞࠺࠽ࡈࠖ࡞Ⴎ ⴊ࿶߿ਇᢛ⣂ࠍ⿠ ㉄Ⴎ᳓๺‛㧔࡟ࡆ ߎߔ߅ߘࠇ߇޽ ࠻࡜㧕 ࠆ㧚 JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ࠪ࡞࠺࠽ࡈࠖ࡞ࠢ ࠛࡦ㉄Ⴎ㧔⢖㜞ⴊ ࿶∝ࠍㆡᔕߣߔࠆ

႐ว㧕 㧔࡟ࡃ࠴ࠝ㧕 ࠲࠳࡜ࡈࠖ࡞ 㧔⢖㜞ⴊ࿶∝ࠍㆡ ᔕߣߔࠆ႐ว㧕 㧔ࠕ࠼ࠪ࡞ࠞ㧕 ࡉࡠ࠽ࡦ࠮࡝ࡦ ࡉࡠ࠽ࡦ࠮࡝ࡦߩ 㧔ࡠ࠽࠮ࡦ㧕 ⴊਛỚᐲ߇਄᣹ ߒ㧘૞↪߇Ⴧᒝߔ ࠆ߅ߘࠇ߇޽ࠆ㧚 ࠦ࡞ࡅ࠴ࡦ ࠦ࡞ࡅ࠴ࡦߩⴊਛ 㧔⢄⤳෶ߪ⣢⤳ߦ Ớᐲ߇਄᣹ߔࠆ߅ 㓚ኂߩ޽ࠆᖚ⠪ߦ ߘࠇ߇޽ࠆ㧚 ૶↪ߔࠆ႐ว㧕 㧔ࠦ࡞ࡅ࠴ࡦ㧕 ࡝ࡈࠔࡦࡇࠪࡦ ࡝ࡈࠔࡦࡇࠪࡦ 600 ࡝ࡈࠔࡦࡇࠪࡦ 㧔ࠕࡊ࠹ࠪࡦ㧘࡝ mg1 ᣣ 1 ࿁ࠍ 7 ᣣ㑆 ߩ CYP3A4 ߦኻ ࡈࠔࠫࡦ㧘࡝ࡑࠢ ᦯↪ᓟ㧘ᧄ೷ 750 ߔࠆ⺃ዉ૞↪ߦ ࠲ࡦ╬㧕 mg 1 ᣣ 1 ࿁ࠍ૬↪ ࠃࠅ㧘ᧄ೷ߩઍ ߒߚߣ߈㧘ᧄ೷ߩ ⻢߇ଦㅴߐࠇ

AUC ߇ 92 % ૐਅߒ ࠆ㧚 ߚ㧚ᧄ೷ߩലᨐ߇ ᷫᒙߔࠆ߅ߘࠇ߇ ޽ࠆ㧚

16 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 㧔1㧕૬↪⑌ᔊ㧔૬↪ߒߥ޿ߎߣ㧕 ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ ᯏᐨ࡮ෂ㒾࿃ሶ

ᣇᴺ

ዊᩊ⢫ḡ ઁߩࠗࡦ࠲࡯ࡈ ૞↪ᯏᐨߪਇ᣿ 㧔࠷ࡓ࡜ዊ ࠚࡠࡦ ࠕ࡞ࡈࠔ ߢ޽ࠆ߇ޔ㑆⾰ ᩊ⢫ḡޔࠢ࡜ ⵾೷ߣߩ૬↪ߢ ᕈ⢖Ἳߩ⊒⃻଀ ࠪࠛዊᩊ⢫ḡ 㑆⾰ᕈ⢖Ἳ߇ႎ ߦߪዊᩊ⢫ḡߣ ╬㧕 ๔ߐࠇߡ޿ࠆޕ ߩ૬↪଀߇ᄙ ޿ޕ

૶↪਄

ߩᵈᗧ

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04

17 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

2㧕૬↪ᵈᗧ㧔૬↪ߦᵈᗧߔࠆߎߣ㧕 㧔2㧕૬↪ᵈᗧ㧔૬↪ߦᵈᗧߔࠆߎߣ㧕 㧔2㧕૬↪ᵈᗧ㧔૬↪ߦᵈᗧߔࠆߎߣ㧕 ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ ⮎೷ฬ╬ ⥃ᐥᣇᴺ࡮ភ⟎ᣇ ᯏᐨ࡮ෂ㒾࿃ሶ ᒝജߥ ᧄ೷ߩⴊẏਛỚᐲ߇ ߎࠇࠄߩ⮎೷ߩ ࠞ࡞ࡃࡑ࠯ࡇ ᧄ೷ߩⴊਛỚᐲ߇ૐ ߎࠇࠄߩ⮎೷ߩ ᴺ CYP3A 㒖ኂ ਄᣹ߒޔ೽૞↪߇⊒ CYP3A 㒖ኂ૞↪ߦ ࡦ ਅߒ㧘ᧄ೷ߩലᨐ߇ CYP3A4 ߦኻߔࠆ⺃ ࠹ࠝࡈࠖ࡝ Ꮐ⸥ߩ⮎೷ߩⴊਛ ⢄࠴࠻ࠢࡠࡓ ೷ ⃻ߔࠆ߅ߘࠇ߇޽ࠆ ࠃࠅޔᧄ೷ߩઍ⻢ ࡝ࡈࠔࡉ࠴ࡦ ᷫᒙߔࠆ߅ߘࠇ߇޽ ዉ૞↪ߦࠃࠅ㧘ᧄ ࡝࠻࠽ࡆ࡞ ߩߢޔCYP3A 㒖ኂ૞ ߇㒖ኂߐࠇࠆޕ ࠆ㧚ߎࠇࠄߩ⮎೷ߩ ೷ߩઍ⻢߇ଦㅴߐ ࡦ Ớᐲ߇㜞߹ࠆߎߣ P450 ࠳࡞࠽ࡆ࡞/ ↪ߩߥ޿෶ߪᒙ޿⮎ ⴊਛỚᐲ߇਄᣹ߔࠆ ࠇࠆ㧚ᧄ೷ߩ ࠕࡦ࠴ࡇ࡝ ߇ႎ๔ߐࠇߡ޿ 㧔CYP1A2㧕ߩ ࡝࠻࠽ࡆ࡞ ೷߳ߩઍᦧࠍ⠨ᘦߔ ߅ߘࠇ߇޽ࠆ㧚ࠞ࡞ CYP3A4/5 ߦኻߔࠆ ࡦ ࠆޕ࠹ࠝࡈࠖ࡝ࡦ ᵴᕈࠍᛥ೙ߒޔ ࠢ࡜࡝ࠬࡠࡑ ࠆߎߣޕᧄ೷ߣߎࠇ ࡃࡑ࠯ࡇࡦߦߟ޿ߡ 㒖ኂ૞↪ߦࠃࠅ㧘 ߩ AUC ߇⚂ 25㧑 ⢄⤳ߢߩฦ⒳ක ࠗࠪࡦ ࠄ⮎೷ࠍ૬↪ߔࠆ႐ ߪ㧘ᦸ߹ߒ޿⥃ᐥ෻ ߎࠇࠄߩ⮎೷ߩઍ Ⴧടߒߚߣߩႎ๔ ⮎ຠߩઍ⻢ࠍᛥ ࠗ࠻࡜ࠦ࠽࠱ วߪޔᖚ⠪ߩ⁁ᘒࠍ ᔕ߇ᓧࠄࠇࠆࠃ߁ߦ ⻢߇㒖ኂߐࠇࠆ㧚 ࡯࡞ ᘕ㊀ߦⷰኤߒޔ೽૞ ⴊਛỚᐲࡕ࠾࠲࡝ࡦ ߇޽ࠆޕ࠹ࠝࡈࠖ ೙ߔࠆߣ⠨߃ࠄ ࡏ࡝ࠦ࠽࠱࡯ ↪⊒⃻ߦචಽᵈᗧߔ ࠣࠍⴕ߁ߥߤᵈᗧߔ ࡝ࡦߩⴊẏਛỚᐲ ࠇߡ޿ࠆޕ ࡞ ࠆߎߣޕ ࠆߎߣ㧚 ࠍ᷹ቯߒޔ࠹ࠝࡈ ࠦࡆࠪࠬ࠲࠶ ᧄ೷ 200mg 1 ᣣ 1 ࿁ߣ ࡈࠚࡁࡃ࡞ࡆ ᧄ೷ߩⴊਛỚᐲ߇ૐ ߎࠇࠄߩ⮎೷ߩ ࠖ࡝ࡦߩ↪㊂ࠍ⺞ ࠻ࠍ฽߻⮎೷ ࡝࠻࠽ࡆ࡞ 100mg 1 ᣣ ࠲࡯࡞࠽࠻࡝ ਅߒ㧘ᧄ೷ߩലᨐ߇ CYP3A4 ߦኻߔࠆ⺃ ▵ߔࠆߎߣ㧔ޣ⮎ ╬ 2 ࿁ࠍ૬↪ߒߚߣ߈ޔ ࠙ࡓ ᷫᒙߔࠆ߅ߘࠇ߇޽ ዉ૞↪ߦࠃࠅ㧘ᧄ ᧄ೷ߩ AUC ߇ 7.2 ୚ ࡈࠚ࠾࠻ࠗࡦ ࠆ㧚ߎࠇࠄߩ⮎೷ߩ ೷ߩઍ⻢߇ଦㅴߐ ‛േᘒޤߩ㗄ෳ ߦ਄᣹ߒߚޕ ⴊਛỚᐲ߇ᄌൻߔࠆ ࠇࠆ㧚 ᾖ㧕ޕ ᧄ೷ 50mg 1 ᣣ 1 ࿁ߣ ߅ߘࠇ߇޽ࠆ㧚ᦸ߹ ఺∉ᛥ೙≮ ⒖ᬀᖚ⠪㧔⣢࡮㛽 ⒖ᬀ ߦኻߔࠆ ࠳࡞࠽ࡆ࡞/࡝࠻࠽ࡆ ߒ޿⥃ᐥ෻ᔕ߇ᓧࠄ ᴺ 㜑⒖ᬀ╬㧕ߦ߅ߌ ᜎ⛘෻ᔕ߇⺃⊒ ࡞ 800mg/100mg 1 ᣣ 1 ࠇࠆࠃ߁ߦⴊਛỚᐲ ࠆ఺∉ᛥ೙≮ᴺߩ ߐࠇࠆߣ⠨߃ࠄ ࿁ࠍ૬↪ߒߚߣ߈ޔ ࡕ࠾࠲࡝ࡦࠣࠍⴕ߁ ᧄ೷ 150mg1 ᣣ 1 ࿁න ߥߤᵈᗧߔࠆߎߣ㧚 ലᨐ߇ᒙ߹ࠆߎߣ ࠇߡ޿ࠆޕ ⁛ᛩਈߒߚߣ߈ߣᲧ ࠺ࠠࠨࡔ࠲࠱ ᧄ೷ߩⴊਛỚᐲ߇ૐ ࠺ࠠࠨࡔ࠲࠱ࡦߩ ߇޽ࠆޕ ߒߡޔᧄ೷ߩ AUC ߇ ࡦ㧔ోりᛩ ਅߒ㧘ᧄ೷ߩലᨐ߇ CYP3A4 ߦኻߔࠆ⺃ 2.6 ୚ߦ਄᣹ߒߚޕ ਈ㧕 ᷫᒙߔࠆ߅ߘࠇ߇޽ ዉ૞↪ߦࠃࠅ㧘ᧄ ࡒ࡞ࠢࠪࠬ࡞ ᧄ೷ߩⴊẏਛỚᐲ߇ ࠆ㧚 ೷ߩઍ⻢߇ଦㅴߐ 㧔ࡑ࡝ࠕࠕࠩ ਄᣹ߒޔ೽૞↪߇⊒ ࠇࠆ㧚 ࡒ㧕฽᦭㘩ຠ ⃻ߔࠆ߅ߘࠇ߇޽ࠆ ࠮࡛ࠗ࠙ࠝ࠻ ᧄ೷ߩⴊਛỚᐲ߇ૐ ࠮࡛ࠗ࠙ࠝ࠻ࠡ࡝ ߩߢޔᖚ⠪ߩ⁁ᘒࠍ ࠡ࡝࠰࠙ ਅߒ㧘ᧄ೷ߩലᨐ߇ ࠰࠙ߦࠃࠆ ᘕ㊀ߦⷰኤߒޔ೽૞ 㧔St.John's ᷫᒙߔࠆ߅ߘࠇ߇޽ CYP3A4 ߦኻߔࠆ⺃ ↪⊒⃻ߦචಽᵈᗧߔ wort㧘࠮ࡦ ࠆ㧚ᧄ೷ᛩਈᤨߪ࠮ ዉ૞↪ߦࠃࠅ㧘ᧄ ࠆߎߣޕ ࠻࡮࡚ࠫ࡯ࡦ ࡛ࠗ࠙ࠝ࠻ࠡ࡝࠰࠙ ೷ߩઍ⻢߇ଦㅴߐ ઁߩ HIV ࡊ ᧄ೷ߩⴊẏਛỚᐲߦ ߎࠇࠄߩ⮎೷ߩ ࠭࡮ࡢ࡯࠻㧕 ฽᦭㘩ຠࠍ៨ขߒߥ ࠇࠆ㧚 ࡠ࠹ࠕ࡯࠯㒖 ᓇ㗀ࠍ෸߷ߔ߅ߘࠇ CYP3A 㒖ኂ૞↪෶ ฽᦭㘩ຠ ޿ࠃ߁ᵈᗧߔࠆߎ ኂ೷ ߇޽ࠆޕᧄ೷ߩⴊẏ ߪ⺃ዉ૞↪ߦࠃ ߣ㧚 ࠕ࠲ࠩ࠽ࡆ࡞ ਛỚᐲ߇ૐਅߒᧄ೷ ࠅޔᧄ೷ߩઍ⻢߇ ࠫࠧࠠࠪࡦ ᧄ೷ 750 mg 1 ᣣ 3 ࿁ ᧄ೷ߩ P̃ ♧Ⱞ⊕⾰ ࡎࠬࠕࡦࡊ࡟ ߩലᨐ߇ᷫᒙߔࠆޔ 㒖ኂ෶ߪଦㅴߐࠇ ࠍ 11 ᣣ㑆᦯↪ᓟ㧘 ࠫ 㒖ኂ૞↪ߦࠃࠆ㧚 ࠽ࡆ࡞ ߽ߒߊߪᧄ೷ߩⴊẏ ࠆޕ ࠧࠠࠪࡦ 0.5 mg 1 ᣣ 1 ࡠࡇ࠽ࡆ࡞ ਛỚᐲ߇਄᣹ߒ೽૞ ࿁ࠍ૬↪ߒߚߣ߈㧘 ࠗࡦࠫ࠽ࡆ࡞ ↪߇⊒⃻ߔࠆ߅ߘࠇ ࠫࠧࠠࠪࡦߩ AUC ߇ ࡀ࡞ࡈࠖ࠽ࡆ ߇޽ࠆߩߢޔᧄ೷ߣ 85%਄᣹ߒߚ㧚ᧄ೷ߣ ࡞ ૬↪ߔࠆ႐วߪචಽ ࠫࠧࠠࠪࡦࠍ૬↪ߔ ࠨࠠ࠽ࡆ࡞ ᵈᗧߔࠆߎߣޕ ࠆ㓙ߪ㧘ࠫࠧࠠࠪࡦ ઁߩ㕖࠿ࠢ࡟ ᧄ೷ߩⴊẏਛỚᐲ߇ ߎࠇࠄߩ⮎೷ߩ ߩᦨૐ↪㊂߆ࠄᛩਈ ࠝࠪ࠼♽ㅒォ ૐਅߒޔᧄ೷ߩലᨐ CYP3A(4)⺃ዉ૞↪ 㐿ᆎߒ㧘ⴊਛỚᐲࡕ ౮㉂⚛㒖ኂ೷ ߇ᷫᒙߔࠆ߅ߘࠇ߇ ߦࠃࠅޔᧄ೷ߩઍ ࠾࠲࡝ࡦࠣࠍⴕ߁ߥ ࠛ࠻࡜ࡆ࡝ࡦ ޽ࠆߩߢޔᧄ೷ߣ૬ ⻢߇ଦㅴߐࠇࠆޕ ߤᵈᗧߔࠆߎߣ㧚 ࡀࡆ࡜ࡇࡦ ↪ߔࠆ႐วߪචಽᵈ ࠗ࠻࡜ࠦ࠽࠱ ᧄ೷ 750 mg ߣࠤ࠻ࠦ ߎࠇࠄߩ⮎೷ߩ ૶↪਄ ᗧߔࠆߎߣޕ ࡯࡞ ࠽࠱࡯࡞ 400 mg ࠍන CYP3A4 ߦኻߔࠆ㒖 ߩᵈᗧ ࠞ࡞ࡃࡑ࠯ࡇ ᧄ೷ߩⴊẏਛỚᐲ߇ ࠤ࠻ࠦ࠽࠱࡯ ࿁૬↪ߒߚߣ߈㧘ᧄ ኂ૞↪ߦࠃࠅ㧘ᧄ ࡦ ૐਅߒޔᧄ೷ߩലᨐ ࡞ ೷ߩ AUC ߇ 62 % ਄ ೷ߩઍ⻢߇㒖ኂߐ ࡈࠚࡁࡃ࡞ࡆ ߇ᷫᒙߔࠆ߅ߘࠇ߇ ࡐࠨࠦ࠽࠱࡯ ᣹ߒߚ㧚ᧄ೷ߩⴊਛ ࠇࠆ㧚ߎࠇࠄߩ⮎ ࠲࡯࡞ ޽ࠆߩߢޔᧄ೷ߣ૬ ࡞㧔࿖ౝᧂᛚ Ớᐲ෸߮ߎࠇࠄߩ⮎ ೷ߪ CYP3A4/5 ߢ ࡈࠚ࠾࠻ࠗࡦ ↪ߔࠆ႐วߪචಽᵈ ⹺㧕 ೷ߩⴊਛỚᐲ߇਄᣹ ઍ⻢ߐࠇࠆߚ߼㧘 ᗧߔࠆߎߣޕ ࠢ࡜࡝ࠬࡠࡑ ߔࠆ߅ߘࠇ߇޽ࠆ㧚 ᧄ೷ߣߩ૬↪ߦࠃ ࠮࡛ࠗ࠙ࠝ࠻ ᧄ೷ߩⴊẏਛỚᐲ߇ ࠗࠪࡦ ᧄ೷ߣߎࠇࠄߩ⮎೷ ࠅઍ⻢߇㒖ኂߐࠇ ࠡ࡝࠰࠙㧔St. ૐਅߒޔᧄ೷ߩലᨐ ࠛ࡝ࠬࡠࡑࠗ ࠍ૬↪ߔࠆߣ㧘QT ᑧ ࠆ㧚

John̉s ߇ᷫᒙߔࠆ߅ߘࠇ߇ ࠪࡦࠛ࠴࡞ࠦ 㐳ࠍ⿠ߎߔ߅ߘࠇ߇ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 Wortޔ࠮ࡦ ޽ࠆߩߢޔᧄ೷ߣ૬ ࡂࠢ㉄ࠛࠬ࠹ ޽ࠆߩߢ㧘ᵈᗧߔࠆ ࠻࡮࡚ࠫ࡯ࡦ ↪ߔࠆ႐วߪචಽᵈ ࡞ ߎߣ㧚 ࠭࡮ࡢ࡯࠻㧕 ᗧߔࠆߎߣޕ ࠹࡝ࠬࡠࡑࠗ ฽᦭㘩ຠ ࠪࡦ ࠺ࠠࠨࡔ࠲ ᧄ೷ߩⴊẏਛỚᐲ߇ ࠻ࡠ࡟ࠕࡦ࠼ ࠱ࡦ㧔ోり ૐਅߒޔᧄ೷ߩലᨐ ࡑࠗࠪࡦ㧔࿖ ᕈ㧕 ߇ᷫᒙߔࠆ߅ߘࠇ߇ ౝᧂᛚ⹺㧕 ޽ࠆߩߢޔᧄ೷ߣ૬ ࡏ࡝ࠦ࠽࠱࡯ ᧄ೷ߩⴊਛỚᐲ߇਄ ࡏ࡝ࠦ࠽࠱࡯࡞ߩ ↪ߔࠆ႐วߪචಽᵈ ࡞ ᣹ߔࠆ߅ߘࠇ߇޽ CYP3A4 ߦኻߔࠆ㒖 ᗧߔࠆߎߣޕ ࠆ㧚ࡏ࡝ࠦ࠽࠱࡯࡞ ኂ૞↪ߦࠃࠅ㧘ᧄ ࠛ࡝ࠬࡠࡑࠗ ᧄ೷෸߮ࠛ࡝ࠬࡠࡑ ᧄ೷෸߮ࠛ࡝ࠬࡠ ߩⴊਛỚᐲ߇਄᣹෶ ೷ߩઍ⻢߇㒖ኂߐ ࠪࡦ ࠗࠪࡦߩⴊẏਛỚᐲ ࡑࠗࠪࡦߩ CYP3A ߪૐਅߔࠆ߅ߘࠇ߇ ࠇࠆ㧚ࡏ࡝ࠦ࠽࠱

߇਄᣹ߒޔ೽૞↪߇ ෸߮ P-gp 㒖ኂ૞↪ ޽ࠆ㧚ᧄ೷ߣࡏ࡝ࠦ ࡯࡞ߪ CYP3A4/5 ⊒⃻ߔࠆ߅ߘࠇ߇޽ ߦࠃࠅޔᧄ೷෸߮ ࠽࠱࡯࡞ࠍ૬↪ߔࠆ ߢઍ⻢ߐࠇࠆߚ ࠆߩߢޔCYP3A 㒖ኂ ࠛ࡝ࠬࡠࡑࠗࠪࡦ ߣ㧘QT ᑧ㐳ࠍ⿠ߎߔ ߼㧘ᧄ೷ߣߩ૬↪ ૞↪ߩߥ޿෶ߪᒙ޿ ߩઍ⻢෸߮ឃ಴߇ ߅ߘࠇ߇޽ࠆߩߢ㧘 ߦࠃࠅઍ⻢߇㒖ኂ ⮎೷߳ߩઍᦧࠍ⠨ᘦ 㒖ኂߐࠇࠆޕ ᵈᗧߔࠆߎߣ㧚 ߐࠇࠆ㧚 ߔࠆߎߣޕᧄ೷ߣࠛ ࡝ࠬࡠࡑࠗࠪࡦࠍ૬ ↪ߔࠆ႐วߪޔᖚ⠪ ߩ⁁ᘒࠍᘕ㊀ߦⷰኤ ߒޔ೽૞↪⊒⃻ߦච ಽᵈᗧߔࠆߎߣޕ ᧄ೷ 150mg 1 ᣣ 1 ࿁ߣ ࠛ࡝ࠬࡠࡑࠗࠪࡦ 500mg 1 ᣣ 3 ࿁ࠍ૬↪

ߒߚߣ߈ޔᧄ೷ߩ AUC ߇ 7.5 ୚ߦ਄᣹ ߒޔࠛ࡝ࠬࡠࡑࠗࠪ ࡦߩ AUC ߪ 1.9 ୚ߦ ਄᣹ߒߚޕ

18 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 㧔2㧕૬↪ᵈᗧ㧔૬↪ߦᵈᗧߔࠆߎߣ㧕 ૬↪ᵈᗧ㧔૬↪ߦᵈᗧߔࠆߎߣ㧕 ૬↪ᵈᗧ㧔૬↪ߦᵈᗧߔࠆߎߣ㧕 ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇ ᯏᐨ࡮ෂ㒾࿃ሶ ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇ ᯏᐨ࡮ෂ㒾࿃ሶ ᴺ ࠫ࠳ࡁࠪࡦ ੃㉄ࠕࠪ࠼࡯ࠪࠬ╬ in vitro ߦ߅޿ߡޔ ᴺ ࠻࡞ࡉ࠲ࡒ ᧄ೷ߩ૬↪ߢ࠻࡞ ⢄ઍ⻢㉂⚛ ߩࠫ࠳ࡁࠪࡦߩ೽૞ ᧄ೷ߪࡊ࡝ࡦ࠿ࠢ ࠿ࠢ࡟ࠝࠪ ૬↪ߦࠃࠅ੃㉄ࠕ ᧄ೷ߪ in vitro ߦ ࠼ ࡉ࠲ࡒ࠼ߩઍ⻢߇ 㧔CYP2C8/9㧕ᵴᕈ ↪ࠍჇᒝߔࠆ߅ߘࠇ ࡟ࠝࠪ࠼ߩ࡝ࡦ㉄ ࠼ࠕ࠽ࡠࠣ ࠪ࠼࡯ࠪࠬޔ⢄ਇ ߅޿ߡࡊ࡝ࡦ࠿ 28% ⚂ ੣ㅴߒߚߣ ߩჇᄢߦࠃࠆ߽ߩ ߇޽ࠆޕ ൻࠍଦㅴߔࠆޕ 㧔ࠫ࠳ࡁࠪ ో߇ႎ๔ߐࠇߡ޿ ࠢ࡟ࠝࠪ࠼ߩ࡝ ߩႎ๔߇޽ࠆޕ ߢ޽ࠅޔ⢄⤳ߢߩ ࠬ࠲ࡉࠫࡦ ᧄ೷ߪޔࠬ࠲ࡉࠫࡦ in vitro ߦ߅޿ߡޔ ࡦޔ⎫㉄ࠕ ࠆߎߣ߆ࠄޔᧄ೷ ࡦ㉄ൻࠍଦㅴߔ ฦ⒳ක⮎ຠߩઍ⻢ ࠫ࠼ࡉࠫࡦ ෸߮ࠫ࠼ࡉࠫࡦߩല ᧄ೷ߪࠬ࠲ࡉࠫ ࡃࠞࡆ࡞ ߪ੃㉄ࠕࠪ࠼࡯ࠪ ࠆޕ߹ߚޔࠫ࠳ ࠍ੣ㅴߔࠆน⢻ᕈ ᨐࠍᷫᒙߔࠆน⢻ᕈ ࡦޔࠫ࠼ࡉࠫࡦߩ ߇޽ࠆޕ ߇޽ࠆޕ૬↪ߔࠆ႐ ࡝ࡦ㉄ൻࠍ㒖ኂߔ ╬㧕 ࠬޔ⢄ਇోࠍჇᒝ ࡁࠪࡦߣߩ૬↪ ࠺ࠠࠬ࠻ࡠ ᧄ೷ߩ૬↪ߢ࠺ࠠ ⢄ઍ⻢㉂⚛ วߦߪޔⴊẏਛ ࠆޕ ߔࠆน⢻ᕈ߇޽ ߦࠃࠅޔ੃㉄ࠕ ࡔ࠻࡞ࡈࠔ ࠬ࠻ࡠࡔ࠻࡞ࡈࠔ 㧔CYP2D6㧕ᵴᕈߩ HIV-RNA ㊂ࠍⷰኤ ࠆޕ߹ߚޔᧄ೷ᛩ ࠪ࠼࡯ࠪࠬޔ⤟ ࡦ⥇ൻ᳓⚛ ࡦߩઍ⻢߇⚂ 67% Ⴧᄢߦࠃࠆ߽ߩߢ ߔࠆߎߣ߇ᦸ߹ߒ ਈ⚳ੌᓟ 2 ࡨ᦬㑆 Ἳߥߤᱫ੢଀ࠍ ㉄Ⴎ᳓๺‛ ੣ㅴߒߚߣߩႎ๔ ޽ࠅޔ⢄⤳ߢߩฦ ޿ޕHIV-RNA ㊂߇ ߪ࠿ࠢ࡟ࠝࠪ࠼ࠕ ฽߻ࡒ࠻ࠦࡦ࠼ ߇޽ࠆޕ ⒳ක⮎ຠߩઍ⻢ࠍ ਄᣹ߒߚ႐วߦߪޔ ࠽ࡠࠣߣߩ⋧੕૞ ࡝ࠕᲥᕈߩ⊒⃻ ੣ㅴߔࠆน⢻ᕈ߇ ᧄ೷ߩਛᱛ╬ㆡಾߥ ↪ߩน⢻ᕈ߇޽ࠆ ߇ႎ๔ߐࠇߡ޿ ޽ࠆޕ ಣ⟎ࠍⴕ߁ߎߣޕ ߩߢᵈᗧߔࠆߎ ࠆޕ ࠹ࠝࡈࠖ࡝ ઁߩࠗࡦ࠲࡯ࡈࠚ ⢄⤳ߢߩฦ⒳ක⮎ ࠕࠩ࠴ࠝࡉ 㛽㜑ᯏ⢻ᛥ೙߇⿠ߎ ᧄ೷߇ࠕࠩ࠴ࠝࡊ ߣޕ ࡦޔ ࡠࡦ⵾೷ߣߩ૬↪ ຠߩઍ⻢ࠍᛥ೙ߔ ࡝ࡦ ࠆ߅ߘࠇ߇޽ࠆޕ૬ ࡝ࡦߩઍ⻢㉂⚛ߢ ࠫ࠼ࡉࠫࡦ ᧄ೷ߪࠫ࠼ࡉࠫࡦ ᧄ೷ߪ in vitro ߦ ࠕࡦ࠴ࡇ࡝ ߢᏀ⸥⮎೷ߩⴊਛ ࠆߎߣ߇޽ࠆޕ ↪ߔࠆ႐วߦߪޔቯ ޽ࠆࠗࡁࠪࡦ৻࡝ ߩലᨐࠍᷫᒙߔࠆ ߅޿ߡࠫ࠼ࡉࠫ ࡦޔ Ớᐲ߇㜞߹ࠆߎߣ ᦼ⊛ߦⴊᶧᬌᩏࠍⴕ ࡦ㉄⣕᳓⚛㉂⚛ ࡢ࡞ࡈࠔ࡝ ߇ႎ๔ߐࠇߡ޿ࠆ ߁ߥߤޔᖚ⠪ߩ⁁ᘒ 㧔IMPDH㧕ࠍ㒖ኂ ߅ߘࠇ߇޽ࠆޕ૬ ࡦߩ࡝ࡦ㉄ൻࠍ ࡦ ߩߢᵈᗧߔࠆߎ ࠍචಽߦⷰኤߔࠆߎ ߔࠆߎߣߦࠃࠅޔ ↪ߔࠆ႐วߪޔⴊ 㒖ኂߔࠆޕ ߣޕ ߣޕᧄ೷ߩᷫ㊂ޔਛ ઍ⻢↥‛ߩࡔ࠴ ẏਛ HIV RNA ࡟ ࠫ࠼ࡉࠫࡦ ઁߩࠗࡦ࠲࡯ࡈࠚ ૞↪ᯏᐨߪਇ᣿ߢ ᱛߦߟ޿ߡߪޔ㧨↪ ࡞࠴ࠝࠗࡁࠪࡦ৻ ࡌ࡞ࠍⷰኤߔࠆߎ ࡠࡦ⵾೷ߣߩ૬↪ ޽ࠆ߇ޔߣ߽ߦ㛽 ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ ࡝ࡦ㉄ ߣ߇ᦸ߹ߒ޿ޕ

ߢ㛽㜑ᯏ⢻ᛥ೙૞ 㜑ᯏ⢻ᛥ೙૞↪ࠍ ૶↪਄ߩᵈᗧ㧪ߩ㗄 㧔meTIMP㧕߇⫾ HIV RNA ࡟ࡌ࡞ ↪߇Ⴧᒝߐࠇޔ⊕ ᦭ߔࠆߚ߼ߣ⠨߃ ࠍෳᾖߔࠆߎߣޕ Ⓧߔࠆߣ⠨߃ࠄࠇ ߇਄᣹ߒߚ႐วߦ ⴊ⃿ᷫዋ╬ߩⴊ⃿ ࠄࠇߡ޿ࠆޕ ࠆޕ ߪޔᧄ೷ߩਛᱛ╬ ᷫዋ߇Ⴧᖡߔࠆߎ ߩㆡಾߥಣ⟎ࠍⴕ ߣ߇޽ࠆޕ ߁ߎߣޕ ఺∉ᛥ೙≮ ઁߩࠗࡦ࠲࡯ࡈࠚ ⒖ᬀ ߦኻߔࠆᜎ ࠕࠩ࠴ࠝࡊ 㛽㜑ᯏ⢻ᛥ೙߇⿠ ᧄ೷߇ࠕࠩ࠴ࠝ ᴺ ࡠࡦ⵾೷ߣߩ૬↪ ⛘෻ᔕ߇⺃⊒ߐࠇ ࡝ࡦ ߎࠆ߅ߘࠇ߇޽ ࡊ࡝ࡦߩઍ⻢㉂ ߢ⒖ᬀᖚ⠪㧔⣢࡮ ࠆߣ⠨߃ࠄࠇߡ޿ 㛽㜑⒖ᬀ╬㧕ߦ߅ ࠆޕ ࠆޕ૬↪ߔࠆ႐ว ⚛ߢ޽ࠆࠗࡁࠪ ߌࠆ఺∉ᛥ೙≮ᴺ ߦߪޔቯᦼ⊛ߦⴊ ࡦ৻࡝ࡦ㉄⣕᳓ ߩലᨐ߇ᒙ߹ࠆߎ ᶧᬌᩏࠍⴕ߁ߥ ⚛㉂⚛ ߣ߇޽ࠆޕ ߤޔᖚ⠪ߩ⁁ᘒࠍ 㧔IMPDH㧕ࠍ㒖

චಽߦⷰኤߔࠆߎ ኂߔࠆߎߣߦࠃ ߣޕᧄ೷ߩᷫ㊂ޔ ࠅޔઍ⻢↥‛ߩ ਛᱛߦߟ޿ߡߪޔ ࡔ࠴࡞࠴ࠝࠗࡁ ޛ↪ᴺ࡮↪㊂ߦ㑐 ࠪࡦ৻࡝ࡦ㉄ ㅪߔࠆ૶↪਄ߩᵈ 㧔meTIMP㧕߇ ᗧޜߩ㗄ࠍෳᾖߔ ⫾Ⓧߔࠆߣ⠨߃ ࠆߎߣޕ ࠄࠇࠆޕ ૶↪਄ ߹ߚޔࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵ ߩᵈᗧ ឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b 㧔ㆮવሶ⚵឵߃㧕ߣߩ૬↪ᤨߦߪޔ਄⸥એᄖߦ ዊᩊ⢫ḡޔ࠹ࠝࡈࠖ࡝ࡦޔࠕࡦ࠴ࡇ࡝ࡦޔࡢ࡞ ࡈࠔ࡝ࡦޔࠫ࠼ࡉࠫࡦޔ࠻࡞ࡉ࠲ࡒ࠼ޔ࠺ࠠࠬ ࠻ࡠࡔ࠻࡞ࡈࠔࡦߣߩ⋧੕૞↪߇ႎ๔ߐࠇߡ޿ ࠆߚ߼ޔᵈᗧߔࠆߎߣޕ

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࡌ࡯࠲ߣߩ૬↪ᤨߦߪޔ਄⸥ એᄖߦዊᩊ⢫ḡޔ࠹ࠝࡈࠖ࡝ࡦޔࡢ࡞ࡈࠔ࡝ࡦ ߣߩ⋧੕૞↪߇ႎ๔ߐࠇߡ޿ࠆߚ߼ޔᵈᗧߔࠆ ߎߣޕ

19 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ ࠪࠢࡠࠬࡐ࡝ࡦ ࠪࠢࡠࠬࡐ࡝ࡦߩⴊ ᧄ೷ߩ ࠕ࡞ࡊ࡜࠱࡜ࡓ ᧄ೷ 750mg 1 ᣣ 3 ࿁ ᧄ೷ߩ ਛỚᐲ߇਄᣹ߔࠆޕ CYP3A(4)㒖ኂ ࠍ 10 ᣣ㑆᦯↪ᓟ㧘ࠕ CYP3A4/5 ߦኻ ࠪࠢࡠࠬࡐ࡝ࡦߩ↪ ૞↪ߦࠃࠅޔߎ ࡞ࡊ࡜࠱࡜ࡓ 0.5mg 1 ߔࠆ㒖ኂ૞↪ߦ ㊂⺞▵ߪᔅⷐߣߒߥ ࠇࠄߩ⮎೷ߩઍ ᣣ 1 ࿁ࠍ૬↪ߒߚߣ ࠃࠅ㧘ߎࠇࠄߩ ޿߇ޔࠪࠢࡠࠬࡐ࡝ ⻢߇㒖ኂߐࠇ ߈㧘ࠕ࡞ࡊ࡜࠱࡜ࡓ ⮎೷ߩઍ⻢߇㒖 ࡦߩⴊਛỚᐲࠍࡕ࠾ ࠆޕ ߩ AUC ߇ 35%਄᣹ ኂߐࠇࠆ㧚 ࠲࡝ࡦࠣߔࠆߎߣޕ ߒߚ㧚 ࠪ࡞࠺࠽ࡈࠖ࡞ ߎࠇࠄߩ⮎೷ߩⴊẏ ࡒ࠳࠱࡜ࡓ㧔ᵈ኿ ᧄ೷ 750mg 1 ᣣ 3 ࿁ ࠲࠳࡜ࡈࠖ࡞ ਛỚᐲ߇਄᣹ߔࠆ߅ ೷㧕 ࠍ 9 ᣣ㑆᦯↪ᓟ㧘ࡒ ߘࠇ߇޽ࠆߚ߼ޔᖚ ࠳࠱࡜ࡓ 0.5mg 㕒⣂ ⠪ߩ⁁ᘒࠍᘕ㊀ߦⷰ ౝᛩਈࠍ૬↪ߒߚߣ

ኤߒޔߎࠇࠄߩ⮎೷ ߈㧘ࡒ࠳࠱࡜ࡓߩ

ߪૐ↪㊂߆ࠄᛩਈࠍ AUC ߇ 240%਄᣹ߒ 㐿ᆎߒޔᔅⷐߦᔕߓ ߚ㧚ㆊᐲߩ㎾㕒߿๭ ߡჇ㊂ߔࠆߎߣࠍ⠨ ๆᛥ೙╬߇⿠ߎࠆ߅ ᘦߔࠆߎߣޕ ߘࠇ߇޽ࠆߩߢᵈᗧ ࠻࡝ࠕ࠱࡜ࡓ ࠻࡝ࠕ࠱࡜ࡓߩⴊẏ ߔࠆߎߣ㧚 ਛỚᐲ߇਄᣹ߔࠆ߅ ࡊ࡟࠼࠾࠱ࡠࡦ ߎࠇࠄߩ⮎೷ߩⴊਛ ߘࠇ߇޽ࠆޕᧄ೷ߣ 㧔ోりᛩਈ㧕 Ớᐲ߇਄᣹ߔࠆ߅ߘ ࠻࡝ࠕ࠱࡜ࡓࠍ૬↪ ࡔ࠴࡞ࡊ࡟࠼࠾࠱ ࠇ߇޽ࠆ㧚 ߔࠆ႐วߪޔᖚ⠪ߩ ࡠࡦ㧔ోりᛩਈ㧕 ⁁ᘒࠍᘕ㊀ߦⷰኤߔ ࡈ࡞࠴ࠞ࠱ࡦࡊࡠ ߎࠇࠄߩ⮎೷ߩⴊਛ ࠆߎߣޕޕ ࡇࠝࡦ㉄ࠛࠬ࠹࡞ Ớᐲ߇਄᣹ߔࠆ߅ߘ ࠕࡒࠝ࠳ࡠࡦ ߎࠇࠄߩ⮎೷ߩⴊਛ ࡉ࠺࠰࠾࠼ ࠇ߇޽ࠆ㧚 ࠫ࠰ࡇ࡜ࡒ࠼ Ớᐲ߇਄᣹ߔࠆ߅ߘ ೽⣢⊹⾰ࠬ࠹ࡠࠗ࠼ ࡈ࡟ࠞࠗ࠾࠼ ࠇ߇޽ࠆޕߎࠇࠄߩ ೷ࠍోりᛩਈߒߚ႐ ࡝࠼ࠞࠗࡦ㧔ోり ⮎೷ߣ૬↪ߔࠆ႐ว วߣห᭽ߩ∝⁁߇޽ ᕈ㧕 ߪޔⴊਛỚᐲࠍࡕ࠾ ࠄࠊࠇࠆ߅ߘࠇ߇޽

ࡔࠠࠪ࡟࠴ࡦ ࠲࡝ࡦࠣߔࠆߎߣޕ ࠆ㧚 ࡊࡠࡄࡈࠚࡁࡦ ࠪࠢࡠࠬࡐ࡝ࡦ ᧄ೷ 750mg 1 ᣣ 3 ࿁ ࠠ࠾ࠫࡦ 8 ࠲ࠢࡠ࡝ࡓࠬ᳓๺ ᣣ㑆᦯↪ᓟ㧘ࠪࠢ ࠪࡦࡃࠬ࠲࠴ࡦ ߎࠇࠄߩ⮎೷ߩⴊẏ ᧄ೷ߩ ‛ ࡠࠬࡐ࡝ࡦࠍ૬↪ߒ

ࠕ࠻࡞ࡃࠬ࠲࠴ࡦ ਛỚᐲ߇਄᣹ߔࠆ߅ OATP1B1 㒖ኂ ࠪࡠ࡝ࡓࠬ㧔࿖ౝ ߚߣ߈㧘ࠪࠢࡠࠬࡐ ߘࠇ߇޽ࠆޕߎࠇࠄ ૞↪෸߮/෶ߪ ᧂᛚ⹺㧕 ࡝ࡦߩ AUC ߇ 4.6 ୚ ߩ⮎೷ߩ↪㊂ࠍẋჇ CYP3A4 㒖ኂ૞ ࠛࡌࡠ࡝ࡓࠬ ߦ਄᣹ߒߚ㧚ᧄ೷ ߒޔലᨐࠍ⊒⃻ߔࠆ ↪ߦࠃࠅޔߎࠇ 750 mg 1 ᣣ 3 ࿁ 8 ᣣ ᦨዊߩ↪㊂ࠍ↪޿ޔ ࠄߩ⮎೷ߩឃ಴ 㑆᦯↪ᓟ㧘࠲ࠢࡠ࡝ ᖚ⠪ߩ⁁ᘒࠍᘕ㊀ߦ ෸߮/෶ߪઍ⻢ ࡓࠬ᳓๺‛ࠍ૬↪ߒ ⷰኤߔࠆߎߣޕ ߇㒖ኂߐࠇࠆޕ ߚߣ߈㧘࠲ࠢࡠ࡝ࡓ ࡠࠬࡃࠬ࠲࠴ࡦ ߎࠇࠄߩ⮎೷ߩⴊẏ ᧄ೷ߩ ࠬߩ AUC ߇ 70 ୚ߦ ࡊ࡜ࡃࠬ࠲࠴ࡦ ਛỚᐲ߇਄᣹ߔࠆ߅ OATP1B1 㒖ኂ ਄᣹ߒߚ㧚㧔ޟ⮎‛ ࡇ࠲ࡃࠬ࠲࠴ࡦ ߘࠇ߇޽ࠆߚ߼ޔᖚ ૞↪ߦࠃࠅޔߎ േᘒޠߩ㗄ෳᾖ㧕૬ ⠪ߩ⁁ᘒࠍᘕ㊀ߦⷰ ࠇࠄߩ⮎೷ߩឃ ↪ߔࠆ႐วߦߪ㧘ⴊ ኤߒޔߎࠇࠄߩ⮎೷ ಴߇㒖ኂߐࠇ ਛỚᐲߩࡕ࠾࠲࡝ࡦ ߩ↪㊂ࠍẋჇߒޔല ࠆޕ ࠣࠍⴕ޿㧘ᔅⷐߦᔕ ᨐࠍ⊒⃻ߔࠆᦨዊߩ ߓߡᷫ㊂╬ߩಣ⟎ࠍ ↪㊂ࠍ↪޿ࠆߎߣޕ ⴕ߁ߎߣ㧚⣢㓚ኂ╬ ߩ೽૞↪ߩ⊒⃻ߦᵈ ࠕࡓࡠࠫࡇࡦ ߎࠇࠄߩ⮎೷ߩⴊẏ ᧄ೷ߩ CYP3A4 ᗧߔࠆߎߣ㧚 ࡌࡊ࡝ࠫ࡞ ਛỚᐲ߇਄᣹ߔࠆ߅ 㒖ኂ૞↪෸߮/ ૶↪਄ P-gp ࡝࠼ࠞࠗࡦႮ㉄Ⴎ ࡝࠼ࠞࠗࡦߩⴊਛỚ ࠫ࡞࠴ࠕ࠯ࡓ ߘࠇ߇޽ࠆޕߎࠇࠄ ෶ߪ 㒖ኂ ࡈࠚࡠࠫࡇࡦ ߩ⮎೷ߣ૬↪ߔࠆ႐ ૞↪ߦࠃࠅޔߎ 㧔ోりᛩਈ㧕 ᐲ߇਄᣹ߔࠆ߅ߘࠇ ߩᵈᗧ ࠾ࠞ࡞ࠫࡇࡦ วߪޔᖚ⠪ߩ⁁ᘒࠍ ࠇࠄߩ⮎೷ߩઍ ߇޽ࠆߩߢ㧘ⴊਛỚ ࠾ࡈࠚࠫࡇࡦ ᘕ㊀ߦⷰኤߔࠆߎ ⻢෸߮/෶ߪឃ ᐲߩࡕ࠾࠲࡝ࡦࠣࠍ ࠾࠰࡞ࠫࡇࡦ ߣޕ ಴߇㒖ኂߐࠇ ⴕ߁ߎߣ߇ផᅑߐࠇ ࡌ࡜ࡄࡒ࡞ ࠆޕ ࠆ㧚 ࠫࠧࠠࠪࡦ ࠫࠧࠠࠪࡦߩⴊਛỚ ᧄ೷ߩ P-gp 㒖 ࠪ࡞࠺࠽ࡈࠖ࡞ࠢ ߎࠇࠄߩ⮎೷ߩⴊਛ

ᐲ߇਄᣹ߔࠆޕࠫࠧ ኂ૞↪ߦࠃࠅޔ ࠛࡦ㉄Ⴎ㧔ഺ⿠ਇ Ớᐲ߇਄᣹ߔࠆ߅ߘ ࠠࠪࡦߩⴊਛỚᐲࠍ ࠫࠧࠠࠪࡦߩឃ ోࠍㆡᔕߣߔࠆ႐ ࠇ߇޽ࠆ㧚

ࡕ࠾࠲࡝ࡦࠣߒޔല ಴߇㒖ኂߐࠇ ว㧕㧔ࡃࠗࠕࠣ ߎࠇࠄߩ⮎೷ߦ㑐ㅪ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ᨐ߇⊒⃻ߔࠆ↪㊂߹ ࠆޕ ࡜㧕 ߔࠆ᦭ኂ੐⽎ࠍ⿠ߎ ߢẋჇߔࠆߎߣޕ ࠲࠳࡜ࡈࠖ࡞㧔ഺ ߔ߅ߘࠇ߇޽ࠆߩߢ ࠲ࠢࡠ࡝ࡓࠬ ࠲ࠢࡠ࡝ࡓࠬߩⴊਛ ᯏᐨਇ᣿ ⿠ਇోࠍㆡᔕߣߔ ᵈᗧߔࠆߎߣ㧚 Ớᐲ߇ૐਅߔࠆޕ࠲ ࠆ႐ว㧕㧔ࠪࠕ࡝ ࠢࡠ࡝ࡓࠬߩ↪㊂⺞ ࠬ㧕 ▵ߪᔅⷐߣߒߥ޿ ࠕࡓࡠࠫࡇࡦࡌࠪ ᧄ೷ 750mg 1 ᣣ 3 ࿁ ߇ޔ࠲ࠢࡠ࡝ࡓࠬߩ ࡞㉄Ⴎ ࠍ 6 ᣣ㑆᦯↪ᓟ㧘ࠕ ⴊਛỚᐲࠍࡕ࠾࠲࡝ ࠫ࡞࠴ࠕ࠯ࡓႮ㉄ ࡓࡠࠫࡇࡦࡌࠪ࡞㉄ ࡦࠣߔࠆߎߣޕ Ⴎ Ⴎ 5mg 1 ᣣ 1 ࿁ࠍ૬

ࡈࠚࡠࠫࡇࡦ ↪ߒߚߣ߈㧘ࠕࡓࡠ

࠾ࠞ࡞ࠫࡇࡦႮ㉄ ࠫࡇࡦߩ AUC ߇ Ⴎ 179%਄᣹ߒߚ㧚 ࠾ࡈࠚࠫࡇࡦ ࠾࠰࡞ࠫࡇࡦ ࡌ࡜ࡄࡒ࡞Ⴎ㉄Ⴎ ࡏ࠮ࡦ࠲ࡦ᳓๺‛ ࡏ࠮ࡦ࠲ࡦߩⴊਛỚ ᐲ߇਄᣹ߔࠆ߅ߘࠇ ߇޽ࠆߩߢᵈᗧߔࠆ ߎߣ㧚 ࠦ࡞ࡅ࠴ࡦ㧔⢄⤳ ࠦ࡞ࡅ࠴ࡦߩⴊਛỚ ෶ߪ⣢⤳ߦ㓚ኂߩ ᐲ߇਄᣹ߔࠆ߅ߘࠇ ޽ࠆᖚ⠪ߦኻߒߡ ߇޽ࠆߩߢ㧘ᷫ㊂޽ ߪ૬↪⑌ᔊ㧕 ࠆ޿ߪૐ↪㊂߆ࠄ㐿 ᆎߔࠆߥߤᵈᗧߔࠆ ߎߣ㧚 ࠨ࡞ࡔ࠹ࡠ࡯࡞ࠠ ࠨ࡞ࡔ࠹ࡠ࡯࡞ߩⴊ ࠪ࠽ࡎ㉄Ⴎ ਛỚᐲ߇਄᣹ߒ㧘QT ᑧ㐳ࠍ⿠ߎߔ߅ߘࠇ ߇޽ࠆߩߢ㧘ᵈᗧߔ ࠆߎߣ㧚

20 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪

૶↪਄

ߩᵈᗧ

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04

21 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾 ࿃ሶ ࠱࡞ࡇ࠺ࡓ㈬ ᧄ೷ 750mg 1 ᣣ 3 ࿁ࠍ 10 ᯏᐨਇ᣿ ⍹㉄Ⴎ ᣣ㑆᦯↪ᓟ㧘࠱࡞ࡇ࠺ࡓ ㈬⍹㉄Ⴎ 5 mg1 ᣣ 1 ࿁ࠍ ૬↪ߒߚߣ߈㧘࠱࡞ࡇ࠺ ࡓߩ AUC ߇ 47%ૐਅߒ ߚ㧚 ࡔࠨ࠼ࡦ ᧄ೷ 750mg 1 ᣣ 3 ࿁ߣࡔ ࠨ࠼ࡦ 1 ᣣ 30㨪130mg ࠍ 7 ᣣ㑆᦯↪ߒߚߣ߈㧘R̃ ࡔࠨ࠼ࡦߩ AUC ߇ 29% ૐਅߒߚ㧚 ࠛ࠴࠾࡞ࠛࠬ ᧄ೷ 750mg 1 ᣣ 3 ࿁ߣࠛ ࠻࡜ࠫࠝ࡯࡞ ࠴࠾࡞ࠛࠬ࠻࡜ࠫࠝ࡯࡞ ࡁ࡞ࠛ࠴ࠬ࠹ 0.035mg ෸߮ࡁ࡞ࠛ࠴ࠬ ࡠࡦ ࠹ࡠࡦ 0.5mg 1 ᣣ 1 ࿁ࠍ 21 ᣣ㑆૬↪ߒߚߣ߈㧘ࠛ ࠴࠾࡞ࠛࠬ࠻࡜ࠫࠝ࡯࡞ ߩ AUC ߇ 28%ૐਅߒߚ㧚 ࠛࠬࠪ࠲ࡠࡊ ᧄ೷ 750mg 1 ᣣ 3 ࿁ 14 ᣣ ࡜ࡓ 㑆ߣࠛࠬࠪ࠲ࡠࡊ࡜ࡓ 10 mg 1 ᣣ 1 ࿁ࠍ 7 ᣣ㑆૬↪ ߒߚߣ߈㧘ࠛࠬࠪ࠲ࡠࡊ ࡜ࡓߩ AUC ߇ 35%ૐਅߒ ߚ㧚 ࠻࡜࠱࠼ࡦႮ ࠻࡜࠱࠼ࡦߩⴊਛỚᐲ߇ ᧄ೷ߩ ㉄Ⴎ ਄᣹ߒ㧘ᖡᔃ㧘⌇ᥝ㧘ૐ CYP3A4/5 ߦ ⴊ࿶෸߮ᄬ␹ߔࠆ߅ߘࠇ ኻߔࠆ㒖ኂ૞ ߇޽ࠆ㧚 ↪ߦࠃࠅ㧘࠻ ࡜࠱࠼ࡦߩઍ ⻢߇㒖ኂߐࠇ ࠆ㧚 ࡢ࡞ࡈࠔ࡝ࡦ ࡢ࡞ࡈࠔ࡝ࡦߩⴊਛỚᐲ ⢄⮎‛ઍ⻢㉂ ࠞ࡝࠙ࡓ ߦᓇ㗀ࠍਈ߃ࠆߎߣ߇޽ ⚛ߩ㑐ਈ߇⠨ ࠆ㧚INR ߩࡕ࠾࠲࡝ࡦࠣ ߃ࠄࠇࠆ߇ᯏ ࠍⴕ߁ߎߣ߇ផᅑߐࠇ ᐨਇ᣿㧚 ࠆ㧚 ࡝࠻࠽ࡆ࡞ ࡝࠻࠽ࡆ࡞ 100mg ߣᧄ೷ ࡝࠻࠽ࡆ࡞ߩ 750mg ࠍන࿁૬↪ߒߚߣ CYP3A4 ߦኻ ߈㧘ᧄ೷ߩ AUC ߇ 100% ߔࠆ㒖ኂ૞↪ ਄᣹ߒߚ㧚 ߦࠃࠅ㧘ᧄ೷ ߩઍ⻢߇㒖ኂ ߐࠇࠆ㧚 ࠕ࠲ࠩ࠽ࡆ࡞ ࠕ࠲ࠩ࠽ࡆ࡞⎫㉄Ⴎ/࡝࠻ ߎࠇࠄߩ⮎ ⎫㉄Ⴎ㧛࡝࠻ ࠽ࡆ࡞ 300/100mg 1 ᣣ 1 ೷ߩⴊਛỚ ࠽ࡆ࡞ ࿁ 20 ᣣ㑆ߣᧄ೷ 750 mg 1 ᐲ਄᣹෶ߪ ࠳࡞࠽ࡆ࡞/࡝ ᣣ 3 ࿁ 10 ᣣ㑆ࠍ૬↪ߒߚ ૐਅߦߪ㧘 ߣ߈㧘ࠕ࠲ࠩ࠽ࡆ࡞ߩ ࠻࠽ࡆ࡞ ᧄ೷ߩ⢄⮎ AUC ߇ 17%਄᣹ߒ㧘ᧄ೷ ࡎࠬࠕࡦࡊ࡟ ‛ઍ⻢㉂⚛ ૶↪਄ ߩ AUC ߇ 20%ૐਅߒߚ㧚 ߩᵈᗧ ࠽ࡆ࡞ࠞ࡞ࠪ ࠳࡞࠽ࡆ࡞/࡝࠻࠽ࡆ࡞ ߳ߩ㑐ਈ߇ ࠙ࡓ᳓๺‛/࡝ 600/100 mg 1 ᣣ 2 ࿁ 20 ᣣ ⠨߃ࠄࠇࠆ ࠻࠽ࡆ࡞ 㑆ߣᧄ೷ 750mg 1 ᣣ 3 ࿁ ߇ᯏᐨਇ ࡠࡇ࠽ࡆ࡞/࡝ 10 ᣣ㑆ࠍ૬↪ߒߚߣ߈㧘 ᣿㧚ߎࠇࠄ ࠻࠽ࡆ࡞ ࠳࡞࠽ࡆ࡞෸߮ᧄ೷ߩ ߩ⮎೷ߣߩ AUC ߇ߘࠇߙࠇ 40%㧘 ૬↪ߦࠃ 35%ૐਅߒߚ㧚ࡎࠬࠕࡦ ࠅ㧘ᧄ೷ߩ ࡊ࡟࠽ࡆ࡞ࠞ࡞ࠪ࠙ࡓ᳓

ઍ⻢߇ଦㅴ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ๺‛/࡝࠻࠽ࡆ࡞ 700/100 ߐࠇࠆ߇ᯏ mg 1 ᣣ 2 ࿁ 20 ᣣ㑆ߣᧄ೷ ᐨਇ᣿㧚 750mg 1 ᣣ 3 ࿁ 10 ᣣ㑆ࠍ ૬↪ߒߚߣ߈㧘ࠕࡦࡊ࡟ ࠽ࡆ࡞෸߮ᧄ೷ߩ AUC ߇ ߘࠇߙࠇ 47%㧘32%ૐਅ ߒߚ㧚ࡠࡇ࠽ࡆ࡞/࡝࠻࠽ ࡆ࡞ 400/100mg 1 ᣣ 2 ࿁ 20 ᣣ㑆ߣᧄ೷ 750mg 1 ᣣ 3 ࿁ 10 ᣣ㑆ࠍ૬↪ߒߚߣ ߈㧘ᧄ೷ߩ AUC ߇ 54%ૐ ਅߒߚ㧚 ࠛࡈࠔࡆ࡟ࡦ ࠛࡈࠔࡆ࡟ࡦ࠷ 600mg1 ࠛࡈࠔࡆ࡟ࡦ ࠷ ᣣ 1 ࿁ 20 ᣣ㑆ߣᧄ೷ ࠷ߩ CYP3A4 750mg 1 ᣣ 3 ࿁ 10 ᣣ㑆ࠍ ߦኻߔࠆ⺃ዉ ૬↪ߒߚߣ߈㧘ᧄ೷ߩ ૞↪ߦࠃࠅ㧘 AUC ߇ 26%ૐਅߒߚ㧚 ᧄ೷ߩઍ⻢߇ ଦㅴߔࠆ㧚 ࠛ࠻࡜ࡆ࡝ࡦ ࠛ࠻࡜ࡆ࡝ࡦ 200mg1 ᣣ 2 ᧄ೷ߩⴊਛỚ ࡝࡞ࡇࡆ࡝ࡦ ࿁ 11 ᣣ㑆ߣᧄ೷ 750mg1 ᐲᷫዋߦߪ㧘 ᣣ 3 ࿁ 18 ᣣ㑆ࠍ૬↪ߒߚ ࠛ࠻࡜ࡆ࡝ࡦ ߣ߈㧘ᧄ೷ߩ AUC ߇ 16% ߩ⢄⮎‛ઍ⻢ ૐਅߒߚ㧚࡝࡞ࡇࡆ࡝ࡦ ㉂⚛߳ߩ㑐ਈ 25mg1 ᣣ 1 ࿁ 11 ᣣ㑆ߣᧄ ߇⠨߃ࠄࠇࠆ ೷ 750mg1 ᣣ 3 ࿁ 18 ᣣ㑆 ߇ᯏᐨਇ᣿㧚 ࠍ૬↪ߒߚߣ߈㧘࡝࡞ࡇ ࡝࡞ࡇࡆ࡝ࡦ ࡆ࡝ࡦߩ AUC ߇ 78㧑਄ ߩⴊਛỚᐲ਄ ᣹ߒߚ㧚 ᣹ߦߪ㧘ᧄ೷ ߩ⢄⮎‛ઍ⻢ ㉂⚛߳ߩ㑐ਈ ߇⠨߃ࠄࠇࠆ ߇ᯏᐨਇ᣿㧚 ࠹ࡁࡎࡆ࡞ࠫ࠰ ᧄ೷ 750 mg 1 ᣣ 3 ࿁ߣ࠹ ᯏᐨਇ᣿ ࡊࡠࠠࠪ࡞ࡈࡑ ࡁࡎࡆ࡞ࠫ࠰ࡊࡠࠠࠪ࡞ ࡞㉄Ⴎ ࡈࡑ࡞㉄Ⴎ 300mg 1 ᣣ 1 ࡜࡞࠹ࠣ࡜ࡆ࡞ ࿁ࠍ 7 ᣣ㑆᦯↪ߒߚߣ ߈㧘࠹ࡁࡎࡆ࡞ߩ AUC ߇ 30%਄᣹ߒߚ㧚࡜࡞࠹ࠣ ࡜ࡆ࡞ 400mg1 ᣣ 2 ࿁ 11 ᣣ㑆ߣᧄ೷ 750 mg 1 ᣣ 3 ࿁ 7 ᣣ㑆ࠍ૬↪ߒߚߣ ߈㧘࡜࡞࠹ࠣ࡜ࡆ࡞ߩ AUC ߇ 31%਄᣹ߒߚ㧚

22 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪

૶↪਄

ߩᵈᗧ

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04

23 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

4㧚೽૞↪ 4㧚೽૞↪ 4㧚೽૞↪ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߦᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈ ᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b㧔ㆮવ 㧨ᧄ೷න⁛ߩ႐ว㧪 ࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪ 2b㧔ㆮ ሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦࠍ૬↪ߒߚ࿖ౝ⥃ᐥ⹜ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ㧦ᧄ೷ વሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߒߚ࿖ౝ╙ 㛎ߦ߅޿ߡ㧘቟ోᕈ⹏ଔኻ⽎଀ 267 ଀ో଀ߦ ߩ࿖ౝ⥃ᐥ⹜㛎ߦ߅޿ߡޔ቟ోᕈ⹏ଔߩኻ⽎ߣ Τ⋧෸߮╙Υ⋧⥃ᐥ⹜㛎㧔ోᛩਈᦼ㑆㧕ߦ߅ߌ 3,903 ઙߩ೽૞↪߇⹺߼ࠄࠇߚ㧚ਥߥ೽૞↪ߪ ߥߞߚ 279 ଀ߦ⥃ᐥᬌᩏ୯ߩ⇣Ᏹࠍ฽߻೽૞↪ ࠆ቟ోᕈ⹏ଔኻ⽎∝଀ 436 ଀ਛ 426 ଀㧔97.7%㧕 ޟ⽺ⴊޠ243 ଀㧔91.0%㧕㧘ޟ⊒ᾲޠ218 ଀ ߇ 278 ଀㧔99. 6㧑㧕ߦ⹺߼ࠄࠇߚޕਥߥ೽૞↪ ߦ೽૞↪㧔⥃ᐥᬌᩏ୯⇣Ᏹࠍ฽߻㧕߇⹺߼ࠄࠇ 㧔81.6%㧕㧘ޟ⊕ⴊ⃿ᢙᷫዋޠ191 ଀㧔71.5%㧕㧘 ߪޔ⊒ᾲ 179 ઙ㧔64. 2㧑㧕ޔ㗡∩ 173 ઙ㧔62. ߚޕᧄ೷ߩ೽૞↪ߪޔ⊒∐ 203 ଀㧔46.6%㧕ޔߘ ޟⴊዊ᧼ᢙᷫዋޠ176 ଀㧔65.9%㧕㧘ޟⴊਛዩ㉄ 0㧑㧕ޔୱᕃᗵ 171 ઙ㧔61. 3㧑㧕╬ߢ޽ߞߚޕ೽ ߁∣∝ 105 ଀㧔24.1%㧕ޔⴊਛࡆ࡝࡞ࡆࡦჇട 97 Ⴧടޠ162 ଀㧔60.7%㧕㧘ޟୱᕃᗵޠ155 ଀ ૞↪ߣߒߡߩ⥃ᐥᬌᩏ୯ߩ⇣Ᏹߪޔᅢਛ⃿ᷫዋ ଀㧔22.2%㧕ޔଢ⒁ 29 ଀㧔6.7%㧕ޔశ✢ㆊᢅᕈ෻ 㧔58.1%㧕㧘ޟࡅࠕ࡞ࡠࡦ㉄Ⴧടޠ135 ଀ 220 ઙ㧔78. 9㧑㧕ޔⴊዊ᧼ᷫዋ 209 ઙ ᔕ 8 ଀㧔1.8%㧕ߢ޽ߞߚޕ㧔↳⺧ᤨ㧕 㧔50.6%㧕㧘ޟ㘩᰼ᷫㅌޠ113 ଀㧔42.3%㧕㧘ޟ⊒ 㧔74.9㧑㧕ޔ⊕ⴊ⃿ᷫዋ 203 ઙ㧔72. 8㧑㧕╬ߢ޽ ∐ޠ103 ଀㧔38.6%㧕㧘ޟ㗡∩ޠ95 ଀㧔35.6%㧕㧘 ߞߚޕ㧔ല⢻ㅊടᛚ⹺ᤨ㧕 ޟ⣕Ძ∝ޠ93 ଀㧔34.8%㧕㧘ޟਇ⌁∝ޠ81 ଀ B ဳᘟᕈᵴേᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷ 㧔30.3%㧕㧘ޟⴊਛࠢ࡟ࠕ࠴࠾ࡦჇടޠ80 ଀ ༀ㧦ᧄ೷ߩ࿖ౝ⥃ᐥ⹜㛎ߦ߅޿ߡޔ቟ోᕈ⹏ଔ

㧔30.0%㧕╬ߢ޽ߞߚ㧚㧔ᛚ⹺ᤨ㧕 ߩኻ⽎ߣߥߞߚ 225 ଀ో଀ߦ⥃ᐥᬌᩏ୯ߩ⇣Ᏹ

 ࠍ฽߻೽૞↪߇⹺߼ࠄࠇߚޕਥߥ೽૞↪ߪޔ⊒  ᾲ 161 ઙ㧔71. 6㧑㧕ޔ㗡∩ 147 ઙ㧔65. 3㧑㧕ޔ  ୱᕃᗵ 142 ઙ㧔63. 1㧑㧕╬ߢ޽ߞߚޕ೽૞↪ߣ  ߒߡߩ⥃ᐥᬌᩏ୯ߩ⇣Ᏹߪޔᅢਛ⃿ᷫዋ 191 ઙ  㧔84. 9㧑㧕ޔ⊕ⴊ⃿ᷫዋ 149 ઙ㧔66. 2㧑㧕ޔALT  㧔GPT㧕Ⴧട 115 ઙ㧔51. 1㧑㧕╬ߢ޽ߞߚޕ㧔ല  ⢻ㅊടᛚ⹺ᤨ㧕

 

 

           

 

             

 

     ૶↪਄ 1) ㊀ᄢߥ೽૞↪ 㧔1㧕㊀ᄢߥ೽૞↪ 㧔㧕㊀ᄢߥ೽૞↪㧔એਅߩ೽૞↪ߪߔߴߡ㗫ᐲ ߩᵈᗧ ᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવ ᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b㧔ㆮવ ਇ᣿㧕ᵈ㧕 ሶ⚵឵߃㧕෶ߪ 2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ ሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩ૬↪ߢ⹺߼ࠄࠇߚ㊀ 1㧕㑆⾰ᕈ⢖Ἳޔ⢖ᶐẢޔ๭ๆ࿎㔍㧦⊒ᾲޔຕ ࡝ࡦߩ૬↪ߢ⹺߼ࠄࠇߚ㊀ᄢߥ೽૞↪ߪએਅߩ ᄢߥ೽૞↪ߪએਅߩߣ߅ࠅߢ޽ࠆ㧚 ༿ޔ๭ๆ࿎㔍╬ߩ⥃ᐥ∝⁁ࠍචಽߦⷰኤߒޔ⇣ ߣ߅ࠅߢ޽ࠆޕ 1㧕ਛᲥᕈ⴫⊹უᱫⲢ⸃∝㧔Toxic Epidermal Ᏹ߇⹺߼ࠄࠇߚ႐วߪޔㅦ߿߆ߦ⢷ㇱ X ✢╬ߩ (1) ⽺ⴊ㧔0.2%㧕㧖㧦⽺ⴊ߇޽ࠄࠊࠇࠆߎߣ߇޽ Necrolysis:TEN㧕㧔㗫ᐲਇ᣿㧕㧘⊹⤏☼⤑⌒∝୥ ᬌᩏࠍታᣉߒޔᧄ೷ߩᛩਈࠍਛᱛߒޔ೽⣢⊹⾰ ࠆߩߢޔቯᦼ⊛ߦⴊᶧᬌᩏࠍⴕ߁ߥߤⷰኤࠍ ⟲㧔Stevens̃Johnson ∝୥⟲㧕㧔1%ᧂḩ㧕㧘ᄙᒻ ࡎ࡞ࡕࡦ೷ߩᛩਈ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ චಽߦⴕ޿㧘⇣Ᏹߩ⒟ᐲ߇⪺ߒ޿႐วߦߪᛩ ⚃᢬㧔1%ᧂḩ㧕㧦ਛᲥᕈ⴫⊹უᱫⲢ⸃∝㧘⊹⤏ ߹ߚޔຕ༿ޔ๭ๆ࿎㔍╬߇޽ࠄࠊࠇߚ႐วߦߪ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ਈߩਛᱛࠍ⠨ᘦߒ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ☼⤑⌒∝୥⟲㧘ᄙᒻ⚃᢬߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆ ⋥ߜߦㅪ⛊ߔࠆࠃ߁ߦᖚ⠪ߦኻߒᵈᗧࠍਈ߃ࠆ (2) ᄙᒻ⚃᢬㧔0.2%㧕㧖㧦ᄙᒻ⚃᢬߇޽ࠄࠊࠇࠆ ߩߢ㧘ⷰኤࠍචಽߦⴕ޿㧘⊒ᾲ㧘᳓∊㧘⴫⊹೸ ߎߣޕߥ߅ޔ㑆⾰ᕈ⢖Ἳߪዊᩊ⢫ḡߣߩ૬↪଀ ߎߣ߇޽ࠆߩߢ㧘ⷰኤࠍචಽߦⴕ޿㧘∝⁁߇޽ 㔌㧘☼⤑ߩ߮ࠄࠎ࡮ẩ≌㧘⌒∛ᄌ╬߇޽ࠄࠊࠇߚ ߢᄙߊႎ๔ߐࠇߡ޿ࠆߚ߼૬↪ߒߥ޿ߎߣޕ ࠄࠊࠇߚ႐วߦߪ㧘ᛩਈࠍਛᱛߒ㧘ㆡಾߥಣ⟎ ႐วߦߪ㧘ᛩਈࠍਛᱛߒ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎ 2㧕߁ߟ∛ޔ⥄Ვᔨᘦޔ⥄Ვડ࿑ޔば⁁ᘒޔ᡹᠄ ࠍⴕ߁ߎߣޕ ߣ㧚 ⊛ⴕേ᧶ⷰኤࠍචಽߦⴕ޿ޔਇ⌁ޔਇ቟ޔὶ 2㧕⮎೷ᕈㆊᢅ∝∝୥⟲㧔Drug̃induced hypersensi 㧖㧦㗫ᐲߪ 3 ೷૬↪ߒߚ࿖ౝ⥃ᐥ⹜㛎ߦ߅ߌࠆ ῎ޔ⥝ᅗޔ᡹᠄ᕈޔᤃೝỗᕈ╬߇޽ࠄࠊࠇߚ႐ ㊀◊∝଀ࠍ␜ߔ ̃tivity syndrome : DIHS㧕㧔1ᧂḩ㧕㧦ೋᦼ∝⁁ วߦߪᛩਈࠍਛᱛߔࠆߥߤޔㆡಾߥಣ⟎ࠍⴕ߁ ߣߒߡ⊒∐㧘⊒ᾲ߇ߺࠄࠇ㧘ᦝߦ⢄ᯏ⢻㓚ኂ㧘࡝ ߎߣޕ㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄ෳᾖ㧕 ࡦࡄ▵⣲⣘㧘⊕ⴊ⃿Ⴧട㧘ᅢ㉄⃿Ⴧᄙ㧘⇣ဳ࡝ࡦ 3㧕᳢ⴊ⃿ᷫዋޔή㗰☸⃿∝ޔ⊕ⴊ⃿ᷫዋ㧔2, ࡄ⃿಴⃻╬ࠍ઻߁ㆃ⊒ᕈߩ㊀◊ߥㆊᢅ∝⁁߇޽ࠄ 000/ǴL ᧂḩ㧕ޔⴊዊ᧼ᷫዋ㧔50, 000/ǴL ᧂ ࠊࠇࠆߎߣ߇޽ࠆߩߢ㧘ⷰኤࠍචಽߦⴕ޿㧘ߎߩ ḩ㧕ޔ⽺ⴊޔ⿒⧘⃿≲᧶ቯᦼ⊛ߦⴊᶧᬌᩏࠍⴕ ࠃ߁ߥ∝⁁߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߒ㧘 ߁ߥߤޔᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤߔࠆߎߣޕᧄ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣ㧚ߥ߅㧘ࡅ࠻ࡋ࡞ࡍࠬ࠙ࠗ ೷ߩᷫ㊂ޔਛᱛߦߟ޿ߡߪޔ㧨↪ᴺ࡮↪㊂ߦ㑐 ࡞ࠬ 6㧔HHṼ6㧕╬ߩ࠙ࠗ࡞ࠬߩౣᵴᕈൻࠍ઻߁ ㅪߔࠆ૶↪਄ߩᵈᗧ㧪ߩ㗄ࠍෳᾖߔࠆߎߣޕ ߎߣ߇ᄙߊ㧘ᛩਈਛᱛᓟ߽⊒∐㧘⊒ᾲ㧘⢄ᯏ⢻㓚 4㧕ⴊᩖᕈⴊዊ᧼ᷫዋᕈ⚡᢬∛㧔TTP㧕ޔṁⴊᕈ ኂ╬ߩ∝⁁߇ౣΆ޽ࠆ޿ߪㆫᑧൻߔࠆߎߣ߇޽ࠆ ዩᲥ∝∝୥⟲㧔HUS㧕㧦ⴊዊ᧼ᷫዋޔ⽺ⴊޔ⣢ ߩߢᵈᗧߔࠆߎߣ㧚 ਇోࠍਥᓽߣߔࠆⴊᩖᕈⴊዊ᧼ᷫዋᕈ⚡᢬∛ 3㧕ᕆᕈ⣢ਇో 㧔㗫ᐲਇ᣿㧕㧦ᕆᕈ⣢ਇో╬ߩ㊀ 㧔TTP㧕ޔṁⴊᕈዩᲥ∝∝୥⟲㧔HUS㧕߇޽ࠄࠊ ◊ߥ⣢ᯏ⢻㓚ኂ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢ㧘ቯ ࠇࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦⴊᶧᬌᩏ㧔ⴊዊ ᦼ⊛ߦ⣢ᯏ⢻ᬌᩏࠍⴕ޿㧘⇣Ᏹ߇⹺߼ࠄࠇߚ႐ว ᧼ޔ⿒ⴊ⃿╬㧕෸߮⣢ᯏ⢻ᬌᩏࠍⴕ߁ߥߤⷰኤ ߦߪᛩਈࠍਛᱛߔࠆߥߤ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎ ࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈ ߣ㧚㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄ෳᾖ㧕 ࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 4㧕⽺ⴊ㧔1%㨪 5%ᧂḩ㧕㧘ࡋࡕࠣࡠࡆࡦᷫዋ 㧔㗫ᐲਇ᣿㧕㧦ቯᦼ⊛ߦⴊᶧᬌᩏࠍⴕ߁ߥߤⷰኤ 5㧕⢄ἻߩჇᖡޔ⢄ᯏ⢻㓚ኂ᧶㤛∏߿⪺ߒ޿࠻࡜ ࠍචಽߦⴕ޿㧘⇣Ᏹߩ⒟ᐲ߇⪺ߒ޿႐วߦߪᛩਈ ࡦࠬࠕࡒ࠽࡯࠯ߩ਄᣹ࠍ઻߁⢄ᯏ⢻㓚ኂ߇ႎ๔ ࠍਛᱛߒ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎߣ㧚 ߐࠇߡ޿ࠆߩߢޔቯᦼ⊛ߦ⢄ᯏ⢻ᬌᩏࠍⴕ߁ߥ 5㧕ᢌⴊ∝㧔1%ᧂḩ㧕㧦ᤃᗵᨴᕈߣߥࠅ㧘ᗵᨴ∝ ߤޔᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤߔࠆߎߣޕ㤛∏߿ ෸߮ᗵᨴ∝ߩჇᖡࠍ⺃⊒ߒᢌⴊ∝ߦ⥋ࠆߎߣ߇޽ ⪺ߒ޿࠻࡜ࡦࠬࠕࡒ࠽࡯࠯਄᣹㨇ALT㧔GPT㧕҈ ࠆߩߢ㧘⥃ᐥ∝⁁㧔⊒ᾲ╬㧕෸߮ቯᦼ⊛ߥ⊕ⴊ⃿ 500IU/L㨉ࠍ઻߁⢄ᯏ⢻㓚ኂ߇޽ࠄࠊࠇߚ႐วߦ ಽ↹㧘CRP ୯᷹ቯ╬චಽߥⷰኤࠍⴕ޿㧘ᖚ⠪ߩో ߪㅦ߿߆ߦᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎ り⁁ᘒࠍචಽߦⷰኤߒ㧘⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦ ߣޕ ߪᛩਈࠍਛᱛߒ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎߣ㧚

24 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 4.೽૞↪ 4.೽૞↪㧔ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a 4.೽૞↪ ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵ ٤ C ဳᘟᕈ⢄Ἳࠍኻ⽎ߣߒߚ࿖ౝ⥃ᐥ⹜㛎ߦ߅ߌ 㧔ㆮવሶ⚵឵߃㧕ߣߩ૬↪ߩ႐ว㧕 ࠆ࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦ߅޿ߡޔ቟ోᕈ⹏ଔߩ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ㧦ᧄ೷ ߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮ ኻ⽎ߣߥߞߚ 332 ଀ో଀ߦ೽૞↪߇⹺߼ࠄࠇ ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵ વሶ⚵឵߃㧕ߣߩ૬↪ߩ႐ว ߚޕਥߥ೽૞↪ߪޔ⊒ᾲ㧔95.5%㧕ޔୱᕃᗵ ឵߃㧕ࠍ૬↪ߒߚ࿖ౝ⥃ᐥ⹜㛎ߦ߅޿ߡޔ቟ోᕈ ᧄ೷ߣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵ 㧔93.4%㧕ޔ㗡∩㧔88.6%㧕╬ߢ޽ࠅޔ⥃ᐥᬌᩏ ⹏ଔߩኻ⽎ߣߥߞߚ 199 ଀ో଀ߦ⥃ᐥᬌᩏ୯ߩ⇣ ឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ୯ߩ⇣Ᏹߪޔ࡝ࡦࡄ⃿ᢙᷫዋ㧔96.7%㧕ޔ⊕ⴊ⃿ Ᏹࠍ฽߻೽૞↪߇⹺߼ࠄࠇߚޕਥߥ೽૞↪ߪޔ⊒ 㧔ㆮવሶ⚵឵߃㧕ࠍ૬↪ߒߚ C ဳᘟᕈ⢄Ἳࠍኻ ᢙᷫዋ㧔95.8%㧕ޔᅢਛ⃿ᢙᷫዋ㧔87.3%㧕ޔࡋ ᾲ 146 ઙ㧔73.4㧑㧕ޔᵈ኿ㇱ૏෻ᔕ 142 ઙ ⽎ߣߒߚ࿖ౝ⥃ᐥ⹜㛎ߦ߅޿ߡޔ቟ోᕈ⹏ଔߩ ࡕࠣࡠࡆࡦᷫዋ㧔85.5%㧕ޔ⿒ⴊ⃿ᢙᷫዋ 㧔71.4㧑㧕ޔୱᕃᗵ 138 ઙ㧔69.3㧑㧕╬ߢ޽ߞ ኻ⽎ߣߥߞߚ 917 ଀ో଀ߦ೽૞↪߇⹺߼ࠄࠇ 㧔79.8%㧕╬ߢ޽ߞߚޕ㧔ല⢻ㅊടᛚ⹺ᤨ㧕 ߚޕ೽૞↪ߣߒߡߩ⥃ᐥᬌᩏ୯ߩ⇣Ᏹߪޔ⊕ⴊ⃿ ߚޕਥߥ೽૞↪ߪ⊒ᾲ㧔96.7㧑㧕ޔୱᕃᗵ C ဳઍఘᕈ⢄⎬ᄌࠍኻ⽎ߣߒߚ࿖ౝ⥃ᐥ⹜㛎ߦ ᷫዋ 184 ઙ㧔92.5㧑㧕ޔᅢਛ⃿ᷫዋ 178 ઙ 㧔91.8㧑㧕ޔ㗡∩㧔86.0㧑㧕╬ߢ޽ࠅޔ⥃ᐥᬌᩏ ߅ߌࠆ࡝ࡃࡆ࡝ࡦߣߩ૬↪ߦ߅޿ߡޔࡍࠣࠗࡦ 㧔89.4㧑㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ 169 ઙ㧔84.9㧑㧕 ୯ߩ⇣Ᏹߪޔ⊕ⴊ⃿ᢙᷫዋ㧔89.6㧑㧕ޔᅢਛ⃿ᢙ ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕1.0 ╬ߢ޽ߞߚޕ㧔ᛚ⹺ᤨ㧕 ᷫዋ㧔83.4㧑㧕ޔ࡝ࡦࡄ⃿ᢙᷫዋ㧔70.6㧑㧕╬ߢ Ǵg/kg ߢᛩਈ߇㐿ᆎߐࠇߚ 102 ଀ో଀ߦ೽૞↪ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ㧦 ޽ߞߚޕ㧔ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ߇⹺߼ࠄࠇߚޕਥߥ೽૞↪ߪޔ⊒ᾲ㧔93.1㧑㧕ޔ ᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવ 㧔ㆮવሶ⚵឵߃㧕ߣߩ૬↪ߦኻߔࠆല⢻ㅊടᛚ ୱᕃᗵ㧔88.2㧑㧕ޔ㗡∩㧔80.4㧑㧕╬ߢ޽ࠅޔ⥃ ሶ⚵឵߃㧕ࠍ૬↪ߒߚ࿖ౝ⥃ᐥ⹜㛎ߦ߅޿ߡޔ቟ ⹺ᤨ㧕 ᐥᬌᩏ୯ߩ⇣Ᏹߪޔ⊕ⴊ⃿ᢙᷫዋ㧔91.2㧑㧕ޔࡋ ోᕈ⹏ଔߩኻ⽎ߣߥߞߚ 61 ଀ో଀ߦ⥃ᐥᬌᩏ୯ ᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવ ࡕࠣࡠࡆࡦᷫዋ㧔89.2㧑㧕ޔ࡝ࡦࡄ⃿ᢙᷫዋ ߩ⇣Ᏹࠍ฽߻೽૞↪߇⹺߼ࠄࠇߚޕਥߥ೽૞↪ ሶ⚵឵߃㧕ࠍ૬↪ߒߚ C ဳઍఘᕈ⢄⎬ᄌࠍኻ⽎ 㧔87.3㧑㧕ޔᅢਛ⃿ᢙᷫዋ㧔85.3㧑㧕ޔ⿒ⴊ⃿ᢙ ߪޔୱᕃᗵ 45 ઙ㧔73.8㧑㧕ޔ⊒ᾲ 41 ઙ ߣߒߚ࿖ౝ⥃ᐥ⹜㛎ߦ߅޿ߡޔࡍࠣࠗࡦ࠲࡯ࡈ ᷫዋ㧔84.3㧑㧕ޔࡋࡑ࠻ࠢ࡝࠶࠻ᷫዋ 㧔67.2㧑㧕ޔហ∣∝ 38 ઙ㧔62.3㧑㧕╬ߢ޽ߞߚޕ ࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕1.0Ǵg/kg ߢ 㧔80.4㧑㧕ޔⴊዊ᧼ᢙᷫዋ㧔63.7㧑㧕╬ߢ޽ߞ ೽૞↪ߣߒߡߩ⥃ᐥᬌᩏ୯ߩ⇣Ᏹߪޔᅢਛ⃿ᷫዋ ᛩਈ߇㐿ᆎߐࠇߚ 102 ଀ో଀ߦ೽૞↪߇⹺߼ࠄ ߚޕ㧔ല⢻ㅊടᛚ⹺ᤨ㧕 58 ઙ㧔95.1㧑㧕ޔ⊕ⴊ⃿ᷫዋ 54 ઙ㧔88.5㧑㧕ޔ⿒ ࠇߚޕਥߥ೽૞↪ߪޔ⊒ᾲ㧔93.1㧑㧕ޔୱᕃᗵ  ⴊ⃿ᷫዋ 48 ઙ㧔78.7㧑㧕ޔⴊዊ᧼ᷫዋ 48 ઙ 㧔88.2㧑㧕ޔ㗡∩㧔80.4㧑㧕╬ߢ޽ࠅޔ⥃ᐥᬌᩏ  㧔78.7㧑㧕╬ߢ޽ߞߚޕ㧔ല⢻ㅊടᛚ⹺ᤨ㧕 ୯ߩ⇣Ᏹߪޔ⊕ⴊ⃿ᢙᷫዋ㧔91.2㧑㧕ޔࡋࡕࠣࡠ

  ࡆࡦᷫዋ㧔89.2㧑㧕ޔ࡝ࡦࡄ⃿ᢙᷫዋ   㧔87.3㧑㧕ޔᅢਛ⃿ᢙᷫዋ㧔85.3㧑㧕ޔ⿒ⴊ⃿ᢙ   ᷫዋ㧔84.3㧑㧕ޔࡋࡑ࠻ࠢ࡝࠶࠻ᷫዋ   㧔80.4㧑㧕ޔⴊዊ᧼ᢙᷫዋ㧔63.7㧑㧕╬ߢ޽ߞ   ߚޕ㧔ല⢻ㅊടᛚ⹺ᤨ㧕   ᧄ೷ߣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵   ឵߃㧕ࠍ૬↪ߒߚ⵾ㅧ⽼ᄁᓟ⺞ᩏߦ߅޿ߡޔ቟   ోᕈ⹏ଔߩኻ⽎ߣߥߞߚ 3,310 ଀ਛ 2,773 ଀   㧔83.8㧑㧕ߦ೽૞↪߇⹺߼ࠄࠇߚޕਥߥ೽૞↪ߪ   ⊒ᾲ㧔27.3㧑㧕ޔୱᕃᗵ㧔13.1㧑㧕ޔ㘩᰼ਇᝄ   㧔11.8㧑㧕╬ߢ޽ࠅޔ⥃ᐥᬌᩏ୯ߩ⇣Ᏹߪޔ⊕ⴊ   ⃿ᢙᷫዋ㧔35.2㧑㧕ޔ⽺ⴊ㧔34.2㧑㧕ޔⴊዊ᧼ᢙ   ᷫዋ㧔26.6㧑㧕ޔᅢਛ⃿ᢙᷫዋ㧔21.0㧑㧕ޔࡋࡕ   ࠣࡠࡆࡦᷫዋ㧔17.5㧑㧕╬ߢ޽ߞߚޕ   㧔ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵   ߃㧕ߣߩ૬↪ߦኻߔࠆౣክᩏ⚳ੌᤨ㧕   㧔1㧕㊀ᄢߥ೽૞↪ 㧔1㧕㊀ᄢߥ೽૞↪ 㧔1㧕㊀ᄢߥ೽૞↪ ᵈ 1㧕 3 ૶↪਄ એਅߩ೽૞↪ߩ߁ߜޔᶏᄖႎ๔෶ߪࠗࡦ࠲࡯ࡈ 1㧕⽺ⴊ㧔⿒ⴊ⃿ᷫዋ㧔250 ਁǴ. ᧂḩ㧕㧔4㧑ᧂ 1㧕⽺ⴊ 㧔⿒ⴊ⃿ᷫዋ㧔250 ਁ/mm ᧂḩ㧕㧔1 ߩᵈᗧ ࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ߣ࡝ࡃࡆ࡝ ḩ㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔8IF. ᧂḩ㧕㧔2㧑ᧂ 㨪5㧑ᧂḩ㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔8g/dL ᧂḩ㧕 ࡦߩ૬↪ߦࠃࠅ⊒⃻ߒߚ೽૞↪ߦߟ޿ߡߪ㗫ᐲ ḩ㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔8 એ਄ 9.5IF. ᧂḩ㧕 㧔1㨪5㧑ᧂḩ㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔8 એ਄ ਇ᣿ߣߒߚޕ 㧔10㧑એ਄㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔9.5 એ਄ 9.5g/dL ḩᧂ㧕㧔10㧑એ਄㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ 1㧕㑆⾰ᕈ⢖Ἳ㧔1㧑ᧂḩ㧕ޔ⢖✢⛽∝ޔ⢖᳓⣲ 11IF. ᧂḩ㧕㧔10㧑એ਄㧕ި㧦ቯᦼ⊛ߦⴊᶧᬌ 㧔9.5 એ਄ 11g/dL ᧂḩ㧕㧔10㧑એ਄㧕㧕㧦ቯᦼ⊛ 㧔㗫ᐲਇ᣿㧕㧦⊒ᾲޔຕ༿ޔ๭ๆ࿎㔍╬ߩ๭ๆ ᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ㊀ᐲߩ⽺ⴊࠍ⹺ ߦⴊᶧᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ ེ∝⁁ޔ߹ߚޔ⢷ㇱ X ✢⇣Ᏹ߇޽ࠄࠊࠇߚ႐ว ߼ߚ႐วߪޔᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎ ߩ⒟ᐲ߇⪺ߒ޿႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥ ߦߪᛩਈࠍਛᱛߒޔ೽⣢⊹⾰ࡎ࡞ࡕࡦ೷ߩᛩਈ ߣޕ ಣ⟎ࠍⴕ߁ߎߣޕ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ߹ߚޔຕ༿ޔ๭ๆ 2㧕᳢ⴊ⃿ᷫዋޔή㗰☸⃿∝ޔ⊕ⴊ⃿ᷫዋ㧔2,000/ 2㧕ή㗰☸⃿∝㧔0.1㨪1㧑ᧂḩ㧕ޔ⊕ⴊ⃿ᷫዋ 3 3 ࿎㔍╬߇޽ࠄࠊࠇߚ႐วߦߪ⋥ߜߦㅪ⛊ߔࠆࠃ ǴL ᧂḩ㧕ޔⴊዊ᧼ᷫዋ㧔50,000/ǴL ᧂḩ㧕᧤㗫 㧔2,000/mm ᧂḩ㧕ޔ㗰☸⃿ᷫዋ㧔1,000/mm ᧂ ḩ㧕㧔10㧑એ਄㧕㧦ቯᦼ⊛ߦⴊᶧᬌᩏࠍⴕ߁ߥ ߁ᖚ⠪ߦኻߒᵈᗧࠍਈ߃ࠆߎߣޕߥ߅ޔઁߩࠗ ᐲਇ᣿ᵈ㧕㧕㧦ቯᦼ⊛ߦⴊᶧᬌᩏࠍⴕ߁ߥߤޔᖚ ߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹߩ⒟ᐲ߇⪺ߒ޿႐ว ࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ⵾೷ߦ߅޿ߡޔ㑆⾰ᕈ ⠪ߩ⁁ᘒࠍචಽߦⷰኤߔࠆߎߣޕᧄ೷ߩᷫ㊂ޔਛ ߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ⢖Ἳߪዊᩊ⢫ḡߣߩ૬↪଀ߢᄙߊႎ๔ߐࠇߡ޿ ᱛߦߟ޿ߡߪޔ㧨↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩ 3㧕ⴊዊ᧼ᷫዋ㧔50,000/mm3 ᧂḩ㧕㧔1 㨪 5 㧑ᧂ ࠆߚ߼ޔ૬↪ࠍㆱߌࠆߎߣޕ ᵈᗧ㧪ߩ㗄ࠍෳᾖߔࠆߎߣޕ 2㧕ᛥ߁ߟ࡮߁ߟ∛㧔㨪㧑ᧂḩ㧕ޔ⥄Ვડ 3㧕ⴊᩖᕈⴊዊ᧼ᷫዋᕈ⚡᢬∛㧔TTP㧕ޔṁⴊᕈ ḩ㧕᧶ቯᦼ⊛ߦⴊᶧᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽ ࿑ޔば⁁ᘒ㧔㧑ᧂḩ㧕ޔ᡹᠄⊛ⴕേ㧔㗫ᐲਇ ዩᲥ∝∝୥⟲㧔HUS㧕㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⴊዊ᧼ ߦⴕ޿ޔ⇣Ᏹߩ⒟ᐲ߇⪺ߒ޿႐วߦߪᛩਈࠍਛ ᣿㧕᧶ⷰኤࠍචಽߦⴕ޿ޔਇ⌁ޔਇ቟ޔὶ῎ޔ ᷫዋޔ⽺ⴊޔ⣢ਇోࠍਥᓽߣߔࠆⴊᩖᕈⴊዊ᧼ᷫ ᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ⥝ᅗޔ᡹᠄ᕈޔᤃೝỗᕈ╬߇޽ࠄࠊࠇߚ႐วߦ ዋᕈ⚡᢬∛㧔TTP㧕ޔṁⴊᕈዩᲥ∝∝୥⟲ 4㧕ౣ↢ਇ⦟ᕈ⽺ⴊ㧔㗫ᐲਇ᣿㧕ޔ᳢ⴊ⃿ᷫዋ ߪᛩਈࠍਛᱛߔࠆߥߤޔㆡಾߥಣ⟎ࠍⴕ߁ߎ 㧔HUS㧕߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦ 㧔0.1㨪1㧑ᧂḩ㧕㧦㛽㜑ᯏ⢻ߩᛥ೙ߦࠃࠆౣ↢ਇ ߣޕ㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄ෳᾖ㧕 ⴊᶧᬌᩏ㧔ⴊዊ᧼ޔ⿒ⴊ⃿╬㧕෸߮⣢ᯏ⢻ᬌᩏࠍ ⦟ᕈ⽺ⴊߩ⊒⃻ࠍ฽߻㜞ᐲߥⴊ⃿ᷫዋ߇ႎ๔ߐ 3㧕⽺ⴊᵈ 1㧕㧔⿒ⴊ⃿ᷫዋ㧔250 ਁ/mm3 ᧂḩ㧕㧔1 ⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐ ࠇߡ޿ࠆߩߢޔቯᦼ⊛ߦ⥃ᐥᬌᩏ㧔ⴊᶧᬌᩏ 㨪5㧑ᧂḩ㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔8g/dL ᧂḩ㧕 วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ╬㧕ࠍⴕ߁ߥߤޔᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤߔࠆ 㧔1㧑ᧂḩ㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔8 એ਄ 9.5g/dL 4㧕ౣ↢ਇ⦟ᕈ⽺ⴊᇬ⿒⧘⃿≲㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦 ߎߣޕ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪޔޛ↪ᴺ࡮↪ ㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧޜߩ㗄ࠍෳᾖߩ਄ޔ ᧂḩ㧕㧔10㧑એ਄㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔9.5 એ ቯᦼ⊛ߦⴊᶧᬌᩏࠍⴕ߁ߥߤޔᖚ⠪ߩ⁁ᘒࠍචಽ ᷫ㊂෶ߪਛᱛ╬ߩಣ⟎ࠍⴕ߁ߎߣޕ ਄ 11g/dL ᧂḩ㧕㧔10㧑એ਄㧕㧕᧶ቯᦼ⊛ߦⴊᶧ ߦⷰኤߔࠆߎߣޕᧄ೷ߩᷫ㊂ޔਛᱛߦߟ޿ߡߪޔ 5㧕ᛥ߁ߟ࡮߁ߟ∛㧔5㨪10㧑ᧂḩ㧕ޔ⥄Ვડ ᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹߩ⒟ᐲ 㧨↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧪ߩ㗄ࠍෳ ࿑ޔば⁁ᘒ㧔0.1㨪1㧑ᧂḩ㧕ޔ᡹᠄⊛ⴕേ㧔㗫ᐲ ߇⪺ߒ޿႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍ ᾖߔࠆߎߣޕ ਇ᣿㧕㧦ⷰኤࠍචಽߦⴕ޿ޔਇ⌁ޔਇ቟ޔὶ ⴕ߁ߎߣޕ 5㧕㑆⾰ᕈ⢖Ἳޔ⢖ᶐẢޔ๭ๆ࿎㔍㧔㗫ᐲਇ᣿ᵈ ῎ޔ⥝ᅗޔ᡹᠄ᕈޔᤃೝỗᕈ╬߇޽ࠄࠊࠇߚ႐ 4㧕ή㗰☸⃿∝㧔㗫ᐲਇ᣿㧕ޔ⊕ⴊ⃿ᷫዋ 2㧕㧕㧦⊒ᾲޔຕ༿ޔ๭ๆ࿎㔍╬ߩ⥃ᐥ∝⁁ࠍචಽ วߦߪᛩਈࠍਛᱛߔࠆߥߤޔㆡಾߥಣ⟎ࠍⴕ߁ 㧔2,000/mm3 ᧂḩ㧕㧔10㧑એ਄㧕ޔ㗰☸⃿ᷫዋ ߦⷰኤߒޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߪޔㅦ߿߆ߦ⢷ ߎߣޕ㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄ෳᾖ㧕 㧔1,000/mm3 ᧂḩ㧕㧔61.9㧑㧕㧦ቯᦼ⊛ߦⴊᶧᬌ ㇱ X ✢╬ߩᬌᩏࠍታᣉߒޔᧄ೷ߩᛩਈࠍਛᱛߒޔ 6㧕ᗧ⼂㓚ኂޔᐛⷡޔᄬ␹ޔ㔍⡬㧔0.1㨪1㧑ᧂ ᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹߩ⒟ᐲ߇ ೽⣢⊹⾰ࡎ࡞ࡕࡦ೷ߩᛩਈ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ ḩ㧕ޔᅦᗐޔ∨ᡨޔߖࠎᅦޔ⹺⍮∝᭽∝⁁㧔․ ⪺ߒ޿႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ ߎߣޕ߹ߚޔຕ༿ޔ๭ๆ࿎㔍╬߇޽ࠄࠊࠇߚ႐ว ߦ㜞㦂⠪㧕ޔ㍲ੂޔᤀㅅޔ⷗ᒰ⼂㓚ኂޔ⛔วᄬ ߁ߎߣޕ ߦߪ⋥ߜߦㅪ⛊ߔࠆࠃ߁ߦᖚ⠪ߦኻߒᵈᗧࠍਈ߃ ⺞∝᭽∝⁁㧔0.1㧑ᧂḩ㧕ޔ⥝ᅗ㧔㗫ᐲਇ᣿㧕㧦 5㧕ⴊዊ᧼ᷫዋ㧔50,000/mm3 ᧂḩ㧕㧔1㨪5㧑ᧂ ࠆߎߣޕ ⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇޽ࠄࠊࠇߚ႐วߦ ḩ㧕㧦ቯᦼ⊛ߦⴊᶧᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽ 6㧕߁ߟ∛ޔ⥄Ვᔨᘦޔ⥄Ვડ࿑ޔば⁁ᘒޔ᡹᠄ ߪޔᛩਈ⛮⛯ߩนุߦߟ޿ߡᬌ⸛ߔࠆߎߣޕ∝ ߦⴕ޿ޔ⇣Ᏹߩ⒟ᐲ߇⪺ߒ޿႐วߦߪᛩਈࠍਛ ⊛ⴕേ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⷰኤࠍචಽߦⴕ޿ޔਇ ⁁ߩỗߒ޿႐ว෸߮ᷫ㊂ߒߡ߽ᶖᄬߒߥ޿႐ว ᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ⌁ޔਇ቟ޔὶ῎ޔ⥝ᅗޔ᡹᠄ᕈޔᤃೝỗᕈ╬߇޽ ߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤޔㆡಾߥಣ

⟎ࠍⴕ߁ߎߣޕ㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄ෳ ᾖ㧕

25 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

6㧕ⴊᶧ㓚ኂ㧔᳢ⴊ⃿ᷫዋ㧔 1 %ᧂḩ㧕㧘ή㗰☸ 6㧕⥄Ꮖ఺∉⃻⽎㧦⥄Ꮖ఺∉⃻⽎ߦࠃࠆߣᕁࠊࠇ ⃿∝㧘ᅢਛ⃿ᷫዋ㧘ⴊዊ᧼ᷫዋ㧘⊕ⴊ⃿ᷫዋ㧔㗫 ࠆ∝⁁࡮ᓽ୥㨇⢄Ἳޔṁⴊᕈ⽺ⴊޔ․⊒ᕈⴊዊ ᐲਇ᣿㧕㧕㧦㜞ᐲߥⴊ⃿ᷫዋ߇ႎ๔ߐࠇߡ޿ࠆߩ ᧼ᷫዋᕈ⚡᢬∛ޔẩ≌ᕈᄢ⣺Ἳޔ㑐▵࡝࠙ࡑ ߢ㧘ቯᦼ⊛ߦ⥃ᐥᬌᩏ㧔ⴊᶧᬌᩏ╬㧕ࠍⴕ߁ߥ ࠴ޔSLEޔⴊ▤Ἳޔࡈࠜ࡯ࠢ࠻࡮ዊᩉ࡮ේ↰∛ޔ ߤ㧘ᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤߔࠆߎߣ㧚⇣Ᏹߩ⒟ ฦ⒳⥄Ꮖ᛫૕ߩ㓁ᕈൻ╬㨉߇޽ࠄࠊࠇࠆߎߣ߇ ᐲ߇⪺ߒ޿႐วߦߪᛩਈࠍਛᱛߒ㧘ㆡಾߥಣ⟎ࠍ ޽ࠆߩߢޔ⥄Ꮖ఺∉∔ᖚߩᖚ⠪෶ߪߘߩ⚛࿃ߩ ⴕ߁ߎߣ㧚 ޽ࠆᖚ⠪ߦߪቯᦼ⊛ߦᬌᩏࠍⴕ߁ߥߤⷰኤࠍච 7㧕⢖Ⴇᩖ∝㧘ⴊᩖႧᩖ∝㧔1%ᧂḩ㧕㧦⢖Ⴇᩖ∝ ಽߦⴕ޿ޔᘕ㊀ߦᛩਈߔࠆߎߣޕ⇣Ᏹ߇⹺߼ࠄ ߇ႎ๔ߐࠇߡ޿ࠆߩߢ㧘ⷰኤࠍචಽߦⴕ޿㧘ᕷಾ ࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ ࠇ㧘⢷∩㧘྾⢇ߩ−∩㧘ᶋ⣲╬߇⹺߼ࠄࠇߚ႐ว ߎߣޕߚߛߒޔ⥄Ꮖ఺∉ᕈ⢄Ἳߩᖚ⠪ߦߪᛩਈ ߦߪ㧘ᛩਈࠍਛᱛߔࠆߥߤㆡಾߥಣ⟎ࠍⴕ߁ߎ ߒߥ޿ߎߣޕ ߣ㧚 7㧕ᔃ╭∝ޔᔃਇోޔ⁜ᔃ∝ޔਇᢛ⣂㧔ᔃቶᕈ㗫 8㧕 ᄬ␹㧘ߖࠎᅦ㧔1%ᧂḩ㧕㧘ᗧ⼂ᶖᄬ㧔㗫ᐲਇ ⣂╬㧕ޔᔃ╭᪪Ⴇޔᔃౝ⤑Ἳ㧦ᔃ∔ᖚߩ޽ࠆᖚ ᣿㧕㧦ⷰኤࠍචಽߦⴕ޿㧘⇣Ᏹ߇޽ࠄࠊࠇߚ႐ว ⠪෶ߪߘߩᣢᓔᱧߩ޽ࠆᖚ⠪ߦߪᘕ㊀ߦᛩਈߔ ߦߪ㧘ᧄ೷ߦࠃࠆᴦ≮⛮⛯ߩนุߦߟ޿ߡᬌ⸛ߔ ࠆߎߣޕ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛ ࠆߎߣ㧚∝⁁ߩỗߒ޿႐วߦߪᛩਈࠍਛᱛߒ㧘ㆡ ߔࠆߥߤޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ಾߥಣ⟎ࠍⴕ߁ߎߣ㧚 8㧕ᢌⴊ∝㧦ᤃᗵᨴᕈߣߥࠅޔᢌⴊ∝ޔ⢖Ἳ߇޽ 9㧕 ば⁁ᘒ㧔1%ᧂḩ㧕㧘ᛥ߁ߟ㧔㗫ᐲਇ᣿㧕㧦ⷰ ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔᖚ⠪ߩోり⁁ᘒࠍච ኤࠍචಽߦⴕ޿㧘ਇ⌁㧘ਇ቟㧘ὶ῎㧘ᤃೝỗᕈ╬ ಽߦⷰኤߒޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍ ߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤ㧘ㆡಾ ਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ߥಣ⟎ࠍⴕ߁ߎߣ㧚 9㧕⣖಴ⴊ㧦ⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇ 10㧕 ๭ๆ࿎㔍㧔㗫ᐲਇ᣿㧕㧦ⷰኤࠍචಽߦⴕ ߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎ ޿㧘⇣Ᏹߩ⒟ᐲ߇⪺ߒ޿႐วߦߪᛩਈࠍਛᱛߒ㧘 ߣޕ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣ㧚 10㧕⣖᪪Ⴇޔ⢖Ⴇᩖ∝㧦ⷰኤࠍචಽߦⴕ޿ޔ⇣

11㧕 ✂⤑∝㧔㗫ᐲਇ᣿㧕㧦✂⤑∝߇޽ࠄࠊࠇࠆ Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥ ߎߣ߇޽ࠆߩߢ㧘✂⤑಴ⴊ߿♧ዩ∛✂⤑∝ߩჇᖡ ಣ⟎ࠍⴕ߁ߎߣޕ ߦᵈᗧߒ㧘ቯᦼ⊛ߦ⌒ᐩᬌᩏࠍⴕ߁ߥߤⷰኤࠍච 11㧕ᗧ⼂㓚ኂޔ∨ᡨޔߡࠎ߆ࠎ⊒૞ޔ⷗ᒰ⼂㓚 ಽߦⴕ޿㧘⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛ ኂޔᤀ⌧ޔߖࠎᅦޔ㍲ੂޔᐛⷡޔ⹺⍮∝᭽∝⁁ ߔࠆߥߤ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎߣ㧚߹ߚ㧘ⷞജૐ 㧔․ߦ㜞㦂⠪㧕㧦⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩ ਅ㧘ⷞ㊁ਛߩᥧὐ߇಴⃻ߒߚ႐วߪㅦ߿߆ߦකᏧ ਈࠍਛᱛߔࠆߥߤㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ߩ⸻ኤࠍฃߌࠆࠃ߁ᖚ⠪ࠍᜰዉߔࠆߎߣ㧚 12㧕♧ዩ∛㧦♧ዩ∛㨇ࠗࡦࠬ࡝ࡦଐሽဳ 12㧕⥄Ꮖ఺∉⃻⽎㧔㗫ᐲਇ᣿㧕㧦⥄Ꮖ఺∉⃻⽎ߦ 㧔IDDM㧕෸߮ࠗࡦࠬ࡝ࡦ㕖ଐሽဳ ࠃࠆߣᕁࠊࠇࠆ∝⁁࡮ᓽ୥㧔↲⁁⣼ᯏ⢻⇣Ᏹ㧘↲ 㧔NIDDM㧕㨉߇Ⴧᖡ෶ߪ⊒∝ߔࠆߎߣ߇޽ࠅޔ ⁁⣼Ἳ㧘ṁⴊᕈ⽺ⴊ㧘㑐▵࡝࠙ࡑ࠴╬㧕߇޽ࠄࠊ ᤀ⌧ߦ⥋ࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦᬌᩏ㧔ⴊ ࠇࠆߎߣ߇޽ࠆߩߢ㧘ቯᦼ⊛ߦᬌᩏࠍⴕ߁ߥߤⷰ ♧୯ޔዩ♧╬㧕ࠍⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐ว ኤࠍචಽߦⴕ޿㧘⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈ ߦߪㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ࠍਛᱛߔࠆߥߤㆡಾߥಣ⟎ࠍⴕ߁ߎߣ㧚 13㧕↲⁁⣼ᯏ⢻⇣Ᏹ㧦↲⁁⣼ᯏ⢻੣ㅴ෶ߪૐਅ 13㧕⊕ౝ㓚㧔1%ᧂḩ㧕㧦⊕ౝ㓚߇޽ࠄࠊࠇࠆߎ ߇Ⴧᖡ෶ߪ⊒∝ߔࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦ ߣ߇޽ࠆߩߢ㧘ⷰኤࠍචಽߦⴕ޿㧘⇣Ᏹ߇޽ࠄࠊ ᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ߁ߎߣޕ↲⁁⣼ ࠇߚ႐วߦߪᧄ೷ߦࠃࠆᴦ≮⛮⛯ߩนุߦߟ޿ߡ ᯏ⢻ߩ▤ℂ߇㔍ߒ޿႐วߦߪޔᛩਈߩਛᱛࠍ⠨ ᬌ⸛ߔࠆߎߣ㧚∝⁁ߩ⒟ᐲ߇⪺ߒ޿႐วߦߪᛩਈ ᘦߔࠆߎߣޕߥ߅ޔ↲⁁⣼ᯏ⢻⇣Ᏹ╬ߢᧄ೷ਛ ࠍਛᱛߔࠆߥߤ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎߣ㧚 ᱛᓟ߽ߥ߅ಣ⟎ߩ⛮⛯ࠍᔅⷐߣߒߚ∝଀߇ႎ๔ ૶↪਄ 14㧕♧ዩ∛㧔㗫ᐲਇ᣿㧕㧦♧ዩ∛߇Ⴧᖡ෶ߪ⊒∝ ߐࠇߡ޿ࠆޕ ߩᵈᗧ ߔࠆߎߣ߇޽ࠆߩߢ㧘ቯᦼ⊛ߦᬌᩏ㧔ⴊ♧୯㧘ዩ 14㧕⊹⤏☼⤑⌒∝୥⟲㧔Stevens-Johnson ∝୥ ♧╬㧕ࠍⴕ޿㧘⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪㆡಾߥ ⟲㧕ޔਛᲥᕈ⴫⊹უᱫⲢ⸃∝㧔Toxic Epidermal ಣ⟎ࠍⴕ߁ߎߣ㧚 Necrolysis㧦TEN㧕ޔᄙᒻ⚃᢬㧦⊹⤏☼⤑⌒∝୥ 15㧕㊀◊ߥ⢄ᯏ⢻㓚ኂ㧔㗫ᐲਇ᣿㧕㧦㊀◊ߥ⢄ᯏ ⟲ޔਛᲥᕈ⴫⊹უᱫⲢ⸃∝ޔᄙᒻ⚃᢬╬ߩ⊹⤏ ⢻㓚ኂ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢ㧘ቯᦼ⊛ߦ⢄ 㓚ኂ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔⷰኤࠍචಽ ᯏ⢻ᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿㧘㤛∏߿⪺ ߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛ ߒ޿࠻࡜ࡦࠬࠕࡒ࠽࡯࠯ߩ਄᣹ࠍ઻߁⢄ᯏ⢻㓚ኂ ߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤ㧘ㆡಾ 15㧕ੇ⊈㧦ੇ⊈߇Ⴧᖡ෶ߪ⊒∝ߔࠆߎߣ߇޽ࠆ ߥಣ⟎ࠍⴕ߁ߎߣ㧚㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄 ߩߢޔቯᦼ⊛ߦᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ ෳᾖ㧕 ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈߩਛᱛࠍ⠨ 16㧕ᮮ⚉╭Ⲣ⸃∝㧔㗫ᐲਇ᣿㧕㧦ᮮ⚉╭Ⲣ⸃∝߇ ᘦߔࠆߎߣޕ ޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢ㧘⣕ജᗵ㧘╭⡺∩㧘 16㧕ᕆᕈ⣢ਇోޔࡀࡈࡠ࡯࠯∝୥⟲㧦ቯᦼ⊛ߦ CK㧔CPK㧕਄᣹╬ߦᵈᗧߒ㧘ߎߩࠃ߁ߥ∝⁁߇ ᬌᩏࠍⴕ߁ߥߤޔᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤߔࠆ ޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤ㧘ㆡಾߥ ߎߣޕ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪޔᛩਈࠍਛᱛ ಣ⟎ࠍⴕ߁ߎߣ㧚 ߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 17㧕㑆⾰ᕈ⢖Ἳ㧔㗫ᐲਇ᣿㧕㧦ຕ༿㧘๭ๆ࿎㔍╬ 17㧕ᶖൻ▤಴ⴊ㧔ਅⴊޔⴊଢ╬㧕ޔᶖൻᕈẩ ߩ๭ๆེ∝⁁߿⊒ᾲ㧘߹ߚ㧘⢷ㇱ X ✢⇣Ᏹ╬߇޽ ≌ޔ⯯ⴊᕈᄢ⣺Ἳ㧦ⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇ ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߒ㧘೽⣢⊹⾰ࡎ࡞ࡕ ⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤޔㆡಾ ࡦ೷ߩᛩਈ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣ㧚߹ߚ㧘ຕ ߥಣ⟎ࠍⴕ߁ߎߣޕ ༿㧘๭ๆ࿎㔍╬߇޽ࠄࠊࠇߚ႐วߦߪ⋥ߜߦㅪ⛊ 18㧕࡚ࠪ࠶ࠢ㧦ⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ ߔࠆࠃ߁ᖚ⠪ߦᵈᗧࠍਈ߃ࠆߎߣ㧚 ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ 18㧕ᶖൻ▤಴ⴊ㧔ਅⴊ㧘ⴊଢ╬㧕㧔㗫ᐲਇ᣿㧕㧘 ߁ߎߣޕ ᶖൻ▤ẩ≌㧔㗫ᐲਇ᣿㧕㧦ⷰኤࠍචಽߦⴕ޿㧘⇣ 19㧕✂⤑∝㧦✂⤑∝߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩ Ᏹ߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߒ㧘ㆡಾߥಣ ߢޔ✂⤑಴ⴊ߿♧ዩ∛✂⤑∝ߩჇᖡߦᵈᗧߒޔ ⟎ࠍⴕ߁ߎߣ㧚 ቯᦼ⊛ߦ⌒ᐩᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆ ߥߤޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ߹ߚޔⷞജૐ ਅޔⷞ㊁ਛߩᥧὐ߇಴⃻ߒߚ႐วߪㅦ߿߆ߦක Ꮷߩ⸻ኤࠍฃߌࠆࠃ߁ᖚ⠪ࠍᜰዉߔࠆߎߣޕ

26 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 6㧕ౣ↢ਇ⦟ᕈ⽺ⴊޔ᳢ⴊ⃿ᷫዋ㧔㗫ᐲਇ᣿㧕㧦 7㧕⢄ἻߩჇᖡޔ⢄ᯏ⢻㓚ኂ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦㤛 7㧕㊀◊ߥ⢄ᯏ⢻㓚ኂ㧔0.1㨪1㧑ᧂḩ㧕㧦ቯᦼ⊛ 㛽㜑ᯏ⢻ߩᛥ೙ߦࠃࠆౣ↢ਇ⦟ᕈ⽺ⴊߩ⊒⃻ࠍ ∏߿⪺ߒ޿࠻࡜ࡦࠬࠕࡒ࠽࡯࠯ߩ਄᣹ࠍ઻߁⢄ᯏ ߦ⢄ᯏ⢻ᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ㤛 ฽߻㜞ᐲߥⴊ⃿ᷫዋ߇ႎ๔ߐࠇߡ޿ࠆߩߢޔቯ ⢻㓚ኂ߇ႎ๔ߐࠇߡ޿ࠆߩߢޔቯᦼ⊛ߦ⢄ᯏ⢻ᬌ ∏߿⪺ߒ޿࠻࡜ࡦࠬࠕࡒ࠽࡯࠯ߩ਄᣹ࠍ઻߁⢄ ᦼ⊛ߦ⥃ᐥᬌᩏ㧔ⴊᶧᬌᩏ╬㧕ࠍⴕ߁ߥߤޔᖚ ᩏࠍⴕ߁ߥߤޔᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤߔࠆߎ ᯏ⢻㓚ኂ߇޽ࠄࠊࠇߚ႐วߦߪㅦ߿߆ߦᛩਈࠍ ⠪ߩ⁁ᘒࠍචಽߦⷰኤߔࠆߎߣޕ⇣Ᏹ߇⹺߼ࠄ ߣޕ㤛∏߿⪺ߒ޿࠻࡜ࡦࠬࠕࡒ࠽࡯࠯਄᣹㨇ALT ਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ࠇߚ႐วߦߪޔޛ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ 㧔GPT㧕҈500IU/L㨉ࠍ઻߁⢄ᯏ⢻㓚ኂ߇޽ࠄࠊ 8㧕࡚ࠪ࠶ࠢ㧔0.1㧑ᧂḩ㧕㧦ⷰኤࠍචಽߦⴕ޿ޔ ߩᵈᗧޜߩ㗄ࠍෳᾖߩ਄ޔᷫ㊂෶ߪਛᱛ╬ߩಣ ࠇߚ႐วߦߪㅦ߿߆ߦᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ ਇᔟᗵޔญౝ⇣Ᏹޔ༎㡆ޔ⌇ᥝޔଢᗧޔ⊒᳨ޔ ⟎ࠍⴕ߁ߎߣޕ ࠍⴕ߁ߎߣޕ ⴊ࿶ਅ㒠╬߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍ⋥ߜߦ 7㧕ᗧ⼂㓚ኂޔᄬ␹㧔1㨪5㧑ᧂḩ㧕ޔ⷗ᒰ⼂㓚 8㧕⥄Ꮖ఺∉⃻⽎㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦⥄Ꮖ఺∉⃻⽎ ਛᱛߔࠆߎߣޕ ኂޔ㔍⡬㧔1%ᧂḩ㧕ޔ∨ᡨޔߖࠎᅦޔ㍲ੂޔᐛ ߦࠃࠆߣᕁࠊࠇࠆ∝⁁࡮ᓽ୥㨇⢄Ἳޔṁⴊᕈ⽺ 9㧕ᶖൻ▤಴ⴊ㧔ਅⴊޔⴊଢ╬㧕ޔᶖൻᕈẩ≌ ⷡޔᅦᗐޔᤀㅅޔ⛔วᄬ⺞∝᭽∝⁁ޔ⹺⍮∝᭽ ⴊޔ․⊒ᕈⴊዊ᧼ᷫዋᕈ⚡᢬∛ޔẩ≌ᕈᄢ⣺Ἳޔ 㧔0.1㨪1㧑ᧂḩ㧕ޔ⯯ⴊᕈᄢ⣺Ἳޔዊ⣺ẩ≌ ∝⁁㧔․ߦ㜞㦂⠪㧕ޔ⥝ᅗ㧔㗫ᐲਇ᣿㧕㧦ⷰኤ 㑐▵࡝࠙ࡑ࠴ޔSLEޔⴊ▤Ἳޔࡈࠜ࡯ࠢ࠻࡮ዊ 㧔0.1㧑ᧂḩ㧕㧦ⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇޽ࠄ ࠍචಽߦⴕ޿ޔ⇣Ᏹ߇޽ࠄࠊࠇߚ႐วߦߪޔᛩ ᩉ࡮ේ↰∛ޔฦ⒳⥄Ꮖ᛫૕ߩ㓁ᕈൻ╬㨉߇޽ࠄࠊ ࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ ਈ⛮⛯ߩนุߦߟ޿ߡᬌ⸛ߔࠆߎߣޕ∝⁁ߩỗ ࠇࠆߎߣ߇޽ࠆߩߢޔ⥄Ꮖ఺∉∔ᖚߩᖚ⠪෶ߪߘ ߁ߎߣޕ ߒ޿႐ว෸߮ᷫ㊂ߒߡ߽ᶖᄬߒߥ޿႐วߦߪᛩ ߩ⚛࿃ߩ޽ࠆᖚ⠪ߦߪቯᦼ⊛ߦᬌᩏࠍⴕ߁ߥߤⷰ 10㧕๭ๆ࿎㔍㧔5㨪10㧑ᧂḩ㧕ޔ໼∷Ⴧട㧔1㨪 ਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ኤࠍචಽߦⴕ޿ޔᘕ㊀ߦᛩਈߔࠆߎߣޕ⇣Ᏹ߇⹺ 5㧑ᧂḩ㧕㧦ⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹߩ⒟ᐲ߇⪺ 8㧕⥄Ꮖ఺∉⃻⽎㧔㗫ᐲਇ᣿㧕㧦⥄Ꮖ఺∉⃻⽎ߦ ߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ ߒ޿႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ ࠃࠆߣᕁࠊࠇࠆ∝⁁࡮ᓽ୥㨇↲⁁⣼ᯏ⢻⇣Ᏹޔ ߁ߎߣޕߚߛߒޔ⥄Ꮖ఺∉ᕈ⢄Ἳߩᖚ⠪ߦߪᛩਈ ߎߣޕ ⢄Ἳޔṁⴊᕈ⽺ⴊޔ․⊒ᕈⴊዊ᧼ᷫዋᕈ⚡᢬∛ ߒߥ޿ߎߣޕ 11㧕⣖಴ⴊ㧔0.1㨪1㧑ᧂḩ㧕㧦⣖಴ⴊ߇↢ߓߚߣ 㧔ITP㧕ޔẩ≌ᕈᄢ⣺Ἳޔ㑐▵࡝࠙ࡑ࠴ޔੇ⊈ޔ 9㧕ᔃ╭∝ޔᔃਇోޔ⁜ᔃ∝ޔਇᢛ⣂㧔ᔃቶᕈ㗫 ߩႎ๔߇޽ࠆߩߢޔⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇ ోりᕈࠛ࡝࠹ࡑ࠻࡯࠺ࠬޔⴊ▤Ἳޔࡈࠜ࡯ࠢ ⣂╬㧕ޔᔃ╭᪪Ⴇᇬᔃౝ⤑Ἳޔᔃ⤑Ἳ㧔㗫ᐲਇ᣿ ⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ ࠻࡮ዊᩉ࡮ේ↰∛ޔ♧ዩ∛㧔1 ဳ㧕ߩჇᖡ෶ߪ⊒ ᵈ 2㧕㧕㧦ᔃ∔ᖚߩ޽ࠆᖚ⠪෶ߪߘߩᣢᓔᱧߩ޽ࠆ ࠍⴕ߁ߎߣޕ ∝╬㨉߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦ ᖚ⠪ߦߪᘕ㊀ߦᛩਈߔࠆߎߣޕ⇣Ᏹ߇⹺߼ࠄࠇߚ 12㧕⣖᪪Ⴇ㧔0.1㨪1㧑ᧂḩ㧕㧦⣖᪪Ⴇ߇޽ࠄࠊࠇ ᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤޔㆡಾߥಣ⟎ࠍⴕ߁ ࠆߎߣ߇޽ࠆߩߢޔⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇

ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤㆡಾߥಣ⟎ ߎߣޕ ⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ ࠍⴕ߁ߎߣޕ 10㧕ᢌⴊ∝㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ᤃᗵᨴᕈߣߥࠅޔ ࠍⴕ߁ߎߣޕ 9㧕ṁⴊᕈዩᲥ∝∝୥⟲㧔*75㧕ޔⴊᩖᕈⴊዊ᧼ ᢌⴊ∝ޔ⢖Ἳ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔᖚ⠪ 13㧕㑆⾰ᕈ⢖Ἳ㧔0.1㨪1㧑ᧂḩ㧕ޔ⢖✢⛽∝ ᷫዋᕈ⚡᢬∛㧔662㧕㧔㗫ᐲਇ᣿㧕㧦ⴊዊ᧼ᷫ ߩోり⁁ᘒࠍචಽߦⷰኤߒޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐ 㧔0.1㧑ᧂḩ㧕ޔ⢖᳓⣲㧔㗫ᐲਇ᣿㧕㧦⊒ᾲޔຕ ዋޔ⽺ⴊޔ⣢ਇోࠍਥᓽߣߔࠆṁⴊᕈዩᲥ∝∝ วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ༿ޔ๭ๆ࿎㔍╬ߩ๭ๆེ∝⁁ޔ߹ߚޔ⢷ㇱ X ✢ ୥⟲㧔HUS㧕ޔⴊᩖᕈⴊዊ᧼ᷫዋᕈ⚡᢬∛ 11㧕⣖಴ⴊ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⷰኤࠍචಽߦⴕ ⇣Ᏹ߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔ೽⣢ 㧔TTP㧕߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦ ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡ ⊹⾰ࡎ࡞ࡕࡦ೷ߩᛩਈ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎ ⴊᶧᬌᩏ㧔ⴊዊ᧼ᢙޔ⿒ⴊ⃿ᢙޔᧃ᪳ⴊᶧ௝ ಾߥಣ⟎ࠍⴕ߁ߎߣޕ ߣޕ߹ߚޔຕ༿ޔ๭ๆ࿎㔍╬߇޽ࠄࠊࠇߚ႐ว ╬㧕෸߮⣢ᯏ⢻ᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ 12㧕⣖᪪Ⴇޔ⢖Ⴇᩖ∝㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⷰኤࠍ ߦߪ⋥ߜߦㅪ⛊ߔࠆࠃ߁ᖚ⠪ߦኻߒᵈᗧࠍਈ߃ ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔ චಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛ ࠆߎߣޕ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 14㧕 ♧ዩ∛㧔1 ဳ෸߮ 2 ဳ㧕㧔0.1㨪1㧑ᧂḩ㧕㧦 10㧕♧ዩ∛㧔 ဳ෸߮  ဳ㧕㧔㧑ᧂḩ㧕㧦♧ዩ 13㧕ᗧ⼂㓚ኂޔ∨ᡨޔߡࠎ߆ࠎ⊒૞ޔ⷗ᒰ⼂㓚 ♧ዩ∛߇Ⴧᖡ෶ߪ⊒∝ߔࠆߎߣ߇޽ࠅޔ♧ዩ∛ ∛߇Ⴧᖡ෶ߪ⊒∝ߔࠆߎߣ߇޽ࠅޔ♧ዩ∛ᕈࠤ ኂޔᤀ⌧ޔߖࠎᅦޔ㍲ੂޔᐛⷡޔ⹺⍮∝᭽∝⁁ ᕈࠤ࠻ࠕࠪ࠼࡯ࠪࠬޔᤀ⌧ߦ⥋ࠆߎߣ߇޽ࠆߩ ࠻ࠕࠪ࠼࡯ࠪࠬޔᤀ⌧ߦ⥋ࠆߎߣ߇޽ࠆߩߢޔ 㧔․ߦ㜞㦂⠪㧕㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦⇣Ᏹ߇⹺߼ࠄ ߢޔቯᦼ⊛ߦᬌᩏ㧔ⴊ♧୯ޔዩ♧╬㧕ࠍⴕ޿ޔ ቯᦼ⊛ߦᬌᩏ㧔ⴊ♧୯ޔዩ♧╬㧕ࠍⴕ޿ޔ⇣Ᏹ ࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤㆡಾߥಣ⟎ࠍⴕ ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪㆡಾߥಣ⟎ࠍⴕ߁ߎ ߇⹺߼ࠄࠇߚ႐วߦߪㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ߁ߎߣޕ ߣޕ 11㧕㊀◊ߥ⢄㓚ኂ㧔1㧑ᧂḩ㧕㧦ቯᦼ⊛ߦ⢄ᯏ⢻ 14㧕♧ዩ∛㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦♧ዩ∛㨇ࠗࡦࠬ࡝ 15㧕ᕆᕈ⣢ਇో╬ߩ㊀◊ߥ⣢㓚ኂ㧔0.1㧑ᧂ ᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ㤛∏߿⪺ߒ ࡦଐሽဳ㧔IDDM㧕෸߮ࠗࡦࠬ࡝ࡦ㕖ଐሽဳ ḩ㧕㧦ቯᦼ⊛ߦ⣢ᯏ⢻ᬌᩏࠍⴕ߁ߥߤⷰኤࠍච ૶↪਄ ޿࠻࡜ࡦࠬࠕࡒ࠽࡯࠯ߩ਄᣹ࠍ઻߁⢄㓚ኂ߇޽ 㧔NIDDM㧕㨉߇Ⴧᖡ෶ߪ⊒∝ߔࠆߎߣ߇޽ࠅޔ ಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛ ߩᵈᗧ ࠄࠊࠇߚ႐วߦߪㅦ߿߆ߦᛩਈࠍਛᱛߒޔㆡಾ ᤀ⌧ߦ⥋ࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦᬌᩏ㧔ⴊ♧ ᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ߥಣ⟎ࠍⴕ߁ߎߣޕ ୯ޔዩ♧╬㧕ࠍⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪ 16㧕⁜ᔃ∝㧔0.1㧑ᧂḩ㧕ޔᔃ╭∝ޔᔃਇోޔᔃ 12㧕ᕆᕈ⣢ਇో╬ߩ㊀◊ߥ⣢㓚ኂ㧔㗫ᐲਇ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ╭᪪Ⴇ㧔㗫ᐲਇ᣿㧕㧦ቯᦼ⊛ߦᔃ㔚࿑ᬌᩏࠍⴕ ᣿㧕᧶ቯᦼ⊛ߦ⣢ᯏ⢻ᬌᩏࠍⴕ߁ߥߤⷰኤࠍච 15㧕↲⁁⣼ᯏ⢻⇣Ᏹ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦↲⁁⣼ᯏ ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔߎࠇࠄ∔ᖚ╬ߩᔃ╭ ಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛ ⢻੣ㅴ෶ߪૐਅ߇Ⴧᖡ෶ߪ⊒∝ߔࠆߎߣ߇޽ࠆߩ 㓚ኂ߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾ

ᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ߢޔቯᦼ⊛ߦᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ߁ߎ ߥಣ⟎ࠍⴕ߁ߎߣޕ 17㧕ਇᢛ⣂㧔0.1㨪1㧑ᧂḩ㧕㧦ᔃቶᕈਇᢛ⣂ޔ㜞

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 13㧕࡚ࠪ࠶ࠢ㧔㗫ᐲਇ᣿㧕㧦ⷰኤࠍචಽߦⴕ ߣޕ↲⁁⣼ᯏ⢻ߩ▤ℂ߇㔍ߒ޿႐วߦߪޔᛩਈߩ ޿ޔਇᔟᗵޔญౝ⇣Ᏹޔߗࠎ㡆ޔ⌇ᥝޔଢᗧޔ ਛᱛࠍ⠨ᘦߔࠆߎߣޕߥ߅ޔ↲⁁⣼ᯏ⢻⇣Ᏹ╬ߢ ᐲᚱቶࡉࡠ࠶ࠢޔᵢ஗ᱛޔ㜞ᐲᓢ⣂ޔᔃᚱ⚦േ ⊒᳨ޔⴊ࿶ਅ㒠╬߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍ ᧄ೷ਛᱛᓟ߽ߥ߅ಣ⟎ߩ⛮⛯ࠍᔅⷐߣߒߚ∝଀߇ ╬߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔ⇣Ᏹ߇⹺߼ࠄ ⋥ߜߦਛᱛߔࠆߎߣޕ ႎ๔ߐࠇߡ޿ࠆޕ ࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ 14㧕ᔃ╭∝ޔᔃਇోޔᔃ╭᪪Ⴇޔ⁜ᔃ∝㧔㗫ᐲ 16㧕⊹⤏☼⤑⌒∝୥⟲㧔Stevens-Johnson ∝୥ ߎߣޕ ਇ᣿㧕㧦ቯᦼ⊛ߦᔃ㔚࿑ᬌᩏࠍⴕ߁ߥߤⷰኤࠍ ⟲㧕ޔਛᲥᕈ⴫⊹უᱫⲢ⸃∝㧔Toxic Epidermal 18㧕ᢌⴊ∝㧔0.1㧑ᧂḩ㧕㧦ᤃᗵᨴᕈߣߥࠅᇬᗵ චಽߦⴕ޿ޔߎࠇࠄ∔ᖚ╬ߩᔃ╭㓚ኂ߇޽ࠄࠊ Necrolysis㧦TEN㧕ޔᄙᒻ⚃᢬㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦 ᨴ∝෸߮ᗵᨴ∝ߩჇᖡࠍ⺃⊒ߒᢌⴊ∝ߦ⥋ࠆߎ ࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ ⊹⤏☼⤑⌒∝୥⟲ޔਛᲥᕈ⴫⊹უᱫⲢ⸃∝ޔᄙᒻ ߣ߇޽ࠆߩߢޔᖚ⠪ߩోり⁁ᘒࠍචಽߦⷰኤ ߎߣޕ ⚃᢬╬ߩ⊹⤏㓚ኂ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔ ߒޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔ 15㧕ਇᢛ⣂㧔1㨪5㧑ᧂḩ㧕㧦ᔃቶᕈਇᢛ⣂ޔ㜞 ⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ᐲᚱቶࡉࡠ࠶ࠢޔᵢ஗ᱛޔ㜞ᐲᓢ⣂ޔᔃᚱ⚦േ ਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 19㧕✂⤑∝㧔1㨪5㧑ᧂḩ㧕㧦✂⤑∝߇޽ࠄࠊࠇ ╬߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔ⇣Ᏹ߇⹺߼ࠄ 17㧕ੇ⊈㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ੇ⊈߇Ⴧᖡ෶ߪ⊒∝ ࠆߎߣ߇޽ࠆߩߢޔ✂⤑಴ⴊޔエᕈ⊕᢬෸߮♧ ࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ ߔࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦᬌᩏࠍⴕ߁ߥߤⷰ ዩ∛✂⤑∝ߩჇᖡߦᵈᗧߒޔቯᦼ⊛ߦ⌒ᐩᬌᩏ ߎߣޕ ኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈ ࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇ 16㧕ᶖൻ▤಴ⴊ㧔ਅⴊޔⴊଢ╬㧕㧔1㨪5㧑ᧂ ߩਛᱛࠍ⠨ᘦߔࠆߎߣޕ ߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤޔㆡಾߥಣ⟎ࠍ ḩ㧕ޔᶖൻᕈẩ≌ޔዊ⣺ẩ≌ޔ⯯ⴊᕈᄢ⣺Ἳ 18㧕ᕆᕈ⣢ਇోޔࡀࡈࡠ࡯࠯∝୥⟲᧤㗫ᐲਇ᣿ᵈ ⴕ߁ߎߣޕ߹ߚޔⷞജૐਅޔⷞ㊁ਛߩᥧὐ߇⹺ 㧔1㧑ᧂḩ㧕㧦ⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇޽ࠄࠊ 2㧕㧕㧦ቯᦼ⊛ߦᬌᩏࠍⴕ߁ߥߤޔᖚ⠪ߩ⁁ᘒࠍච ߼ࠄࠇߚ႐วߪㅦ߿߆ߦකᏧߩ⸻ኤࠍฃߌࠆࠃ ࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ ಽߦⷰኤߔࠆߎߣޕ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪޔ ߁ᖚ⠪ࠍᜰዉߔࠆߎߣޕ ߎߣޕ ᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 20㧕 ⥄Ꮖ఺∉⃻⽎㧔㗫ᐲਇ᣿㧕㧦⥄Ꮖ఺∉⃻⽎ 17㧕๭ๆ࿎㔍㧔10㧑એ਄㧕ޔ໼∷Ⴧട㧔5㨪10㧑 19㧕ᶖൻ▤಴ⴊ㧔ਅⴊޔⴊଢ╬㧕ޔᶖൻᕈẩ≌ޔ ߦࠃࠆߣᕁࠊࠇࠆ∝⁁࡮ᓽ୥㨇↲⁁⣼ᯏ⢻⇣ ᧂḩ㧕㧦ⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹߩ⒟ᐲ߇⪺ߒ ⯯ⴊᕈᄢ⣺Ἳ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⷰኤࠍචಽߦⴕ Ᏹޔ⢄Ἳޔṁⴊᕈ⽺ⴊޔ․⊒ᕈⴊዊ᧼ᷫዋᕈ⚡ ޿႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎ ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥ ᢬∛㧔ITP㧕ޔẩ≌ᕈᄢ⣺Ἳޔ㑐▵࡝࠙ࡑ࠴ޔੇ ߣޕ ߤޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ⊈ޔోりᕈࠛ࡝࠹ࡑ࠻࡯࠺ࠬޔⴊ▤Ἳޔࡈࠜ࡯ 18㧕⣖಴ⴊ㧔1㧑ᧂḩ㧕㧦⣖಴ⴊ߇޽ࠄࠊࠇࠆߎ 20㧕࡚ࠪ࠶ࠢ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⷰኤࠍචಽߦⴕ ࠢ࠻࡮ዊᩉ࡮ේ↰∛ޔ♧ዩ∛㧔1 ဳ㧕ߩჇᖡ෶ߪ ߣ߇޽ࠆߩߢޔⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡ ⊒∝╬㨉߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ ಾߥಣ⟎ࠍⴕ߁ߎߣޕ ߦᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺ ߁ߎߣޕ 21㧕✂⤑∝㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦✂⤑∝߇޽ࠄࠊࠇ ߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤㆡಾߥಣ 19㧕⣖᪪Ⴇ㧔1㧑ᧂḩ㧕㧦⣖᪪Ⴇ߇޽ࠄࠊࠇࠆߎ ࠆߎߣ߇޽ࠆߩߢޔ✂⤑಴ⴊ߿♧ዩ∛✂⤑∝ߩჇ ⟎ࠍⴕ߁ߎߣޕ ߣ߇޽ࠆߩߢޔⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ ᖡߦᵈᗧߒޔቯᦼ⊛ߦ⌒ᐩᬌᩏࠍⴕ߁ߥߤⷰኤࠍ 21㧕ṁⴊᕈዩᲥ∝∝୥⟲㧔HUS㧕ޔⴊᩖᕈⴊዊ ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ චಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛ ᧼ᷫዋᕈ⚡᢬∛㧔TTP㧕㧔㗫ᐲਇ᣿㧕㧦ⴊዊ᧼ᷫ ߁ߎߣޕ ᱛߔࠆߥߤޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ߹ߚޔⷞജ ዋޔ⽺ⴊޔ⣢ਇోࠍਥᓽߣߔࠆṁⴊᕈዩᲥ∝∝ ૐਅޔⷞ㊁ਛߩᥧὐ߇಴⃻ߒߚ႐วߪㅦ߿߆ߦක ୥⟲㧔HUS㧕ޔⴊᩖᕈⴊዊ᧼ᷫዋᕈ⚡᢬∛ Ꮷߩ⸻ኤࠍฃߌࠆࠃ߁ᖚ⠪ࠍᜰዉߔࠆߎߣޕ 㧔TTP㧕߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦ ⴊᶧᬌᩏ㧔ⴊዊ᧼ᢙޔ⿒ⴊ⃿ᢙޔᧃ᪳ⴊᶧ௝ ╬㧕෸߮⣢ᯏ⢻ᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ

27 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

2) ߘߩઁߩ೽૞↪ 㧔2㧕ߘߩઁߩ೽૞↪ 㧔2㧕ߘߩઁߩ೽૞↪ ᧄ೷ࠍࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવ ೽૞↪߇⹺߼ࠄࠇߚ႐วߦߪ㧘ᛩਈࠍਛᱛߔࠆߥ ᰴߩࠃ߁ߥ೽૞↪߇޽ࠄࠊࠇߚ႐วߦߪޔᛩਈ ሶ⚵឵߃㧕෶ߪ 2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ ߤㆡಾߥಣ⟎ࠍⴕ߁ߎߣ㧚 ࠍਛᱛߔࠆߥߤޔ∝⁁ߦᔕߓߡㆡಾߥಣ⟎ࠍⴕ ࡝ࡦߣ૬↪ߒߚ㓙ߩᧄ೷ߩ೽૞↪ߪએਅߩߣ߅ 㗫ᐲ 㗫ᐲ ߁ߎߣޕ 5%એ਄ 5%ᧂḩ ࠅߢ޽ࠆޕᰴߩࠃ߁ߥ೽૞↪߇޽ࠄࠊࠇߚ႐ว ⒳㘃 ਇ᣿ 㗫ᐲਇ᣿ 10㧑એ਄ 10㧑ᧂḩ ߦߪޔ∝⁁ߦᔕߓߡㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ⊹⤏ ⊒∐ Ḩ∐㧘⊹⤏ੇ ᵈ 2) 10㧑એ਄ 5㧑એ਄ 5㧑ᧂḩ 㧔38.6%㧕㧘 ῎㧘ᄙᒻ⚃᢬㧘 ⊒ᾲ෸ ⊒ᾲ ᖡኙޔ⣕ജ 10㧑ᧂḩ ⣕Ძ∝ ਛᲥᕈ⊹∐㧘⭄ ߮ࠗࡦ 㧔67.5㧑㧕ޔ ⢗⣺㓚ኂ ଢ⒁ 㧔34.8%㧕㧘 㤗∐㧘⊹⢽ᰳਲ ࡈ࡞ࠛ 㗡∩ ⢄⢙㆏♽ ⴊਛࡆ࡝࡞ ⮎∐㧘ߘ߁∣ ᕈḨ∐㧘⊹⤏೸ ࡦࠩ᭽ 㧔63.3㧑㧕ޔ 㓚ኂ ࡆࡦჇട ∝㧘⚃᢬ ⣕㧘ਐ∐㧘ੇ⊹ ∝⁁ ୱᕃᗵ ⊹⤏߅ࠃ ⊒∐㧘ߘ߁ శ✢ㆊᢅ ∝㧘ߑ≙㧘೸⣕ 㧔62.1㧑㧕ޔ ߮⊹ਅ⚵ ∣∝ ᕈ෻ᔕ ᕈ⊹⤏Ἳ㧘᢬⁁ 㑐▵∩ ❱㓚ኂ ਐ∐⁁⊹∐㧘⢽ 㧔30.8㧑㧕ޔ ૶↪਄ ⥃ᐥᬌᩏ 㜞ࡆ࡝࡞ Al-P Ⴧട ṳᕈ⊹⤏Ἳ㧘㗡 ╭∩ ߩᵈᗧ ࡆࡦⴊ∝ ㇱ☰♰∐㧘ࠕ࠻ 㧔20.8㧑㧕

ࡇ࡯ᕈ⊹⤏Ἳ㧘 ᶖൻེ ⤟Ἳ㧔⣻ 㘩᰼ᷫㅌ ⣻ㇱਇᔟ ធ⸅⊹⤏Ἳ㧘⊒ ∩ޔࠕࡒ 㧔26.2㧑㧕ޔ ᗵޔཌྷฯޔ ᳨㓚ኂ㧘⚃⦡᳨ ࡜࡯࠯਄ ਅ∯࡮エଢ ⣻ㇱ⤘ḩޔ ∐㧘Ὺᄌ⦡㧘⊹ ᣹ޔ࡝ࡄ 㧔24.4㧑㧕ޔ ᱤ⡺಴ⴊޔ ⢽ᰳਲ∝㧘ⴊ▤ ࡯࠯਄ ཌྷ᳇ ᱤ∩ޔ⢗ ᶋ⣲㧘ㆊⷺൻ㧘 ᣹㧕 㧔21.6㧑㧕ޔ Ἳޔᶖൻਇ

⊹⤏ਇᔟᗵ㧘ߑ ⣻∩ ⦟ޔ๧ⷡ⇣ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ≙᭽⊹⤏Ἳ㧘⚿ 㧔21.0㧑㧕ޔ Ᏹޔᱤ⡺ ▵ᕈ⚃᢬㧘ᗵᨴ ଢ⒁ޔญౝἻ Ἳޔญᷢޔ ᕈ⴫⊹ྙ⣲㧘Ძ ෸߮ญ⣧ౝẩ ᱤ๟Ἳޔญ ൮Ἳ㧘⤥∘∐㧘 ≌ᒻᚑ ౝੇ῎ޔ⥠ ⊹ਅ⚵❱⤥≌㧘 Ἳޔญໃ ᗵᨴᕈྙ⣲㧘ߖ Ἳޔྚਅ㓚 ߟ㧘Ꮺ⁁∊∐㧘 ኂ ⊹⤏੃㗡⣲ ╭࡮㛽 ╭Ἳ ⢛ㇱ∩ 㑐▵⎬⋥ޔ ⴊᶧ ⽺ⴊ ṁⴊᕈ⽺ⴊ㧘ᅢ ᩰ 㧔20.2㧑㧕 ╭∨ᡨޔ㗖 㧔91.0%㧕㧘 ਛ⃿ᷫዋ∝㧘ⴊ ㇱ∩ޔ╭㛽 ⊕ⴊ⃿ᢙᷫዋ ዊ᧼ᷫዋ∝㧘ᅢ ᩰ∩ޔ྾⢇ 㧔71.5%㧕㧘 ㉄⃿ᢙᷫዋ㧘ࡋ ∩ޔ╭࡮㛽 ⴊዊ᧼ᢙᷫዋ ࡕࠣࡠࡆࡦᷫ ᩰ⎬⋥ޔ㛽 㧔65.9%㧕㧘 ዋ㧘⿒ⴊ⃿ᢙᷫ ∩ޔ╭⣕ ᅢਛ⃿ᢙᷫዋ ዋ㧘ࡋࡑ࠻ࠢ࡝ ജޔ㑐▵Ἳ ࠶࠻ᷫዋ㧘✂⁁ ♖␹࡮ ᧃ᪳ᕈ࠾ ⌧⌁㓚ኂ㧔 ਇ ᗵⷡᷫㅌޔ ⿒ⴊ⃿ᢙᷫዋ㧘 ␹⚻♽ ࡘ࡯ࡠࡄ ⌁∝㧕 ᤃೝỗᕈޔ ✂⁁⿒ⴊ⃿ᢙჇ ࠪ࡯ޔ⸥ 㧔22.2㧑㧕ޔ ਇ቟ޔ᳇ಽ ട㧘࡝ࡦࡄ⃿ᢙ ᙘ㓚ኂޔ ߼߹޿ ᄌേޔஜ ᷫዋ㧘ᅢႮၮ⃿ ᕈ᰼ᷫ ᔓޔ㗻㕙␹ ᢙᷫዋ㧘න⃿ᢙ ㅌޔ␹⚻ ⚻㓚ኂޔ⇣ Ⴧട㧘࡝ࡦࡄ⃿ ㆊᢅޔ᡹ Ᏹᗵⷡޔ༵ ᢙჇട㧘⊕ⴊ⃿ ᠄ᕈޔᖡ ⌁ޔ௑⌁ޔ ᢙჇട㧘⊕ⴊ⃿ ᄞޔᄬ␹ 㓸ਛജૐ ಽ↹⇣Ᏹ㧘APTT ਅޔᝄᚢޔ ⍴❗㧘࡝ࡦࡄ▵ ⍮ⷡㆊᢅ ∝

28 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 20㧕ᢌⴊ∝㧔1㧑ᧂḩ㧕㧦ᤃᗵᨴᕈߣߥࠅޔᗵᨴ 22㧕ਛᲥᕈ⴫⊹უᱫⲢ⸃∝㧔Toxic Epidermal ∝෸߮ᗵᨴ∝ߩჇᖡࠍ⺃⊒ߒᢌⴊ∝ߦ⥋ࠆߎߣ Necrolysis㧦TEN㧕ޔ⊹⤏☼⤑⌒∝୥⟲㧔Stevens- ߇޽ࠆߩߢޔᖚ⠪ߩోり⁁ᘒࠍචಽߦⷰኤߒޔ Johnson ∝୥⟲㧕㧔㗫ᐲਇ᣿㧕㧦ਛᲥᕈ⴫⊹უᱫ

⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾ Ⲣ⸃∝ޔ⊹⤏☼⤑⌒∝୥⟲╬ߩ㊀◊ߥ⊹⤏㓚ኂ

ߥಣ⟎ࠍⴕ߁ߎߣޕ ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔⷰኤࠍචಽߦⴕ 21㧕✂⤑∝㧔1㨪5㧑ᧂḩ㧕㧦✂⤑∝߇޽ࠄࠊࠇ ޿ޔߎߩࠃ߁ߥ∝⁁߇޽ࠄࠊࠇߚ႐วߦߪᛩਈ ࠆߎߣ߇޽ࠆߩߢޔ✂⤑಴ⴊ߿♧ዩ∛✂⤑∝ߩ ࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ Ⴧᖡߦᵈᗧߒޔቯᦼ⊛ߦ⌒ᐩᬌᩏࠍⴕ߁ߥߤⷰ 23㧕ᮮ⚉╭Ⲣ⸃∝㧔㗫ᐲਇ᣿㧕㧦ᮮ⚉╭Ⲣ⸃∝ ኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩ ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔ⣕ജᗵޔ╭⡺ ਈࠍਛᱛߔࠆߥߤޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ߹ ∩ޔCK㧔CPK㧕਄᣹╬ߦᵈᗧߒޔߎߩࠃ߁ߥ∝ ߚޔⷞജૐਅޔⷞ㊁ਛߩᥧὐ߇಴⃻ߒߚ႐วߪ ⁁߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥ

ㅦ߿߆ߦකᏧߩ⸻ኤࠍฃߌࠆࠃ߁ᖚ⠪ࠍᜰዉߔ ಣ⟎ࠍⴕ߁ߎߣޕ

ࠆߎߣޕ ᵈ 1㧕⽺ⴊߪਥߦṁⴊᕈ⽺ⴊ 22㧕ਛᲥᕈ⴫⊹უᱫⲢ⸃∝㧔Toxic Epidermal Necrolysis㧦TEN㧕ޔ⊹⤏☼⤑⌒∝୥⟲㧔Stevens- Johnson ∝୥⟲㧕㧔㗫ᐲਇ᣿㧕㧦ਛᲥᕈ⴫⊹უᱫ

Ⲣ⸃∝ޔ⊹⤏☼⤑⌒∝୥⟲╬ߩ㊀◊ߥ⊹⤏㓚ኂ

߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔⷰኤࠍචಽߦⴕ ޿ޔߎߩࠃ߁ߥ∝⁁߇޽ࠄࠊࠇߚ႐วߦߪᛩਈ

ࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ

23㧕ᮮ⚉╭Ⲣ⸃∝㧔㗫ᐲਇ᣿㧕㧦ᮮ⚉╭Ⲣ⸃∝ ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔ⣕ജᗵޔ╭⡺ ∩ޔCK㧔CPK㧕਄᣹╬ߦᵈᗧߒޔߎߩࠃ߁ߥ∝ ⁁߇޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥ

ಣ⟎ࠍⴕ߁ߎߣޕ

ᵈ 1㧕⽺ⴊߪਥߦṁⴊᕈ⽺ⴊ

㧔2㧕ߘߩઁߩ೽૞↪ 2㧕ߘߩઁߩ೽૞↪ 㧔2㧕ߘߩઁߩ೽૞↪ ᰴߩࠃ߁ߥ೽૞↪߇޽ࠄࠊࠇߚ႐วߦߪޔᔅⷐ ᰴߩࠃ߁ߥ೽૞↪߇⹺߼ࠄࠇߚ႐วߦߪޔᔅⷐ ᰴߩࠃ߁ߥ೽૞↪߇޽ࠄࠊࠇߚ႐วߦߪޔᛩਈࠍ ߦᔕߓޔᷫ㊂ޔᛩਈਛᱛ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ ߦᔕߓޔᷫ㊂ޔભ⮎ޔᛩਈਛᱛ╬ߩㆡಾߥಣ⟎ ਛᱛߔࠆߥߤޔ∝⁁ߦᔕߓߡㆡಾߥಣ⟎ࠍⴕ߁ߎ ߎߣޕ ࠍⴕ߁ߎߣޕ ߣޕ ᵈ 5㧑એ਄෶ߪ㗫 0.1㨪5㧑ᧂḩ 0.1㧑ᧂḩ 5%એ਄ 5%ᧂḩ 㗫ᐲਇ᣿ 㗫ᐲਇ᣿ 10%એ਄ 10%ᧂḩ 㧞㧕 ᐲਇ᣿㧔㗫ᐲਇ ᵈ 2㧕 ᣿ߪޛޜౝ㧕 ⊒ᾲ෸ ⣕ജ ⊒ᾲ ోり∝ ⊒ᾲ ࠗࡦࡈ࡞ࠛ ోり ⊒ᾲޔୱᕃᗵޔ ࠗࡦࡈ࡞ࠛࡦࠩ ⁁ 㧔94.9㧑㧕ޔ ࡦࠩ᭽∝⁁ ߮ࠗࡦ 㧔71.2㧑㧕ޔ ∝⁁ ᖡኙ ᭽∝⁁ ୱᕃᗵ ࡈ࡞ࠛ ୱᕃᗵ ♖␹ 㗡∩ޔਇ⌁ޔ߼ ᤃೝỗᕈޔ⡊ ⡬ⷡㆊᢅޔ 㧔91.4㧑㧕ޔ ࡦࠩ᭽ 㧔70.4㧑㧕ޔ ␹⚻ ߹޿ޔޛỗ⿧ޜ 㡆ޔ⌁᳇ޔ⇣Ᏹ ᕁ⠨⇣Ᏹޔ ᖡኙ ∝⁁ 㗡∩ ♽ ᗵޔ᳇ಽਇᔟޔ 㗡∩ ♖␹࡮ 㗡∩ ⇣Ᏹᗵޔ᳇ ỗ⿧ 㧔57.7㧑㧕ޔ ᳇ജૐਅޔஜ ᔓޔ⡊㐽ޔ␹⚻ ␹⚻♽ 㧔86.5㧑㧕ޔ ജૐਅޔஜ 㑐▵∩ ㆊᢅޔ⍮ⷡㆊ ਇ⌁ ᔓޔ⡊㐽ޔ 㧔37.7㧑㧕ޔ ╭∩ ᢅ࡮ᷫㅌޔᵈᗧ ૶↪਄ 㧔58.5㧑㧕ޔ ਇ቟ޔ⌁ 㧔20.4㧑㧕ޔ ജ㓚ኂޔਇ቟ޔ ߩᵈᗧ ߼߹޿ޔᤃೝ ᳇ޔ⍮ⷡㆊ ᖡኙ ᗵᖱਇ቟ቯޔᗵ ỗᕈޔ⡊㡆 ᢅ࡮ᷫㅌޔ ᖱ㊰㤗ޔ᭴⺆㓚 ᶖൻེ ⤟Ἳ㧔⣻ 㘩᰼ᷫㅌ ⣻ㇱ⤘ḩޔ ⡬ⷡㆊᢅޔ ኂ 38.1 㗡∩ޔᗵ ∩ޔࠕࡒ࡜ 㧔 㧑㧕ޔ ᱤ⡺಴ⴊޔ ⴊᶧ ⊕ⴊ⃿ᢙᷫዋޔ ᅢਛ⃿ᢙჇᄙޔ ᖱਇ቟ቯޔ ࡯࠯਄᣹ޔ ਅ∯࡮エଢ ᱤ∩ޔ⢗ ᅢਛ⃿ᢙᷫዋޔ ᅢ㉄⃿ᢙჇᄙޔ ᳇ಽਇᔟޔ ࡝ࡄ࡯࠯਄ 㧔23.5㧑㧕ޔ Ἳޔᶖൻਇ ࡝ࡦࡄ⃿ᢙᷫ ᅢႮၮ⃿ᢙჇ ᗵᖱ㊰㤗ޔ ᣹㧕ޔྚਅ ཌྷ᳇ ⦟ޔญᷢޔ ዋޔࡋࡕࠣࡠࡆ ᄙޔන⃿ᢙჇ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ␹⚻ㆊᢅޔ 㓚ኂ 㧔22.3㧑㧕ޔ ⥠∩ޔญౝ ࡦᷫዋޔⴊዊ᧼ ᄙޔ⿒ⴊ⃿ᢙჇ ᭴⺆㓚ኂޔ ⣻∩ ੇ῎ޔ⥠ ᢙᷫዋޔ⿒ⴊ⃿ ᄙޔ⊕ⴊ⃿ᢙჇ ᢙᷫዋޔࡋࡑ࠻ ᄙޔⴊዊ᧼ᢙჇ ᵈᗧജ㓚ኂ 㧔21.9㧑㧕ޔ Ἳޔᱤ⡺Ἳ ࠢ࡝࠶࠻ᷫዋޔ ᄙޔESR ੣ㅴ ⣻ㇱਇᔟᗵޔ ⴊᶧ ࡝ࡦࡄ⃿ᢙᷫ ⿒ⴊ⃿ᢙჇ ⽺ⴊޔ࡝ࡦࡄ⃿ ዋ ᄙޔ⊕ⴊ⃿ ଢ⒁ޔཌྷฯޔ ญౝἻ෸߮ญ ᢙჇᄙޔ✂⁁⿒ 㧔94.4㧑㧕ޔ ᢙჇᄙ ⴊ⃿ᢙᷫዋޔ✂ ⣧ౝẩ≌ᒻ ⊕ⴊ⃿ᢙᷫዋ ⁁⿒ⴊ⃿ᢙჇᄙ ᚑޔ๧ⷡ⇣Ᏹ 㧔94.6㧑㧕ޔ ⢄⤳ AST㧔GOT㧕਄ ⢽⢌⢄ޔǫ-GTP ⢙⍹∝ޔ⢙ ᅢਛ⃿ᢙᷫዋ ╭࡮㛽 㛽∩ޔ╭Ἳ ⢛ㇱ∩ 㗖ㇱ∩ޔ╭ ᣹ޔALT ਄᣹ޔLDH ਄ ྙࡐ࡝࡯ 㧔87.4 㧑㧕ޔ ᩰ 㧔24.2㧑㧕 㛽ᩰ∩ޔ╭ 㧔GPT㧕਄᣹ޔ ᣹ޔ㤛∏ޔAl-P ࡊޔAFP Ⴧ ࡋࡕࠣࡠࡆࡦ 㛽ᩰ⎬⋥ޔ ࡆ࡝࡞ࡆࡦ਄᣹ ਄᣹ޔ࠙ࡠࡆ࡝ ട ᷫዋ ྾⢇∩ޔ╭ ࡦዩޔࡆ࡝࡞ࡆ 㧔85.9㧑㧕ޔ ∨ᡨޔ╭⣕ ࡦዩޔࡆ࡝࡞ࡆ ࡦૐਅޔZTT ਄ ⿒ⴊ⃿ᢙᷫዋ ജޔ㑐▵Ἳ ᣹ޔPIVKAΤ ਄ 㧔80.9㧑㧕ޔ ♖␹࡮ ᳇ಽᄌേޔ ⌧⌁㓚ኂ㧔ਇ ᤃೝỗᕈޔਇ ␹⚻♽ ␹⚻ㆊᢅޔ ⌁∝㧕 ቟ޔ⇣Ᏹᗵ ᣹ޔΦဳࠦ࡜࡯ ࡋࡑ࠻ࠢ࡝࠶ ࠥࡦ୯਄᣹ ᡹᠄ᕈޔ 㧔30.4㧑㧕ޔ ⷡޔ௑⌁ޔ⸥ ࠻ᷫዋ ⣢⤳ 㗫ዩޔⴊዩޔⰮ ⣢⚿⍹ ᕈ᰼ᷫㅌޔ ߼߹޿ ᙘ㓚ኂޔ㓸ਛ 㧔79.0 㧑㧕ޔ ⊕ዩޔឃዩ㓚 ᖡᄞޔ༵⌁ 㧔28.1㧑㧕 ജૐਅޔᧃ᪳ ✂⁁⿒ⴊ⃿ᢙ ᕈ࠾ࡘ࡯ࡠࡄ ኂޔ⣾⢲Ἳޔ Ⴧᄙ ࠪ࡯ޔᗵⷡᷫ BUN࡮ࠢ࡟ࠕ࠴ 㧔67.9㧑㧕ޔ ㅌޔਇᔟᗵޔ ࠾ࡦ਄᣹ ⴊዊ᧼ᢙᷫዋ ␹⚻∩ޔ༦ⷡ ᓴⅣ ޛᚱቶࡉࡠ࠶ 㗫⣂ޔầ⚃ޔ⢷ 㧔51.2㧑㧕ޔ ㍲⺋ޔᝄᚢޔ ེ ࠢޜޔޛⴊ▤ᶋ ∩ޔⴊ࿶਄᣹ޔ ⽺ⴊޔ࡝ࡦࡄ ⍮ⷡㆊᢅޔᄬ ⣲ޜ ⴊ࿶ૐਅޔᶋ⣲ ⃿ᢙჇᄙޔᅢ ␹ 㧔྾⢇࡮㗻 ㉄⃿ᢙჇᄙޔ ⊹⤏ ហ∣∝ ⊹⤏Ἳޔ⭄ 㕙㧕ޔᧃ᪳ᕈ⯯ ⴊ ᅢਛ⃿ᢙჇ 㧔58.1㧑㧕ޔ 㤗∐ޔᄙ ᄙޔᅢႮၮ⃿ ⣕Ძ∝ ᳨ޔኢ᳨ޔ ᢙჇᄙޔන⃿ 㧔40.0㧑㧕ޔ ⊹⢽ᰳਲᕈ ᢙჇᄙޔ✂⁁ ⊒∐ Ḩ∐ޔ⢽ṳ ⿒ⴊ⃿ᢙᷫዋ 㧔37.3㧑㧕ޔ ᕈ⊹⤏Ἳޔ Ḩ∐ ធ⸅ᕈ⊹⤏ 㧔24.6㧑㧕ޔ Ἳޔశ✢ㆊ ⚃᢬ޔ⊹⤏ੇ ᢅ∝ ῎

29 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

㗫ᐲ 㗫ᐲਇ᣿ 10㧑એ਄ 10㧑ᧂḩ 5%એ਄ 5%ᧂḩ ਇ᣿ ᵈ 2) ోり∝ ⊒ᾲ ⢷ㇱਇᔟᗵ㧘ᧃ ⊹⤏ శ✢ㆊᢅ ⣕Ძ∝ ⊹⤏ἻޔḨ ⁁ 㧔81.6 %㧕㧘 ᪳ᕈᶋ⣲㧘 ∝ 㧔33.5㧑㧕ޔ ∐ޔ⊕⊈ޔ⚃ ୱᕃᗵ ⇣Ᏹᗵ㧘ᤃೝỗ ≒∣∝ ᢬ޔ⭄㤗∐ޔ 㧔58.1%㧕㧘 ᕈ㧘㗻㕙ᶋ 㧔25.2㧑㧕ޔ ਛᲥᕈ⊹∐ޔ ࠗࡦࡈ࡞ࠛࡦ ⣲㧘ᖡኙ㧘∋ ⊒∐ ⊹⤏ੇ῎ޔᄙ ࠩ᭽∝⁁ ഭ㧘ήജ∝㧘 ᳨ޔኢ᳨ޔ⊹ ⢷∩㧘ੇ῎∝㧘 ⢽ᰳਲᕈḨ ᵈ኿⋥ᓟ෻ ∐ޔ⊹ਅ಴ⴊ ᔕ㧘಄ᗵ㧘⣲ ⴊᶧ ᅢਛ⃿ᢙᷫዋ ⽺ⴊޔᅢ㉄⃿ ≜㧘ᶋ⣲ 㧔81.6㧑㧕ޔ⊕ ᢙჇടޔ࡝ࡦ ♖␹࡮ 㗡∩ ਇ቟㧘ਇ቟㓚 ⴊ⃿ᢙᷫዋ ࡄ⃿ᢙჇടޔ ␹⚻♽ 㧔35.6 %㧕㧘 ኂ㧘⪭ߜ⌕߈ 㧔69.8㧑㧕ޔⴊ PTT ᑧ㐳 ਇ⌁∝ ߩߥߐ㧘ᗵᖱਇ ዊ᧼ᢙᷫዋ 㧔30.3%㧕㧘๧ ቟ቯ㧘ᗵᖱ㓚 㧔61.5㧑㧕ޔ࡝ ⷡ⇣Ᏹ㧘ᶋേ ኂ㧘♖␹㓚ኂ㧘 ࡦࡄ⃿ᢙᷫዋ ᕈ߼߹޿㧘ᗵ ߁ߟ∛㧘ᛥ߁ߟ 㧔31.2㧑㧕ޔࡋ ⷡ㊰㤗 ∝⁁㧘᳇ജૐ ࡕࠣࡠࡆࡦᷫዋ ਅ㧘ᄬ␹㧘ᗧ⼂ 㧔23.4㧑㧕ޔࡋ ᶖᄬ㧘ਇᔟ᳇ ࡑ࠻ࠢ࡝࠶࠻ᷫ ಽ㧘૕૏ᕈ߼߹ ዋ㧔22.0㧑㧕ޔ ޿㧘௑⌁㧘๧ⷡ ⿒ⴊ⃿ᢙᷫዋ ᷫㅌ㧘㍲ᗵⷡ㧘 ᓴⅣ ⢷∩ޔേᖪޔ

㗖⣨∝୥⟲㧘ᝄ ེ ầ⚃ޔ㜞ⴊ࿶ ᚢ㧘⍮ⷡㆊᢅ㧘 ⢄⤳ ⢙▤Ἳ ALT㧔GPT㧕 LDH ਄᣹ޔ 㗡∩㧘༦ⷡ㍲ ਄᣹ Al-P ਄᣹ޔࡆ ⺋㧘᭴⺆㓚ኂ㧘 㧔34.9㧑㧕ޔ ࡝࡞ࡆࡦ਄ ᧃ᪳ᕈ࠾ࡘ࡯ࡠ AST㧔GOT㧕 ᣹ޔ⢽⢌⢄ ࡄ࠴࡯㧘ᵈᗧജ ਄᣹ 㓚ኂ㧘න␹⚻ 㧔32.9㧑㧕ޔǫ Ἳ㧘ࠕࠞࠪࠫࠕ -GTP ਄᣹ ᶖൻེ 㘩᰼ᷫㅌ ญ⣧ࡋ࡞ࡍࠬ㧘 ⤟Ἳ 㧔22.6㧑㧕 ᵈ㧕, 㧔42.3%㧕㧘 ໜᶧ⣼Ἳ㧘ࠕࡈ ⣢⤳ Ⱞ⊕ዩ㓁ᕈޔ ཌྷฯ㧘ਅ∯㧘 ࠲ᕈญౝἻ㧘ญ ⣻᳓ ⴊዩ㓁ᕈޔ㗫 ᖡᔃ㧘 ⣻ㇱਇ ໃἻ㧘ญໃ⣲ ዩޔឃዩ㓚 ᔟᗵ㧘ญౝ ⣘㧘⥠Ἳ㧘⥠㓚 ኂޔBUN ਄ Ἳ㧘ଢ⒁㧘਄ ኂ㧘⥠⧡㧘⥠ ᣹ ⣻ㇱ∩㧘ญᷢ ∩㧘ᱤ⡺Ἳ㧘ᱤ ๭ๆ ຕ༿ 㥦಴ⴊޔ༥ ⡺∩㧘ᱤ⡺಴ ེ 㧔25.4㧑㧕ޔຜ ჿޔ㥦㐽ޔߊ ⴊ㧘ᱤ๟Ἳ㧘ᱤ ༄㗡∩ ߒ߾ߺޔ໼ 㜑Ἳ㧘㦏ᱤ㧘ᱤ 㧔22.4㧑㧕ޔ㥦 ∷ޔຜ㗡ਇᔟ ૶↪਄ ∩㧘ญߩ㍲ᗵ ṳޔ㥦࡮ຜ㗡 㙚ᗵޔຜ㗡⚃ ߩᵈᗧ ⷡ㧘ญౝੇ῎㧘 Ἳ㧔20.2㧑㧕 ᢬ޔᚳ᩶Ἳ ㅒᵹᕈ㘩㆏Ἳ㧘 ⌒ ⷺ⤑ẩ≌ ⌒∩ޔ㔵ⷞޔ ᔃ┃ㇱਇᔟᗵ㧘 ✂⤑ߩᓸዊᓴ ⢗Ἳ㧘⣻∩㧘ᶖ Ⅳ㓚ኂᵈ 3㧕ޔ ൻਇ⦟㧘߅ߊ ⌒ߩἻ∝㧔⚿ ߮㧘⢗⣺Ἳ㧘⢗ ⤑Ἳ╬㧕ޔ⌒

⣺㓚ኂ㧘⣻ㇱ⤘ ≒∣∝ޔ⚿⤑ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ḩ㧘⎬ଢ㧘ⴊଢ లⴊޔ✂⤑಴ ឃᴭ㧘ㆊᢅᕈ⣺ ⴊޔ⌒♖∋ ∝୥⟲㧘∤ᩭ㧘 ഭޔ⌒ߩ⇣Ᏹ ⋥⣺ߒ߱ࠅ㧘⢂ ᗵޔ⌒ੇ῎ 㐷߮ࠄࠎ㧘⢂㐷 ߘ߁∣∝㧘⢂㐷 ๟࿐∩ ⢄⤳ ⴊਛࡆ࡝࡞ࡆ ⢄㓚ኂ㧘⢄㉂⚛ ࡦჇട㧘Φဳ ਄᣹㧘AST

ࠦ࡜࡯ࠥࡦ਄ 㧔GOT㧕਄᣹㧘

᣹㧘LDH ਄᣹ ALT㧔GPT㧕਄ ᣹㧘ǫԟGTP ਄ ᣹㧘ALP ਄᣹㧘 㑆ធࡆ࡝࡞ࡆࡦ ਄᣹㧘⋥ធࡆ࡝ ࡞ࡆࡦ਄᣹㧘⢽ ⢌⢄ ⣢⤳߅ ⴊਛࠢ࡟ࠕ࠴ ⣢ᯏ⢻㓚ኂ㧘⣢ ࠃ߮ዩ ࠾ࡦჇട ᯏ⢻ᬌᩏ⇣Ᏹ㧘 〝 㧔30.0%㧕㧘 BUN ૐਅ㧘BUN Ⱞ⊕ዩ ਄᣹㧘⣢⋃⣢ Ἳ㧘⣢⚿⍹∝㧘 ⣾⢲ᯏ⢻㓚ኂ㧘 ⣾⢲Ἳ㧘ᄛ㑆㗫 ዩ㧘㗫ዩ㧘ዩ〝 ᗵᨴ㧘ዩਛⴊ㓁 ᕈ㧘ዩਛ⊕ⴊ⃿ 㓁ᕈ ᓴⅣེ 㗫⣂㧘േᖪ㧘ᵢ ᕈ㗫⣂㧘ᓢ⣂㧘 ߶ߡࠅ㧘ࠦࡦ࠻ ࡠ࡯࡞ਇ⦟ߩⴊ ࿶㧘⿠┙ᕈૐⴊ ࿶㧘ⴊ࿶ૐਅ㧘 㜞ⴊ࿶㧘ⴊ࿶਄ ᣹

30 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 5%એ਄ 5%ᧂḩ 㗫ᐲਇ᣿ 㗫ᐲਇ᣿ᵈ 10%એ਄ 10%ᧂḩ 5㧑એ਄෶ߪ㗫 0.1㨪5㧑ᧂḩ 0.1㧑ᧂḩ ᵈ 2㧕 㧞㧕 ᐲਇ᣿㧔㗫ᐲਇ ⢄⤳ AST㧔GOT㧕 㤛∏ޔ⢽⢌ ZTT ਄᣹ ⴊᶧ ⊕ⴊ⃿ᢙᷫዋ ⽺ⴊޔᅢ㉄ ᣿ߪޛޜౝ㧕 ਄᣹ޔALT ⢄ޔ⢙⍹ 㧔91.5㧑㧕ޔ ⃿ᢙჇടޔ ᶖൻ 㘩᰼ਇᝄޔᖡ ญᷢޔ⢗ਇᔟ ญ⣧ౝ಴

㧔GPT㧕਄ ∝ޔ⢙ྙࡐ ᅢਛ⃿ᢙᷫዋ PTT ᑧ㐳 ེ ᔃ࡮ཌྷฯޔ⣻ ᗵޔᶖൻਇ⦟ޔ ⴊޔ㘩㆏㕒 ∩ޔਅ∯ޔଢ ⣻ㇱ⤘ḩᗵޔᱤ ⣂≜ ᣹ޔǫ-GTP ࡝࡯ࡊޔAl-P 㧔90.8㧑㧕ޔ ⒁ޔญౝ࡮ญໃ 㜑࡮ᱤ๟࡮ᱤ⡺ ਄᣹ޔLDH ਄᣹ޔAFP ࡋࡕࠣࡠࡆࡦ ᷫዋ Ἳޔޛ⤟Ἳᵈ Ἳޔ⢗Ἳޔྚਅ ਄᣹ޔࡆ࡝࡞ Ⴧടޔ 2㧕 㧔83.1㧑㧕ޔ ޜ 㓚ኂޔ⣺▤ᯏ⢻ ࡆࡦ਄᣹ PIVKA II ਄ ⿒ⴊ⃿ᢙᷫዋ ⇣Ᏹޔ⣻ㇱਇᔟ ᣹ޔΦဳࠦ 㧔81.9㧑㧕ޔ ᗵޔญ⣧ౝਇᔟ ࡜࡯ࠥࡦ୯ ࡋࡑ࠻ࠢ࡝࠶ ᗵޔᱤ∩ޔ⥠ ਄᣹ ࠻ᷫዋ Ἳޔ㥏⣺᡼ያޔ ⣢⤳ ⴊዩޔឃዩ 㧔76.5㧑㧕ޔ ∤ᩭޔ߅ߊ߮ޔ 㓚ኂޔⰮ⊕ ⴊዊ᧼ᢙᷫዋ ⣺Ἳޔญౝੇ ዩޔBUN࡮ 㧔74.6㧑㧕ޔ ῎ޔឃଢ㓚ኂޔ ⢂㐷๟࿐Ἳޔᱤ ࠢ࡟ࠕ࠴࠾ ࡝ࡦࡄ⃿ᢙᷫ ߩ⇣Ᏹޔࠕࡒ࡜ ࡦ਄᣹ޔ⣢ ዋ㧔60.8㧑㧕 ࡯࠯਄᣹ޔ࡝ࡄ ⚿⍹ޔ⣾⢲ ᓴⅣེ േᖪ ⢷∩ޔầ ⚃ޔ㜞ⴊ࿶ ࡯࠯਄᣹ޔㅒᵹ Ἳޔ㗫ዩ ᕈ㘩㆏Ἳޔᶖൻ ⢄⤳ ⢙▤Ἳޔ AST㧔GOT㧕 ᓴⅣེ ⢷∩ޔⴊ࿶਄ ᧃ᪳ᕈ⯯ ⴊ▤ᶋ LDH ₙ㢖ᇬ ▤ࡐ࡝࡯ࡊޔ㦏 ⢽⢌⢄ ਄᣹ޔALT ᣹ޔầ⚃ޔ㗫 ⴊޔⴊ࿶ૐ ⣲ޔᚱቶ AlP ਄᣹ ᱤ ⣂ޔᶋ⣲㧔྾ ਅޔ⫷⊕ ࡉࡠ࠶ࠢ 㧔GPT㧕਄ ⊹⤏ ⣕Ძޔ ⚃᢬ޔ⊹⤏ੇ శ✢ㆊᢅ ⢇࡮㗻㕙㧕 ᣹ޔǫ-GTP ߘ߁∣ޔ⊒ ῎ޔḨ∐ޔ⊹⤏ ∝ޔᲫ⾰ ᵈ 3㧕 ਄᣹ޔࡆ࡝࡞ ᶖൻེ 㘩᰼ਇᝄ ⢗Ἳޔ⣺ ⤟Ἳ ∐ޔޛ⢽ Ἳޔ⊕⊈ޔ⚡ ⇣Ᏹޔߖ ࡆࡦ਄᣹ 㧔75.6㧑㧕ޔ Ἳޔ⣺▤ᯏ ṳޜޔ ᢬ޔធ⸅ᕈ⊹⤏ ߟޔᄙᒻ Ἳޔ⭄㤗∐ޔ⪭ ᖡᔃ࡮ཌྷฯޔ ⢻⇣Ᏹޔឃ ⣢⤳ Ⱞ⊕ዩ㓁 ޛ⊹⤏ೝỗޜ ⚃᢬ޔ⊹ ድޔῪߩ⇣Ᏹޔ ⣻∩ޔ⢗ਇᔟ ଢ㓚ኂޔ∤ ᕈޔⴊዩ㓁 ⤏ẩ≌ޔ ㆊⷺൻޔߑ≙ ᗵޔਅ∯ޔญ ᩭޔ㥏⣺᡼ ᕈޔ㗫ዩޔ ᳓∊ޔ᳨ ᷢޔญౝ࡮ญ ያޔญ⣧ౝ ឃዩ㓚ኂޔ ∊ ໃἻޔᱤ㜑࡮ ਇᔟᗵޔᱤ ዩ〝⚿⍹ ␹⚻ 㑐▵∩ޔ╭⡺ ╭∨⋥ޔ྾⢇ ฝቄ⡻ㇱ

ᱤ๟࡮ᱤ⡺ ߩ⇣Ᏹޔᱤ ๭ๆེ ຕ༿ ༥ჿޔ㥦 ࡮ ∩ޔ⢛ㇱ࡮⣶ ∩ޔᗵⷡ⇣Ᏹޔ ∩ޔ㤗∽ Ἳޔᶖൻਇ ∩ޔ㦏ᱤޔ 㧔32.7㧑㧕ޔ 㐽ޔຜ㗡ਇ ╭ ㇱ∩ޔޛ⥠㤗 㑐▵Ἳޔ╭⎬ 㧔྾⢇࡮ ⦟ޔ⣻ㇱਇᔟ ߅ߊ߮ޔญ 㥦࡮ຜ㗡Ἳ ᔟᗵޔ೽㥦 ∽ޜ ⋥ޔ✕ᒛ੣ㅴޔ 㗻㕙㧕ޔ ᗵޔ⣻ㇱ⤘ḩ ౝੇ῎ޔ⥠ 㧔22.7㧑㧕ޔ ⣧Ἳޔຜ㗡 㗖ㇱ∩ޔᝄᚢޔ CK ␹⚻∩ޔήജ ᗵޔଢ⒁ޔࠕ Ἳޔ⢂㐷๟ ຜ༄㗡∩ ⚃᢬ޔ᳇▤ 㧔CPK㧕 ∝ޔ⡻㛽∩ޔ− ࡒ࡜࡯࠯਄ ࿐Ἳޔྚਅ 㧔20.4㧑㧕ޔ ᡰἻ ਄᣹ 㥦ṳޔ໼∷ޔ ∩ޔ࠾ࡘ࡯ࡠࡄ ᣹ޔ࡝ࡄ࡯࠯ 㓚ኂޔㅒᵹ ࠪ࡯ޔ྾⢇ਇᔟ 㥦಴ⴊ ਄᣹ ᕈ㘩㆏Ἳޔ ᗵޔ⣲⣘ޔ╭ജ

ᶖൻ▤ࡐ࡝ ⌒ ⷺ⤑ẩ≌ ⌒∩ޔ㔵 ૐਅޔ㊀ᗵ ࡯ࡊޔ㘩㆏ ⷞޔ✂⤑ߩ ๭ๆ ຕ༿ޔ਄᳇㆏ 㥦಴ⴊޔ᳇▤ᡰ ޽ߊ߮ޔ 㕒⣂≜ ᓸዊᓴⅣ㓚 ེ Ἳޔޛ᳇▤ᡰ Ἳޔᚳ᩶Ἳޔ㥦 ⢷᳓ޔຜ ᵈ 3㧕 ⊹⤏ ⣕Ძ ⊹⤏ẩ≌ޔ శ✢ㆊᢅ ኂ ޔ⌒ ∨ᡨޜޔޛ⢖ Ἳޔ೽㥦⣧Ἳޔ 㗡⣲⣘ ૶↪਄ 㧔61.9㧑㧕ޔ ⊹⤏Ἳޔ⚡ ∝ޔ⊹⤏ ߩἻ∝㧔⚿ ᶐẢޜ 㥦ੇ῎ޔ㥦ṳޔ

ߩᵈᗧ ⊒∐ ᢬ޔធ⸅ᕈ ೝỗޔᲫ ⤑Ἳޔⷺ⤑ ༥ჿޔߊߒ߾ 㧔50.7㧑㧕ޔ ⊹⤏Ἳޔ⭄ ⾰⇣Ᏹޔ Ἳ╬㧕ޔ⚿ ߺޔ⢖Ἳޔⴊ ∷ޔ㥦㐽ޔຜ㗡 ߘ߁∣ޔ⊕ 㤗∐ޔㆊⷺ ᳓∊ ⤑లⴊޔ✂ ⤑಴ⴊޔ⌒ ⚃᢬ޔ㥦㆏ೝỗ ⊈ޔ⚃᢬ޔḨ ൻޔῪߩ⇣ ᗵ ∐ޔ⊹⤏ੇ῎ Ᏹޔᄙᒻ⚃ ߩ⇣Ᏹᗵޔ ⌒ੇ῎ ⌒ ޛⷞ㊁⁜ ⷺ⤑࡮⚿⤑Ἳޔ ⷞ㊁ᰳ ᢬ޔ⪭ድޔ ⌒∩ޔ⌒ߘ߁∣ ߘߩઁ ഺ⿠ᯏ⢻ਇ ᵈ኿ㇱ૏෻ᔕ TSH ᷫዋޔ ⓰ޜޔޛⷞ␹ ៊ޔ✂⤑ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ߑ≙ޔ᳨∊ ∝ޔ⌒ߩ⇣๺ ᵈ ⚻Ἳޜޔޛⷞ േ⣂࡮㕒 ␹⚻࡮ 㑐▵∩ ࠾ࡘ࡯ࡠࡄࠪ CK ో 㧔40.0㧑㧕 ⴊ♧਄᣹ޔ ᗵޔ⌒లⴊޔ⌒ 4㧕 ജ༚ᄬޜޔ ⣂㐽Ⴇޔ ࡯ޔᝄᚢޔ╭ 㧔CPK㧕 ޔ࠻࡝ࠣ࡝ ಄ᗵޔⴊਛ ╭ 㧔69.4㧑㧕ޔ ޛ੃㗡ᶋ⣲ޜ ♖∋ഭޔ⌒⍘ ⷞജ⇣ ⎬⋥ޔ㑐▵ ਄᣹ ࠮࡜ࠗ࠼਄᣹ ࠕ࡞ࡉࡒࡦ Ἳޔ⌒⍘ᶋ⣲ޔ ╭⡺∩ Ᏹޔᵹ Ἳޔ㗖ㇱ∩ޔ 㧔23.1㧑㧕ޔ ᷫዋޔT4 ਄ ⷞⷡ⇣Ᏹޔⷞജ 㧔64.7㧑㧕ޔ ᶡޔ✂⤑ ᗵⷡ⇣Ᏹޔ╭ ⣲⣘ޔ␹⚻ 㔚⸃⾰⇣Ᏹ ᣹࡮ᷫዋޔ ૐਅޔ⎣ሶ૕ᶋ ∩ޔ⡻㛽∩ޔ ⵚሹޔ㤛 㧔ࠞ࡞ࠪ࠙ ᶋ⣲ޔT3 ਄ ㆆ‛ޔ✂⤑಴ⴊ ∨⋥ޔ⢛ㇱ࡮ −∩ޔ྾⢇ ࡓޔ࡝ࡦ╬㧕 ᣹ޔ∤಴ ╬ߩ✂⤑ߩᓸዊ ᢬ᶋ⣲ ⣶ㇱ∩ ᵈ 3㧕 ∩ޔήജ∝ޔ 㧔21.5㧑㧕ޔ ⴊޔ⡊㡆ޔ ᓴⅣ㓚ኂ ޔ ྾⢇ਇᔟᗵޔ ૕㊀ᷫዋޔᗵ 㔍⡬ޔ− ✂⤑ṡ಴‛ޔ⌒ 㤗∽㧔྾⢇࡮ ੇ῎ޔ㔵ⷞޔ㤈 ᨴ∝㧔⚦⩶࡮ ∩ޔ⢷ㇱਇ 㗻㕙㧕ޔ╭ജ ☸⣲ޔ⌒⍘⚃ ⌀⩶࡮࠙ࠗ࡞ ᔟᗵޔ⡊ ૐਅޔ㊀ᗵ ᢬ޔ⟮᣿ ࠬ╬㧕ߩ⺃⊒ ∩ޔ⡊㐽 ๭ๆེ ਄᳇㆏Ἳޔຕ ⢖Ἳޔຜ㗡 ⢖ᶐẢޔ ᛩਈ ޛᵈ኿ㇱ෻ᔕ ᵈ኿ㇱ෻ᔕ㧔⚃ ᵈ኿ㇱ෻ ෶ߪჇᖡޔ ᗵޔዩ♧㓁 ༿ޔ㥦಴ⴊޔ ⚃᢬ޔຜ㗡 ⢷᳓ ㇱ૏ 㧔უᱫ㧕ޜ ᢬ޔߘ߁∣ޔἻ ᔕ㧔⦡⚛ CRP ਄᣹ޔ ᕈޔਛ⡊ 㥦ṳ ⣲⣘ޔᚳ᩶ ∝ޔ⎬⚿ޔ⣲ ᴉ⌕ޔẩ TSH ਄᣹ޔ Ἳޔᄖ⡊ Ἳޔ᳇▤ᡰ ⣘ޔᾲᗵޔ⊒ ≌㧕 Ἳޔ㥦Ἳޔ ∋ഭޔᾲᗵ Ἳޔᧃ᪳⣲ ∐ޔ−∩ޔ಴ ⣘ޔᘟᕈ↲ ⴊޔ⊹⤏Ἳ㧕 ೽㥦⣧Ἳޔ 㥦ੇ῎ޔ㥦 ⁁⣼Ἳޔࠨ 㐽ޔ㥦㆏ೝ ࡞ࠦࠗ࠼࡯ ỗᗵޔ༥ ࠪࠬޔ࡝ࡦ ჿޔߊߒ߾ ࡄ▵∝ޔή ߺޔ޽ߊ ജ∝ޔ⇣Ᏹ ߮ޔⴊ∷ ᗵޔዩ〝ᗵ ᨴ ᵈ 2㧕࿖ᄖߩ⥃ᐥ⹜㛎ߩ೽૞↪෶ߪ⥄⊒ႎ๔ߦߡ ႎ๔ߐࠇߚ㗫ᐲࠍ▚಴ߢ߈ߥ޿೽૞↪ߦߟ޿ߡߪ 㗫ᐲਇ᣿ߣߒߚޕ ᵈ 3㧕✂⤑ṡ಴‛ޔ✂⤑േ⣂࡮㕒⣂ⴊᩖ∝ޔ⎣ሶ ૕ᶋㆆ‛ޔ੃㗡ᶋ⣲ޔⷞജૐਅޔⷞ㊁ᰳ៊╬ࠍ઻ ߁ߎߣ߇޽ࠆߩߢޔߎߩࠃ߁ߥ∝⁁߇޽ࠄࠊࠇߚ ႐วߦߪㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ᵈ 4㧕ᵈ኿ㇱ૏ߦἻ∝ޔೝỗᗵޔᝂ்ޔ⊹⤏Ἳޔ ⚃᢬ޔ−∩ޔហ∣ޔ⎬⚿ޔ⣲⣘ޔẩ≌╬ࠍߺࠆߎ ߣ߇޽ࠆޕ

31 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

㗫ᐲ 㗫ᐲਇ᣿ 10㧑એ਄ 10㧑ᧂḩ 5%એ਄ 5%ᧂḩ ਇ᣿ ᵈ 2㧕 ╭࡮㛽 㑐▵∩㧘╭⡺ ╭㛽ᩰ⎬⋥㧘╭ ߘߩ ᵈ኿ㇱ૏෻ᔕ CRP ਄᣹ޔ૕ ᩰ♽ ∩㧘⢛ㇱ∩ 㛽ᩰ∩㧘஥⣻ㇱ ઁ 㧔33.3㧑㧕ᵈ ㊀ᷫዋޔT S ∩㧘╭ജૐਅ㧘 4㧕ޔ H ਄᣹࡮ᷫ ྾⢇∩㧘㑐▵࡝ ࠻࡝ࠣ࡝࠮࡜ ዋޔⴊ♧਄ ࠙ࡑ࠴㧘የ㛽 ࠗ࠼਄᣹ޔᗵ ᣹ޔᾲᗵޔ಄ ∩㧘㗶∩㧘㗶㑐 ᨴ∝㧔⚦⩶࡮ ᗵޔ∋ഭޔⴊ ▵∝୥⟲㧘╭㛽 ⌀⩶࡮࠙ࠗ࡞ ਛࠕ࡞ࡉࡒࡦ

ᩰ♽⢷∩㧘╭∨ ࠬ╬㧕ߩ⺃⊒ ᷫዋޔT4 ਄ ❗㧘྾⢇ਇᔟᗵ ෶ߪჇᖡޔ㔚 ᣹࡮ᷫዋޔ㔍 ๭ๆེ ຕ༿ 㥦ຜ㗡Ἳ㧘ຜ㗡 ⢷᳓ ⸃⾰⇣Ᏹ㧔ࠞ ⡬ޔᶋ⣲࡮⣲ Ἳ㧘೽㥦⣧Ἳ㧘 ࡞ࠪ࠙ࡓޔ࡝ ⣘ޔT3 ਄᣹࡮ 㥦Ἳ㧘ࠕ࡟࡞ࠡ ࡦ╬㧕 ᷫዋޔ∤ᩭޔ ࡯ᕈ㥦Ἳ㧘㥦 ⴊᷡ✚Ⱞ⊕Ⴧ ṳ㧘㥦಴ⴊ㧘㥦 ട࡮ᷫዋޔ⡊ ∩㧘ᚳ᩶Ἳ㧘ญ 㡆ޔ࡝ࡦࡄ▵ ⣧ຜ㗡ਇᔟᗵ㧘 ∝ޔഺ⿠ᯏ⢻ ญ⣧ຜ㗡∩㧘∷ ਇోޔ᦬⚻⇣ ⾂⇐㧘਄᳇㆏ߩ Ᏹޔࠨ࡞ࠦࠗ Ἳ∝㧘᳇▤ᡰ ࠼࡯ࠪࠬޔ− Ἳ㧘ഭ૞ᕈ๭ๆ ∩ޔࠕ࡟࡞ࠡ ࿎㔍㧘๭ๆ࿎ ࡯ᕈ㥦Ἳޔ⢷ 㔍㧘༎ᕷ ㇱਇᔟᗵޔᘟ

ౝಽᴲ ↲⁁⣼ᯏ⢻ૐਅ ᕈ↲⁁⣼Ἳޔ ∝㧘↲⁁⣼ᯏ⢻ ਛ⡊Ἳޔᄖ⡊ ੣ㅴ∝㧘↲⁁⣼ Ἳޔ⡊∩ޔ⡊ Ἳ㧘⥄Ꮖ఺∉ᕈ 㐽ᗵޔήജ ↲⁁⣼Ἳ㧘TSH ∝ޔ⇣Ᏹᗵޔ ૐਅ㧘TSH ਄ ዩ〝ᗵᨴ ᣹㧘 ↲⁁⣼ᯏ⢻ ᵈ 2㧕࿖ᄖߩ⥃ᐥ⹜㛎ߩ೽૞↪෶ߪ⥄⊒ႎ๔ߦߡ

ᬌᩏ⇣Ᏹ㧘FT3 ૐ ႎ๔ߐࠇߚ㗫ᐲࠍ▚಴ߢ߈ߥ޿೽૞↪ߦߟ޿ߡ ਅ㧘ⴊਛ㤛૕ᒻ ߪ㗫ᐲਇ᣿ߣߒߚޕ ᚑࡎ࡞ࡕࡦჇട ᵈ 3㧕✂⤑ṡ಴‛ޔ✂⤑േ⣂࡮㕒⣂ⴊᩖ∝ޔ⎣ሶ ⌒ 㔸☸⣲㧘㤈☸ ૕ᶋㆆ‛ޔ੃㗡ᶋ⣲ޔⷞജૐਅޔⷞ㊁ᰳ៊╬ࠍ ⣲㧘⌒⍘Ἳ㧘ࡑ ઻߁ߎߣ߇޽ࠆߩߢޔߎߩࠃ߁ߥ∝⁁߇޽ࠄࠊ ࠗࡏ࡯ࡓ⣼ᯏ⢻ ࠇߚ႐วߦߪㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ਇో㧘⌒⍘ߘ߁ ᵈ 4㧕ᵈ኿ㇱ૏ߦἻ∝ޔೝỗᗵޔᝂ்ޔ⊹⤏Ἳޔ ∣∝㧘⌒ߘ߁∣ ⚃᢬ޔ−∩ޔ≒∣ޔ⎬⚿ޔ⣲⣘ޔẩ≌╬ࠍߺࠆ ∝㧘ⷺ⤑㓚ኂ㧘 ߎߣ߇޽ࠆޕ ⚿⤑Ἳ㧘⚿⤑಴ ⴊ㧘ࠕ࡟࡞ࠡ࡯ 㧨࡝ࡃࡆ࡝ࡦߣߩ૬↪ߩ႐ว㧪 ૶↪਄ ᕈ⚿⤑Ἳ㧘ὐ⁁ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ㧦ᧄ೷ ߩᵈᗧ ⷺ⤑Ἳ㧘⎣ሶ૕ ߣ࡝ࡃࡆ࡝ࡦࠍ૬↪ߒߚ࿖ౝ⥃ᐥ⹜㛎ߦ߅޿ ᶋㆆ‛㧘✂⤑ṡ ߡޔ቟ోᕈ⹏ଔߩኻ⽎ߣߥߞߚ 199 ଀ో଀ߦ⥃ ಴‛㧘✂⤑∝㧘 ᐥᬌᩏ୯ߩ⇣Ᏹࠍ฽߻೽૞↪߇⹺߼ࠄࠇߚޕਥ ✂⤑಴ⴊ㧘৻ㆊ ߥ೽૞↪ߪޔ⊒ᾲ 146 ઙ㧔73. 4㧑㧕ޔᵈ኿ㇱ૏ ᕈ㤥ౝ㓚㧘⌒ߩ ෻ᔕ 142 ઙ㧔71. 4㧑㧕ޔୱᕃᗵ 138 ઙ㧔69. ⇣Ᏹᗵ㧘⌒ੇ 3㧑㧕╬ߢ޽ߞߚޕ೽૞↪ߣߒߡߩ⥃ᐥᬌᩏ୯ߩ ⇣Ᏹߪޔ⊕ⴊ⃿ᷫዋ 184 ઙ㧔92. 5㧑㧕ޔᅢਛ⃿

῎㧘㔵ⷞ㧘⟮ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ᣿㧘⌒∩㧘⌒♖ ᷫዋ 178 ઙ㧔89. 4㧑㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ 169 ∋ഭ㧘ⷞജ㓚 ઙ㧔84. 9㧑㧕╬ߢ޽ߞߚޕ㧔ല⢻ㅊടᛚ⹺ᤨ㧕 ኂ㧘ⶄⷞ C ဳઍఘᕈ⢄⎬ᄌߦ߅ߌࠆ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ㧦 ⡊ ਛ⡊Ἳ㧘ᄖ⡊ ᧄ೷ߣ࡝ࡃࡆ࡝ࡦࠍ૬↪ߒߚ࿖ౝ⥃ᐥ⹜㛎ߦ߅ Ἳ㧘⡊ਅ⣼Ἳ㧘 ޿ߡޔ቟ోᕈ⹏ଔߩኻ⽎ߣߥߞߚ 61 ଀ో଀ߦ⥃ ࿁ォᕈ߼߹޿㧘 ᐥᬌᩏ୯ߩ⇣Ᏹࠍ฽߻೽૞↪߇⹺߼ࠄࠇߚޕਥ ⡊ਇᔟᗵ㧘⡊ ߥ೽૞↪ߪޔୱᕃᗵ 45 ઙ㧔73. 8㧑㧕ޔ⊒ᾲ 41 㡆㧘⡊∩㧘⡊ߘ ઙ㧔67. 2㧑㧕ޔ≒∣∝ 38 ઙ㧔62. 3㧑㧕╬ߢ޽ߞ ߁∣∝㧘⡊▤⁜ ߚޕ೽૞↪ߣߒߡߩ⥃ᐥᬌᩏ୯ߩ⇣Ᏹߪޔᅢਛ ⓰ ⃿ᷫዋ 58 ઙ㧔95.1㧑㧕ޔ⊕ⴊ⃿ᷫዋ 54 ઙ㧔88. 5 48 78. 7 ઍ⻢ ⴊਛዩ㉄Ⴧട ∩㘑㧘♧ዩ∛㧘 㧑㧕ޔ⿒ⴊ⃿ᷫዋ ઙ㧔 㧑㧕ޔⴊዊ᧼ᷫ 48 78. 7 㧔60.7%㧕㧘㜞 ૐⴊ♧∝㧘⢽⾰ ዋ ઙ㧔 㧑㧕╬ߢ޽ߞߚޕ㧔ല⢻ㅊടᛚ⹺

ዩ㉄ⴊ∝㧘 ⢽ Ⴧട㧘㜞࠻࡝ࠣ ᤨ㧕 1 ⾰⇣Ᏹ∝㧘 㜞 ࡝࠮࡝࠼ⴊ∝㧘 㧔 㧕㊀ᄢߥ೽૞↪ 1 250 / L 4 ࠦ࡟ࠬ࠹ࡠ࡯ HDL ࠦ࡟ࠬ࠹ࡠ 㧕⽺ⴊ㨇⿒ⴊ⃿ᷫዋ㧔 ਁ Ǵ ᧂḩ㧕㧔 㧑ᧂ 8g/dL 2 ࡞ⴊ∝㧘ⴊਛ ࡯࡞ૐਅ㧘LDL ḩ㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔 ᧂḩ㧕㧔 㧑ᧂ 8 9.5g/dL ࠻࡝ࠣ࡝࠮࡝ ࠦ࡟ࠬ࠹ࡠ࡯࡞ ḩ㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔 એ਄ ᧂḩ㧕 10 9.5 ࠼Ⴧട ਄᣹㧘ⴊਛࡉ࠼ 㧔 㧑એ਄㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔 એ਄ 11g/dL 10 ࠙♧Ⴧട㧘ⴊਛ ᧂḩ㧕㧔 㧑એ਄㧕㨉㧦ቯᦼ⊛ߦⴊᶧᬌ ࡉ࠼࠙♧ᷫዋ㧘 ᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ㊀ᐲߩ⽺ⴊࠍ ዩਛࡉ࠼࠙♧㓁 ⹺߼ߚ႐วߪޔᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ

ᕈ ߁ߎߣޕ 2㧕᳢ⴊ⃿ᷫዋޔή㗰☸⃿∝ޔ⊕ⴊ⃿ᷫዋ㧔2, 000/ǴL ᧂḩ㧕ޔⴊዊ᧼ᷫዋ㧔50,000/ǴL ᧂḩ㧕 㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ቯᦼ⊛ߦⴊᶧᬌᩏࠍⴕ߁ߥ ߤޔᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤߔࠆߎߣޕᧄ೷ߩ ᷫ㊂ޔਛᱛߦߟ޿ߡߪޔ㧨↪ᴺ࡮↪㊂ߦ㑐ㅪߔ ࠆ૶↪਄ߩᵈᗧ㧪ߩ㗄ࠍෳᾖߔࠆߎߣޕ



32 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 5%એ਄ 5%ᧂḩ 㗫ᐲਇ᣿ 5㧑એ਄෶ 0.1㨪5㧑ᧂḩ 0.1㧑ᧂḩ ᵈ 2㧕 ߪ㗫ᐲਇ᣿ ⌒ ✂⤑಴ⴊޔ✂ ✂⤑േ⣂࡮㕒 ⷞജ༚ 㧔㗫ᐲਇ᣿ ⤑ṡ಴‛ޔⷺ ⣂㐽Ⴇޔ✂⤑ ᄬޔ✂⤑ ߪޛޜౝ㧕 ⤑࡮⚿⤑Ἳޔ ⵚሹޔⷞ㊁ᰳ ⊕᢬ޔ㤛 ߘ ૕㊀ᷫዋޔ CRP ਄᣹ޔ㋕ઍ⻢ ೨┙⣼ 㔵ⷞ ៊ޔ⌒⍘Ἳޔ ᢬ᶋ⣲ޔ ߩ ๧ⷡ㓚ኂޔ 㓚ኂޔᄙ᳨ޔ㜞ⴊ Ἳޔࠨ࡞ ⌒⍘⚃᢬ޔ⌒ ੃㗡ᶋ ઁ ↲⁁⣼ᯏ⢻ ♧ޔ∋ഭޔ㜞ዩ㉄ⴊ ࠦࠗ࠼࡯ ⍘ᶋ⣲ޔⷞⷡ ⣲ޔⷞ␹ ⇣Ᏹޔޛ⣻ ∝ޔᗵᨴ∝ޔ࡝ࡦࡄ ࠪࠬޔⴊ ⇣Ᏹޔⷞജૐ ⚻Ἳޔᵹ ᳓ޜޔޛᕈ ▵Ἳޔ⧎☳∝ޔᄖ⡊ ਛዩ㉄ૐ ਅޔ⎣ሶ૕ᶋ Ἳޔⴊᷡ㋕ૐਅޔⴊ ᶡ ᰼ᷫㅌޜ ਅޔഺ⿠ ㆆ‛ޔ㤈☸ ਛࠦ࡟ࠬ࠹ࡠ࡯࡞Ⴧ ⣲ޔ⟮᣿ޔ⌒ ടޔ㜞Ⱞ⊕ⴊ∝ޔ⡊ 㓚ኂޔ∩ లⴊޔ⌒ߩ⇣ ∩ޔ⥄Ꮖ᛫૕↥↢ޔ 㘑ޔഃ் ๺ᗵޔ⌒ߘ߁ ಣ⟎ᓟዪᚲ෻ᔕޔන ᴦ≹ㆃ ∣∝ޔ⌒♖∋ ⚐∊∐ޔਛ⡊Ἳޔૐ ᑧޔ⣛ ഭޔ⌒∩ ࠕ࡞ࡉࡒࡦⴊ∝ޔૐ ⣲ޔ⣾⢲ ᛩਈㇱ ᵈ኿ㇱ෻ᔕ ᵈ኿ㇱ෻ᔕ ᵈ኿ㇱ෻ Ⱞ⊕ⴊ∝ޔ༦ⷡ⇣ ≸ᵈ 4㧕ޔ ૏ 㧔⚃᢬ޔߘ߁ 㧔⣲⣘ޔἻ ᔕ㧔უ Ᏹޔⴊਛࠦ࡟ࠬ࠹ࡠ ᄢ⣺≸ᵈ ∣ޔ⊒∐ޔ− ∝ޔ⎬⚿ޔ಴ ᱫ㧕 ࡯࡞ᷫዋޔዩ♧ޔਇ 4㧕ޔᖡᕈ ∩㧕 ⴊޔ⊹⤏Ἳޔ ᱜ಴ⴊޔⴊᷡ㋕਄ ࡝ࡦࡄ⣲ᵈ ᾲᗵޔ⦡⚛ᴉ ᣹ޔ⣕᳓ޔ⤥≌ޔ᦬ 5㧕 ⌕ޔẩ≌㧕 ⚻⇣Ᏹޔ㔚⸃⾰⇣Ᏹ 㧔ࠞ࡝࠙ࡓޔ࠽࠻࡝ ߘߩઁ ↲⁁⣼ᯏ⢻⇣ ࡝ࡦࡄ▵Ἳޔ ࠨ࡞ࠦࠗ ࠙ࡓޔࠢࡠ࡯࡞ޔࠞ ᏱޔCRP ਄ Ꮺ⁁∊∐ޔන ࠼࡯ࠪ ࡞ࠪ࠙ࡓޔ࡝ࡦ ᣹ޔᗵᨴ∝ޔ ⚐∊∐ޔⴊਛ ࠬޔ⥄Ꮖ ╬㧕ޔᏪ⁁∊∐ޔ಄

๧ⷡ㓚ኂޔ૕ ࠦ࡟ࠬ࠹ࡠ࡯ ᛫૕↥ ᳨ޔ⣪Ἳޔ㜞࠻࡝ࠣ ㊀ᷫዋޔ∋ ࡞Ⴧടޔ㜞Ⱞ ↢ޔᕈ᰼ ࡝࠮࡜ࠗ࠼ⴊ∝ޔࡅ ഭޔᄙ᳨ޔࡅ ⊕ⴊ∝ޔૐࠕ ᷫㅌޔ㋕ ࠕ࡞ࡠࡦ㉄Ⴧടޔࡋ ࠕ࡞ࡠࡦ㉄Ⴧ ࡞ࡉࡒࡦⴊ ઍ⻢㓚 ࡕࠣࡠࡆࡦ A1c ᷫዋ ടޔ㜞࠻࡝ࠣ ∝ޔಣ⟎ᓟዪ ኂޔዩ ᵈ 2㧕⣻∩ޔⴊᷡࠕࡒ࡜࡯࠯୯ߩ਄᣹╬߇⹺߼ࠄ ࡝࠮࡜ࠗ࠼ⴊ ᚲ෻ᔕޔഃ் ♧ޔഺ⿠ ࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ ∝ޔ㜞ዩ㉄ⴊ ᴦ≹ㆃᑧޔਛ 㓚ኂޔ ߎߣޕ ∝ޔ㔚⸃⾰⇣ ⡊Ἳޔᄖ⡊ ∩㘑ޔ⣻ ᵈ 3㧕㘧Ⰶⷞޔⷞജૐਅᗵ╬ࠍ઻߁ߎߣ߇޽ࠆߩ Ᏹ㧔ࠞ࡝࠙ Ἳޔ⡊∩ޔ༦ ᳓ޔ⣾⢲ ߢޔߎߩࠃ߁ߥ∝⁁߇޽ࠄࠊࠇߚ႐วߦߪㆡಾ ࡓޔ࠽࠻࡝࠙ ⷡ⇣Ᏹޔ᦬⚻ ≸ᵈ 5㧕ޔ ߥಣ⟎ࠍⴕ߁ߎߣޕ ࡓޔࠢࡠ࡯ ⇣Ᏹޔ೨┙⣼ ᄢ⣺≸ᵈ ᵈ 4㧕ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵ ࡞ޔࠞ࡞ࠪ࠙ Ἳޔ಄᳨ޔ⧎ 5㧕 ឵߃㧕ߣ࡝ࡃࡆ࡝ࡦߩ૬↪ߦ߅޿ߡ⊒⃻߇⹺߼ ࡓޔ࡝ࡦ╬㧕 ☳∝ޔૐⰮ⊕ ࠄࠇߡ޿ࠆ߇ޔ࿃ᨐ㑐ଥ߇᣿⏕ߥ߽ߩߢߪߥ ⴊ∝ޔⴊਛࠦ ޿ޕ ࡟ࠬ࠹ࡠ࡯࡞ ᵈ 5㧕࿖ౝ⥃ᐥ⹜㛎ߦ߅޿ߡ⹺߼ࠄࠇߡ޿ࠆ߇ޔ ᷫዋޔਇᱜ಴ ࿃ᨐ㑐ଥ߇᣿⏕ߥ߽ߩߢߪߥ޿ޕ ⴊޔ⣕᳓ޔ⤥ ⊒⃻㗫ᐲߪࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવ ≌ޔᖡᕈ࡝ࡦ ሶ⚵឵߃㧕ߣߩ૬↪ߦኻߔࠆᛚ⹺ᤨߩ⥃ᐥ⹜㛎 ૶↪਄ ࡄ⣲ᵈ 4㧕ޔ㘩 ෸߮⵾ㅧ⽼ᄁᓟ⺞ᩏޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ ߩᵈᗧ ㆏≸ᵈ 4㧕ޔࡋ ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ߣߩ૬↪ߦኻߔࠆᛚ ࡕࠣࡠࡆࡦ ⹺ᤨߩ⥃ᐥ⹜㛎ߩว⸘ࠃࠅ▚಴ߒߚޕߥ߅ޔᛚ

A1C ᷫዋޔ⣛ ⹺ᤨߩ⥃ᐥ⹜㛎෸߮⵾ㅧ⽼ᄁᓟ⺞ᩏߢ⹺߼ࠄࠇ ⣲ޔ⣪Ἳޔ㜞 ߥ߆ߞߚ೽૞↪ߦߟ޿ߡߪ㗫ᐲਇ᣿ߣߒߚޕ ⴊ♧ ᵈ 2㧕㗫ᐲ߇᣿⏕ߣߥࠆ⺞ᩏߦࠃࠆ߽ߩߢߪߥ޿ ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࡌ࡯࠲ߣߩ૬↪ߩ႐ว 㧔ᶏᄖႎ๔╬㧕 ᧄ೷ߣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࡌ࡯࠲ࠍ૬↪ߒߚ࿖ౝ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ᵈ 3㧕⣻∩ޔⴊᷡࠕࡒ࡜࡯࠯୯ߩ਄᣹╬߇⹺߼ࠄ ⥃ᐥ⹜㛎ߦ߅޿ߡޔ቟ోᕈ⹏ଔߩኻ⽎ߣߥߞߚ ࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ 174 ଀ో଀ߦ೽૞↪߇⹺߼ࠄࠇߚޕਥߥ೽૞↪ߪ ߎߣޕ ⊒ᾲ㧔98.3㧑㧕ޔోりୱᕃᗵ㧔88.5㧑㧕ޔᖡኙ ᵈ 4㧕࿖ౝ⥃ᐥ⹜㛎ߦ߅޿ߡ⊒⃻߇⹺߼ࠄࠇߡ޿ 㧔82.2㧑㧕ޔ㗡∩࡮㗡㊀㧔80.5㧑㧕ߢ޽ࠅޔ⥃ᐥ ࠆ߇ޔ࿃ᨐ㑐ଥ߇᣿⏕ߥ߽ߩߢߪߥ޿ޕ ᬌᩏ୯ߩ⇣Ᏹߪޔᅢਛ⃿ᢙᷫዋ㧔79.3㧑㧕ޔ⊕ⴊ ᵈ 5㧕ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵ ⃿ᢙᷫዋ㧔75.3㧑㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ ឵߃㧕ߣ࡝ࡃࡆ࡝ࡦߩ૬↪ߦ߅޿ߡ⊒⃻߇⹺߼ 㧔76.4㧑㧕ޔ⿒ⴊ⃿ᢙᷫዋ㧔70.7㧑㧕ޔࡋࡑ࠻ࠢ ࠄࠇߡ޿ࠆ߇ޔ࿃ᨐ㑐ଥ߇᣿⏕ߥ߽ߩߢߪߥ ࡝࠶࠻ᷫዋ㧔71.3㧑㧕ޔⴊዊ᧼ᢙᷫዋ ޿ޕ 㧔62.1㧑㧕ޔⴊᷡࠕ࡞ࡉࡒࡦૐਅ㧔54.0㧑㧕ߢ޽ ߞߚޕ 㧔ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࡌ࡯࠲ߣߩ૬↪ߦࠃࠆ⵾ㅧ ⽼ᄁᓟ⥃ᐥ⹜㛎⚳ੌᤨ㧕

㧔1㧕㊀ᄢߥ೽૞↪ 1㧕⽺ⴊᵈ 6㧕㧔⿒ⴊ⃿ᷫዋ㧔250 ਁ/mm3 ᧂḩ㧕 㧔5%ᧂḩ㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔8g/dL ᧂḩ㧕 㧔5%ᧂḩ㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔8 એ਄ 9.5g/dL ᧂḩ㧕㧔5%એ਄㧕ޔࡋࡕࠣࡠࡆࡦᷫዋ㧔9.5 એ਄ 11g/dL ᧂḩ㧕㧔5%એ਄㧕㧕㧦ቯᦼ⊛ߦⴊᶧᬌᩏ ࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹߩ⒟ᐲ߇⪺ ߒ޿႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ ߎߣޕ 2㧕⊕ⴊ⃿ᷫዋ㧔2,000/mm3 ᧂḩ㧕㧔5%એ਄㧕ޔ 㗰☸⃿ᷫዋ㧔1,000/mm3 ᧂḩ㧕㧔5%એ਄㧕ޔⴊዊ ᧼ᷫዋ㧔50,000/mm3 ᧂḩ㧕㧔5%ᧂḩ㧕᧶ቯᦼ⊛ ߦⴊᶧᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ ߇⹺߼ࠄࠇߚ႐วߦߪᷫ㊂෶ߪભ⮎ߔࠆߥߤㆡ ಾߥಣ⟎ࠍⴕ߁ߎߣޕ 3㧕㊀◊ߥ⢄㓚ኂ㧔5%ᧂḩ㧕㧦⪺ߒ޿࠻࡜ࡦࠬࠕ ࡒ࠽࡯࠯ߩ਄᣹ࠍ઻߁⢄㓚ኂ߇޽ࠄࠊࠇࠆߎߣ ߇޽ࠆߩߢޔቯᦼ⊛ߦ⢄ᯏ⢻ᬌᩏ㧔AST 㧔GOT㧕ޔALT㧔GPT㧕╬㧕ࠍⴕ߁ߥߤⷰኤࠍච ಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛ ᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ

33 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

㗫ᐲ 3㧕ⴊᩖᕈⴊዊ᧼ᷫዋᕈ⚡᢬∛㧔TTP㧕ޔṁⴊᕈ 5%એ਄ 5%ᧂḩ ਇ᣿ ዩᲥ∝∝୥⟲㧔*75㧕㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⴊዊ᧼ ߘߩઁ ࡅࠕ࡞ࡠࡦ㉄ ⿷⊕⊈㧘Ὺ⌀⩶ ᷫዋޔ⽺ⴊޔ⣢ਇోࠍਥᓽߣߔࠆⴊᩖᕈⴊዊ᧼ Ⴧട ∝㧘≾㘑㧘ࠗࡦ ᷫዋᕈ⚡᢬∛㧔TTP㧕ޔṁⴊᕈዩᲥ∝∝୥⟲ 㧔50.6 %㧕㧘 ࡈ࡞ࠛࡦࠩ㧘⚦ 㧔HUS㧕߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ ᵈ኿ㇱ૏⚃ ⩶ᕈ⣪Ἳ㧘⣪ᗵ ߦⴊᶧᬌᩏ㧔ⴊዊ᧼ޔ⿒ⴊ⃿╬㧕෸߮⣢ᯏ⢻ᬌ ᢬㧘 ᵈ኿ㇱ૏ ᨴ㧘⤯Ἳ㧘㔚⸃ ᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄ ෻ᔕ㧘 ⴊਛ࡝ ⾰ᄬ⺞㧘⣕᳓㧘 ࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ ࡦᷫዋ㧘 ⴊਛ ૐࠞ࡝࠙ࡓⴊ ߎߣޕ ࠞ࡝࠙ࡓᷫዋ ∝㧘ૐ࠽࠻࡝࠙ 4㧕ౣ↢ਇ⦟ᕈ⽺ⴊޔ⿒⧘⃿≲᧤㗫ᐲਇ᣿ᵈ ࡓⴊ∝㧘ૐ࡝ࡦ 㧕㧕㧦ቯᦼ⊛ߦⴊᶧᬌᩏࠍⴕ߁ߥߤޔᖚ⠪ߩ⁁ᘒ ㉄ⴊ∝㧘ૐࠞ࡞ ࠍචಽߦⷰኤߔࠆߎߣޕᧄ೷ߩᷫ㊂ޔਛᱛߦߟ ࠪ࠙ࡓⴊ∝㧘ૐ ޿ߡߪޔ㧨↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ ࠕ࡞ࡉࡒࡦⴊ 㧪ߩ㗄ࠍෳᾖߔࠆߎߣޕ ∝㧘ਇᱜሶች಴ 5㧕㑆⾰ᕈ⢖Ἳޔ⢖ᶐẢޔ๭ๆ࿎㔍᧤㗫ᐲਇ᣿ᵈ ⴊ㧘᦬⚻㓚ኂ㧘 2㧕㧕㧦⊒ᾲޔຕ༿ޔ๭ๆ࿎㔍╬ߩ⥃ᐥ∝⁁ࠍච ᵈ኿ㇱ૏ߘ߁∣ ಽߦⷰኤߒޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߪޔㅦ߿߆ ᗵ㧘ᵈ኿ㇱ૏⊒ ߦ⢷ㇱ X ✢╬ߩᬌᩏࠍታᣉߒޔᧄ೷ߩᛩਈࠍਛ ∐㧘ᵈ኿ㇱ૏− ᱛߒޔ೽⣢⊹⾰ࡎ࡞ࡕࡦ೷ߩᛩਈ╬ߩㆡಾߥಣ ∩㧘ᵈ኿ㇱ૏ੇ ⟎ࠍⴕ߁ߎߣޕ߹ߚޔຕ༿ޔ๭ๆ࿎㔍╬߇޽ࠄ ῎㧘૕㊀ᷫዋ㧘 ࠊࠇߚ႐วߦߪ⋥ߜߦㅪ⛊ߔࠆࠃ߁ߦᖚ⠪ߦኻ ✚Ⱞ⊕ᷫዋ㧘ⴊ ߒᵈᗧࠍਈ߃ࠆߎߣޕ ਛ㔚⸃⾰ᷫዋ㧘 6㧕߁ߟ∛ޔ⥄Ვᔨᘦޔ⥄Ვડ࿑ޔば⁁ᘒޔ᡹᠄ ⴊਛ࠽࠻࡝࠙ࡓ ⊛ⴕേ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⷰኤࠍචಽߦⴕ޿ޔਇ

ᷫዋ㧘ⴊਛࠞ࡞ ⌁ޔਇ቟ޔὶ῎ޔ⥝ᅗޔ᡹᠄ᕈޔᤃೝỗᕈ╬߇ ࠪ࠙ࡓᷫዋ㧘 ⴊ ޽ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤޔㆡಾ ਛࠢࡠ࡯࡞ᷫ ߥಣ⟎ࠍⴕ߁ߎߣޕ㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ ዋ㧘ⴊਛࠕ࡞ࡉ 㗄ෳᾖ㧕 ࡒࡦᷫዋ㧘ⴊਛ 7㧕⢄ἻߩჇᖡޔ⢄ᯏ⢻㓚ኂ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦 ࠦ࡝ࡦࠛࠬ࠹࡜ 㤛∏߿⪺ߒ޿࠻࡜ࡦࠬࠕࡒ࠽࡯࠯ߩ਄᣹ࠍ઻߁ ࡯࠯Ⴧട㧘ⴊਛ ⢄ᯏ⢻㓚ኂ߇ႎ๔ߐࠇߡ޿ࠆߩߢޔቯᦼ⊛ߦ⢄ ࠕࡒ࡜࡯࠯Ⴧ ᯏ⢻ᬌᩏࠍⴕ߁ߥߤޔᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤ ട㧘⤟㉂⚛Ⴧ ߔࠆߎߣޕ㤛∏߿⪺ߒ޿࠻࡜ࡦࠬࠕࡒ࠽࡯࠯਄ ട㧘CRP ਄᣹ ᣹㨇ALT㧔GPT㧕҈500IU/L㨉ࠍ઻߁⢄ᯏ⢻㓚ኂ ᵈ㧕 ⣻∩㧘ⴊᷡࠕࡒ࡜࡯࠯୯ߩ਄᣹╬߇⹺߼ࠄ ߇޽ࠄࠊࠇߚ႐วߦߪㅦ߿߆ߦᛩਈࠍਛᱛߒޔ ࠇߚ႐วߦߪᛩਈࠍਛᱛߒ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ߣ㧚 8㧕⥄Ꮖ఺∉⃻⽎㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦⥄Ꮖ఺∉⃻

⽎ߦࠃࠆߣᕁࠊࠇࠆ∝⁁࡮ᓽ୥㨇⢄Ἳޔṁⴊᕈ ⽺ⴊޔ․⊒ᕈⴊዊ᧼ᷫዋᕈ⚡᢬∛ޔẩ≌ᕈᄢ⣺ Ἳޔ㑐▵࡝࠙ࡑ࠴ޔSLEޔⴊ▤Ἳޔࡈࠜ࡯ࠢ࠻࡮ ૶↪਄ ዊᩉ࡮ේ↰∛ޔฦ⒳⥄Ꮖ᛫૕ߩ㓁ᕈൻ╬㨉߇޽ ߩᵈᗧ ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔ⥄Ꮖ఺∉∔ᖚߩᖚ⠪ ෶ߪߘߩ⚛࿃ߩ޽ࠆᖚ⠪ߦߪቯᦼ⊛ߦᬌᩏࠍⴕ ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔᘕ㊀ߦᛩਈߔࠆߎ ߣޕ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕߚߛߒޔ⥄Ꮖ఺∉ᕈ⢄ Ἳߩᖚ⠪ߦߪᛩਈߒߥ޿ߎߣޕ 9㧕ᔃ╭∝ޔᔃਇోޔ⁜ᔃ∝ޔਇᢛ⣂㧔ᔃቶᕈ㗫 ⣂╬㧕ޔᔃ╭᪪Ⴇޔᔃౝ⤑Ἳޔᔃ⤑Ἳ㧔㗫ᐲਇ

᣿ᵈ 2㧕㧕㧦ᔃ∔ᖚߩ޽ࠆᖚ⠪෶ߪߘߩᣢᓔᱧߩ޽ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ࠆᖚ⠪ߦߪᘕ㊀ߦᛩਈߔࠆߎߣޕ⇣Ᏹ߇⹺߼ࠄ ࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤޔㆡಾߥಣ⟎ ࠍⴕ߁ߎߣޕ 10㧕ᢌⴊ∝㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ᤃᗵᨴᕈߣߥࠅޔ ᢌⴊ∝ޔ⢖Ἳ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔᖚ ⠪ߩోり⁁ᘒࠍචಽߦⷰኤߒޔ⇣Ᏹ߇⹺߼ࠄࠇ ߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎ ߣޕ 11㧕⣖಴ⴊ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⷰኤࠍචಽߦⴕ ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 12㧕⣖᪪Ⴇޔ⢖Ⴇᩖ∝㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⷰኤࠍ චಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍ ਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 13㧕ᗧ⼂㓚ኂޔ∨ᡨޔߡࠎ߆ࠎ⊒૞ޔ⷗ᒰ⼂㓚 ኂޔᤀ⌧ޔߖࠎᅦޔ㍲ੂޔᐛⷡޔ⹺⍮∝᭽∝⁁ 㧔․ߦ㜞㦂⠪㧕㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦⇣Ᏹ߇⹺߼ࠄ ࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤㆡಾߥಣ⟎ࠍ ⴕ߁ߎߣޕ 14㧕♧ዩ∛㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦♧ዩ∛㨇ࠗࡦࠬ࡝ ࡦଐሽဳ㧔IDDM㧕෸߮ࠗࡦࠬ࡝ࡦ㕖ଐሽဳ 㧔NIDDM㧕㨉߇Ⴧᖡ෶ߪ⊒∝ߔࠆߎߣ߇޽ࠅޔ ᤀ⌧ߦ⥋ࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦᬌᩏ㧔ⴊ ♧୯ޔዩ♧╬㧕ࠍⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐ว ߦߪㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 15᧥↲⁁⣼ᯏ⢻⇣Ᏹ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦↲⁁⣼ᯏ ⢻੣ㅴ෶ߪૐਅ߇Ⴧᖡ෶ߪ⊒∝ߔࠆߎߣ߇޽ࠆ ߩߢޔቯᦼ⊛ߦᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ ߁ߎߣޕ↲⁁⣼ᯏ⢻ߩ▤ℂ߇㔍ߒ޿႐วߦߪޔ ᛩਈߩਛᱛࠍ⠨ᘦߔࠆߎߣޕߥ߅ޔ↲⁁⣼ᯏ⢻ ⇣Ᏹ╬ߢᧄ೷ਛᱛᓟ߽ߥ߅ಣ⟎ߩ⛮⛯ࠍᔅⷐߣ ߒߚ∝଀߇ႎ๔ߐࠇߡ޿ࠆޕ

34 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 4㧕⥄Ꮖ఺∉⃻⽎ߦࠃࠆߣᕁࠊࠇࠆ∝⁁࡮ᓽ୥ ާ↲⁁⣼ᯏ⢻⇣Ᏹ㧔5%એ਄㧕╬ި㧦ⷰኤࠍචಽ ߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛ ߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 5㧕⣖᪪Ⴇ㧔5㧑ᧂḩ㧕㧦ⷰኤࠍචಽߦⴕ޿ޔ⇣ Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥ ಣ⟎ࠍⴕ߁ߎߣޕ 6㧕㊀◊ߥ߁ߟ⁁ᘒޔ⥄Ვડ࿑ޔば⁁ᘒޔ᡹᠄⊛ ⴕേ㧔㗫ᐲਇ᣿㧕㧦ⷰኤࠍචಽߦⴕ޿ޔਇ⌁ޔ ਇ቟ޔὶ῎ޔ⥝ᅗޔ᡹᠄ᕈޔᤃೝỗᕈ╬߇޽ࠄ ࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤޔㆡಾߥಣ ⟎ࠍⴕ߁ߎߣޕ㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄ෳ ᾖ㧕 7㧕ߖࠎᅦޔᐛⷡ㧔㗫ᐲਇ᣿㧕㧦ⷰኤࠍචಽߦⴕ ޿ޔ⇣Ᏹ߇޽ࠄࠊࠇߚ႐วߦߪޔᛩਈ⛮⛯ߩน ุߦߟ޿ߡᬌ⸛ߔࠆߎߣޕ∝⁁ߩỗߒ޿႐ว෸ ߮ᷫ㊂ߒߡ߽ᶖᄬߒߥ޿႐วߦߪᛩਈࠍਛᱛ ߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 8㧕㑆⾰ᕈ⢖Ἳ㧔㗫ᐲਇ᣿㧕᧶⊒ᾲޔຕ༿ޔ๭ๆ ࿎㔍╬ߩ๭ๆེ∝⁁ޔ߹ߚޔ⢷ㇱ X ✢⇣Ᏹ߇޽ ࠄࠊࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔ೽⣢⊹⾰ࡎ࡞ ࡕࡦ೷ߩᛩਈ╬ߩㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ߹ ߚޔຕ༿ޔ๭ๆ࿎㔍╬߇޽ࠄࠊࠇߚ႐วߦߪ⋥ ߜߦㅪ⛊ߔࠆࠃ߁ᖚ⠪ߦኻߒᵈᗧࠍਈ߃ࠆߎ

ߣޕ 9㧕ᔃਇో㧔㗫ᐲਇ᣿㧕㧦ⷰኤࠍචಽߦⴕ޿ޔ⇣ Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤޔ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 10㧕ṁⴊᕈዩᲥ∝∝୥⟲㧔HUS㧕㧔㗫ᐲਇ ᣿㧕᧶ⴊዊ᧼ᷫዋޔ⽺ⴊޔ⣢ਇోࠍਥᓽߣߔࠆ ṁⴊᕈዩᲥ∝∝୥⟲㧔HUS㧕߇޽ࠄࠊࠇࠆߎߣ ߇޽ࠆߩߢޔቯᦼ⊛ߦⴊᶧᬌᩏ㧔ⴊዊ᧼ᢙޔ⿒ ⴊ⃿ᢙޔᧃ᪳ⴊᶧ௝╬㧕෸߮⣢ᯏ⢻ᬌᩏࠍⴕ߁ ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐ว ߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 11㧕ࡀࡈࡠ࡯࠯∝୥⟲㧔㗫ᐲਇ᣿㧕᧶ⴊᷡ✚Ⱞ ⊕ᷫዋޔⴊᷡࠕ࡞ࡉࡒࡦૐਅࠍ઻߁㊀◊ߥⰮ⊕ ዩ߇⹺߼ࠄࠇࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦዩᬌ ᩏ㧔ዩⰮ⊕㧕ࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣ Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔㆡಾߥ ૶↪਄ ಣ⟎ࠍⴕ߁ߎߣޕ ߩᵈᗧ 12㧕♧ዩ∛㧔1 ဳ෸߮ 2 ဳ㧕㧔㗫ᐲਇ᣿㧕᧶♧ዩ ∛߇Ⴧᖡ෶ߪ⊒∝ߔࠆߎߣ߇޽ࠅޔᤀ⌧ߦ⥋ࠆ ߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦᬌᩏ㧔ⴊ♧୯ޔዩ♧ ╬㧕ࠍⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍ ਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ᵈ 6㧕⽺ⴊߪਥߦṁⴊᕈ⽺ⴊ 13㧕ᢌⴊ∝㧔㗫ᐲਇ᣿㧕㧦ᤃᗵᨴᕈߣߥࠅޔᢌ

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ⴊ∝߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔᖚ⠪ߩోり ⁁ᘒࠍචಽߦⷰኤߒޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦ ߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 14㧕✂⤑∝㧔㗫ᐲਇ᣿㧕㧦✂⤑∝߇޽ࠄࠊࠇࠆ ߎߣ߇޽ࠆߩߢޔ✂⤑಴ⴊޔエᕈ⊕᢬෸߮♧ዩ ∛✂⤑∝ߩჇᖡߦᵈᗧߒޔቯᦼ⊛ߦ⌒ᐩᬌᩏࠍ ⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ ႐วߦߪᛩਈࠍਛᱛߔࠆߥߤޔㆡಾߥಣ⟎ࠍⴕ ߁ߎߣޕ߹ߚޔⷞജૐਅޔⷞ㊁ਛߩᥧὐ߇⹺߼ ࠄࠇߚ႐วߪㅦ߿߆ߦකᏧߩ⸻ኤࠍฃߌࠆࠃ߁ ᖚ⠪ࠍᜰዉߔࠆߎߣޕ

35 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

16㧕⊹⤏☼⤑⌒∝୥⟲㧔Stevens-Johnson ∝୥ ⟲㧕ޔਛᲥᕈ⴫⊹უᱫⲢ⸃∝㧔Toxic Epidermal Necrolysis㧦TEN㧕ޔᄙᒻ⚃᢬㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦 ⊹⤏☼⤑⌒∝୥⟲ޔਛᲥᕈ⴫⊹უᱫⲢ⸃∝ޔᄙ ᒻ⚃᢬╬ߩ⊹⤏㓚ኂ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩ ߢޔⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐ว ߦߪᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 17᧥ੇ⊈㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ੇ⊈߇Ⴧᖡ෶ߪ⊒∝ ߔࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦᬌᩏࠍⴕ߁ߥߤ ⷰኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪ ᛩਈߩਛᱛࠍ⠨ᘦߔࠆߎߣޕ 18㧕ᕆᕈ⣢ਇోޔࡀࡈࡠ࡯࠯∝୥⟲᧤㗫ᐲਇ᣿ᵈ 2㧕㧕᧶ቯᦼ⊛ߦᬌᩏࠍⴕ߁ߥߤޔᖚ⠪ߩ⁁ᘒࠍ චಽߦⷰኤߔࠆߎߣޕ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦ ߪޔᛩਈࠍਛᱛߒޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 19㧕ᶖൻ▤಴ⴊ㧔ਅⴊޔⴊଢ╬㧕ޔᶖൻᕈẩ ≌ޔ⯯ⴊᕈᄢ⣺Ἳ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⷰኤࠍචಽ ߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛ ߔࠆߥߤޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 20㧕࡚ࠪ࠶ࠢ㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦ⷰኤࠍචಽߦⴕ ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩਈࠍਛᱛߒޔ ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 21㧕✂⤑∝㧔㗫ᐲਇ᣿ᵈ 2㧕㧕㧦✂⤑∝߇޽ࠄࠊࠇ

ࠆߎߣ߇޽ࠆߩߢޔ✂⤑಴ⴊ߿♧ዩ∛✂⤑∝ߩ Ⴧᖡߦᵈᗧߒޔቯᦼ⊛ߦ⌒ᐩᬌᩏࠍⴕ߁ߥߤⷰ ኤࠍචಽߦⴕ޿ޔ⇣Ᏹ߇⹺߼ࠄࠇߚ႐วߦߪᛩ ਈࠍਛᱛߔࠆߥߤޔㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ߹ ߚޔⷞജૐਅޔⷞ㊁ਛߩᥧὐ߇಴⃻ߒߚ႐วߪ ㅦ߿߆ߦකᏧߩ⸻ኤࠍฃߌࠆࠃ߁ᖚ⠪ࠍᜰዉߔ ࠆߎߣޕ

㧔2㧕ߘߩઁߩ೽૞↪ ᰴߩࠃ߁ߥ೽૞↪߇޽ࠄࠊࠇߚ႐วߦߪޔᛩਈ ࠍਛᱛߔࠆߥߤޔ∝⁁ߦᔕߓߡㆡಾߥಣ⟎ࠍⴕ ߁ߎߣޕ 㗫ᐲਇ᣿ᵈ 10㧑એ਄ 10㧑ᧂḩ 2㧕 ⊒ᾲ෸ ⣕ജ ⊒ᾲ ߮ࠗࡦ 㧔71.2㧑㧕ޔ ࡈ࡞ࠛ ୱᕃᗵ ૶↪਄ ࡦࠩ᭽ 㧔70.4㧑㧕ޔ ߩᵈᗧ ∝⁁ 㗡∩ 㧔57.7㧑㧕ޔ 㑐▵∩ 㧔37.7㧑㧕ޔ ╭∩ 㧔20.4㧑㧕ޔ ᖡኙ ᶖൻེ ⤟Ἳ㧔⣻ 㘩᰼ᷫㅌ ⣻ㇱ⤘ḩޔᱤ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ∩ޔࠕࡒ 㧔38.1㧑㧕ޔ ⡺಴ⴊޔᱤ ࡜࡯࠯਄ ਅ∯࡮エଢ ∩ޔ⢗Ἳޔᶖ ᣹ޔ࡝ࡄ 㧔23.5㧑㧕ޔ ൻਇ⦟ޔญ ࡯࠯਄ ཌྷ᳇ ᷢޔ⥠∩ޔญ ᣹㧕ޔྚ 㧔22.3㧑㧕ޔ ౝੇ῎ޔ⥠ ਅ㓚ኂ ⣻∩ Ἳޔᱤ⡺Ἳ 㧔21.9㧑㧕ޔ ⣻ㇱਇᔟᗵޔ ଢ⒁ޔཌྷฯޔ ญౝἻ෸߮ญ ⣧ౝẩ≌ᒻ ᚑޔ๧ⷡ⇣Ᏹ ╭࡮㛽 㛽∩ޔ╭ ⢛ㇱ∩ 㗖ㇱ∩ޔ╭㛽 ᩰ Ἳ 㧔24.2%㧕 ᩰ∩ޔ╭㛽ᩰ ⎬⋥ޔ྾⢇ ∩ޔ╭∨ᡨޔ ╭⣕ജޔ㑐▵ Ἳ ♖␹࡮ ᳇ಽᄌ ⌧⌁㓚ኂ㧔ਇ ᤃೝỗᕈޔਇ ␹⚻♽ േޔ␹⚻ ⌁∝㧕 ቟ޔ⇣Ᏹᗵ ㆊᢅޔ᡹ 㧔30.4㧑㧕ޔ ⷡޔ௑⌁ޔ⸥ ᠄ᕈޔᕈ ߼߹޿ ᙘ㓚ኂޔ㓸ਛ ᰼ᷫㅌޔ 㧔28.1㧑㧕 ജૐਅޔᧃ᪳ ᖡᄞޔ༵ ᕈ࠾ࡘ࡯ࡠࡄ ⌁ ࠪ࡯ޔᗵⷡᷫ ㅌޔਇᔟᗵޔ ␹⚻∩ޔ༦ⷡ ㍲⺋ޔᝄᚢޔ ⍮ⷡㆊᢅޔᄬ ␹

36 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 㧔2㧕ߘߩઁߩ೽૞↪ 5%એ਄ 5%ᧂḩ 㗫ᐲ ਇ᣿ ోり ⊒ᾲᵈ 7㧕ޔᖡኙ ࠗࡦࡈ࡞ࠛࡦ ∝⁁ 㧔82.2 㧑㧕ޔోり ࠩ᭽∝⁁ ୱᕃᗵ 㧔88.5㧑㧕ޔ߆ߗ ∝୥⟲ ㆊᢅ ⊒∐ޔߘ߁∣ᗵ ⭄㤗∐ ∝ ⴊᶧ ⊕ⴊ⃿ᢙᷫዋ ಴ⴊ௑ะޔ⊕ 㧔75.3㧑㧕ޔⴊዊ ⴊ⃿ᢙჇᄙ ᧼ᢙᷫዋ 㧔62.1㧑㧕ޔ㗰☸ ⃿ᢙᷫዋ 㧔81.6㧑㧕ޔ⊕ⴊ ⃿ಽ↹⇣Ᏹ 㧔96.6㧑㧕ޔ⿒ⴊ ⃿ᢙᷫዋ 㧔70.7 㧑㧕ޔࡋࡕ ࠣࡠࡆࡦᷫዋ 㧔76.4 㧑㧕ޔࡋࡑ ࠻ࠢ࡝࠶࠻ᷫዋ 㧔71.3㧑㧕ޔ✂⁁

⿒ⴊ⃿ᢙᷫዋޔ✂ ⁁⿒ⴊ⃿ᢙჇᄙ 㧔75.9㧑㧕ޔᅢ㉄ ⃿ᢙჇᄙޔᅢਛ⃿ ᢙჇᄙޔⴊዊ᧼ᢙ Ⴧᄙ ⢄⤳ AST㧔GOT㧕਄ ᣹ޔALT㧔GPT㧕 ਄᣹ޔAl-P ਄᣹ޔ LDH ਄᣹ޔ✚ࡆ࡝ ࡞ࡆࡦ਄᣹ޔǫ- GTP ਄᣹ ⣢⤳ Ⱞ⊕ዩ ࠢ࡟ࠕ࠴࠾ࡦ 㧔50.6㧑㧕ޔBUN ਄᣹ޔ⣾⢲ ਄᣹ޔⴊዩ Ἳޔ㗫ዩޔឃ ዩ㓚ኂ ♖␹ 㗡∩࡮㗡㊀ ᗧ⼂㓚ኂޔ௑ ␹⚻ 㧔80.5㧑㧕ޔਇ ⌁ޔ⍮ⷡ⇣ ૶↪਄ ♽ ⌁ޔ߼߹޿ޔᛥ߁ Ᏹޔᝄᚢޔή ߩᵈᗧ ߟޔὶ῎ޔᚻ⿷ߩ ᳇ജޔᱠⴕ࿎ ߒ߮ࠇޔਇ቟ 㔍ޔஜᔓޔ⇣ Ᏹᗵޔᗵᖱਇ ቟ቯޔ⡊㐽ޔ ᵈᗧജ㓚ኂ ᓴⅣ ⴊ࿶਄᣹ޔേᖪޔ ਇᢛ⣂ޔⴊ࿶

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ེ ầ⚃ޔ྾⢇಄ᗵ ૐਅ ๭ๆ ຕ༿ޔ਄᳇㆏Ἳޔ ⢖Ἳޔ㥦ṳޔ ེ ๭ๆ࿎㔍ޔ㥦಴ⴊ ⴊ∷ޔ༥ჿޔ 㥦Ἳޔ᳇▤ᡰ Ἳޔ㥦㐽 ᶖൻ 㘩᰼ਇᝄ ⣻ㇱ⤘ḩᗵޔ ⤟Ἳ ེ 㧔59.2㧑㧕ޔᖡ ญᷢޔᱤ๟࡮ ᔃ࡮ཌྷฯޔਅ∯ޔ ᱤ㜑࡮ᱤ⡺ ⣻∩ޔᶖൻਇ⦟ޔ Ἳޔᱤ∩ޔ⢗ ଢ⒁ޔญౝ࡮ญໃ Ἳޔᱤߩ⇣ Ἳޔ๧ⷡ⇣Ᏹ Ᏹޔឃଢ㓚 ኂޔ⣺Ἳޔ⥠ Ἳޔ∤ᩭޔ߅ ߊ߮ޔ㥏⣺᡼ ያޔ⣺▤ᯏ⢻ ⇣Ᏹ ⊹⤏ Ḩ∐ޔ⣕Ძ ߑ≙ޔ⊒᳨ޔ ਐ∐ ⊹⤏ੇ῎ޔ⊕ ⊈ޔ⚃᢬ޔ⚡ ᢬ޔ⢽ṳޔῪ ߩ⇣Ᏹޔㆊⷺ ൻޔ⊹⤏ẩ ≌ޔᲫ⾰⇣ Ᏹޔ⪭ድ ⌒ ⌒ᐩ಴ⴊ╬ߩ✂⤑ ⌒∩ޔⷞജ⇣ ߩᓸዊᓴⅣ㓚ኂᵈ Ᏹޔ⚿⤑ਅ಴ 8㧕 ⴊޔ⌒⃿ల ⴊޔ⚿⤑Ἳޔ ⌒ߩ⇣๺ᗵޔ ⌒ߘ߁∣∝ޔ ⌒♖∋ഭޔ⎣ ሶ૕ᶋㆆ‛ޔ ⟮᣿ޔⷞⷡ⇣ Ᏹޔⷞ㊁ᰳ ៊ޔ㤈☸⣲

37 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

㗫ᐲਇ᣿ᵈ 10㧑એ਄ 10㧑ᧂḩ 2㧕 ⊹⤏ ≒∣∝ ⊹⤏Ἳޔ⭄㤗 㧔58.1㧑㧕ޔ ∐ޔᄙ᳨ޔኢ ⣕Ძ∝ ᳨ޔ⊹⢽ᰳਲ 㧔40.0㧑㧕ޔ ᕈḨ∐ޔ⢽ṳ ⊒∐ ᕈ⊹⤏Ἳޔធ 㧔37.3㧑㧕ޔ ⸅ᕈ⊹⤏Ἳޔ Ḩ∐ శ✢ㆊᢅ∝ 㧔24.6㧑㧕ޔ ⚃᢬ޔ⊹⤏ੇ ῎ ⴊᶧ ⊕ⴊ⃿ᢙᷫዋ ⽺ⴊޔᅢ㉄⃿ 㧔91.5㧑㧕ޔ ᢙჇടޔPTT ᅢਛ⃿ᢙᷫዋ ᑧ㐳 㧔90.8㧑㧕ޔ ࡋࡕࠣࡠࡆࡦ ᷫዋ 㧔83.1㧑㧕ޔ ⿒ⴊ⃿ᢙᷫዋ 㧔81.9㧑㧕ޔ ࡋࡑ࠻ࠢ࡝࠶ ࠻ᷫዋ 㧔76.5㧑㧕ޔ

ⴊዊ᧼ᢙᷫዋ 㧔74.6㧑㧕ޔ ࡝ࡦࡄ⃿ᢙᷫ ዋ㧔60.8㧑㧕 ᓴⅣེ േᖪ ⢷∩ޔầ⚃ޔ 㜞ⴊ࿶ ⢄⤳ ⢙▤Ἳޔ AST㧔G O LDH ਄᣹ޔ ⢽⢌⢄ T㧕਄᣹ޔ Al-P ਄᣹ ALT㧔GPT㧕 ਄᣹ޔǫ- GTP ਄᣹ޔ ࡆ࡝࡞ࡆࡦ਄ ᣹ ⣢⤳ Ⱞ⊕ዩ㓁 ᕈޔⴊዩ㓁 ᕈޔ㗫ዩޔឃ ዩ㓚ኂޔዩ〝 ૶↪਄ ⚿⍹ ߩᵈᗧ ๭ๆེ ຕ༿ ༥ჿޔ㥦㐽ޔ 㧔32.7㧑㧕ޔ ຜ㗡ਇᔟᗵޔ 㥦࡮ຜ㗡Ἳ ೽㥦⣧Ἳޔຜ 㧔22.7㧑㧕ޔ 㗡⚃᢬ޔ᳇▤ ຜ༄㗡∩ ᡰἻ 㧔20.4%㧕ޔ 㥦ṳޔ໼∷ޔ

㥦಴ⴊ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ⌒ ⷺ⤑ẩ≌ ⌒∩ޔ㔵 ⷞޔ✂⤑ߩᓸ ዊᓴⅣ㓚ኂᵈ 3㧕ޔ⌒ߩἻ∝ 㧔 ⚿⤑Ἳޔ ⷺ⤑Ἳ╬㧕ޔ ⚿⤑లⴊޔ✂ ⤑಴ⴊޔ⌒ߩ ⇣Ᏹᗵޔ⌒ੇ ῎ ߘߩઁ ഺ⿠ᯏ⢻ ᵈ኿ㇱ૏෻ᔕ TSH ᷫዋޔ ਇో 㧔40.0㧑㧕ᵈ ⴊ♧਄᣹ޔ಄ 4㧕ޔ࠻࡝ࠣ࡝ ᗵޔⴊਛࠕ࡞ ࠮࡜ࠗ࠼਄᣹ ࡉࡒࡦᷫዋޔ

㧔23.1㧑㧕ޔ T4 ਄᣹࡮ᷫ 㔚⸃⾰⇣Ᏹ ዋޔᶋ⣲ޔT3 㧔ࠞ࡞ࠪ࠙ ਄᣹ޔ∤಴ ࡓޔ࡝ࡦ╬㧕 ⴊޔ⡊㡆ޔ㔍 㧔21.5㧑㧕ޔ ⡬ޔ−∩ޔ⢷ ૕㊀ᷫዋޔᗵ ㇱਇᔟᗵޔ⡊ ᨴ∝㧔⚦⩶࡮ ∩ޔ⡊㐽ᗵޔ ⌀⩶࡮࠙ࠗ࡞ ዩ♧㓁ᕈޔਛ ࠬ╬㧕ߩ⺃⊒ ⡊Ἳޔᄖ⡊ ෶ߪჇᖡ Ἳޔᧃ᪳⣲ CRP ਄᣹ޔ ⣘ޔᘟᕈ↲⁁ TSH ਄᣹ޔ ⣼Ἳޔࠨ࡞ࠦ ∋ഭޔᾲᗵ ࠗ࠼࡯ࠪࠬޔ ࡝ࡦࡄ▵∝ޔ ήജ∝ޔ⇣Ᏹ ᗵޔዩ〝ᗵᨴ

38 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 5%એ਄ 5%ᧂḩ 㗫ᐲਇ ᣿ ᵈ኿ ⊒⿒ −∩ޔᾲᗵޔ ㇱ૏ ⣲⣘ޔ⦡⚛ᴉ ⌕ޔߘ߁∣ޔ ಴ⴊ ߘߩ 㑐▵∩ ∋ഭޔ⣕ജ CK ઁ 㧔58.0㧑㧕ޔ╭⡺ ᗵޔ㔍⡬ޔන 㧔CPK㧕 ∩ޔ⢋ߎࠅ╬ߩ✕ ⚐∊∐ޔᏪ⁁ ਄᣹ޔ ᒛ੣ㅴޔ⢛ㇱ࡮⣶ ∊∐ޔⱎ┃❱ ⴊᷡࠞ ㇱ∩ޔᶋ⣲ޔ⢷ㇱ Ἳޔ╭∨⋥ޔ ࡝࠙ࡓ ࿶ㄼᗵޔ−∩ޔຜ ᚻᜰ㑐▵᜔ ਄᣹ޔ 㗡Ἳޔ૕㊀ᷫዋޔ ❗ޔ⡊㡆ޔ಄ ࡋࡕࠣ ዩ♧ޔⴊᷡࠕ࡞ࡉ ᳨ޔਇᱜ಴ ࡠࡆࡦ ࡒࡦૐਅ ⴊޔ␹⚻∩ޔ A1c ਄᣹ 㧔54.0㧑㧕ޔⴊᷡ 㗖ㇱ∩ޔᤃᗵ ✚Ⱞ⊕ᷫዋޔⴊᷡ ᨴᕈޔ⧎☳ ࠦ࡟ࠬ࠹ࡠ࡯࡞਄ ∝ޔᄖ⡊Ἳޔ ᣹ޔⴊਛࠦ࡟ࠬ࠹ ⡊∩ޔਛ⡊ ࡠ࡯࡞ૐਅޔⴊਛ Ἳޔ೨┙⣼ ዩ㉄਄᣹ޔⴊᷡࠞ Ἳޔ༦ⷡ⇣ ࡞ࠪ࠙ࡓૐਅޔⴊ Ᏹޔ྾⢇ਇᔟ ᷡήᯏ࡝ࡦૐਅޔ ᗵޔࠨ࡞ࠦࠗ CRP ਄᣹ ࠼࡯ࠪࠬޔ࠻

࡝ࠣ࡝࠮࡜ࠗ ࠼਄᣹ޔⴊᷡ ࠕࡒ࡜࡯࠯਄ ᣹ޔⴊ♧਄᣹ ᵈ 7㧕⊒ᾲ㧔⊒⃻㗫ᐲ 98.3%㧕ߦኻߒߡߪ⸃ᾲ೷ ߩᛩਈ╬ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ᵈ 8㧕 㘧Ⰶⷞޔⷞജૐਅᗵ╬ࠍ઻߁ߎߣ߇޽ࠆ ߩߢޔߎߩࠃ߁ߥ∝⁁߇޽ࠄࠊࠇߚ႐วߦߪㆡ ಾߥಣ⟎ࠍⴕ߁ߎߣޕ

૶↪਄ ߩᵈᗧ

JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04

39 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

ᵈ 2㧕࿖ᄖߩ⥃ᐥ⹜㛎ߩ೽૞↪෶ߪ⥄⊒ႎ๔ߦߡ ႎ๔ߐࠇߚ㗫ᐲࠍ▚಴ߢ߈ߥ޿೽૞↪ߦߟ޿ߡ ߪ㗫ᐲਇ᣿ߣߒߚޕ

ᵈ 3㧕✂⤑ṡ಴‛ޔ✂⤑േ⣂࡮㕒⣂ⴊᩖ∝ޔ⎣ሶ

૕ᶋㆆ‛ޔ੃㗡ᶋ⣲ޔⷞജૐਅޔⷞ㊁ᰳ៊╬ࠍ ઻߁ߎߣ߇޽ࠆߩߢޔߎߩࠃ߁ߥ∝⁁߇޽ࠄࠊ ࠇߚ႐วߦߪㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ᵈ 4㧕ᵈ኿ㇱ૏ߦἻ∝ޔೝỗᗵޔᝂ்ޔ⊹⤏Ἳޔ ⚃᢬ޔ−∩ޔ≒∣ޔ⎬⚿ޔ⣲⣘ޔẩ≌╬ࠍߺࠆ ߎߣ߇޽ࠆޕ

5㧚㜞㦂⠪߳ߩᛩਈ 5㧚㜞㦂⠪߳ߩᛩਈ 5.㜞㦂⠪߳ߩᛩਈ 㜞㦂⠪ߢߪ৻⥸ߦ↢ℂᯏ⢻߇ૐਅߒߡ߅ࠅޔ߹ ࿖ౝ⥃ᐥ⹜㛎ߦ߅޿ߡ㧘㜞㦂⠪ߦᧄ೷ߣࡍࠣࠗࡦ ࿖ౝᄖߢታᣉߐࠇߚ⥃ᐥ⹜㛎ߦ߅޿ߡޔട㦂ߦ ߚว૬∝߿૬↪⮎૶↪ߩ㗫ᐲ߇Ⴧ߃ࠆߎߣ߆ࠄ ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b㧔ㆮવሶ⚵឵߃㧕෸߮ ઻޿㊀◊ߥ೽૞↪ߩ⊒⃻㗫ᐲ߇㜞ߊߥࠆ௑ะ߇ ᘕ㊀ߦᛩਈߔࠆߎߣޕ ࡝ࡃࡆ࡝ࡦࠍ૬↪ᛩਈߒߚ⚻㛎ߪߥ޿㧚৻⥸ߦ㜞 ⹺߼ࠄࠇߡ޿ࠆߩߢޔᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤ 㦂⠪ߢߪ↢ℂᯏ⢻߇ૐਅߒߡ޿ࠆߎߣ㧘߹ߚ㧘ᶏ ߒߥ߇ࠄޔᘕ㊀ߦᛩਈߔࠆߎߣޕ ᄖ⥃ᐥ⹜㛎ߦ߅޿ߡ㧘65 ᱦએਅߩᖚ⠪ߣᲧセ ߒ㧘㜞㦂⠪ߦ߅޿ߡ㧘⽺ⴊ㧘ᶋേᕈ߼߹޿㧘๧ⷡ

⇣Ᏹ㧘㗫ዩ㧘᳇▤ᡰἻ╬ߩ⊒⃻₸߇㜞߆ߞߚߎߣ

߆ࠄ㧘೽૞↪ߩ⊒⃻ߦ⇐ᗧߒ㧘චಽߥⷰኤࠍⴕ߁ ߎߣ㧚

6. ᅧᇚޔ↥ᇚޔ᝼੃ᇚ╬߳ߩᛩਈ 6㧚ᅧᇚ㧘↥ᇚ㧘᝼੃ᇚ╬߳ߩᛩਈ 6㧚ᅧᇚ㧘↥ᇚ㧘᝼੃ᇚ╬߳ߩᛩਈ 㧨ᧄ೷න⁛ߩ႐ว㧪 1㧕ᧄ೷ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ෶ 㧔1㧕 ᅧᇚ෶ߪᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚੱߦ 㧔1㧕ᅧᇚ෶ߪᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚੱߦ ߪ 2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߔ ߪ૶↪ߒߥ޿ߎߣ㧚ާᧄ೷ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠ ߪޔᴦ≮਄ߩ᦭⋉ᕈ߇ෂ㒾ᕈࠍ਄࿁ࠆߣ್ᢿߐ ࠆߚ߼ޔᅧᇚ෶ߪᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚ ࡦ ࠕ࡞ࡈࠔ̃2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦ ࠇࠆ႐วߦߩߺᛩਈߔࠆߎߣޕ㨇ᅧᆼࠕࠞࠥࠩ ੱߦߪ૶↪ߒߥ޿ߎߣޕ߹ߚޔᅧᆼߒߡ޿ߥ޿ ߣ૬↪ߔࠆ㧚࡝ࡃࡆ࡝ࡦߩേ‛ታ㛎ߢ௅ᄸᒻᕈ૞ ࡞ߦኻߒޔ⢝ఽᦼೋᦼ߆ࠄਛᦼߦ߆ߌߡࠗࡦ࠲ ߎߣࠍ⏕⹺ߔࠆߚ߼ޔ࡝ࡃࡆ࡝ࡦߩᷝઃᢥᦠࠍ ↪෸߮⢦࡮⢝ఽ⥌ᱫ૞↪߇⹺߼ࠄࠇߡ޿ࠆ㧚ި ࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a100ޔ500ޔ2, 500 ਁ ෳᾖߒޔᅧᆼᬌᩏࠍታᣉߔࠆߎߣޕ㨇࡝ࡃࡆ࡝ࡦ 㧔2㧕 ᝼੃ਛߩᇚੱߦߪ㧘૶↪ࠍㆱߌࠆߎߣ㧚߿ IU/kg/ᣣࠍᛩਈߒߚߣߎࠈ↪㊂ଐሽᕈߩᵹ↥⺃⊒ ߩേ‛ታ㛎ߢ௅ᄸᒻᕈ෸߮⢦࡮⢝ఽ⥌ᱫ૞↪߇ ߻ࠍᓧߕ૶↪ߔࠆ႐วߪ㧘᝼੃ࠍㆱߌߐߖࠆߎ ૞↪߇ߺࠄࠇߡ޿ࠆޕ㨉 ⹺߼ࠄࠇߡ޿ࠆޕ㨉 ߣ㧚ާേ‛ታ㛎㧔࡜࠶࠻㧕ߢ੃᳝ਛߦ⒖ⴕߔࠆߎ 㧔2㧕᝼੃ᇚߦᛩਈߔࠆ႐วߦߪ᝼੃ࠍㆱߌߐߖ ᧄ೷ߦ߅޿ߡ࠙ࠨࠡ⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜㛎 ߣ߇ႎ๔ߐࠇߡ޿ࠆ㧚ި ࠆߎߣޕ ߪታᣉߒߡ޿ߥ޿ޕ࡜࠶࠻⢦࡮⢝ఽ⊒↢ߦ㑐ߔ 㨇േ‛ታ㛎㧔࡜࠶࠻㧕ߢ੃᳝ਛߦ⒖ⴕ㧔6. ࠆ⹜㛎ߦ߅޿ߡޔᦨᄢᛩਈ㊂㧔⥃ᐥᦑ㔺㊂ࠃࠅ 5mg/kg න࿁ᛩਈ㧕ߔࠆߎߣ߇ႎ๔ߐࠇߡ޿ࠆ ૐ޿㧕ߢߪޔ௅ᄸᒻᕈߪ⹺߼ࠄࠇߥ߆ߞߚޕࡑ 㧔ޣ⮎‛േᘒޤߩ㗄ෳᾖ㧕ޕ㨉 ࠙ࠬ⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜㛎ߢߪޔᲣ૕Ქᕈ 㧨࡝ࡃࡆ࡝ࡦߣߩ૬↪ߩ႐ว㧪 ෸߮⢝ఽ૕㊀ૐ୯ࠍ઻ࠊߥ޿↪㊂㧔ᦑ㔺㊂ߣߒ 㧔1㧕ᅧᇚ෶ߪᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚੱߦ ߡߪ⥃ᐥᦑ㔺㊂ߣ߶߷ห╬㧕߆ࠄޔ⢝ఽߩ㛽ᩰ ߪᛩਈߒߥ޿ߎߣޕ㨇࡝ࡃࡆ࡝ࡦߩേ‛ታ㛎ߢ ᄌ⇣෸߮㛽ൻㆃᑧߩ⊒↢㗫ᐲჇട߇⹺߼ࠄࠇ ௅ᄸᒻᕈ૞↪㧔࡜࠶࠻㧦10mg/kg/ᣣޔ࠙ࠨࠡ㧦1. ߚޕ࡜࠶࠻಴↢೨෸߮಴↢ᓟߩ⊒↢ߦ㑐ߔࠆ⹜ 0mg/kg/ᣣ㧕෸߮⢦࡮⢝ఽ⥌ᱫ૞↪㧔࡜࠶࠻㧦 㛎ߢߪޔ⥃ᐥᦑ㔺㊂ࠃࠅૐ޿ᦑ㔺㊂㧔Უേ‛㧕 10mg/kg/ᣣޔ࠙ࠨࠡ㧦1. 0mg/kg/ᣣએ਄㧕߇⹺߼ ߢޔᲣേ‛ߩ૕㊀Ⴧടᛥ೙෸߮಴↢ఽߩ⊒⢒ㆃ ࠄࠇߡ޿ࠆޕ㨉 ᑧ߇⹺߼ࠄࠇߚޕ ૶↪਄ 㧔2㧕᝼੃ᇚߦᛩਈߔࠆ႐วߦߪ᝼੃ࠍㆱߌߐߖ 2㧕᝼੃ਛߩᇚੱߦߪޔᛩਈࠍㆱߌࠆߎߣޕ߿߻ ߩᵈᗧ ࠆߎߣޕ㨇േ‛ታ㛎㧔࡜࠶࠻㧕ߢ੃᳝ਛ߳ߩ⒖ ࠍᓧߕᛩਈߔࠆ႐วߪޔ᝼੃ࠍㆱߌߐߖࠆߎ ⴕ߇⹺߼ࠄࠇߡ޿ࠆޕ㨉 ߣޕ㨇ࡅ࠻ߦ߅ߌࠆ੃᳝߳ߩ⒖ⴕߪਇ᣿ߢ޽ࠆ ߇ޔ࡜࠶࠻ߢ੃ఽ߳ߩ⒖ⴕ߇⹺߼ࠄࠇߡ޿ ࠆޕ㨉

7.ዊఽ╬߳ߩᛩਈ

7㧚ዊఽ╬߳ߩᛩਈ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 7㧚ዊఽ╬߳ߩᛩਈ 㧔1㧕ૐ಴↢૕㊀ఽޔᣂ↢ఽޔ੃ఽޔ3 ᱦᧂḩߩ ૐ಴↢૕㊀ఽ㧘ᣂ↢ఽ㧘੃ఽ㧘ᐜఽ෶ߪዊఽߦኻ ૐ಴↢૕㊀ఽޔᣂ↢ఽޔ੃ఽޔᐜఽ෶ߪዊఽߦ ᐜఽߦߪᛩਈߒߥ޿ߎߣޕ㨇ᧄ೷ߦ฽߹ࠇߡ޿ ߔࠆ቟ోᕈߪ⏕┙ߒߡ޿ߥ޿㧚㧔૶↪⚻㛎߇ߥ ኻߔࠆ቟ోᕈߪ⏕┙ߒߡ޿ߥ޿ޕ㧔૶↪⚻㛎߇ߥ ࠆࡌࡦࠫ࡞ࠕ࡞ࠦ࡯࡞ߩㆊ೾᥸㔺ߦ㑐ㅪߒߚᣂ ޿㧚㧕 ޿ޕ㧕 ↢ఽޔ੃ఽߩᱫ੢߇ႎ๔ߐࠇߡ޿ࠆޕ㨉

㧔2㧕3 ᱦએ਄ߩᐜ࡮ዊఽߦኻߔࠆ቟ోᕈߪ⏕┙

ߒߡ޿ߥ޿ޕ㨇૶↪⚻㛎߇ߥ޿ޕ㨉

8. ㆡ↪਄ߩᵈᗧ 8㧚ㆊ㊂ᛩਈ 8㧚ㆊ㊂ᛩਈ (1)ᛩਈ⚻〝㧦ᧄ೷ߪ⊹ਅᵈ኿ߩߺߦ૶↪ߔࠆߎ ᓽ୥ޔ∝⁁㧦 ᶏᄖ⥃ᐥ⹜㛎ߦ߅޿ߡᧄ೷ 1,875mg ࠍ 1 ᣣ 3 ࿁ᛩ ߣޕ ㆊ㊂ᛩਈߦ㑐ߔࠆ࠺࡯࠲ߪ㒢ࠄࠇߡ޿ࠆޕஜᐽ ਈߒߚߣ߈ߦ QT ᑧ㐳߇ႎ๔ߐࠇߡ޿ࠆߩߢ㧘ㆊ (2)ᛩਈᣇᴺ㧦ᵈ኿ㇱ૏ߪᲤ࿁ᄌᦝߒޔห৻ㇱ૏ ᚑੱߦ 1 ᣣ 1 ࿁ 400mg ࠍ 5 ᣣ㑆෻ᓳᛩਈߒߚ႐ ෰ߦ QT ᑧ㐳ߩᣢᓔߩ޽ࠆᖚ⠪෶ߪ QT ᑧ㐳߇⍮ ߳ߩ෻ᓳᵈ኿ߪⴕࠊߥ޿ߎߣޕ วޔ߹ߚᄖ࿖ੱߩஜᐽᚑੱߦ 600mg න࿁ᛩਈ෸ ࠄࠇߡ޿ࠆ⮎೷ࠍ૶↪ߔࠆᔅⷐ߇޽ࠆᖚ⠪ߥߤߦ (3)ᵈ኿ㇱ૏෻ᔕ㧦ᵈ኿ㇱ૏ߦἻ∝ޔೝỗᗵޔᝂ ߮ 1 ᣣ 1 ࿁ 400mg ࠍ 5 ᣣ㑆෻ᓳᛩਈߒߚ႐ว෶ ૶↪ߔࠆ႐วߪ㧘ᔃ㔚࿑⇣Ᏹ߿㔚⸃⾰⇣Ᏹ㧔ૐࠞ ்ޔ⊹⤏Ἳޔ⚃᢬ޔ−∩ޔ≒∣ޔ⎬⚿ޔ⣲⣘ޔ ߪ C ဳᘟᕈ⢄Ἳᖚ⠪ߦ 1 ᣣ 1 ࿁ 200mg ࠍ 4 ㅳ㑆 ࡝࠙ࡓⴊ∝㧘ૐࡑࠣࡀࠪ࠙ࡓⴊ∝㧘ૐࠞ࡞ࠪ࠙ࡓ ẩ≌╬ࠍߺࠆߎߣ߇޽ࠆޕ ᛩਈߒߚ႐วߦޔ⥃ᐥ⊛ᓽ୥෸߮∝⁁ߪⷰኤߐ ⴊ∝ߥߤ㧕ߩ⊒⃻ߦᵈᗧߔࠆߎߣ㧚․ߦ㧘వᄤᕈ (4)ᧄ೷ߪઁߩ⵾೷ߣߩᷙᵈࠍⴕࠊߥ޿ߎߣޕ ࠇߥ߆ߞߚޕ QT ᑧ㐳∝୥⟲ߩᖚ⠪߿㧘ኅᣖߦవᄤᕈ QT ᑧ㐳

ಣ⟎㧦 ∝୥⟲߿⓭ὼᱫ߇⹺߼ࠄࠇߡ޿ࠆᖚ⠪߳ߩᧄ೷ߩ ᧄ೷ߦኻߔࠆ․೎ߥ⸃Ქ೷ߪߥ޿ޕㆊ㊂ᛩਈߒ ૶↪ߪน⢻ߥ㒢ࠅㆱߌࠆߎߣ߇ᦸ߹ߒ޿㧚 ߚ႐วߦߪޔࡃࠗ࠲࡞ࠨࠗࡦ෸߮⥃ᐥ∝⁁ߩⷰ

ኤ߿ᶖൻ▤㒰ᨴߥߤ৻⥸⊛ߥᡰᜬ≮ᴺࠍⴕ߁ޕ

ᧄ೷ߪⴊẏⰮ⊕⚿ว₸߇㜞޿ߚ߼ޔㅘᨆߢࠪࡔ ࡊ࡟ࡆ࡞߇㒰෰ߐࠇࠆน⢻ᕈߪૐ޿ޕ

40 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪

5.㜞㦂⠪߳ߩᛩਈ 5.㜞㦂⠪߳ߩᛩਈ 5.㜞㦂⠪߳ߩᛩਈ ࿖ౝߢታᣉߒߚ⥃ᐥ⹜㛎ߦ߅޿ߡޔ㜞㦂⠪ߢ ࿖ౝߢታᣉߒߚ⥃ᐥ⹜㛎ߦ߅޿ߡޔ㜞㦂⠪ߢߪࡋ ࿖ౝߢታᣉߒߚ⥃ᐥ⹜㛎ߦ߅޿ߡޔ㜞㦂⠪ߢ ߪޔ㜞ᐲߩ⥃ᐥᬌᩏ୯⇣Ᏹ╬ߩ⊒⃻㗫ᐲ෸߮ᷫ ࡕࠣࡠࡆࡦᷫዋޔⴊዊ᧼ᷫዋ╬ߩ⥃ᐥᬌᩏ୯⇣Ᏹ ߪޔ㜞ᐲߩ⥃ᐥᬌᩏ୯⇣Ᏹ╬ߩ⊒⃻㗫ᐲ෸߮ᷫ ㊂ࠍⷐߔࠆ㗫ᐲ߇㜞ߊߥࠆ௑ะ߇⹺߼ࠄࠇߡ޿ ߩ⊒⃻㗫ᐲ߇㜞ߊߥࠆ௑ะ߇⹺߼ࠄࠇߡ޿ࠆߩ ㊂ࠍⷐߔࠆ㗫ᐲ߇㜞ߊߥࠆ௑ะ߇⹺߼ࠄࠇߡ޿ ࠆߩߢޔᖚ⠪ߩ⁁ᘒࠍⷰኤߒߥ߇ࠄᘕ㊀ߦᛩਈ ߢޔᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤߒߥ߇ࠄޔᘕ㊀ߦᛩ ࠆߩߢޔᖚ⠪ߩ⁁ᘒࠍⷰኤߒߥ߇ࠄᘕ㊀ߦᛩਈ ߒޔᔅⷐߦᔕߓߡᷫ㊂ޔભ⮎ޔᛩਈਛᱛ╬ߩㆡ ਈߔࠆߎߣޕ ߒޔᔅⷐߦᔕߓߡᷫ㊂ޔભ⮎ޔᛩਈਛᱛ╬ߩㆡ ಾߥಣ⟎ࠍⴕ߁ߎߣޕ ಾߥಣ⟎ࠍⴕ߁ߎߣޕ

6.ᅧᇚޔ↥ᇚޔ᝼੃ᇚ╬߳ߩᛩਈ 6.ᅧᇚޔ↥ᇚޔ᝼੃ᇚ╬߳ߩᛩਈ 6.ᅧᇚޔ↥ᇚޔ᝼੃ᇚ╬߳ߩᛩਈ ᧄ೷ߪ࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߚ߼ޔએਅߩὐߦ 㧔1㧕ᅧᇚ෶ߪᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚੱߦ (1)ᅧᇚ෶ߪᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚੱߦߪ ᵈᗧߔࠆߎߣޕ ߪᛩਈߒߥ޿ߎߣޕ㨇േ‛ታ㛎ߢ௅ᄸᒻᕈ૞↪ ᛩਈߒߥ޿ߎߣޕ㨇േ‛ታ㛎ߢ௅ᄸᒻᕈ૞↪(࡜

㧔1㧕ᅧᇚ෶ߪᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚੱߦ 㧔࡜࠶࠻㧦10mg/kg/ᣣޔ࠙ࠨࠡ㧦1.0mg/kg/ᣣ㧕෸ ࠶࠻෸߮࠙ࠨࠡ㧦 1mg/kg/ᣣ)෸߮⢦࡮⢝ఽ⥌ᱫ ߪᛩਈߒߥ޿ߎߣޕ㨇ᅧᆼࠕࠞࠥࠩ࡞ߦࠗࡦ࠲ ߮⢦࡮⢝ఽ⥌ᱫ૞↪㧔࡜࠶࠻㧦10mg/kg/ᣣޔ࠙ࠨ ૞↪(࡜࠶࠻㧦10mg/kg/ᣣ)߇⹺߼ࠄࠇߡ޿ࠆޕ㨉 ࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ߩ ࠡ㧦1.0mg/kg/ᣣએ਄㧕߇⹺߼ࠄࠇߡ޿ࠆ㧔ޣ⑌ (ޣ⑌ᔊޤߩ㗄ෳᾖ) 750ޔ1,500ޔ3,000 ਁ࿖㓙න૏/kg/ᣣࠍᛩਈߒߚߣ ᔊޤߩ㗄ෳᾖ㧕ޕ㨉 (2)᝼੃ਛߩᇚੱߦߪޔᛩਈࠍㆱߌࠆߎߣޕ߿߻ ߎࠈޔ1,500 ਁ࿖㓙න૏/kg/ᣣએ਄ߢᵹ↥ߩ᦭ᗧ 㧔2㧕᝼੃ᇚߦᛩਈߔࠆ႐วߦߪ᝼੃ࠍㆱߌߐߖ ࠍᓧߕᛩਈߔࠆ႐วߪޔ᝼੃ࠍㆱߌߐߖࠆߎ ߥჇട߇⹺߼ࠄࠇߡ߅ࠅޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠ ࠆߎߣޕ㨇േ‛ታ㛎㧔࡜࠶࠻㧕ߢ੃᳝ਛ߳ߩ⒖ⴕ ߣޕ㨇േ‛ታ㛎(࡜࠶࠻)ߢ੃᳝ਛ߳ߩ⒖ⴕ߇⹺߼ ࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ߦ߅޿ߡ߽ห᭽ ߇⹺߼ࠄࠇߡ޿ࠆ㧔ޣ⑌ᔊޤߩ㗄ෳᾖ㧕ޕ㨉 ࠄࠇߡ޿ࠆޕ㨉(ޣ⑌ᔊޤߩ㗄ෳᾖ) ߦᵹ↥ߩน⢻ᕈ߇ุቯߢ߈ߥ޿ߚ߼ޕ࡝ࡃࡆ࡝ ࡦߦ߅޿ߡޔേ‛⹜㛎ߢ௅ᄸᒻᕈ૞↪㧔࡜࠶࠻

෸߮࠙ࠨࠡ㧦1mg/kg/ᣣ㧕෸߮⢦࡮⢝ఽ⥌ᱫ૞↪

㧔࡜࠶࠻㧦10mg/kg/ᣣ㧕߇⹺߼ࠄࠇߡ޿ࠆޕ㨉

㧔2㧕᝼੃ਛߩᇚੱߦߪޔᛩਈࠍㆱߌࠆߎߣޕ߿ ߻ࠍᓧߕᛩਈߔࠆ႐วߪޔ᝼੃ࠍㆱߌߐߖࠆߎ ߣޕ㨇ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵ ឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩേ‛⹜㛎㧔࡜࠶࠻㧕ߢ ੃᳝ਛ߳ߩ⒖ⴕ߇⹺߼ࠄࠇߡ޿ࠆޕ㨉

૶↪਄

ߩᵈᗧ

7.ዊఽ╬߳ߩᛩਈ 7.ዊఽ╬߳ߩᛩਈ 7.ዊఽ╬߳ߩᛩਈ JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04 ૐ಴↢૕㊀ఽޔᣂ↢ఽޔ੃ఽޔᐜఽ෶ߪዊఽߦ ૐ಴↢૕㊀ఽޔᣂ↢ఽޔ੃ఽޔᐜఽ෶ߪዊఽߦኻ ૐ಴↢૕㊀ఽޔᣂ↢ఽޔ੃ఽޔᐜఽ෶ߪዊఽߦ ኻߔࠆ቟ోᕈߪ⏕┙ߒߡ޿ߥ޿ޕ㨇૶↪⚻㛎߇ ߔࠆ቟ోᕈߪ⏕┙ߒߡ޿ߥ޿ޕ㨇૶↪⚻㛎߇ߥ ኻߔࠆ቟ోᕈߪ⏕┙ߒߡ޿ߥ޿ޕ㨇૶↪⚻㛎߇ ߥ޿ޕ㨉 ޿ޕ㨉 ߥ޿ޕ㨉

8.ㆡ↪਄ߩᵈᗧ 8.ㆡ↪਄ߩᵈᗧ 8.ㆡ↪਄ߩᵈᗧ 㧔1㧕ᛩਈ⚻〝㧦ᧄ೷ߪ⊹ਅᵈ኿ߦߩߺ૶↪ߔࠆ ⮎೷੤ઃᤨ㧦PTP ൮ⵝߩ⮎೷ߪ PTP ࠪ࡯࠻߆ࠄข ⮎೷੤ઃᤨ㧦PTP ൮ⵝߩ⮎೷ߪ PTP ࠪ࡯࠻߆ࠄ ߎߣޕ ࠅ಴ߒߡ᦯↪ߔࠆࠃ߁ᜰዉߔࠆߎߣޕ[PTP ࠪ࡯ ขࠅ಴ߒߡ᦯↪ߔࠆࠃ߁ᜰዉߔࠆߎߣޕ㨇PTP 㧔2㧕એਅߩᚻ㗅ߦᓥ޿⺞⵾ࠍⴕ߁ߎߣޕ ࠻ߩ⺋㘶ߦࠃࠅޔ⎬޿㍈ⷺㇱ߇㘩㆏☼⤑߳ೝ౉ ࠪ࡯࠻ߩ⺋㘶ߦࠃࠅ⎬޿㍈ⷺㇱ߇㘩㆏☼⤑߳ೝ 1㧕⺞⵾ᣇᴺ㧦ᷝઃߩᣣᧄ⮎ዪᣇޟᵈ኿↪᳓ޠ ߒޔᦝߦߪ⓫ሹࠍ߅ߎߒߡ❑㓒ᵢἻ╬ߩ㊀◊ߥว ౉ߒޔᦝߦߪ⓫ሹࠍ⿠ߎߒߡ❑㓒ᵢἻ╬ߩ㊀◊ 0.7mL ࠍᵃ┙ߡߥ޿ࠃ߁ߦᷝടߒޔẴ᣿ߦߥࠆ ૬∝ࠍ૬⊒ߔࠆߎߣ߇ႎ๔ߐࠇߡ޿ࠆޕ] ߥว૬∝ࠍ૬⊒ߔࠆߎߣ߇ႎ๔ߐࠇߡ޿ࠆޕ㨉 ߹ߢ㕒߆ߦ౞ࠍឬߊࠃ߁ߦ࿁ߒߡචಽߦṁ⸃ߐ

ߖ㧔ᝄࠅᷙߗߥ޿ߎߣ㧕ޔߒ߫ࠄߊ㕒⟎ߒߡᶖ

ᵃߒߚᓟޔᔅⷐ㊂ࠍᛮ߈ขࠆߎߣޕ1 ࡃࠗࠕ࡞޽ ߚࠅᛩਈߢ߈ࠆᦨᄢߩᶧ㊂ߪ 0.5mL ߢ޽ࠆޕ 2㧕↪ᤨ⺞⵾ߒޔṁ⸃ᓟߪㅦ߿߆ߦ૶↪ߔࠆߎ ߣޕߥ߅ޔ߿߻ࠍᓧߕ଻ሽࠍᔅⷐߣߔࠆ႐วߢ ߽ 2㧙8͠ߢ଻ሽߒޔ24 ᤨ㑆એౝߦ૶↪ߔࠆߎ ߣޕ߹ߚᱷᶧߪᑄ᫈ߔࠆߎߣޕ 3㧕ಓ⚿ੇ῎⵾೷ߣṁ⸃ᶧࠍᷙ๺ߒߚ㓙ޔṁᶧ߇

ᄌ⦡ߒߡ޿ߚࠅޔᶋㆆ‛߇޽ࠆ႐วߦߪ૶↪ߒ

ߥ޿ߎߣޕ 㧔3㧕ᛩਈᤨ㧦 1㧕ᵈ኿ㇱ૏ߪ਄⣨ޔᄢ⣽ޔ⣻ㇱޔ⤦ㇱ╬ߩ⊹ਅ ߣߔࠆޕᵈ኿ㇱ૏෻ᔕ㧔⚃᢬ޔߘ߁∣╬㧕߇ႎ ๔ߐࠇߡ޿ࠆߩߢޔห৻ㇱ૏߳ߩ෻ᓳᵈ኿ߪⴕ ࠊߥ޿ߎߣޕ 2㧕ᵈ኿㊎ࠍೝ౉ߒߚߣ߈ỗ∩ࠍ⸷߃ߚࠅޔⴊᶧ ߩㅒᵹࠍ⷗ߚ႐วߪ⋥ߜߦ㊎ࠍᛮ߈ޔㇱ૏ࠍᄌ ߃ߡᵈ኿ߔࠆߎߣޕ

41 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ࠹࡜ࡊ࡟ࡆ࡞ ฬ⒓ 㧔ㆮવሶ⚵឵߃㧕

⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100 mg ࠹࡜ࡆ࠶ࠢo㍤ 250 mg ࡍࠟࠪࠬo⊹ਅᵈ 90 ȝg㧘ห 180 ȝg

9㧚ㆡ↪਄ߩᵈᗧ 9㧚ㆡ↪਄ߩᵈᗧ 9.ߘߩઁߩᵈᗧ ⮎೷੤ઃᤨ㧦PTP ൮ⵝߩ⮎೷ߪ PTP ࠪ࡯࠻߆ࠄ ⮎೷੤ઃᤨ㧦PTP ൮ⵝߩ⮎೷ߪ PTP ࠪ࡯࠻߆ࠄข ࿖ౝ⥃ᐥ⹜㛎ߦ߅޿ߡޔਛ๺᛫૕ߩ⊒⃻߇ 4. 1㧑 ขࠅ಴ߒߡ᦯↪ߔࠆࠃ߁ߦᜰዉߔࠆߎߣޕ㨇PTP ࠅ಴ߒߡ᦯↪ߔࠆࠃ߁ߦᜰዉߔࠆߎߣ㧚ާPTP ࠪ ߦߺࠄࠇߡ޿ࠆޕ ࠪ࡯࠻ߩ⺋㘶ߦࠃࠅޔ⎬޿㍈ⷺㇱ߇㘩㆏☼⤑߳ ࡯࠻ߩ⺋㘶ߦࠃࠅ㧘⎬޿㍈ⷺㇱ߇㘩㆏☼⤑߳ೝ౉ ೝ౉ߒޔᦝߦߪ⓫ሹࠍ⿠ߎߒߡ❑㓒ᵢἻ╬ߩ㊀ ߒ㧘ᦝߦߪ⓫ሹࠍ⿠ߎߒߡ❑㓒ᵢἻ╬ߩ㊀◊ߥว ◊ߥว૬∝ࠍ૬⊒ߔࠆߎߣ߇ႎ๔ߐࠇߡ޿ࠆޕ㨉 ૬∝ࠍ૬⊒ߔࠆߎߣ߇ႎ๔ߐࠇߡ޿ࠆ㧚ި

10㧚ߘߩઁߩᵈᗧ 10㧚ߘߩઁߩᵈᗧ ᧄ೷ߪ in vitro ⹜㛎ߢశᲥᕈࠍ␜ߒߚߣߩႎ๔߇ ࡆ࡯ࠣ࡞›ߩ෻ᓳ⚻ญᛩਈᲥᕈ⹜㛎ߦ߅޿ߡ㧘ⴊ ޽ࠆޕ ▤Ἳ㧔․⊒ᕈᄙ⊒ᕈേ⣂Ἳ㧕߇⹺߼ࠄࠇߚߣߩႎ ๔߇޽ࠆ㧚

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JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04

ᷝઃᢥ ᦠ૞ᚑ ̆㧔ㇱળ↪ 2013 ᐕ 8 ᦬ 29 ᣣ㧕 2013 ᐕ 3 ᦬ᡷ⸓㧔╙ 6 㧕 2011 ᐕ 9 ᦬ᡷ⸓㧔╙ 15 㧕 ߩᐕ᦬ ஻⠨

42 TMC435 1.7 ห⒳หലຠ৻ⷩ⴫

৻⥸⊛ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b ࡝ࡃࡆ࡝ࡦ ࡝ࡃࡆ࡝ࡦ ฬ⒓ (ㆮવሶ⚵឵߃) ࡍࠣࠗࡦ࠻ࡠࡦo⊹ਅᵈ↪ 50ȝg / 0.5 mL ↪㧘 ⽼ᄁฬ ࠦࡍࠟࠬo㍤ 200 mg ࡟ࡌ࠻࡯࡞oࠞࡊ࠮࡞200 mg ห 100ȝg / 0.5 mL ↪㧘ห 150ȝg / 0.5 mL ↪ 9.ߘߩઁߩᵈᗧ 9.ߘߩઁߩᵈᗧ 9.ߘߩઁߩᵈᗧ ᧄ೷ߦኻߔࠆਛ๺᛫૕߇಴⃻ߔࠆߎߣ߇޽ࠆޕ 㧔1㧕࡜࠶࠻㓶ฃ⢝⢻⹜㛎ߢ♖ሶᢙߩࠊߕ߆ߥᷫ (1)ࡑ࠙ࠬ 3 ෸߮ 6 ࡨ᦬㑆ᛩਈ⹜㛎(1㨪150mg/kg/ 㧔ᶏᄖ⥃ᐥ⹜㛎㧕 ዋ㧔100mg/kg/ᣣ㧕߇ߺࠄࠇߚ㧔ભ⮎ߦࠃࠅ࿁ ᣣ)ߢ♖ሶ⇣Ᏹ(15mg/kg/ᣣએ਄)߇ߺࠄࠇߚߣߩႎ ᓳ㧕ޕ߹ߚޔࡑ࠙ࠬ㧠ㅳ㑆⹜㛎ߢ♖Ꮍ਄૕ߦ߅ߌ ๔߇޽ࠆ(ભ⮎ߦࠃࠅ࿁ᓳ)ޕ ࠆ♖ሶᷫዋ㧔400mg/kg/ᣣߩㅜਛᱫ੢଀㧕߇ႎ๔ (2)࡜࠶࠻㐳ᦼᛩਈ⹜㛎(24 ࡨ᦬㑆ޔ10㨪40mg/kg/ ߐࠇߡ޿ࠆޕ ᣣ)ߢ✂⤑ᄌᕈߩ⊒↢㗫ᐲ߇ኻᾖ⟲ߦᲧߴߡჇട 㧔2㧕⚦⩶ࠍ↪޿ߚᓳᏫ⓭ὼᄌ⇣⹜㛎ޔࡑ࠙ࠬዊ ߒߚߣߩႎ๔߇޽ࠆޕ ᩭ⹜㛎ߪ㒶ᕈߢ޽ߞߚ߇ޔࡑ࠙ࠬ࡝ࡦࡄ⣲⚦⢩ᩣ (3)⚦⩶ࠍ↪޿ࠆᓳᏫᄌ⇣⹜㛎ޔࡅ࠻࡝ࡦࡄ⃿ࠍ ࠍ↪޿ߚㆮવሶ⓭ὼᄌ⇣⹜㛎ߪ㓁ᕈߢ޽ߞߚޕ߇ ↪޿ࠆᨴ⦡૕⇣Ᏹ⹜㛎෸߮࡜࠶࠻ఝᕈ⥌ᱫ⹜㛎 ࠎේᕈ⹜㛎ߢ࡜࠶࠻ߦ 60mg/kg/ᣣ߹ߢࠍ㧞ᐕ㑆ޔ ߪ㒶ᕈߢ޽ߞߚ߇ޔࡑ࠙ࠬ࡝ࡦࡈࠜ࡯ࡑ⹜㛎ޔ p53+/-ࡁ࠶ࠢࠕ࠙࠻ࡑ࠙ࠬߦ 100mg/kg/ᣣ߹ߢࠍ ࡑ࠙ࠬ Balb/3T3 ᒻ⾰ォ឵⹜㛎෸߮ࡑ࠙ࠬዊᩭ⹜ 26 ㅳ㑆ᛩਈߒߡ߽ᧄ⮎ᛩਈߦࠃࠆ⣲≌⊒↢ߩჇ 㛎ߪ㓁ᕈߢ޽ߞߚޕ≸ේᕈ⹜㛎ߢࡑ࠙ࠬߦ ടߪߺࠄࠇߥ߆ߞߚߣߩႎ๔߇޽ࠆޕ 75mg/kg/ᣣ߹ߢࠍ 18 ࡨ᦬㑆ޔ࡜࠶࠻ߦ 40mg/kg/ ᣣ߹ߢࠍ 24 ࡨ᦬㑆ޔp53+/-࠻࡜ࡦࠬࠫࠚ࠾࠶ࠢࡑ ࠙ࠬߦ 300mg/kg/ᣣ߹ߢࠍ 6 ࡨ᦬㑆ᛩਈߒߡ߽ᧄ ⮎ᛩਈߦࠃࠆ⣲≌⊒↢ߩჇടߪߺࠄࠇߥ߆ߞߚ ߣߩႎ๔߇޽ࠆޕ

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JEDI_DEV00 \ 0900fde980403d72 2.6 2013-08-30 12:04

ᷝઃᢥ ᦠ૞ᚑ 2012 ᐕ 11 ᦬ᡷ⸓㧔╙ 12 㧕 2011 ᐕ 7 ᦬ᡷ⸓㧔╙ 13 㧕 2013 ᐕ 6 ᦬ᡷ⸓㧔╙ 17 㧕 ߩᐕ᦬ ஻⠨

43 㪘㪥㩷 ᷝઃᢥᦠ㧔᩺㧕㩷 XXXX ᐕ X ᦬૞ᚑ㧔╙ X 㧕 ⾂ ᴺ㧦ㆤశޔቶ᷷଻ሽ ᣣᧄᮡḰ໡ຠಽ㘃⇟ภ ૶↪ᦼ㒢㧦൮ⵝߦ⴫␜ 87625 ᛫࠙ࠗ࡞ࠬ೷

㪁 㫤 ಣᣇߖࠎක⮎ຠ 㩷 ࠰ࡉ࡝ࠕ࡯࠼ ࠞࡊ࠮࡞ 100mg

ᛚ⹺⇟ภ㩷 㪯㪯㪯㪯㪯㪯㪯㪯㪯㪯㪯㪯㪯㪯㪯㪯㩷 ® SOVRIAD capsules 100mg ⮎ଔ෼タ㩷 㪯㪯㪯㪯 ᐕ 㪯 ᦬㩷 ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓࠞࡊ࠮࡞ ⽼ᄁ㐿ᆎ㩷 㪯㪯㪯㪯 ᐕ 㪯 ᦬㩷 㧖ᵈᗧ㧙කᏧ╬ߩಣᣇߖࠎߦࠃࠅ૶↪ߔࠆߎߣ ࿖㓙⺀↢㩷 㪯㪯㪯㪯 ᐕ 㪯 ᦬㩷

ޣ⼊๔ޤ ᦼߩᴦ≮ലᨐߦᔕߓߡޔߎߩ2೷૬↪ᛩਈࠍᦝߦ24ㅳ㑆ᛩ ᧄ೷ߪޔ࠙ࠗ࡞ࠬᕈ⢄∔ᖚߩᴦ≮ߦචಽߥ⍮⼂࡮⚻㛎ࠍᜬߟකᏧߩ ਈߔࠆߎߣࠍ⠨ᘦߔࠆޕߚߛߒޔᧄ೷ߣ૬↪ߔࠆ႐วޔࡍ ߽ߣߢޔᧄ೷ߩᛩਈ߇ㆡಾߣ್ᢿߐࠇࠆᖚ⠪ߦኻߒߡߩߺᛩਈߔࠆ ࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍ ߎߣޕ ࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ޔ෸߮ ࡝ࡃࡆ࡝ࡦߩ✚ᛩਈᦼ㑆ߪ48ㅳࠍ⿥߃ߥ޿ߎߣޕ 3㧕 ᴦ≮ਛ䈱᛫䉡䉟䊦䉴ലᨐ䈏ਇචಽ䈭႐ว䇮⮎೷⠴ᕈ䉡䉟䊦䉴 ޣ⑌ᔊ㧔ᰴߩᖚ⠪ߦߪᛩਈߒߥ޿ߎߣ㧕ޤ 䈏಴⃻䈚䈩䈇䉎䈖䈫䈏䈅䉎䈢䉄䇮ᴦ≮ਛᱛࠍ⠨ᘦߔࠆߎߣޕ 1㧕ᧄ೷ߩᚑಽߦኻߒߡㆊᢅ∝ߩᣢᓔᱧߩ޽ࠆᖚ⠪ 㪋㧕 ೽૞↪䉇ᴦ≮ലᨐਇචಽ╬䈮䉋䉍ᧄ೷䉕ਛᱛ䈚䈢႐ว䈮䈲䇮 2㧕ࠛࡈࠔࡆ࡟ࡦ࠷ޔ࡝ࡈࠔࡦࡇࠪࡦޔ࡝ࡈࠔࡉ࠴ࡦࠍᛩਈਛߩᖚ ᧄ೷䈱ᛩਈ䉕ౣ㐿䈚䈭䈇䈖䈫䇯㩷 ⠪㨇ޟ⋧੕૞↪ޠߩ㗄ෳᾖ㨉 5㧕 ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2 a㧔ㆮવሶ⚵឵߃㧕ޔࡍ

ࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2 b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ ޣ⚵ ᚑ࡮ᕈ ⁁ޤ ࡃࡆ࡝ࡦߩᛩਈ㊂ߪޔฦ⵾ຠߩᷝઃᢥᦠߦቯ߼ࠄࠇߚ↪ ⽼ᄁฬ ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100mg ᴺ࡮↪㊂ߦᓥ߁ߎߣޕ૬↪ߦ޽ߚߞߡߪޔᛩਈ㐿ᆎ೨ߦฦ

ᚑಽ࡮฽㊂ 1ࠞࡊ࠮࡞ਛࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ ⵾ຠߩᷝઃᢥᦠߦቯ߼ࠄࠇߚ⥃ᐥᬌᩏ୯ၮḰࠍḩߚߒߡ 102.93 mg㧔ࠪࡔࡊ࡟ࡆ࡞ߣߒߡ 100 mg㧕 ޿ࠆߎߣࠍ⏕⹺ߔࠆߎߣޕ߹ߚޔᛩਈਛߦฦ⵾ຠߩ↪㊂⺞ ੃♧᳓๺‛ޔࠢࡠࠬࠞ࡞ࡔࡠ࡯ࠬ࠽࠻࡝ ▵߿ᛩਈਛᱛࠍᔅⷐߣߔࠆ೽૞↪߇⊒⃻ߒߚ႐วߦߪޔฦ ᷝട‛ ࠙ࡓޔࠬ࠹ࠕ࡝ࡦ㉄ࡑࠣࡀࠪ࠙ࡓޔ࡜࠙ ⵾ຠߩᷝઃᢥᦠࠍෳᾖߔࠆߎߣޕ ࡝࡞⎫㉄࠽࠻࡝࠙ࡓޔシ⾰ή᳓ࠤࠗ㉄ ᯍ⦡ߩࠠࡖ࠶ࡊ࡮⊕⦡ߩࡏ࠺ࠖߩ ⦡࡮೷ᒻ 1 ภ⎬ࠞࡊ࠮࡞ ޣ૶↪਄ߩᵈᗧޤ 1㧚ᘕ㊀ᛩਈ㧔ᰴߩᖚ⠪ߦߪᘕ㊀ߦᛩਈߔࠆߎߣ㧕 1 ᄖᒻ 㧕ⴊਛ✚ࡆ࡝࡞ࡆࡦ߇㜞୯ߩᖚ⠪㨇ⴊਛ✚ࡆ࡝࡞ࡆࡦ୯߇ 㜞޿ᖚ⠪ߦ߅ߌࠆ૶↪⚻㛎߇ߥ޿ޕ߹ߚޔᧄ೷ᛩਈᤨߦ ⴊਛࡆ࡝࡞ࡆࡦ୯ߩ਄᣹߇ႎ๔ߐࠇߡ޿ࠆ㧔ޟ㊀ⷐߥၮ ⋥ᓘ㧔mm㧕 㐳ߐ㧔mm㧕 ㊀㊂㧔g㧕 ᄢ߈ߐ ᧄ⊛ᵈᗧޠߩ㗄ෳᾖ㧕ޕ㨉 6.91 19.4 0.24 2㧕ਛ╬ᐲએ਄ߩ⢄ᯏ⢻㓚ኂᖚ⠪㨇Cmax ෸߮ AUC ߇਄᣹ߔ ⼂೎⸥ภ TMC435 100 ࠆߎߣ߇ႎ๔ߐࠇߡ޿ࠆ㧔ޟ⮎‛േᘒޠߩ㗄ෳᾖ㧕ޕ㨉

ޣല ⢻࡮ല ᨐޤ 2㧚㊀ⷐߥၮᧄ⊛ᵈᗧ ࠮ࡠࠣ࡞࡯ࡊ 1㧔ࠫࠚࡁ࠲ࠗࡊΣ㧔1a㧕෶ߪΤ㧔1b㧕㧕ߩ C ဳ 1㧕ᧄ೷ߩᛩਈߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2 a㧔ㆮવ ᘟᕈ⢄Ἳߦ߅ߌࠆᰴߩ޿ߕࠇ߆ߩ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ ሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2 b㧔ㆮવ 1 HCV RNA 㧕 ⴊਛ ㊂߇㜞୯ߩᧂᴦ≮ᖚ⠪ ሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ᛩਈߔࠆߚ߼ޔฦ⵾ຠߩ

JEDI_DEV00 \ 0900fde980405154 3.1 2013-09-03 11:46 2 㧕 ࠗࡦ࠲࡯ࡈࠚࡠࡦࠍ฽߻ᴦ≮ᴺߢήല෶ߪౣΆߣߥ ᷝઃᢥᦠߦ⸥タߐࠇߡ޿ࠆ⼊๔ޔ⑌ᔊޔ૬↪⑌ᔊޔᘕ㊀ᛩ

ߞߚᖚ⠪ ਈޔ㊀ⷐߥၮᧄ⊛ᵈᗧޔ㊀ᄢߥ೽૞↪╬ߩޣ૶↪਄ߩᵈᗧޤ

ࠍᔅߕ⏕⹺ߔࠆߎߣޕ ޝല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧޞ 2㧕శ✢ㆊᢅ∝߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߚ߼ޔᧄ೷ޔࡍࠣࠗࡦ 1㧚 ᧄ೷ߩ૶↪ߦ޽ߚߞߡߪޔⴊਛ HCV RNA ߇㓁ᕈߢ޽ࠆߎ ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2aޔ2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ ߣޔ෸߮⚵❱௝෶ߪ⢄੍஻⢻ޔⴊዊ᧼ᢙ╬ߦࠃࠅޔᘟᕈ⢄ ࡝ࡦߩ૬↪ਛߪޔㆊ೾ߥᄥ㓁శ✢߳ߩᦑ㔺ࠍㆱߌޔశᦑ㔺 Ἳߢ޽ࠆߎߣࠍ⏕⹺ߔࠆߎߣޕ ߦኻߔࠆ㒐⼔╷ࠍ⻠ߓࠆࠃ߁ᖚ⠪ߦኻߒᜰዉߔࠆߎߣޕ 2㧚ᧂᴦ≮ᖚ⠪ߦ↪޿ࠆ႐วߪޔⴊਛ HCV RNA ㊂߇ RT-PCR ᴺ 㨇ޟߘߩઁߩᵈᗧޠߩ㗄ෳᾖ㨉 ߢ 5.0 Log IU/mL એ਄ߦ⋧ᒰߔࠆߎߣࠍ⏕⹺ߔࠆߎߣޕ 3㧕ᧄ೷ᛩਈᤨߦⴊਛࡆ࡝࡞ࡆࡦ୯ߩ਄᣹߇ႎ๔ߐࠇߡ޿ࠆߩ 3㧚ࠗࡦ࠲࡯ࡈࠚࡠࡦࠍ฽߻ᴦ≮ᴺߩ߁ߜޔઁߩࡊࡠ࠹ࠕ࡯࠯㒖ኂ ߢޔᧄ೷ᛩਈਛߪⴊਛࡆ࡝࡞ࡆࡦ୯ޔ⢄ᯏ⢻ᬌᩏ୯ޔᖚ⠪ ೷ߦࠃࠆᣢᴦ≮଀ߦኻߔࠆᛩਈ⚻㛎ߪߥ޿ޕߎࠇࠄߩᖚ⠪ߦኻ ߩ⁁ᘒࠍචಽߦⷰኤߒޔ⢄ᯏ⢻ߩᖡൻ߇⹺߼ࠄࠇߚ႐วߦ ߒߡߪޔ࠙ࠗ࡞ࠬᕈ⢄∔ᖚߩᴦ≮ߦචಽߥ⍮⼂࡮⚻㛎ࠍᜬߟක ߪㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ Ꮷ߇೨ᴦ≮ߩ⒳㘃ޔ೨ᴦ≮ߦኻߔࠆ෻ᔕᕈޔ⠴ᕈᄌ⇣ߩ᦭ήޔ ᖚ⠪ߩᔋኈᕈ╬ࠍ⠨ᘦߒߚ਄ߢޔᧄ೷ᛩਈߩนุࠍ್ᢿߔࠆߎ 3㧚⋧੕૞↪ ߣޕ ࠪࡔࡊ࡟ࡆ࡞ߪਥߦ CYP3A ߦࠃࠅઍ⻢ߐࠇࠆޕࠪࡔࡊ࡟ࡆ ࡞ߪ࠻࡜ࡦࠬࡐ࡯࠲࡯㨇P ♧Ⱞ⊕㧔P-gp㧕ޔOATP1B1㨉ߩၮ ޣ↪ ᴺ࡮↪ ㊂ޤ ⾰ߢ޽ࠅޔ߹ߚޔCYP3AޔP-gp ෸߮ OATP1B1 ࠍ㒖ኂߔࠆޕ ㅢᏱޔᚑੱߦߪࠪࡔࡊ࡟ࡆ࡞ߣߒߡ100mgࠍ1 ᣣ1 ࿁⚻ญᛩਈ 㨇ޟ⮎‛േᘒޠߩ㗄ෳᾖ㨉 ߒޔᛩਈᦼ㑆ߪ12ㅳ㑆ߣߔࠆޕᧄ೷ߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ 1㧕૬↪⑌ᔊ㧔૬↪ߒߥ޿ߎߣ㧕 ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߎߣޕ ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ ޝ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧޞ ࠛࡈࠔࡆ࡟ࡦ࠷ 1) ᧄ೷ߩⴊẏਛỚᐲ߇⪺ ߎࠇࠄߩ⮎೷ߩᒝ޿ 1㧕 ᧄ೷ࠍන⁛ᛩਈߒߚ㓙ߩ᦭ലᕈ෸߮቟ోᕈߪ⏕┙ߒߡ޿ ࠬ࠻࠶ࠢ࡝ࡦ ߒߊૐਅߒޔᧄ೷ߩല %;2#  ⺃ዉ૞↪ߦࠃ ߥ޿ޕ ࡝ࡈࠔࡦࡇࠪࡦ   ᨐ߇ᷫᒙߔࠆޕ ࠅޔᧄ೷ߩઍ⻢߇ଦㅴ 2㧕 ᧄ೷ߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵ ࡝ࡈࠔࠫࡦ╬ ߐࠇࠆޕ ߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵ ࡝ࡈࠔࡉ࠴ࡦ ߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆ߇ޔᦨೋߩ12ㅳ㑆ߪ3೷૬ ࡒࠦࡉ࠹ࠖࡦ ↪ᛩਈߒޔ⛯ߊ12ㅳ㑆ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ -2a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ

-2b㧔ㆮવሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߦࠃࠆ2೷૬↪ᛩਈ

ࠍታᣉߔࠆߎߣޕߥ߅ޔᖚ⠪ߩᴦ≮ᱧ߿⢛᥊࿃ሶޔ෸߮ೋ 㧕૬૬↪ᵈᗧ㧔૬↪ߦᵈᗧߔࠆߎߣ㧕 ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ ࠛ࡝ࠬࡠࡑࠗࠪࡦ 4) ᧄ೷෸߮ࠛ࡝ࠬࡠࡑ ᧄ೷෸߮ࠛ࡝ࠬࡠࡑ ᒝജߥ CYP3A 㒖ኂ ᧄ೷ߩⴊẏਛỚᐲ߇ ߎࠇࠄߩ⮎೷ߩ ࠗࠪࡦߩⴊẏਛỚᐲ ࠗࠪࡦߩ CYP3A ෸߮ ೷ ਄᣹ߒޔ೽૞↪߇⊒⃻ CYP3A 㒖ኂ૞↪ߦࠃ ߇਄᣹ߒޔ೽૞↪߇⊒ P-gp 㒖ኂ૞↪ߦࠃࠅޔ ࡝࠻࠽ࡆ࡞ 3) ߔࠆ߅ߘࠇ߇޽ࠆߩ ࠅޔᧄ೷ߩઍ⻢߇㒖ኂ ⃻ߔࠆ߅ߘࠇ߇޽ࠆ ᧄ೷෸߮ࠛ࡝ࠬࡠࡑ ࠳࡞࠽ࡆ࡞/࡝࠻࠽ ߢޔCYP3A 㒖ኂ૞↪ ߐࠇࠆޕ ߩߢޔCYP3A 㒖ኂ૞ ࠗࠪࡦߩઍ⻢෸߮ឃ ࡆ࡞ 4) ߩߥ޿෶ߪᒙ޿⮎೷ ↪ߩߥ޿෶ߪᒙ޿⮎ ಴߇㒖ኂߐࠇࠆޕ ࠢ࡜࡝ࠬࡠࡑࠗࠪ ߳ߩઍᦧࠍ⠨ᘦߔࠆ ೷߳ߩઍᦧࠍ⠨ᘦߔ ࡦ ߎߣޕᧄ೷ߣߎࠇࠄ⮎ ࠆߎߣޕᧄ೷ߣࠛ࡝ࠬ ࠗ࠻࡜ࠦ࠽࠱࡯࡞ ೷ࠍ૬↪ߔࠆ႐วߪޔ ࡠࡑࠗࠪࡦࠍ૬↪ߔ ࡏ࡝ࠦ࠽࠱࡯࡞ ᖚ⠪ߩ⁁ᘒࠍᘕ㊀ߦ ࠆ႐วߪޔᖚ⠪ߩ⁁ᘒ ࠦࡆࠪࠬ࠲࠶࠻ࠍ ⷰኤߒޔ೽૞↪⊒⃻ߦ ࠍᘕ㊀ߦⷰኤߒޔ೽૞ ฽߻⮎೷ චಽᵈᗧߔࠆߎߣޕ ↪⊒⃻ߦචಽᵈᗧߔ ╬ ᧄ೷ 200mg 1 ᣣ 1 ࿁ߣ ࠆߎߣޕ ࡝࠻࠽ࡆ࡞ 100mg 1 ᧄ೷ 150mg 1 ᣣ 1 ࿁ߣ ᣣ 2 ࿁ࠍ૬↪ߒߚߣ ࠛ࡝ࠬࡠࡑࠗࠪࡦ ߈ޔᧄ೷ߩ AUC ߇ 7.2 500mg 1 ᣣ 3 ࿁ࠍ૬↪ ୚ߦ਄᣹ߒߚޕ ߒߚߣ߈ޔᧄ೷ߩ ᧄ೷ 50mg 1 ᣣ 1 ࿁ AUC ߇ 7.5 ୚ߦ਄᣹ ߣ࠳࡞࠽ࡆ࡞/࡝࠻࠽ ߒޔࠛ࡝ࠬࡠࡑࠗࠪࡦ ࡆ࡞ 800mg/100mg 1 ߩ AUC ߪ 1.9 ୚ߦ਄ ᣣ 1 ࿁ࠍ૬↪ߒߚߣ ᣹ߒߚޕ ߈ޔᧄ೷ 150mg1 ᣣ 1 ࠪࠢࡠࠬࡐ࡝ࡦ 5) ࠪࠢࡠࠬࡐ࡝ࡦߩⴊ ᧄ೷ߩ CYP3A(4)㒖ኂ ࿁න⁛ᛩਈߒߚߣ߈ ਛỚᐲ߇਄᣹ߔࠆޕࠪ ૞↪ߦࠃࠅޔߎࠇࠄߩ ߣᲧߒߡޔᧄ೷ߩ ࠢࡠࠬࡐ࡝ࡦߩ↪㊂ ⮎೷ߩઍ⻢߇㒖ኂߐ AUC ߇ 2.6 ୚ߦ਄᣹ ⺞▵ߪᔅⷐߣߒߥ޿ ࠇࠆޕ ߒߚޕ ߇ޔࠪࠢࡠࠬࡐ࡝ࡦߩ ࡒ࡞ࠢࠪࠬ࡞㧔ࡑ࡝ࠕ ᧄ೷ߩⴊẏਛỚᐲ߇ ⴊਛỚᐲࠍࡕ࠾࠲࡝ ࠕࠩࡒ㧕฽᦭㘩ຠ ਄᣹ߒޔ೽૞↪߇⊒⃻ ࡦࠣߔࠆߎߣޕ

ߔࠆ߅ߘࠇ߇޽ࠆߩ ࠪ࡞࠺࠽ࡈࠖ࡞ ߎࠇࠄߩ⮎೷ߩⴊẏ ߢޔᖚ⠪ߩ⁁ᘒࠍᘕ㊀ ࠲࠳࡜ࡈࠖ࡞ ਛỚᐲ߇਄᣹ߔࠆ߅ ߦⷰኤߒޔ೽૞↪⊒⃻ ߘࠇ߇޽ࠆߚ߼ޔᖚ⠪ ߦචಽᵈᗧߔࠆߎߣޕ ߩ⁁ᘒࠍᘕ㊀ߦⷰኤ ઁߩ HIV ࡊࡠ࠹ࠕ࡯ ᧄ೷ߩⴊẏਛỚᐲߦ ߎࠇࠄߩ⮎೷ߩ ߒޔߎࠇࠄߩ⮎೷ߪૐ ࠯㒖ኂ೷ ᓇ㗀ࠍ෸߷ߔ߅ߘࠇ CYP3A 㒖ኂ૞↪෶ߪ ↪㊂߆ࠄᛩਈࠍ㐿ᆎ ࠕ࠲ࠩ࠽ࡆ࡞ ߇޽ࠆޕᧄ೷ߩⴊẏਛ ⺃ዉ૞↪ߦࠃࠅޔᧄ೷ ߒޔᔅⷐߦᔕߓߡჇ㊂ ࡎࠬࠕࡦࡊ࡟࠽ࡆ Ớᐲ߇ૐਅߒᧄ೷ߩ ߩઍ⻢߇㒖ኂ෶ߪଦ ߔࠆߎߣࠍ⠨ᘦߔࠆ ࡞ ലᨐ߇ᷫᒙߔࠆޔ߽ߒ ㅴߐࠇࠆޕ ߎߣޕ ࡠࡇ࠽ࡆ࡞ ߊߪᧄ೷ߩⴊẏਛỚ ࠻࡝ࠕ࠱࡜ࡓ ࠻࡝ࠕ࠱࡜ࡓߩⴊẏ ࠗࡦࠫ࠽ࡆ࡞ ᐲ߇਄᣹ߒ೽૞↪߇ ਛỚᐲ߇਄᣹ߔࠆ߅ ࡀ࡞ࡈࠖ࠽ࡆ࡞ ⊒⃻ߔࠆ߅ߘࠇ߇޽ ߘࠇ߇޽ࠆޕᧄ೷ߣ࠻ ࠨࠠ࠽ࡆ࡞ ࠆߩߢޔᧄ೷ߣ૬↪ߔ ࡝ࠕ࠱࡜ࡓࠍ૬↪ߔ ࠆ႐วߪචಽᵈᗧߔ ࠆ႐วߪޔᖚ⠪ߩ⁁ᘒ ࠆߎߣޕ ࠍᘕ㊀ߦⷰኤߔࠆߎ ઁߩ㕖࠿ࠢ࡟ࠝࠪ࠼ ᧄ೷ߩⴊẏਛỚᐲ߇ ߎࠇࠄߩ⮎೷ߩ ߣޕ ♽ㅒォ౮㉂⚛㒖ኂ೷ ૐਅߒޔᧄ೷ߩലᨐ߇ CYP3A(4)⺃ዉ૞↪ߦ ࠕࡒࠝ࠳ࡠࡦ ߎࠇࠄߩ⮎೷ߩⴊਛỚ ࠛ࠻࡜ࡆ࡝ࡦ ᷫᒙߔࠆ߅ߘࠇ߇޽ ࠃࠅޔᧄ೷ߩઍ⻢߇ଦ ࠫ࠰ࡇ࡜ࡒ࠼ ᐲ߇਄᣹ߔࠆ߅ߘࠇ߇ ࡀࡆ࡜ࡇࡦ ࠆߩߢޔᧄ೷ߣ૬↪ߔ ㅴߐࠇࠆޕ ࡈ࡟ࠞࠗ࠾࠼ ޽ࠆޕߎࠇࠄߩ⮎೷ߣ ࠆ႐วߪචಽᵈᗧߔ ࡝࠼ࠞࠗࡦ㧔ోりᕈ㧕 ૬↪ߔࠆ႐วߪޔⴊਛ ࠆߎߣޕ ࡔࠠࠪ࡟࠴ࡦ Ớᐲࠍࡕ࠾࠲࡝ࡦࠣߔ ࠞ࡞ࡃࡑ࠯ࡇࡦ ᧄ೷ߩⴊẏਛỚᐲ߇ ࡊࡠࡄࡈࠚࡁࡦ ࠆߎߣޕ JEDI_DEV00 \ 0900fde980405154 3.1 2013-09-03 11:46 ࡈࠚࡁࡃ࡞ࡆ࠲࡯࡞ ૐਅߒޔᧄ೷ߩലᨐ߇ ࠠ࠾ࠫࡦ ࡈࠚ࠾࠻ࠗࡦ ᷫᒙߔࠆ߅ߘࠇ߇޽ ࠪࡦࡃࠬ࠲࠴ࡦ 6) ߎࠇࠄߩ⮎೷ߩⴊẏ ᧄ೷ߩ OATP1B1 㒖ኂ ࠆߩߢޔᧄ೷ߣ૬↪ߔ ࠕ࠻࡞ࡃࠬ࠲࠴ࡦ 6) ਛỚᐲ߇਄᣹ߔࠆ߅ ૞↪෸߮/෶ߪ ࠆ႐วߪචಽᵈᗧߔ ߘࠇ߇޽ࠆޕߎࠇࠄߩ CYP3A4 㒖ኂ૞↪ߦ ࠆߎߣޕ ⮎೷ߩ↪㊂ࠍẋჇߒޔ ࠃࠅޔߎࠇࠄߩ⮎೷ߩ ࠮࡛ࠗ࠙ࠝ࠻ࠡ࡝࠰ ᧄ೷ߩⴊẏਛỚᐲ߇ ലᨐࠍ⊒⃻ߔࠆᦨዊ ឃ಴෸߮/෶ߪઍ⻢߇ ࠙㧔St. John’s Wortޔ ૐਅߒޔᧄ೷ߩലᨐ߇ ߩ↪㊂ࠍ↪޿ޔᖚ⠪ߩ 㒖ኂߐࠇࠆޕ ࠮ࡦ࠻࡮࡚ࠫ࡯ࡦ࠭࡮ ᷫᒙߔࠆ߅ߘࠇ߇޽ ⁁ᘒࠍᘕ㊀ߦⷰኤߔ ࡢ࡯࠻㧕฽᦭㘩ຠ ࠆߩߢޔᧄ೷ߣ૬↪ߔ ࠆߎߣޕ ࠆ႐วߪචಽᵈᗧߔ ࡠࠬࡃࠬ࠲࠴ࡦ 7) ߎࠇࠄߩ⮎೷ߩⴊẏ ᧄ೷ߩ OATP1B1 㒖ኂ ࠆߎߣޕ ࡊ࡜ࡃࠬ࠲࠴ࡦ ਛỚᐲ߇਄᣹ߔࠆ߅ ૞↪ߦࠃࠅޔߎࠇࠄߩ ࠺ࠠࠨࡔ࠲࠱ࡦ㧔ోり ᧄ೷ߩⴊẏਛỚᐲ߇ ࡇ࠲ࡃࠬ࠲࠴ࡦ ߘࠇ߇޽ࠆߚ߼ޔᖚ⠪ ⮎೷ߩឃ಴߇㒖ኂߐ ᕈ㧕 ૐਅߒޔᧄ೷ߩലᨐ߇ ߩ⁁ᘒࠍᘕ㊀ߦⷰኤ ࠇࠆޕ ᷫᒙߔࠆ߅ߘࠇ߇޽ ߒޔߎࠇࠄߩ⮎೷ߩ↪ ࠆߩߢޔᧄ೷ߣ૬↪ߔ ㊂ࠍẋჇߒޔലᨐࠍ⊒ ࠆ႐วߪචಽᵈᗧߔ ⃻ߔࠆᦨዊߩ↪㊂ࠍ ࠆߎߣޕ ↪޿ࠆߎߣޕ ࠕࡓࡠࠫࡇࡦ ߎࠇࠄߩ⮎೷ߩⴊẏ ᧄ೷ߩ CYP3A4 㒖ኂ ࡌࡊ࡝ࠫ࡞ ਛỚᐲ߇਄᣹ߔࠆ߅ ૞↪෸߮/෶ߪ P-gp 㒖 ࠫ࡞࠴ࠕ࠯ࡓ ߘࠇ߇޽ࠆޕߎࠇࠄߩ ኂ૞↪ߦࠃࠅޔߎࠇࠄ ࡈࠚࡠࠫࡇࡦ ⮎೷ߣ૬↪ߔࠆ႐ว ߩ⮎೷ߩઍ⻢෸߮/෶ ࠾ࠞ࡞ࠫࡇࡦ ߪޔᖚ⠪ߩ⁁ᘒࠍᘕ㊀ ߪឃ಴߇㒖ኂߐࠇࠆޕ ࠾ࡈࠚࠫࡇࡦ ߦⷰኤߔࠆߎߣޕ ࠾࠰࡞ࠫࡇࡦ ࡌ࡜ࡄࡒ࡞ ࠫࠧࠠࠪࡦ 7) ࠫࠧࠠࠪࡦߩⴊਛỚᐲ ᧄ೷ߩ P-gp 㒖ኂ૞↪ ߇਄᣹ߔࠆޕࠫࠧࠠࠪ ߦࠃࠅޔࠫࠧࠠࠪࡦߩ ࡦߩⴊਛỚᐲࠍࡕ࠾࠲ ឃ಴߇㒖ኂߐࠇࠆޕ ࡝ࡦࠣߒޔലᨐ߇⊒⃻ ߔࠆ↪㊂߹ߢẋჇߔࠆ ߎߣޕ

㪄㩷㪉㩷㪄㩷 ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ  ࠲ࠢࡠ࡝ࡓࠬ 5) ࠲ࠢࡠ࡝ࡓࠬߩⴊਛ ᯏᐨਇ᣿ 8㧚ㆊ㊂ᛩਈ Ớᐲ߇ૐਅߔࠆޕ࠲ࠢ ᓽ୥ޔ∝⁁㧦 ࡠ࡝ࡓࠬߩ↪㊂⺞▵ ㆊ㊂ᛩਈߦ㑐ߔࠆ࠺࡯࠲ߪ㒢ࠄࠇߡ޿ࠆޕஜᐽᚑੱߦ 1 ߪᔅⷐߣߒߥ޿߇ޔ࠲ ᣣ 1 ࿁ 400mg ࠍ 5 ᣣ㑆෻ᓳᛩਈߒߚ႐วޔ߹ߚᄖ࿖ੱߩ ࠢࡠ࡝ࡓࠬߩⴊਛỚ ஜᐽᚑੱߦ 600mg න࿁ᛩਈ෸߮ 1 ᣣ 1 ࿁ 400mg ࠍ 5 ᣣ㑆 ᐲࠍࡕ࠾࠲࡝ࡦࠣߔ ෻ᓳᛩਈߒߚ႐ว෶ߪ C ဳᘟᕈ⢄Ἳᖚ⠪ߦ 1 ᣣ 1 ࿁ ࠆߎߣޕ 200mg ࠍ 4 ㅳ㑆ᛩਈߒߚ႐วߦޔ⥃ᐥ⊛ᓽ୥෸߮∝⁁ߪ 4㧚೽૞↪ ⷰኤߐࠇߥ߆ߞߚޕ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߦᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ ಣ⟎㧦 ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪ 2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ ᧄ೷ߦኻߔࠆ․೎ߥ⸃Ქ೷ߪߥ޿ޕㆊ㊂ᛩਈߒߚ႐วߦ ࡦߣ૬↪ߒߚ࿖ౝ╙Τ⋧෸߮╙Υ⋧⥃ᐥ⹜㛎㧔ోᛩਈᦼ㑆㧕ߦ ߪޔࡃࠗ࠲࡞ࠨࠗࡦ෸߮⥃ᐥ∝⁁ߩⷰኤ߿ᶖൻ▤㒰ᨴߥ ߅ߌࠆ቟ోᕈ⹏ଔኻ⽎∝଀ 436 ଀ਛ 426 ଀㧔97.7%㧕ߦ೽૞↪㧔⥃ ߤ৻⥸⊛ߥᡰᜬ≮ᴺࠍⴕ߁ޕᧄ೷ߪⴊẏⰮ⊕⚿ว₸߇㜞 ᐥᬌᩏ୯⇣Ᏹࠍ฽߻㧕߇⹺߼ࠄࠇߚޕᧄ೷ߩ೽૞↪ߪޔ⊒∐ 203 ޿ߚ߼ޔㅘᨆߢࠪࡔࡊ࡟ࡆ࡞߇㒰෰ߐࠇࠆน⢻ᕈߪૐ޿ޕ

଀㧔46.6%㧕ޔߘ߁∣∝ 105 ଀㧔24.1%㧕ޔⴊਛࡆ࡝࡞ࡆࡦჇട 97 9㧚ㆡ↪਄ߩᵈᗧ ଀㧔22.2%㧕ޔଢ⒁ 29 ଀㧔6.7%㧕ޔశ✢ㆊᢅᕈ෻ᔕ 8 ଀㧔1.8%㧕 ⮎೷੤ઃᤨ㧦PTP ൮ⵝߩ⮎೷ߪ PTP ࠪ࡯࠻߆ࠄขࠅ಴ߒߡ ߢ޽ߞߚޕ㧔↳⺧ᤨ㧕 ᦯↪ߔࠆࠃ߁ߦᜰዉߔࠆߎߣޕ㨇PTP ࠪ࡯࠻ߩ⺋㘶ߦࠃࠅޔ 1) ㊀ᄢߥ೽૞↪ ⎬޿㍈ⷺㇱ߇㘩㆏☼⤑߳ೝ౉ߒޔᦝߦߪ⓫ሹࠍ⿠ߎߒߡ❑㓒 ᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ ᵢἻ╬ߩ㊀◊ߥว૬∝ࠍ૬⊒ߔࠆߎߣ߇ႎ๔ߐࠇߡ޿ࠆޕ㨉 ߪ 2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩ૬↪ߢ⹺߼ࠄࠇߚ㊀ᄢ  ߥ೽૞↪ߪએਅߩߣ߅ࠅߢ޽ࠆޕ 10㧚ߘߩઁߩᵈᗧ (1) ⽺ⴊ㧔0.2%㧕㧖㧦⽺ⴊ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ ᧄ೷ߪin vitro ⹜㛎ߢశᲥᕈࠍ␜ߒߚߣߩႎ๔߇޽ࠆޕ ߦⴊᶧᬌᩏࠍⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿㧘⇣Ᏹߩ⒟ᐲ߇⪺ ߒ޿႐วߦߪᛩਈߩਛᱛࠍ⠨ᘦߒ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ޣ⮎ ‛ േ ᘒޤ (2) ᄙᒻ⚃᢬㧔0.2%㧕㧖㧦ᄙᒻ⚃᢬߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢ㧘 1㧚ⴊẏਛỚᐲ 11) ⷰኤࠍචಽߦⴕ޿㧘∝⁁߇޽ࠄࠊࠇߚ႐วߦߪ㧘ᛩਈࠍਛ 1) ஜᐽᚑੱߦ߅ߌࠆ⮎‛േᘒ ᱛߒ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ஜᐽᚑੱ㧔23 ଀㧕ߦᧄ೷ 100 mg ࠍⓨ⣻ᤨ෸߮㘩ᓟߦන 㧖㧦㗫ᐲߪ 3 ೷૬↪ߒߚ࿖ౝ⥃ᐥ⹜㛎ߦ߅ߌࠆ㊀◊∝଀ࠍ␜ߔ ࿁⚻ญᛩਈߒߚߣ߈ޔⴊẏਛࠪࡔࡊ࡟ࡆ࡞ߪ޿ߕࠇ߽ᛩ ਈᓟ 6.0 ᤨ㑆㧔ਛᄩ୯㧕ߦ Cmax㨇1.02㨪1.08 μg/mL㧔ᐔဋ 2) ߘߩઁߩ೽૞↪ ୯㧕㨉ߦ㆐ߒޔ⚂ 8 ᤨ㑆㧔ᐔဋ୯㧕ߩ t1/2 ߢᶖᄬߒߚޕᧄ ᧄ೷ࠍࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2a㧔ㆮવሶ⚵឵߃㧕 ೷ࠍන࿁⚻ญᛩਈߒߚߣ߈ߩⴊẏਛࠪࡔࡊ࡟ࡆ࡞ߩ⮎ ෶ߪ 2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߒߚ㓙ߩᧄ ‛േᘒߦ㘩੐ߩᓇ㗀ߪ⹺߼ࠄࠇߥ߆ߞߚޕ ೷ߩ೽૞↪ߪએਅߩߣ߅ࠅߢ޽ࠆޕᰴߩࠃ߁ߥ೽૞↪߇޽ࠄ ࠊࠇߚ႐วߦߪޔ∝⁁ߦᔕߓߡㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ ࿑ 1 ஜᐽᚑੱߦᧄ೷ 100 mg ࠍⓨ⣻ᤨ෸߮㘩ᓟߦන࿁⚻ญᛩਈߒߚ ߣ߈ߩⴊẏਛࠪࡔࡊ࡟ࡆ࡞Ớᐲ-ᤨ㑆ផ⒖㧔ᐔဋ୯+ᮡḰ஍Ꮕޔ23 ଀㧕 10 %એ਄ 5%એ਄ 5%ᧂḩ 10 %ᧂḩ

⢗⣺㓚ኂ ଢ⒁

⢄⢙㆏♽㓚ኂ ⴊਛࡆ࡝࡞ࡆࡦ

Ⴧട

⊹⤏߅ࠃ߮⊹ ⊒∐ޔ ߘ߁∣∝ శ✢ㆊᢅᕈ෻

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⥃ᐥᬌᩏ 㜞ࡆ࡝࡞ࡆࡦ Al-P Ⴧട

ⴊ∝

JEDI_DEV00 \ 0900fde980405154 3.1 2013-09-03 11:46 5㧚㜞㦂⠪߳ߩᛩਈ 㜞㦂⠪ߢߪ৻⥸ߦ↢ℂᯏ⢻߇ૐਅߒߡ߅ࠅޔ߹ߚว૬∝߿ ⴫ 1 ஜᐽᚑੱߦᧄ೷ 100 mg ࠍⓨ⣻ᤨ෸߮㘩ᓟߦන࿁⚻ญᛩਈߒߚߣ߈ ૬↪⮎૶↪ߩ㗫ᐲ߇Ⴧ߃ࠆߎߣ߆ࠄᘕ㊀ߦᛩਈߔࠆߎߣޕ ߩⴊẏਛࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒࡄ࡜ࡔ࡯࠲㨇ᐔဋ୯㧔ᮡḰ஍Ꮕ㧕㨉 ⮎‛േᘒࡄ࡜ࡔ࡯࠲ ⓨ⣻ᤨᛩਈ 㘩ᓟᛩਈ ᦨዊੑਸ਼ᐔဋᲧ a) 6㧚ᅧᇚޔ↥ᇚޔ᝼੃ᇚ╬߳ߩᛩਈ 㧔90%ା㗬඙㑆㧕 1㧕ᧄ೷ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ෶ߪ 2b㧔ㆮવሶ⚵ 23 ଀ 23 ଀

឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߚ߼ޔᅧᇚ෶ߪᅧᆼߒߡ Cmax (μg/mL) 1.08 (0.52) 1.02 (0.33) 1.02 (0.87 - 1.19) ޿ࠆน⢻ᕈߩ޽ࠆᇚੱߦߪ૶↪ߒߥ޿ߎߣޕ߹ߚޔᅧᆼ tmax (h) 6.0 [4.0 - 8.0] 6.0 [4.0 - 8.0] 11.9 (7.15) 10.6 (4.31) 0.97 (0.84 - 1.12) ߒߡ޿ߥ޿ߎߣࠍ⏕⹺ߔࠆߚ߼ޔ࡝ࡃࡆ࡝ࡦߩᷝઃᢥᦠ AUCп (μg·h/mL) ࠍෳᾖߒޔᅧᆼᬌᩏࠍታᣉߔࠆߎߣޕ㨇࡝ࡃࡆ࡝ࡦߩേ‛ t1/2 (h) 8.56 (1.38) 8.38 (1.35) tmax: ਛᄩ୯[▸࿐] ታ㛎ߢ௅ᄸᒻᕈ෸߮⢦࡮⢝ఽ⥌ᱫ૞↪߇⹺߼ࠄࠇߡ޿ a) ⓨ⣻ᤨᛩਈ/㘩ᓟᛩਈ ࠆޕ㨉 ᧄ೷ߦ߅޿ߡ࠙ࠨࠡ⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜㛎ߪታᣉߒ 2) C ဳᘟᕈ⢄Ἳᖚ⠪ߦ߅ߌࠆ⮎‛േᘒ 12), 13), 14), 15) ߡ޿ߥ޿ޕ࡜࠶࠻⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜㛎ߦ߅޿ߡޔ C ဳᘟᕈ⢄Ἳᖚ⠪ߦޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2a ෶ ᦨᄢᛩਈ㊂㧔⥃ᐥᦑ㔺㊂ࠃࠅૐ޿㧕ߢߪޔ௅ᄸᒻᕈߪ⹺ ߪ 2b ෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߒߡᧄ೷ 100 mg ࠍ 1 ᣣ 1 ࿁෻ᓳ ߼ࠄࠇߥ߆ߞߚ 8)ޕࡑ࠙ࠬ⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜㛎ߢ ⚻ญᛩਈߒߚߣ߈ߩⴊẏਛࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒࡄ࡜ࡔ࡯ ߪޔᲣ૕Ქᕈ෸߮⢝ఽ૕㊀ૐ୯ࠍ઻ࠊߥ޿↪㊂㧔ᦑ㔺㊂ ࠲㧔Უ㓸࿅⮎‛േᘒ⸃ᨆߦࠃࠆផቯ୯㧕ࠍ⴫ 2 ߦ␜ߔޕC ဳ ߣߒߡߪ⥃ᐥᦑ㔺㊂ߣ߶߷ห╬㧕߆ࠄޔ⢝ఽߩ㛽ᩰᄌ⇣ ᘟᕈ⢄Ἳᖚ⠪ߩⴊẏਛࠪࡔࡊ࡟ࡆ࡞ߩᦑ㔺㊂ߪஜᐽᚑੱߦᧄ 9) ෸߮㛽ൻㆃᑧߩ⊒↢㗫ᐲჇട߇⹺߼ࠄࠇߚ ޕ࡜࠶࠻಴ ೷ 100 mg ࠍ 1 ᣣ 1 ࿁෻ᓳ⚻ญᛩਈߒߚߣ߈ߩᦑ㔺㊂㧔C0h:

↢೨෸߮಴↢ᓟߩ⊒↢ߦ㑐ߔࠆ⹜㛎ߢߪޔ⥃ᐥᦑ㔺㊂ࠃ 0.308 μg/mL, Cmax: 1.66 μg/mL, AUC24h: 17.3 μg·h/mL㧕ߣᲧセߒ ࠅૐ޿ᦑ㔺㊂㧔Უേ‛㧕ߢޔᲣേ‛ߩ૕㊀Ⴧടᛥ೙෸߮ ߡ㜞߆ߞߚޕ ಴↢ఽߩ⊒⢒ㆃᑧ߇⹺߼ࠄࠇߚ 10)ޕ 2㧕᝼੃ਛߩᇚੱߦߪޔᛩਈࠍㆱߌࠆߎߣޕ߿߻ࠍᓧߕᛩਈ ߔࠆ႐วߪޔ᝼੃ࠍㆱߌߐߖࠆߎߣޕ㨇ࡅ࠻ߦ߅ߌࠆ੃᳝ ⴫ 2 C ဳᘟᕈ⢄Ἳᖚ⠪ߦࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2a ෶ߪ 2b ෸ ߮࡝ࡃࡆ࡝ࡦߣᧄ೷ 100 mg ࠍ 1 ᣣ 1 ࿁෻ᓳ⚻ญᛩਈߒߚߣ߈ߩⴊẏਛ ߳ߩ⒖ⴕߪਇ᣿ߢ޽ࠆ߇ޔ࡜࠶࠻ߢ੃ఽ߳ߩ⒖ⴕ߇⹺߼ ࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒࡄ࡜ࡔ࡯࠲ផቯ୯㨇ᐔဋ୯㧔ᮡḰ஍Ꮕ㧕㨉 ࠄࠇߡ޿ࠆޕ㨉 ⮎‛േᘒ ೨ᴦ≮ ೨ᴦ≮ ೋ࿁ᴦ≮ᖚ⠪ ࡄ࡜ࡔ࡯࠲ ౣΆᖚ⠪ ήലᖚ⠪ 7㧚ዊఽ╬߳ߩᛩਈ PegIFNa-2a ૐ಴↢૕㊀ఽޔᣂ↢ఽޔ੃ఽޔᐜఽ෶ߪዊఽߦኻߔࠆ቟ో 123 ଀ 49 ଀ 53 ଀ C0h (μg/mL) 1.58 (1.72) 2.67 (2.45) 2.26 (1.99) ᕈߪ⏕┙ߒߡ޿ߥ޿ޕ㧔૶↪⚻㛎߇ߥ޿ޕ㧕 Cmax (μg/mL) 3.15(1.76) 4.26 (2.48) 3.86 (2.01) AUC24h (μg·h/mL) 55.8 (42.8) 82.8 (59.9) 73.1 (48.8)

㪄㩷㪊㩷㪄㩷 PegIFNa-2b TMC435 ߩਥⷐߥઍ⻢⚻〝ߪᄢⅣ⁁ߩ㉄ൻޔ⧐㚅ᣖߩ㉄ൻ෸ 24 ଀ 29 ଀ 26 ଀ ߮ᄢⅣ⁁ߣ⧐㚅ᣖਔᣇߩ㉄ൻਗ߮ߦ O-⣕ࡔ࠴࡞ൻߢ޽ߞߚޕ C0h (μg/mL) 1.03 (0.78) 2.75 (2.59) 1.75 (2.14) Cmax (μg/mL) 2.59 (0.82) 4.34 (2.61) 3.33 (2.17) AUC24h (μg·h/mL) 42.4 (20.1) 84.9 (63.1) 60.2 (52.4) 4㧚ឃᴭ㧔ᄖ࿖ੱᚑ❣㧕25)

ஜᐽᚑੱ㧔6 ଀㧕ߦ 14C ᮡ⼂ࠪࡔࡊ࡟ࡆ࡞ 200 mg ࠍන࿁⚻ 3) ⢄ᯏ⢻㓚ኂᖚ⠪ߦ߅ߌࠆ⮎‛േᘒ㧔ᄖ࿖ੱᚑ❣㧕16) ญᛩਈߒߚߣ߈ޔ✚᡼኿⢻ߩ 91%㧔ᐔဋ୯㧕߇♮ਛ߆ࠄ࿁ ਛ╬ᐲ⢄ᯏ⢻㓚ኂᖚ⠪㧔Child-Pugh ࠬࠦࠕ B㧘8 ଀㧕෸߮㜞 ෼ߐࠇޔዩਛ࿁෼₸ߪ 1%ᧂḩߢ޽ߞߚޕ♮ਛߦ࿁෼ߐࠇߚ ᐲ⢄ᯏ⢻㓚ኂᖚ⠪㧔Child-Pugh ࠬࠦࠕ C㧘8 ଀㧕ߦᧄ೷ 150 mg ࠪࡔࡊ࡟ࡆ࡞ߩᧂᄌൻ૕ߪޔᛩਈ㊂ߩ 31%㧔ᐔဋ୯㧕ߢ޽ ࠍ 1 ᣣ 1 ࿁෻ᓳ⚻ญᛩਈߒߚߣ߈ޔⴊẏਛࠪࡔࡊ࡟ࡆ࡞ߩ ߞߚޕ ᐔဋ C ෸߮ AUC ߪޔ⢄ᯏ⢻ᱜᏱⵍ㛎⠪㧔8 ଀㧕ߣᲧセ max 24h ߒߡਛ╬ᐲ⢄ᯏ⢻㓚ኂᖚ⠪ߢߘࠇߙࠇ 1.71 ୚෸߮ 2.44 ୚ޔ 5㧚⋧੕૞↪㧔in vitro ෸߮ᄖ࿖ੱᚑ❣㧕 㜞ᐲ⢄ᯏ⢻㓚ኂᖚ⠪ߢߘࠇߙࠇ 3.13 ୚෸߮ 5.22 ୚㜞߆ߞߚޕ 1) In vitro ⹜㛎ᚑ❣ 26), 27), 28), 29), 30), 31), 32)

ࡅ࠻⢄⚦⢩ࠍ↪޿ߚ in vitro ⹜㛎ߢޔࠪࡔࡊ࡟ࡆ࡞ߪ ⴫ 3⢄ᯏ⢻ᱜᏱⵍ㛎⠪ਗ߮ߦਛ╬ᐲ෸߮㜞ᐲ⢄ᯏ⢻㓚ኂⵍ㛎⠪ߦᧄ೷ OI ࠍ  ᣣ  ࿁෻ᓳ⚻ญᛩਈߒߚߣ߈ߩⴊẏਛࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛ CYP1A2 ෸߮ CYP3A4 ࠍ⺃ዉߒߥ߆ߞߚޕ߹ߚ⢄ࡒࠢࡠ േᘒࡄ࡜ࡔ࡯࠲㨇ᐔဋ୯㧔ᮡḰ஍Ꮕ㧕㨉 ࠰࡯ࡓࠍ↪޿ߚ in vitro ⹜㛎ߢޔࠪࡔࡊ࡟ࡆ࡞ߪ CYP2A6ޔ CYP2C8 ෸߮ CYP2D6 ࠍਛ╬ᐲ㧔IC 㧦㧪32 g/mL㧕ޔ ⮎‛േᘒ ⢄ᯏ⢻ᱜᏱ ਛ╬ᐲ 㜞ᐲ 50 ȝ CYP2C19 ෸߮ CYP3A ࠍシᐲ㧔IC50㧦㧪64 ȝg/mL㧕㒖ኂߒ ࡄ࡜ࡔ࡯࠲ ⵍ㛎⠪ ⢄ᯏ⢻㓚ኂᖚ⠪ ⢄ᯏ⢻㓚ኂᖚ⠪ ߚޕࡅ࠻⢄⚦⢩෶ߪࡅ࠻⮎‛࠻࡜ࡦࠬࡐ࡯࠲࡯⊒⃻♽ࠍ 8଀ 8଀ 8଀ ↪޿ߚ in vitro ⹜㛎ߢޔࠪࡔࡊ࡟ࡆ࡞ߪ P-gpޔMRP2ޔBCRPޔ tmax (h) 6.0 [4.0 – 9.0] 6.0 [6.0 – 9.0] 6.0 [3.0 – 12.0] OATP1B1ޔOATP1B3 ෸߮ OATP2B1 ߩၮ⾰ߢ޽ࠆߎߣ߇

Cmax (μg/mL) 2.10 (0.96) 3.78 (1.98) 7.18 (4.27) ␜ߐࠇߚޕ߹ߚޔࠪࡔࡊ࡟ࡆ࡞ߪ⢄ขࠅㄟߺ࠻࡜ࡦࠬࡐ

AUC24h (μg˜h/mL) 23.7 (10.9) 65.1 (38.1) 138 (89.9) ࡯࠲࡯ߩ OATP1B1 ෸߮ NTCP ਗ߮ߦ⮎‛ឃ಴࠻࡜ࡦࠬ tmax: ਛᄩ୯[▸࿐] ࡐ࡯࠲࡯ߩ P-gpޔMRP2 ෸߮ BSEP ࠍ㒖ኂߒߚޕ  2) ⥃ᐥᚑ❣ 4) ⣢ᯏ⢻㓚ኂᖚ⠪ߦ߅ߌࠆ⮎‛േᘒ㧔ᄖ࿖ੱᚑ❣㧕17) ᣣᧄੱ෶ߪᄖ࿖ੱ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߣߒߚ⹜㛎ߦ 㜞ᐲ⣢ᯏ⢻㓚ኂᖚ⠪㧔eGFR ” 29 mL/min/1.73 m2ޔ8 ଀㧕ߦ ߅޿ߡ㧘ࠪࡔࡊ࡟ࡆ࡞ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ

ᧄ೷ 150 mg ࠍ 1 ᣣ 1 ࿁෻ᓳ⚻ญᛩਈߒߚߣ߈ޔⴊẏਛࠪࡔ ̃2a㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣߩ㑆ߦ⮎‛േᘒቇ

ࡊ࡟ࡆ࡞ߩᐔဋ Cmax ෸߮ AUC24h ߪޔ⣢ᯏ⢻ᱜᏱⵍ㛎⠪ ⊛⋧੕૞↪ߪ⹺߼ࠄࠇߥ߆ߞߚޕ 㧔eGFR• 80 mL/min/1.73 m2ޔ8 ଀㧕ߣᲧセߒߡߘࠇߙࠇ 1.34 ᄖ࿖ੱࠍኻ⽎ߣߒߚ⮎‛⋧੕૞↪⹜㛎ߩ⚿ᨐࠍ⴫ 6 ෸߮ ୚෸߮ 1.62 ୚㜞߆ߞߚޕ ⴫ 7 ߦ␜ߔޕ

⴫ 4 ⣢ᯏ⢻ᱜᏱⵍ㛎⠪෸߮㜞ᐲ⣢ᯏ⢻㓚ኂᖚ⠪ߦᧄ೷ 150 mg ࠍ 1 ᣣ 1 ⴫ 6 ૬↪⮎ߩ⮎‛േᘒߦ෸߷ߔࠪࡔࡊ࡟ࡆ࡞ߩᓇ㗀 ࿁෻ᓳ⚻ญᛩਈߒߚߣ߈ߩⴊẏਛࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒࡄ࡜ࡔ࡯࠲ ૬↪⮎ߩ⮎‛േᘒࡄ࡜ࡔ࡯࠲Ყ ૬↪⮎ߩ ᧄ೷ߩ 㨇ᐔဋ୯㧔ᮡḰ஍Ꮕ㧕㨉 ૬↪⮎ ଀ᢙ ૬↪ᤨන⁛ᛩਈᤨ㧔90%ା㗬඙㑆㧕 ᛩਈ㊂ ᛩਈ㊂ ⮎‛േᘒࡄ࡜ࡔ࡯࠲ ⣢ᯏ⢻ᱜᏱⵍ㛎⠪ 㜞ᐲ⣢ᯏ⢻㓚ኂ Cmax AUC Cmin ࡠࠬࡃࠬ࠲ 10 mg 150 mg 3.17 2.81 17 ଀ NA ⵍ㛎⠪ ࠴ࡦ 7) න࿁ᛩਈ q.d (2.57~3.91) (2.34~3.37) 8଀ 8଀ ࠕ࠻࡞ࡃࠬ࠲࠴ࡦ 1.70 2.12 t (h) 6.0 [4.0 – 9.0] 6.0 [4.0 – 9.0] NA max ࠕ࠻࡞ࡃࠬ 40 mg 150 mg (1.42~2.04) (1.72~2.62) 18 ଀ 6) න࿁ᛩਈ q.d Cmax (μg/mL) 3.38 (2.64) 4.67 (3.82) ࠲࠴ࡦ ࠝ࡞࠻ࡅ࠼ࡠࠠࠪࠕ࠻࡞ࡃࠬ࠲࠴ࡦ 1.98 2.29 AUC (μg˜h/mL) 44.4 (39.9) 76.7 (71.7) NA 24h (1.70~2.31) (2.08~2.52) tmax: ਛᄩ୯ [▸࿐] ࠛ࡝ࠬࡠࡑ 500 mg 150 mg 1.59 1.90 3.08 24 ଀ ࠗࠪࡦ 4) t.i.d. q.d (1.23~2.05) (1.53~2.36) (2.54~3.73) 18), 19), 20) 5) ᣣᧄੱߣᄖ࿖ੱߩᲧセ ࠪࡦࡃࠬ࠲࠴ࡦ 1.46 1.51 ᣣᧄੱ C ဳᘟᕈ⢄Ἳᖚ⠪㧔12 ଀㧕ߦᧄ೷ 100 mg ࠍ 1 ᣣ 1 NA ࠪࡦࡃࠬ࠲ 40 mg 150 mg (1.17~1.82) (1.32~1.73) ࿁෻ᓳ⚻ญᛩਈߒߚߣ߈ߩⴊẏਛࠪࡔࡊ࡟ࡆ࡞ߩᐔဋ Cmax 6) 18 ଀ ࠴ࡦ න࿁ᛩਈ q.d ࠪࡦࡃࠬ࠲࠴ࡦ㉄ ෸߮ AUC ߪޔᄖ࿖ੱ C ဳᘟᕈ⢄Ἳᖚ⠪㧔22㨪26 ଀㧕ߦᧄ JEDI_DEV00 \ 0900fde980405154 3.1 2013-09-03 11:46 24h 3.03 1.88 NA ೷ 150 mg ࠍ 1 ᣣ 1 ࿁෻ᓳ⚻ญᛩਈߒߚߣ߈ߣห⒟ᐲߢ޽ߞ (2.49~3.69) (1.63~2.17) 0.075 mg/kg ߚޕ 150 mg 1.31 1.45 න࿁⚻ญ 16 ଀ NA q.d (1.19~1.45) (1.35~1.57) ࡒ࠳࠱࡜ࡓ ᛩਈ ⴫ 5 ᣣᧄੱ෸߮ᄖ࿖ੱ C ဳᘟᕈ⢄Ἳᖚ⠪ߦᧄ೷ࠍߘࠇߙࠇ 100 mg ෸߮ 33) 0.025 mg/kg 150 mg 0.78 1.10 150 mg1 ᣣ 1 ࿁෻ᓳ⚻ญᛩਈߒߚߣ߈ߩⴊẏਛࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒ න࿁㕒⣂ౝ 16 ଀ NA q.d (0.52~1.17) (0.95~1.26) ࡄ࡜ࡔ࡯࠲㨇ᐔဋ୯㧔ᮡḰ஍Ꮕ㧕㨉 ᛩਈ ࠫࠧࠠࠪࡦ 0.25 mg 150 mg 1.31 1.39 ᣣᧄੱ ᄖ࿖ੱ 16 ଀ NA 7) න࿁ᛩਈ q.d (1.14~1.51) (1.16~1.67) ⮎‛േᘒࡄ࡜ࡔ࡯࠲ ࠞࡈࠚࠗࡦ 150 mg 150 mg 1.12 1.26 ೋ࿁ᴦ≮ᖚ⠪ ೋ࿁ᴦ≮ᖚ⠪ ᣢᴦ≮ᖚ⠪ 16 ଀ NA 33) න࿁ᛩਈ q.d (1.06~1.19) (1.21~1.32) 12 ଀ 23 ଀ 26 ଀ ࠝࡔࡊ࡜࠱ 40 mg 1.14 1.21 150 mg q.d 16 ଀ NA ࡯࡞ 33) න࿁ᛩਈ (0.93~1.39) (1.00~1.46) Cmax (μg/mL) 4.07 (3.45) 4.39 (4.43) 3.95 (2.89) ࠪࠢࡠࠬࡐ 100 mg 1.16 1.19 a) 5) 150 mg q.d 14 ଀ NA AUC24h (μg˜h/mL) 60.2 (65.4) 70.1 (93.4) 59.8 (55.7) ࡝ࡦ න࿁ᛩਈ (1.07~1.26) (1.13~1.26) a) 22 ଀ ࠹ࡁࡎࡆ࡞ ࠫ࠰ࡊࡠࠠ 300 mg 150 mg 1.19 1.18 1.24 24 ଀ 2㧚ⴊẏⰮ⊕⚿ว 21), 22), 23) ࠪ࡞ࡈࡑ࡞ q.d. q.d (1.10~1.30) (1.13~1.24) (1.15~1.33) 34) ࠪࡔࡊ࡟ࡆ࡞ߩⴊẏⰮ⊕⚿ว₸ߪ 99.9%ࠃࠅᄢ߈ߊޔਥߦࠕ ㉄Ⴎ ࠛ࠴࠾࡞ࠛࠬ࠻࡜ࠫࠝ࡯࡞ ࠛ࠴࠾࡞ࠛ ࡞ࡉࡒࡦߦ⚿วߒߚ㧔ᐔⴧㅘᨆᴺ㧕ޕ߹ߚޔࠕ࡞ࡉࡒࡦࠃࠅ 1.18 1.12 1.00 ࠬ࠻࡜ࠫࠝ ⚿ว₸ߪૐ޿߇ Į1 ㉄ᕈ♧Ⱞ⊕ߦ߽⚿วߒߚޕ⣢ᯏ⢻㓚ኂᖚ 35 ȝg/1.0 mg 150 mg (1.09~1.27) (1.05~1.20) (0.89~1.13) ࡯࡞ࡁ࡞ࠛ 18 ଀ q.d. q.d ⠪෸߮⢄ᯏ⢻㓚ኂᖚ⠪߆ࠄᓧߚⴊẏࠍ↪޿ߚࠪࡔࡊ࡟ࡆ࡞ ࠴ࠬ࠹ࡠࡦ ࡁ࡞ࠛ࠴ࠬ࠹ࡠࡦ ߩⴊẏⰮ⊕⚿ว₸ߪޔஜᐽᚑੱ߆ࠄᓧߚⴊẏࠍ↪޿ߚߣ߈ 35) 1.06 1.15 1.24 (0.99~1.14) (1.08~1.22) (1.13~1.35) ߣห᭽ߢ޽ߞߚޕ ࡝࡞ࡇࡆ࡝ 25 mg 150 mg 1.04 1.12 1.25 24 ଀ ࡦ 34) q.d. q.d. (0.95~1.13) (1.05~1.19) (1.16~1.35) ࠺ࠠࠬ࠻ࡠ 30 mg 150 mg 1.21 1.08 24), 25) ࡔ࠻࡞ࡈࠔ 16 ଀ NA 3㧚ઍ⻢㧔in vitro ෸߮ᄖ࿖ੱᚑ❣㧕 න࿁ᛩਈ q.d (0.93~1.57) (0.87~1.35) ࡦ 33) ࡅ࠻⢄ࡒࠢࡠ࠰࡯ࡓ෸߮ࡅ࠻ CYP ⊒⃻♽ࠍ↪޿ߚ in vitro ࡜࡞࠹ࠣ࡜ 400 mg 150 mg 1.03 1.08 1.14 24 ଀ ⹜㛎ߢޔࠪࡔࡊ࡟ࡆ࡞ߪਥߦ CYP3A ߦࠃࠅઍ⻢ߐࠇޔ ࡆ࡞ 1) b.i.d. q.d (0.78~1.36) (0.85~1.38) (0.97~1.36) ࡢ࡞ࡈࠔ࡝ 10 mg 150 mg 1.00 1.04 CYP2C8 ෸߮ CYP2C19 ߽ઍ⻢ߦ㑐ਈߔࠆߎߣ߇␜ໂߐࠇߚޕ 33) 16 ଀ NA 14 ࡦ න࿁ᛩਈ q.d (0.94~1.06) (1.00~1.07) ஜᐽᚑੱ㧔6 ଀㧕ߦ C ᮡ⼂ࠪࡔࡊ࡟ࡆ࡞ 200 mg ࠍන࿁⚻ ࠛࠬࠪ࠲ࡠ 10 mg 150 mg 1.03 1.00 1.00 36) 20 ଀ ญᛩਈߒߚߣ߈ޔᄢㇱಽ㧔AUClast ߩᧂᄌൻ૕/✚᡼኿⢻Ყ㧦 ࡊ࡜ࡓ q.d. q.d (0.99~1.07) (0.97~1.03) (0.95~1.05) ࡝ࡈࠔࡦࡇ 600 mg 200 mg 0.92 1.00 83%㧕߇ᧂᄌൻ૕ߣߒߡⴊẏਛߦሽ࿷ߒޔઍ⻢‛߇ࠊߕ߆ߦ 21 ଀ NA 2) q.d. q.d (0.80~1.07) (0.93~1.08) ᬌ಴ߐࠇߚޕ ࠪࡦ

㪄㩷㪋㩷㪄㩷 ૬↪⮎ߩ⮎‛േᘒࡄ࡜ࡔ࡯࠲Ყ ⴊẏਛ HCV RNA ߇㒶ᕈൻޠߦ⹥ᒰߒߥ߆ߞߚ႐วޔ48 ㅳ߹ߢᛩਈߔ ૬↪⮎ߩ ᧄ೷ߩ ૬↪⮎ ଀ᢙ ૬↪ᤨන⁛ᛩਈᤨ㧔90%ା㗬඙㑆㧕 ࠆ㧕ߦᓥߞߡޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2a㧔ㆮવሶ⚵឵߃㧕 ᛩਈ㊂ ᛩਈ㊂ Cmax AUC Cmin ෸߮࡝ࡃࡆ࡝ࡦߩᛩਈᦼ㑆ࠍ 48 ㅳ㑆ߣߒߚ R(-)ࡔࠨ࠼ࡦ 1.03 0.99 1.02 2㧚 ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b㧔ㆮવሶ⚵឵߃㧕෸߮ 30~150 mg 150 mg (0.97~1.09) (0.91~1.09) (0.93~1.12) 15) ࡔࠨ࠼ࡦ 37) 12 ଀ ࡝ࡃࡆ࡝ࡦߣߩ 3 ೷૬↪ q.d. q.d S(+)ࡔࠨ࠼ࡦ ࠫࠚࡁ࠲ࠗࡊ I ߆ߟ㜞࠙ࠗ࡞ࠬ㊂㧔ࠦࡃࠬ TaqMan HCVޟࠝ 1.09 1.03 1.02 (1.02~1.16) (0.91~1.16) (0.89~1.12) ࡯࠻ޠ㧦5.0 Log IU/mL એ਄㧕ߩ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߣ ࠛࡈࠔࡆ࡟ 600 mg 150 mg 0.97 0.90 0.87 ߒߡޔᧄ೷㧔12 ㅳ㑆ᛩਈ㧕ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ 1) 24 ଀ ࡦ࠷ q.d. q.d (0.89~1.06) (0.85~0.95) (0.81~0.93) ࡈࠔ̃2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦ㧔ೋ࿁ᴦ≮෸߮ ࠲ࠢࡠ࡝ࡓ 2 mg 150 mg 14 ଀ 0.76 0.83 NA ࠬ 5) න࿁ᛩਈ q.d (0.65~0.90) (0.59~1.16) ೨ᴦ≮ౣΆᖚ⠪ߢߪ 24 ㅳ㑆ᛩਈޔ೨ᴦ≮ήലᖚ⠪ߢߪ 48 q.d.㧦1 ᣣ 1 ࿁㧘b.i.d.㧦1 ᣣ 2 ࿁㧘t.i.d.㧦1 ᣣ 3 ࿁㧘NA㧦▚಴ߖߕ ㅳ㑆ᛩਈ㧕ߩ 3 ೷૬↪ߦࠃࠆ⥃ᐥ⹜㛎ࠍታᣉߒߚޕ ᛩਈ⚳ੌᓟ 12 ㅳ෸߮ 24 ㅳߩ HCV RNA 㒶ᕈൻ₸ߪޔೋ࿁ ⴫ 7 ࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒߦ෸߷ߔ૬↪⮎ߩᓇ㗀 ᴦ≮ᖚ⠪ߢ޿ߕࠇ߽ 91.7%㧔22/24 ଀㧕ޔ೨ᴦ≮ౣΆᖚ⠪ߢ ࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒࡄ࡜ࡔ࡯࠲Ყ ߘࠇߙࠇ 100.0%㧔29/29 ଀㧕෸߮ 96.6%㧔28/29 ଀㧕ޔ೨ᴦ ૬↪⮎ߩ ᧄ೷ߩ ૬↪⮎ ଀ᢙ ૬↪ᤨන⁛ᛩਈᤨ㧔90%ା㗬඙㑆㧕 ᛩਈ㊂ ᛩਈ㊂ ≮ήലᖚ⠪ߢߘࠇߙࠇ 38.5%㧔10/26 ଀㧕෸߮ 38.5%㧔10/26 C AUC C max min ଀㧕ߢ޽ߞߚޕ ࠛ࡝ࠬࡠࡑ 500 mg 150 mg 4.53 7.47 12.7 24 ଀ ࠗࠪࡦ 4) t.i.d. q.d (3.91~5.25) (6.41~8.70) (10.2~15.9) ⴫ 9 ࿖ౝ╙Υ⋧⥃ᐥ⹜㛎ᚑ❣㧔ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b㧔ㆮ ࡝࠻࠽ࡆ࡞ 100 mg 200 mg 4.70 7.18 14.4 12 ଀ 3) b.i.d. q.d. (3.84~5.76) (5.63~9.15) (10.3~20.0) વሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣߩ 3 ೷૬↪ ࠳࡞࠽ࡆ࡞ 800 mg/ HCV RNA 㒶ᕈൻ₸ 50 mg 1.79 a) 2.59 a) 4.58 a) ࡝࠻࠽ࡆ 100 mg 25 ଀ q.d. (1.55~2.06) (2.15~3.11) (3.54~5.92) ೨ᴦ≮ᱧ ᛩਈ⚳ੌᓟ 12 ㅳ ᛩਈ⚳ੌᓟ 24 ㅳ 4) q.d. ࡞ ೋ࿁ᴦ≮*㧝 91.7%㧔22/24 ଀㧕 91.7%㧔22/24 ଀㧕 ࡝࡞ࡇࡆ࡝ 25 mg 150 mg 1.10 1.06 0.96 24 ଀ *㧝 ࡦ 34) q.d. q.d. (0.97~1.26) (0.94~1.19) (0.83~1.11) ೨ᴦ≮ౣΆ 100.0%㧔29/29 ଀㧕 96.6%㧔28/29 ଀㧕 ࡜࡞࠹ࠣ࡜ 400 mg 150 mg 0.93 0.89 0.86 ೨ᴦ≮ήല 38.5%㧔10/26 ଀㧕 38.5%㧔10/26 ଀㧕 24 ଀ ࡆ࡞ 1) b.i.d. q.d (0.85~1.02) (0.81~0.98) (0.75~0.98) *1 ᛩਈ⛮⛯ၮḰߦᓥߞߡࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2b㧔ㆮ ࠹ࡁࡎࡆ࡞ વሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩᛩਈᦼ㑆ࠍ 48 ㅳ㑆ߣߒߚᖚ⠪ߪ ࠫ࠰ࡊࡠࠠ 300 mg 150 mg 0.85 0.86 0.93 24 ଀ ޿ߥ߆ߞߚ ࠪ࡞ࡈࡑ࡞ q.d. q.d (0.73~0.99) (0.76~0.98) (0.78~1.11) 34) ㉄Ⴎ ࠛࠬࠪ࠲ࡠ 10 mg 150 mg 0.80 0.75 0.68 20 ଀ ࡊ࡜ࡓ 36) q.d. q.d (0.71~0.89) (0.68~0.83) (0.59~0.79) ޣ⮎ ല ⮎ ℂޤ ࡝ࡈࠔࡦࡇ 600 mg 200 mg 1.31 0.52 0.08 39) 21 ଀ 1㧚૞↪ᯏᐨ 2) q.d. q.d (1.03~1.66) (0.41~0.67) (0.06~0.11) ࠪࡦ 䉲䊜䊒䊧䊎䊦䈲䇮HCV 䈱ⶄ⵾䈮ᔅ㗇䈪䈅䉎NS3/4A 䊒䊨䊁䉝䊷䉷 ࠛࡈࠔࡆ࡟ 600 mg 150 mg 0.49 0.29 0.09 24 ଀ ࡦ࠷ 1) q.d. q.d (0.44~0.54) (0.26~0.33) (0.08~0.12) 䉕㒖ኂ䈜䉎䇯HCV genotype 1a ෸䈶 1b 䈱 NS3/4A 䊒䊨䊁䉝䊷䉷 q.d.㧦1 ᣣ 1 ࿁㧘b.i.d.㧦1 ᣣ 2 ࿁㧘t.i.d.㧦1 ᣣ 3 ࿁ ᵴᕈ䈮ኻ䈜䉎䉲䊜䊒䊧䊎䊦䈱㉂⚛㒖ኂቯᢙ䋨Ki䋩䈲䇮䈠䉏䈡䉏 a) ᧄ೷ 150 mg න⁛ᛩਈߒߚߣ߈ߩࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒࡄ࡜ࡔ࡯࠲ߣᲧセ 0.5 ෸䈶 1.4 nmol/L 䈪䈅䈦䈢䇯

38) 6㧚QT/QTc 㑆㓒ߦኻߔࠆᓇ㗀㧔ᄖ࿖ੱᚑ❣㧕 2㧚In vitro ᛫ HCV ᵴᕈ 40), 41), 42) ᄖ࿖ੱஜᐽᚑੱ㧔60 ଀㧕ߦᧄ೷ 150 mg ෸߮ 350 mg ࠍ 1 ᣣ 䊧䊘䊷䉺䊷ㆮવሶ䉕⚵䉂ㄟ䉖䈣 HCV genotype 1b 䊧䊒䊥䉮䊮⚦ 1 ࿁ 7 ᣣ㑆෻ᓳ⚻ญᛩਈߒߚߣ߈ޔ޿ߕࠇߩ↪㊂ߢ߽ QTc ⢩䈱 RNA ⶄ⵾䈮ኻ䈜䉎䉲䊜䊒䊧䊎䊦䈱 50%෸䈶 90%᦭ലỚᐲ 㑆㓒㧔Fridericia ᴺ㧕ߦኻߒ᦭ᗧߥᓇ㗀ࠍ෸߷ߐߥ߆ߞߚޕ 䋨EC50 ෸䈶 EC90䋩䈲䇮䈠䉏䈡䉏 9.4 ෸䈶 19 nmol/L 䈪䈅䈦䈢䇯

HCV genotype 1a ෸䈶1b ⥃ᐥಽ㔌ᩣ䈱䊧䊒䊥䉮䊮⚦⢩䈮ኻ䈜䉎 ޣ⥃ ᐥ ᚑ ❣ޤ 䉲䊜䊒䊧䊎䊦䈱ਛᄩ୯ fold change䋨FC䋺⥃ᐥಽ㔌ᩣ䈮ኻ䈜䉎䉲

䊜䊒䊧䊎䊦䈱 EC50 / ㊁↢ᩣ䈮ኻ䈜䉎䉲䊜䊒䊧䊎䊦䈱 EC50䋩䈲䇮䈠 1㧚 ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2a㧔ㆮવሶ⚵឵߃㧕෸߮ 䉏䈡䉏 1.4 ෸䈶 0.4 䈪䈅䈦䈢䇯Q80K 䈱ㆮવሶᄙဳ䉕ᜬ䈧 12), 13), 14) ࡝ࡃࡆ࡝ࡦߣߩ 3 ೷૬↪ genotype 1a ෸䈶 1b ⥃ᐥಽ㔌ᩣ䈱䊧䊒䊥䉮䊮⚦⢩䈮ኻ䈜䉎䉲䊜 ࠫࠚࡁ࠲ࠗࡊ I ߆ߟ㜞࠙ࠗ࡞ࠬ㊂㧔ࠦࡃࠬ TaqMan HCVޟࠝ 䊒䊧䊎䊦䈱ਛᄩ୯ FC 䈲䇮䈠䉏䈡䉏 11䋨33 ᩣ䋩෸䈶 8.4䋨2 ᩣ䋩䈪

JEDI_DEV00 \ 0900fde980405154 3.1 2013-09-03 11:46 ࡯࠻ޠ㧦5.0 Log IU/mL એ਄㧕ߩ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߣ 䈅䈦䈢䇯 ߒߡޔᧄ೷㧔12 ㅳ㑆ᛩਈ㧕ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈ HCV genotype 2䋬3 ෸䈶 4 ⥃ᐥಽ㔌ᩣ䈱䊧䊒䊥䉮䊮⚦⢩䈮ኻ䈜 ࠔ̃2a㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦ㧔24 ㅳ㑆ᛩਈ㧕ߩ 3 䉎䉲䊜䊒䊧䊎䊦䈱ਛᄩ୯ FC 䈲䇮䈠䉏䈡䉏 25䋨4 ᩣ䋩䇮1014䋨2 ᩣ䋩 ೷૬↪ߦࠃࠆ⥃ᐥ⹜㛎ࠍታᣉߒߚޕ ෸䈶 0.3䋨8 ᩣ䋩䈪䈅䈦䈢䇯 ㆊ෰ߦࠗࡦ࠲࡯ࡈࠚࡠࡦ≮ᴺࠍฃߌߚߎߣߩߥ޿㧔ೋ࿁ᴦ 50%䊍䊃ⴊᷡᷝടᤨ䈱䉲䊜䊒䊧䊎䊦䈱 EC50 䈲䇮2.4 ୚䈪䈅䈦䈢䇯 ≮㧕ᖚ⠪ߦ߅ߌࠆᛩਈ⚳ੌᓟ 12 ㅳߩ HCV RNA 㒶ᕈൻ₸ߪޔ 䉲䊜䊒䊧䊎䊦䈫䉟䊮䉺䊷䊐䉢䊨䊮䇮䊥䊋䊎䊥䊮䇮NS5A 㒖ኂ⮎෶䈲 ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2a㧔ㆮવሶ⚵឵߃㧕෸߮ NS5B 㒖ኂ⮎䈫䈱૬↪䈮䉋䉍䇮⋧ട෶䈲⋧ਸ਼⊛䈭᛫䉡䉟䊦䉴ᵴ ࡝ࡃࡆ࡝ࡦ㧔48 ㅳ㑆ᛩਈ㧕ߩ 2 ೷૬↪⟲߇ 61.7%㧔37/60 ଀㧕ޔ ᕈ䈏⹺䉄䉌䉏䈢䇯 ᧄ೷ࠍᛩਈߒߚ 3 ೷૬↪⟲ߢߪ 88.6%㧔109/123 ଀㧕ߢ޽ࠅޔ ⛔⸘ቇ⊛ߦ᦭ᗧߢ޽ߞߚ㧔ᐕ㦂෸߮ IL28B ㆮવሶᄙဳࠍጀ 3㧚⮎೷⠴ᕈ 41), 43), 44) ߣߒߚ Cochran-Mantel-Haenszel ᬌቯ㧘p<0.0001㧕ޕ߹ߚޔᛩ HCV genotype 1a ෸䈶1b 䊧䊒䊥䉮䊮⚦⢩䉕↪䈇䈢䉲䊜䊒䊧䊎䊦䈱 ਈ⚳ੌᓟ 24 ㅳߩ HCV RNA 㒶ᕈൻ₸ߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚ in vitro ⠴ᕈ⊒⃻⹜㛎䈮䈍䈇䈩䇮䉲䊜䊒䊧䊎䊦䈮䉋䈦䈩ㆬᛯ䈘䉏 ࡠࡦ ࠕ࡞ࡈࠔ̃2a㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦ㧔48 ㅳ 䈢 96䋦䈱䉝䊚䊉㉄㈩೉䈲䇮NS3 䊒䊨䊁䉝䊷䉷㗔ၞ䈱 43䋬80䋬155䋬 㑆ᛩਈ㧕ߩ 2 ೷૬↪⟲߇ 56.7%㧔34/60 ଀㧕ޔᧄ೷ࠍᛩਈߒ 156 ෸䈶 168 ૏䈮 1 ▎ᚲએ਄䈱ᄌ⇣䈏⹺䉄䉌䉏䈢䇯䈖䈱䈉䈤 ߚ 3 ೷૬↪⟲ߢߪ 88.6%㧔109/123 ଀㧕ߢ޽ߞߚޕ D168 䈱ᄌ⇣䈏ᦨ䉅㜞㗫ᐲ䈮䉂䉌䉏䈢䋨78%䋩䇯 ㆊ෰ߩࠗࡦ࠲࡯ࡈࠚࡠࡦ≮ᴺ╬ߩᓟߦౣΆߒߚ㧔೨ᴦ≮ౣ ㇱ૏․⇣⊛ᄌ⇣䋨SDM䋺site directed mutant䋩෸䈶⥃ᐥಽ㔌ᩣ Ά㧕ᖚ⠪ߦ߅ߌࠆᛩਈ⚳ੌᓟ 12 ㅳ෸߮ 24 ㅳߩ HCV RNA 䈱䊧䊒䊥䉮䊮⚦⢩䉕↪䈇䈩䉲䊜䊒䊧䊎䊦䈱᛫䉡䉟䊦䉴ᵴᕈ䉕ᬌ⸛ 㒶ᕈൻ₸ߪߘࠇߙࠇ 95.9%㧔47/49 ଀㧕෸߮ 89.8%㧔44/49 䈚䈢䈫䈖䉐䇮43䋬80䋬122䋬155䋬156 ෸䈶 168 ૏䈱䉝䊚䊉㉄ᄌ⇣䈮 ଀㧕ޔㆊ෰ߩࠗࡦ࠲࡯ࡈࠚࡠࡦ≮ᴺ╬߇ήലߛߞߚ㧔೨ᴦ≮ 䉋䈦䈩䉲䊜䊒䊧䊎䊦䈮ኻ䈜䉎ᗵฃᕈૐਅ䈏䉂䉌䉏䈢䇯D168A/V ήല㧕ᖚ⠪ߦ߅ߌࠆᛩਈ⚳ੌᓟ 12 ㅳ෸߮ 24 ㅳߩ HCV RNA ෸䈶 R155K 䈱ᄌ⇣䈲䇮䉲䊜䊒䊧䊎䊦䈮ኻ䈚䈩㜞ᐲ⠴ᕈ䋨FCt50䋩䇮 㒶ᕈൻ₸ߪߘࠇߙࠇ 52.8%㧔28/53 ଀㧕෸߮ 50.9%㧔27/53 Q80K/R䋬S122R ෸䈶 D168E 䈱ᄌ⇣䈲シᐲ⠴ᕈ䋨FC!2䌾 50䋩 ଀㧕ߢ޽ߞߚޕ 䈪䈅䉍䇮Q80G/L ෸䈶 S122G/N/T 䈱䉝䊚䊉㉄ᄌ⇣䈲ᗵฃᕈ䈮ᓇ 㗀䉕෸䈿䈘䈭䈎䈦䈢䋨FCd2䋩䇯䉲䊜䊒䊧䊎䊦䈱᛫䉡䉟䊦䉴ᵴᕈ䈮 ⴫ 8 ࿖ౝ╙Υ⋧⥃ᐥ⹜㛎ᚑ❣㧔ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2a㧔ㆮ ᄢ䈐䈭ᓇ㗀䉕෸䈿䈘䈭䈇 80䋬122䋬155 ෸䈶 168 ૏䉝䊚䊉㉄䈱න વሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣߩ 3 ೷૬↪㧕 ⁛ᄌ⇣䉅䇮ᄙ㊀ᄌ⇣䈮䉋䈦䈩䉲䊜䊒䊧䊎䊦䈮ኻ䈚䈩㜞ᐲ⠴ᕈ HCV RNA 㒶ᕈൻ₸ ೨ᴦ≮ᱧ ᛩਈ⚳ੌᓟ 12 ㅳ ᛩਈ⚳ੌᓟ 24 ㅳ 䋨FCt50䋩䈏䉂䉌䉏䈢䇯 ೋ࿁ᴦ≮*1 88.6%㧔109/123 ଀㧕 88.6%㧔109/123 ଀㧕 ೨ᴦ≮ౣΆ 95.9%㧔47/49 ଀㧕 89.8%㧔44/49 ଀㧕 ޣ᦭ലᚑಽߦ㑐ߔࠆℂൻቇ⊛⍮⷗ޤ ೨ᴦ≮ήല*1 52.8%㧔28/53 ଀㧕 50.9%㧔27/53 ଀㧕 ৻⥸ฬ㧦ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ㧔JAN) *1 1 ଀㧔ೋ࿁ᴦ≮㧕෸߮ 2 ଀㧔೨ᴦ≮ήല㧕ߪޔᛩਈ⛮⛯ၮḰ㧔ޟ4 ㅳ ൻቇฬ㧦 ߩⴊẏਛ HCV RNA ㊂߇ 1.2 Log IU/mL ᧂḩ෶ߪ㒶ᕈൻޔ෸߮ 12 ㅳߩ

㪄㩷㪌㩷㪄㩷 Monosodium (cyclopropylsulfonyl)[(2R,3aR,10Z,11aS,12aR, 28) ࠪࡔࡊ࡟ࡆ࡞ߩ࠻࡜ࡦࠬࡐ࡯࠲࡯ߦ㑐ߔࠆᬌ⸛㧔␠ౝ⾗ᢱ 14aR)-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)-1,3-thiazol- 1986_0029247㧕 29) ࠪࡔࡊ࡟ࡆ࡞ߩ࠻࡜ࡦࠬࡐ࡯࠲࡯ߦ㑐ߔࠆᬌ⸛㧔␠ౝ⾗ᢱ 2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo-1,2,3,3a,4,5,6,7,8,9 NC275㧕 ,11a,12,12a,13,14,14a-hexadecahydrocyclopenta[c]cyclopropa 30) ࠪࡔࡊ࡟ࡆ࡞ߩ࠻࡜ࡦࠬࡐ࡯࠲࡯ߦ㑐ߔࠆᬌ⸛㧔␠ౝ⾗ᢱ [g][1,6]diazacyclotetradecine-12a-carbonyl]azanide NC239㧕 ಽሶᑼ㧦C38H46N5NaO7S2 31) ࠪࡔࡊ࡟ࡆ࡞ߩ࠻࡜ࡦࠬࡐ࡯࠲࡯ߦ㑐ߔࠆᬌ⸛㧔␠ౝ⾗ᢱ ಽሶ㊂㧦771.92 NC242㧕 ൻቇ᭴ㅧᑼ㧦 32) ࠪࡔࡊ࡟ࡆ࡞ߩ⚦⢩⤑ㅘㆊᕈߦ㑐ߔࠆᬌ⸛㧔␠ౝ⾗ᢱ O NC113㧕 CH O S O 3 33) ࠪࡔࡊ࡟ࡆ࡞ߩ⋧੕૞↪ߩᬌ⸛㧔␠ౝ⾗ᢱ C107㧕 CH 34) ࡝࡞ࡇࡆ࡝ࡦ෶ߪ࠹ࡁࡎࡆ࡞ߣࠪࡔࡊ࡟ࡆ࡞ߩ⋧੕૞↪ߩᬌ O NNa 3 O ⸛㧔␠ౝ⾗ᢱ C114㧕 H N 35) ࠛ࠴࠾࡞ࠛࠬ࠻࡜ࠫࠝ࡯࡞/ࡁ࡞ࠛ࠴ࠬ࠹ࡠࡦߣࠪࡔࡊ࡟ࡆ࡞ N H CH ߩ⋧੕૞↪ߩᬌ⸛㧔␠ౝ⾗ᢱ C124㧕 H N 3 H O 36) ࠛࠬࠪ࠲ࡠࡊ࡜ࡓߣࠪࡔࡊ࡟ࡆ࡞ߩ⋧੕૞↪ߩᬌ⸛㧔␠ౝ⾗ᢱ H S CH3 C112㧕 37) ࡔࠨ࠼ࡦߩ⮎‛േᘒߦ෸߷ߔࠪࡔࡊ࡟ࡆ࡞ߩᓇ㗀ߩᬌ⸛㧔␠ౝ N O ⾗ᢱ C110㧕 CH3  38) ࠪࡔࡊ࡟ࡆ࡞ߩ QT 㑆㓒ߦኻߔࠆ૞↪ߩᬌ⸛㧔␠ౝ⾗ᢱ C117㧕 ᕈ ⁁㧦⊕⦡ߩ☳ᧃ 39) HCV NS3/4A ࡊࡠ࠹ࠕ࡯࠯ߦኻߔࠆࠪࡔࡊ࡟ࡆ࡞ߩ㉂⚛㒖ኂ૞ ṁ⸃ᕈ㧦N,N-ࠫࡔ࠴࡞ࡎ࡞ࡓࠕࡒ࠼෸߮ࠕ࠮࠻ࡦߦṁߌ߿ߔߊޔࠛ ↪㧔␠ౝ⾗ᢱ BiochemActivity-AVMR㧕 ࠲ࡁ࡯࡞㧔99.5㧕ߦ߿߿ṁߌ߿ߔߊޔ᳓ߦṁߌߦߊ޿ޕ 40) HCV ࡟ࡊ࡝ࠦࡦ⚦⢩ߦኻߔࠆࠪࡔࡊ࡟ࡆ࡞ߩ᛫࠙ࠗ࡞ࠬ૞↪ 4 ಽ㈩ଥᢙ㧦D>1.07˜10 㧔1-ࠝࠢ࠲ࡁ࡯࡞/pH2.0 ࠢࠛࡦ㉄✭ⴣᶧ㧕 㧔␠ౝ⾗ᢱ Replicon-AVMR㧕 4  D>1.07˜10 㧔1-ࠝࠢ࠲ࡁ࡯࡞/pH4.0 ࠢࠛࡦ㉄Ⴎ㉄✭ⴣ 41) HCV ⥃ᐥಽ㔌ᩣ࡟ࡊ࡝ࠦࡦ⚦⢩ߦኻߔࠆࠪࡔࡊ࡟ࡆ࡞ߩ᛫࠙ ᶧ㧕 ࠗ࡞ࠬ૞↪㧔␠ౝ⾗ᢱ ClinicalIsolates-AVMR㧕 4  D>1.07˜10 㧔1-ࠝࠢ࠲ࡁ࡯࡞/pH7.0 ࡝ࡦ㉄✭ⴣᶧ㧕 42) ࠪࡔࡊ࡟ࡆ࡞ߣઁߩ᛫ HCV ⮎ߣߩ૬↪૞↪㧔␠ౝ⾗ᢱ Combination-AVMR㧕 ޣขࠅᛒ޿਄ߩᵈᗧޤ 43) ࠪࡔࡊ࡟ࡆ࡞ߦኻߔࠆ in vitro ⠴ᕈ⊒⃻⹜㛎㧔␠ౝ⾗ᢱ ዊఽߩᚻߩዯ߆ߥ޿ᚲߦ଻▤ߔࠆߎߣޕ IVS-AVMR㧕 44) ㇱ૏․⇣⊛ᄌ⇣࡟ࡊ࡝ࠦࡦ⚦⢩ߦኻߔࠆࠪࡔࡊ࡟ࡆ࡞ߩ᛫࠙ ޣ൮ ⵝޤ ࠗ࡞ࠬ૞↪㧔␠ౝ⾗ᢱ SDM-AVMR㧕 14 ࠞࡊ࠮࡞㧔7 ࠞࡊ࠮࡞㨤2㧕

ޣਥⷐᢥ₂෸߮ᢥ₂⺧᳞వޤ ޛᢥ₂⺧᳞వ࡮⵾ຠᖱႎ߅໧޿วࠊߖవޜ ਥⷐᢥ₂ߦ⸥タߩ␠ౝ⾗ᢱߦߟ߈߹ߒߡ߽ਅ⸥ߦߏ⺧᳞ߊߛߐ޿ޕ ޛਥⷐᢥ₂ޜ

1) ࠛࡈࠔࡆ࡟ࡦ࠷෶ߪ࡜࡞࠹ࠣ࡜ࡆ࡞ߣࠪࡔࡊ࡟ࡆ࡞ߩ⋧੕૞↪ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑᩣᑼળ␠ ࡔ࠺ࠖࠞ࡞ࠗࡦࡈࠜࡔ࡯࡚ࠪࡦ࠮ࡦ࠲࡯ ߩᬌ⸛㧔␠ౝ⾗ᢱ C123㧕 ޥ101-0065 ᧲੩ㇺජઍ↰඙⷏␹↰ 3-5-2 2) ࡝ࡈࠔࡦࡇࠪࡦߣࠪࡔࡊ࡟ࡆ࡞ߩ⋧੕૞↪ߩᬌ⸛㧔␠ౝ⾗ᢱ ࡈ࡝࡯࠳ࠗࡗ࡞ 0120-23-6299 C105㧕 FAX 03-4411-5031 3) ࡝࠻࠽ࡆ࡞ߣࠪࡔࡊ࡟ࡆ࡞ߩ⋧੕૞↪ߩᬌ⸛㧔␠ౝ⾗ᢱ C104㧕 ฃઃᤨ㑆 9:00㨪17:40㧔࿯࡮ᣣ࡮␸ᣣࠍ㒰ߊ㧕 4) ࠛ࡝ࠬࡠࡑࠗࠪࡦ෶ߪ࠳࡞࠽ࡆ࡞/࡝࠻࠽ࡆ࡞ߣࠪࡔࡊ࡟ࡆ࡞ߩ ⋧੕૞↪ߩᬌ⸛㧔␠ౝ⾗ᢱ C115㧕 5) ࠪࠢࡠࠬࡐ࡝ࡦ෸߮࠲ࠢࡠ࡝ࡓࠬߩ⮎‛േᘒߦ෸߷ߔࠪࡔࡊ࡟ ࡆ࡞ߩᓇ㗀ߩᬌ⸛㧔␠ౝ⾗ᢱ C120㧕 JEDI_DEV00 \ 0900fde980405154 3.1 2013-09-03 11:46 6) ࠕ࠻࡞ࡃࠬ࠲࠴ࡦ෶ߪࠪࡦࡃࠬ࠲࠴ࡦߩ⮎‛േᘒߦ෸߷ߔࠪࡔ ࡊ࡟ࡆ࡞ߩᓇ㗀ߩᬌ⸛㧔␠ౝ⾗ᢱ HPC1006㧕  7) ࠫࠧࠠࠪࡦ෶ߪࡠࠬࡃࠬ࠲࠴ࡦߣࠪࡔࡊ࡟ࡆ࡞ߩ⋧੕૞↪ߩᬌ AN

⸛㧔␠ౝ⾗ᢱ C108㧕 8) ࠪࡔࡊ࡟ࡆ࡞ߩ↢ᱺ⊒↢Ქᕈ⹜㛎㧔␠ౝ⾗ᢱ NC188㧕 9) ࠪࡔࡊ࡟ࡆ࡞ߩ↢ᱺ⊒↢Ქᕈ⹜㛎㧔␠ౝ⾗ᢱ NC189㧕 10) ࠪࡔࡊ࡟ࡆ࡞ߩ↢ᱺ⊒↢Ქᕈ⹜㛎㧔␠ౝ⾗ᢱ NC224㧕 11) ࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒߦ෸߷ߔ㘩੐ߩᓇ㗀ߩᬌ⸛㧔␠ౝ⾗ᢱ HPC1007㧕 12) ࿖ౝ╙ III ⋧⹜㛎ᚑ❣㧔␠ౝ⾗ᢱ HPC3003㧕 13) ࿖ౝ╙ III ⋧⹜㛎ᚑ❣㧔␠ౝ⾗ᢱ HPC3004㧕 14) ࿖ౝ╙ III ⋧⹜㛎ᚑ❣㧔␠ౝ⾗ᢱ HPC3008㧕 15) ࿖ౝ╙ III ⋧⹜㛎ᚑ❣㧔␠ౝ⾗ᢱ HPC3010㧕 16) ࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒߩᬌ⸛㧔␠ౝ⾗ᢱ C113㧕 17) ࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒߩᬌ⸛㧔␠ౝ⾗ᢱ C126㧕 18) ࿖ౝ╙ II ⋧⹜㛎ᚑ❣㧔␠ౝ⾗ᢱ C215㧕 19) ᶏᄖᓟᦼ╙ II ⋧⹜㛎ᚑ❣㧔␠ౝ⾗ᢱ C205㧕 20) ᶏᄖᓟᦼ╙ II ⋧⹜㛎ᚑ❣㧔␠ౝ⾗ᢱ C206㧕 21) ࠪࡔࡊ࡟ࡆ࡞ߩߚࠎ⊕⚿วߦ㑐ߔࠆᬌ⸛㧔␠ౝ⾗ᢱ NC202㧕 22) ⣢ᯏ⢻㓚ኂᖚ⠪ߩⴊẏࠍ↪޿ߚࠪࡔࡊ࡟ࡆ࡞ߩߚࠎ⊕⚿วߦ 㑐ߔࠆᬌ⸛㧔␠ౝ⾗ᢱ FK10224㧕 23) ⢄ᯏ⢻㓚ኂᖚ⠪ߩⴊẏࠍ↪޿ߚࠪࡔࡊ࡟ࡆ࡞ߩߚࠎ⊕⚿วߦ 㑐ߔࠆᬌ⸛㧔␠ౝ⾗ᢱ 1986_0045257㧕 24) ࠪࡔࡊ࡟ࡆ࡞ߩ in vitro ઍ⻢㉂⚛ߦ㑐ߔࠆᬌ⸛㧔␠ౝ⾗ᢱ NC116㧕 25) ࠪࡔࡊ࡟ࡆ࡞ߩ⮎‛േᘒߩᬌ⸛㧔␠ౝ⾗ᢱ C103㧕 26) ࠪࡔࡊ࡟ࡆ࡞ߩ in vitro ㉂⚛⺃ዉߦ㑐ߔࠆᬌ⸛㧔␠ౝ⾗ᢱ NC121㧕 27) ࠪࡔࡊ࡟ࡆ࡞ߩ in vitro ㉂⚛㒖ኂߦ㑐ߔࠆᬌ⸛㧔␠ౝ⾗ᢱ NC117㧕

㪄㩷㪍㩷㪄㩷 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

⋡ᰴ 1.8 ᷝઃᢥᦠ㧔᩺㧕 ...... 3 1.8.1 ല⢻࡮ലᨐ㧔᩺㧕෸߮ߘߩ⸳ቯᩮ᜚ ...... 3 1.8.1.1 ല⢻࡮ലᨐ㧔᩺㧕 ...... 3 1.8.1.2 ല⢻࡮ലᨐ㧔᩺㧕ߩ⸳ቯᩮ᜚ ...... 3 1.8.2 ↪ᴺ࡮↪㊂㧔᩺㧕෸߮ߘߩ⸳ቯᩮ᜚ ...... 4 1.8.2.1 ↪ᴺ࡮↪㊂㧔᩺㧕 ...... 4 1.8.2.2 ↪ᴺ࡮↪㊂㧔᩺㧕ߩ⸳ቯᩮ᜚ ...... 4 1.8.3 ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕෸߮ߘߩ⸳ቯᩮ᜚ ...... 7 1.8.3.1 ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕 ...... 7 1.8.3.2 ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕ߩ⸳ቯᩮ᜚ ...... 7 1.8.4 ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕෸߮ߘߩ⸳ቯᩮ᜚ ...... 8 1.8.4.1 ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕 ...... 8 1.8.4.2 ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕ߩ⸳ቯᩮ᜚ ...... 8 1.8.5 ૶↪਄ߩᵈᗧ㧔᩺㧕෸߮ߘߩ⸳ቯᩮ᜚ ...... 11

JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55

1 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55

2 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

1.8 ᷝઃᢥᦠ㧔᩺㧕

1.8.1 ല⢻࡮ലᨐ㧔᩺㧕෸߮ߘߩ⸳ቯᩮ᜚

1.8.1.1 ല⢻࡮ലᨐ㧔᩺㧕 ࠮ࡠࠣ࡞࡯ࡊ 1㧔ࠫࠚࡁ࠲ࠗࡊ I㧔1a㧕෶ߪ II㧔1b㧕㧕ߩ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆᰴߩ޿ߕࠇ ߆ߩ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ 1㧕 ⴊਛ HCV RNA ㊂߇㜞୯ߩᧂᴦ≮ᖚ⠪

2㧕 ࠗࡦ࠲࡯ࡈࠚࡠࡦࠍ฽߻ᴦ≮ᴺߢήല෶ߪౣΆߣߥߞߚᖚ⠪

1.8.1.2 ല⢻࡮ലᨐ㧔᩺㧕ߩ⸳ቯᩮ᜚

ല⢻࡮ലᨐ㧔᩺㧕ߪ㧘ਥߦ㧘Genotype 1 ဳ㜞࠙ࠗ࡞ࠬ㊂㧔ⴊẏਛ HCV RNA ߇ 5.0 Log IU/mL એ਄㧕ߩ C ဳᘟᕈ⢄Ἳߩೋ࿁ᴦ≮ᖚ⠪㧘೨ᴦ≮ౣΆᖚ⠪෸߮೨ᴦ≮ήലᖚ⠪ࠍኻ⽎ߣߒߡ㧘 TMC435 100 mg 1 ᣣ 1 ࿁ࠍࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦࠕ࡞ࡈࠔ-2a㧔PegIFNĮ-2a㧕෸߮࡝ࡃࡆ࡝ࡦ 㧔RBV㧕ߣ૬↪ᛩਈߒߚ࿖ౝ╙ III ⋧⹜㛎㧔HPC3003㧘HPC3008 ෸߮ HPC3004 ⹜㛎㧕ߦࠃࠅ㧘᦭ ലᕈ෸߮ᔋኈᕈ߇⏕⹺ߐࠇߚߎߣߦၮߠ޿ߡ⸳ቯߒߚޕ࿖ౝ╙ III ⋧⹜㛎ߩ⚿ᨐࠍએਅߦ␜ߔ ޣ2.7.3.3.2.1(1)1)ޤޣ2.7.6.30ޤޣ2.7.6.31ޤޣ2.7.6.32ޤޕ к ೋ࿁ᴦ≮଀ߩᛩਈ⚳ੌᤨ෸߮ᛩਈ⚳ੌᓟ 12 ㅳߩᜬ⛯⊛࠙ࠗ࡞ࠬ㒶ᕈൻ₸㧔SVR12 ₸㧧ਥ ⷐ⹏ଔ㗄⋡㧕ߪ㧘TMC435 ⟲ 88.6%㧘ࡊ࡜࠮ࡏ⟲ 61.7%ߢ޽ߞߚޕᐕ㦂෸߮ IL28B ㆮવሶ ᄙဳࠍጀ೎࿃ሶߣߒߡ⺞ᢛߒߚ⵬ᱜ୯ߩ⟲㑆Ꮕߪ⛔⸘ቇ⊛ߦ᦭ᗧ㧔p<0.0001㧘Cochran- Mantel-Haenszel ᬌቯ㧕ߢ޽ࠅ㧘ࡊ࡜࠮ࡏ⟲ߦኻߔࠆ TMC435 ⟲ߩఝ⿧ᕈ߇ᬌ⸽ߐࠇߚ 㧔HPC3003 ⹜㛎㧕ޕ JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55 к ೨ᴦ≮ౣΆ଀ߩ SVR12 ₸㧔ਥⷐ⹏ଔ㗄⋡㧕ߪ 95.9%ߢ޽ࠅ㧘೨ᴦ≮ౣΆ଀ߦኻߔࠆࡍࠣ ࠗࡦ࠲࡯ࡈࠚࡠࡦ㧔PegIFN㧕෸߮ RBV ߩ 48 ㅳᛩਈߦࠃࠆౣᴦ≮ߩ⥃ᐥᚑ❣ߦၮߠߊᦼᓙ ᦭ല₸㨇ᛩਈ⚳ੌᤨ෸߮ᛩਈ⚳ੌᓟ 24 ㅳߩᜬ⛯⊛࠙ࠗ࡞ࠬ㒶ᕈൻ₸㧔SVR24 ₸㧕㧦 50%㨉ߣᲧߴߡ㧘᣿ࠄ߆ߦ㜞޿ߎߣ߇␜ߐࠇߚ㧔p<0.0001㧧HPC3008 ⹜㛎㧕ޕ

к ೨ᴦ≮ήല଀ߩ SVR12 ₸㧔ਥⷐ⹏ଔ㗄⋡㧕ߪ㧘TMC435 12 ㅳ⟲ 52.8%㧘TMC435 24 ㅳ⟲ 35.8%ߢ޽ࠅ㧘೨ᴦ≮ήല଀ߦኻߔࠆ PegIFN ෸߮ RBV ߩ 72 ㅳᛩਈߦࠃࠆౣᴦ≮ߩ⥃ᐥᚑ ❣ߦၮߠߊᦼᓙ᦭ല₸㧔SVR24 ₸㧦14%㧕ߣᲧߴߡ㧘޿ߕࠇߩ⟲߽᣿ࠄ߆ߦ㜞޿ߎߣ߇␜ ߐࠇߚ㧔TMC435 12 ㅳ⟲ p<0.0001㧘TMC435 24 ㅳ⟲ p=0.0001㧧HPC3004 ⹜㛎㧕ޕ

к ޿ߕࠇߩⵍ㛎⠪㓸࿅㧔ೋ࿁ᴦ≮଀㧘೨ᴦ≮ౣΆ଀෸߮೨ᴦ≮ήല଀㧕ߢ߽㧘TMC435 100 mg 1 ᣣ 1 ࿁ࠍ 12 ㅳ㑆ᛩਈߒߚߣ߈ߩᔋኈᕈߪ⦟ᅢߢ޽ߞߚ㧔HPC3003㧘HPC3008 ෸߮ HPC3004 ⹜㛎㧕ޕ

࿖ౝ╙ III ⋧⹜㛎ߦ⚵ߺ౉ࠇߚⵍ㛎⠪ߩ HCV genotype ߪ㧘߶ߣࠎߤ߇ 1b ߢ޽ࠅ㧘1a ߪዋᢙߢ ޽ߞߚ߽ߩߩ㧘᦭ലᕈ߇⹺߼ࠄࠇߚ㧔TMC435 ⟲ߩ Genotype 1a ߩⵍ㛎⠪ߢ SVR12 ࠍ㆐ᚑߒߚⵍ 㛎⠪ߪ㧘ೋ࿁ᴦ≮଀ 2/2 ଀㧘೨ᴦ≮ౣΆ଀ 1/1 ଀㧘೨ᴦ≮ήല଀ 1/4 ଀㧕ޕ৻ᣇ㧘Genotype 1 ဳߩ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߣߒߚᶏᄖ╙ II ⋧⹜㛎㧔C205 ෸߮ C206 ⹜㛎㧕ߢߪ㧘Genotype 1a ߩⵍ

3 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

㛎⠪ߩഀวߪ㧘C205 ⹜㛎ߢ 45.2%㧔173/383 ଀㧕㧘C206 ⹜㛎ߢ 41.3%㧔188/455 ଀㧕ߢ޽ࠅ㧘 TMC435 150 mg 1 ᣣ 1 ࿁ࠍ PegIFNĮ-2a ෸߮ RBV ߣ૬↪ᛩਈߔࠆߎߣߦࠃࠅ㧘Genotype 1a ෸߮ 1b ߩ޿ߕࠇߩⵍ㛎⠪ߢ߽㧘ࡊ࡜࠮ࡏ㧔PegIFNĮ-2a ෸߮ RBV ᛩਈ㧕⟲ࠃࠅ㜞޿ SVR ₸߇␜ߐࠇ ߚޣ2.7.3.3.3(3)ޤޕߎࠇࠄߩᶏᄖ╙ II ⋧⹜㛎ߩ⚿ᨐߪ㧘࿖ౝ⹜㛎ߩ⚿ᨐࠍⵣઃߌࠆ߽ߩߢ޽ߞߚޕ ߘߩߚ߼㧘Genotype 1a ߩ࿖ౝ C ဳᘟᕈ⢄Ἳᖚ⠪ߦኻߒߡ߽ห᭽ߩ᦭ലᕈ߇ᦼᓙߢ߈ࠆߣ⠨߃㧘 Genotype 1a ߩ C ဳᘟᕈ⢄Ἳߦߟ޿ߡ߽ല⢻࡮ലᨐ㧔᩺㧕ߦ฽߼ߚޕ ⴊẏਛ HCV RNA ߇ 5.0 Log IU/mL ᧂḩ㧔ૐ࠙ࠗ࡞ࠬ㊂㧕ߩᖚ⠪ߦ㑐ߒߡߪ㧘࿖ౝ╙ III ⋧⹜㛎 ߢߪኻ⽎ߣߒߡ޿ߥ޿ޕⴊẏਛ HCV RNA ߇ 4.0 Log IU/mL ࠍ⿥߃ࠆ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߣ ߒߚᶏᄖ╙ II ⋧⹜㛎㧔C206 ⹜㛎㧕ߢ߽㧘⚵ߺ౉ࠇࠄࠇߚૐ࠙ࠗ࡞ࠬ㊂ߩᖚ⠪ߪ 5 ଀㧔೨ᴦ≮ౣ Ά଀ 1 ଀෸߮೨ᴦ≮ㇱಽ෻ᔕ଀ 4 ଀㧕ߩߺߢ޽ߞߚ㧔Breakthrough ߇⹺߼ࠄࠇߚ೨ᴦ≮ㇱಽ෻ᔕ ଀ 1 ଀ࠍ㒰޿ߡ㧘ᱷࠅ 4 ଀ߪ SVR24 ࠍ㆐ᚑߒߚ㧕ޣ2.5.4.4.6.2ޤޕߒ߆ߒ㧘ౣᴦ≮ࠍⷐߔࠆૐ࠙ ࠗ࡞ࠬ㊂ߩᖚ⠪ߦኻߔࠆᴦ≮ᴺߪ㒢ࠄࠇߡ߅ࠅ㧘TMC435 ߦࠃࠅᣂߚߥᴦ≮ᯏળࠍឭଏߢ߈ࠆߣ

⠨߃㧘ല⢻࡮ലᨐ㧔᩺㧕ߩᣢᴦ≮ᖚ⠪ߢߪ㧘㜞࠙ࠗ࡞ࠬ㊂ߩᖚ⠪ߦ㒢ቯߒߥ߆ߞߚޕ

1.8.2 ↪ᴺ࡮↪㊂㧔᩺㧕෸߮ߘߩ⸳ቯᩮ᜚

1.8.2.1 ↪ᴺ࡮↪㊂㧔᩺㧕 ㅢᏱޔᚑੱߦߪࠪࡔࡊ࡟ࡆ࡞ߣߒߡ 100mg ࠍ 1 ᣣ 1 ࿁⚻ญᛩਈߒޔᛩਈᦼ㑆ߪ 12 ㅳ㑆ߣߔ ࠆޕᧄ೷ߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠ ࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߎߣޕ

1.8.2.2 ↪ᴺ࡮↪㊂㧔᩺㧕ߩ⸳ቯᩮ᜚

1.8.2.2.1 ޡ100 mg ࠍ 1 ᣣ 1 ࿁⚻ญᛩਈߒ㧘ᛩਈᦼ㑆ߪ 12 ㅳ㑆ޢߩ⸳ቯᩮ᜚ JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55 TMC435 ߩ↪ᴺ࡮↪㊂ߦ㑐ߒߡ㧘ᶏᄖߢవⴕߒߡᬌ⸛ࠍ㐿ᆎߒߚޕᶏᄖߢߪ㧘TMC435 න೷ᛩ ਈ㧘ਗ߮ߦ TMC435㧘PegIFNĮ-2a ෸߮ RBV ߩ⍴ᦼ㑆૬↪ᛩਈߦࠃࠆ᛫࠙ࠗ࡞ࠬലᨐࠍ Genotype 1 ဳߩ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߦᬌ⸛ߒߚ C201 ⹜㛎ߩ⚿ᨐߦၮߠ޿ߡ㧘ߘߩᓟߩᶏᄖ⥃ᐥ⹜㛎 ߢߪ㧘TMC435 ࠍ PegIFN ෸߮ RBV ߣ૬↪ᛩਈߔࠆߎߣߣߒ㧘TMC435 ߩᬌ⸛↪㊂ߩ਄㒢ࠍ 150 mg 1 ᣣ 1 ࿁ߣ⸳ቯߒߚޣ2.7.3.4.1(1)ޤޕ ࿖ౝߢ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߣߒߚ⥃ᐥ⹜㛎ࠍ㐿ᆎߔࠆ೨ߦ㧘ᣣᧄੱ෸߮ᄖ࿖ੱߩஜᐽᚑੱ

ߢߩⴊẏਛ TMC435 ߩ AUC24h ࠍᲧセߒߚߣߎࠈ㧘ᣣᧄੱஜᐽᚑੱߦ TMC435 100 mg㧘200 mg ෸

߮ 400 mg ࠍ 1 ᣣ 1 ࿁෻ᓳᛩਈߒߚߣ߈㧔C109 ⹜㛎㧕ߩ AUC24h ߪ㧘ᄖ࿖ੱஜᐽᚑੱ㧔C101 ⹜ 㛎㧕ߣᲧセߒߡ㧘ߘࠇߙࠇ 2.27㧘1.13 ෸߮ 1.62 ୚㜞୯ࠍ␜ߒߚޕߘߩߚ߼㧘ᶏᄖ⥃ᐥ⹜㛎ߢߩ

TMC435 ߩᬌ⸛↪㊂ߩ਄㒢㧔150 mg 1 ᣣ 1 ࿁㧕ߣห⒟ᐲߩ AUC24h ߇ᓧࠄࠇࠆߣផቯߐࠇࠆ 100 mg 1 ᣣ 1 ࿁ࠍ㧘࿖ౝߢߩ TMC435 ߩᬌ⸛↪㊂ߩ਄㒢ߣߒߚޕ ࿖ౝߢߪ㧘߹ߕ㧘Genotype 1 ဳߩ C ဳᘟᕈ⢄Ἳߩೋ࿁ᴦ≮ᖚ⠪ࠍኻ⽎ߦ㧘TMC435 ߩ↪㊂ࠍ 50 ෶ߪ 100 mg 1 ᣣ 1 ࿁㧘TMC435 ߩᛩਈᦼ㑆ࠍ 12 ෶ߪ 24 ㅳ㑆ߣߒߚ╙ II ⋧⹜㛎㧔C215 ⹜㛎㧕ࠍ ታᣉߒߚޕC215 ⹜㛎ߩ⚿ᨐࠍਅ⸥ߦ␜ߔޣ2.7.3.2.2(1)ޤޣ2.7.6.27ޤޕ · ࠦࡦ࠻ࡠ࡯࡞㧔PegIFNĮ-2a ෸߮ RBV㧕⟲ߣᲧߴߡ㧘TMC435 ⟲ߢ㜞޿ SVR24 ₸߇ᓧࠄࠇߚޕ

4 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

· TMC435 ߩ↪㊂㧔50 ෶ߪ 100 mg㧕෸߮ TMC435 ߩᛩਈᦼ㑆㧔12 ෶ߪ 24 ㅳ㑆㧕ߣ SVR ₸ߦ ৻ቯߩ௑ะߪ⹺߼ࠄࠇߥ߆ߞߚޕ

· TMC435 50 mg ⟲ߣᲧߴߡ㧘TMC435 100 mg ⟲ߢᣧᦼߩ᛫࠙ࠗ࡞ࠬലᨐ߇߿߿㜞߆ߞߚޕ

· TMC435 50 mg ෶ߪ 100 mg 1 ᣣ 1 ࿁ࠍ 12 ෶ߪ 24 ㅳ㑆ᛩਈߒߚߣ߈ߩᔋኈᕈߪ⦟ᅢߢ޽ߞߚޕ ⴊਛࡆ࡝࡞ࡆࡦ୯ߩシᐲჇട߇ TMC435 ⟲ߢ⹺߼ࠄࠇߚ߇㧘TMC435 ᛩਈᦼ㑆⚳ੌᓟߦ㧘޿ ߕࠇ߽ࡌ࡯ࠬ࡜ࠗࡦ୯⒟ᐲ߹ߢ࿁ᓳߒߚޕ

ߘߎߢ㧘࿖ౝ╙ III ⋧⹜㛎ߢߩ TMC435 ߩ↪ᴺ࡮↪㊂ࠍ 100 mg 1 ᣣ 1 ࿁ 12 ㅳ㑆ᛩਈߣߒߚޕߚ ߛߒ㧘೨ᴦ≮ήലᖚ⠪ࠍኻ⽎ߣߒߚ HPC3004 ⹜㛎ߢߪ㧘೨ᴦ≮ήല଀߇㧘ೋ࿁ᴦ≮଀෸߮೨ᴦ ≮ౣΆ଀ߣᲧߴߡ IFN ≮ᴺߦኻߔࠆ෻ᔕᕈ߇ૐ޿ߎߣࠍ⠨ᘦߒ㧘TMC435 ߩᛩਈᦼ㑆ࠍ 12 ෶ߪ 24 ㅳ㑆ߣߒߡ㧘೨ᴦ≮ήല଀ߦኻߔࠆ TMC435 ߩᛩਈᦼ㑆ࠍត⚝⊛ߦᬌ⸛ߔࠆߎߣߣߒߚޕ 20 ᱦએ਄ߩ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߦ TMC435 100 mg 1 ᣣ 1 ࿁ 12 ㅳ㑆ᛩਈߩ᦭ലᕈ෸߮቟ో

ᕈࠍᬌ⸛ߒߚ࿖ౝ╙ III ⋧⹜㛎ߩਅ⸥⚿ᨐߦၮߠ޿ߡ㧘TMC435 ߩ↪ᴺ࡮↪㊂㧔᩺㧕ࠍޡㅢᏱ㧘 ᚑੱߦߪࠪࡔࡊ࡟ࡆ࡞ߣߒߡ 100 mg ࠍ 1 ᣣ 1 ࿁⚻ญᛩਈߒ㧘ᛩਈᦼ㑆ߪ 12 ㅳ㑆ߣߔࠆޢߣ⸳ቯ ߒߚޣ2.7.3.3.2.1(1)1)ޤޣ2.7.3.3.2.1(1)2)ޤޣ2.7.6.30ޤޣ2.7.6.31ޤޣ2.7.6.32ޤޣ2.7.6.33ޤޕ к ೋ࿁ᴦ≮଀ߦ TMC435 100 mg 1 ᣣ 1 ࿁ࠍ PegIFNĮ-2a ෸߮ RBV ߣ૬↪ᛩਈߒߚߣ߈ߩ SVR12 ₸㧔ਥⷐ⹏ଔ㗄⋡㧕ߪ㧘TMC435 ⟲ 88.6%㧘ࡊ࡜࠮ࡏ⟲ 61.7%ߢ޽ߞߚޕᐕ㦂෸߮ IL28B ㆮવሶᄙဳࠍጀ೎࿃ሶߣߒߡ⺞ᢛߒߚ⵬ᱜ୯ߩ⟲㑆Ꮕߪ⛔⸘ቇ⊛ߦ᦭ᗧ㧔p<0.0001㧘 Cochran-Mantel-Haenszel ᬌቯ㧕ߢ޽ࠅ㧘ࡊ࡜࠮ࡏ⟲ߦኻߔࠆ TMC435 ⟲ߩఝ⿧ᕈ߇ᬌ⸽ߐ ࠇߚ㧔HPC3003 ⹜㛎㧕ޕ

к ೨ᴦ≮ౣΆ଀ߦ TMC435 100 mg 1 ᣣ 1 ࿁ࠍ PegIFNĮ-2a ෸߮ RBV ߣ૬↪ᛩਈߒߚߣ߈ߩ SVR12 ₸㧔ਥⷐ⹏ଔ㗄⋡㧕ߪ 95.9%ߢ޽ࠅ㧘೨ᴦ≮ౣΆ଀ߦኻߔࠆ PegIFN ෸߮ RBV ߩ 48 ㅳᛩਈߦࠃࠆౣᴦ≮ߩ⥃ᐥᚑ❣ߦၮߠߊᦼᓙ᦭ല₸㧔SVR24 ₸㧦50%㧕ߣᲧߴߡ㧘᣿ࠄ

JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55 ߆ߦ㜞޿ߎߣ߇␜ߐࠇߚ㧔p<0.0001㧧HPC3008 ⹜㛎㧕ޕ

к ೨ᴦ≮ήല଀ߦ TMC435 100 mg 1 ᣣ 1 ࿁ࠍ PegIFNĮ-2a ෸߮ RBV ߣ૬↪ᛩਈߒߚߣ߈ߩ SVR12 ₸㧔ਥⷐ⹏ଔ㗄⋡㧕ߪ㧘TMC435 12 ㅳ⟲ 52.8%㧘TMC435 24 ㅳ⟲ 35.8%ߢ޽ࠅ㧘೨ ᴦ≮ήല଀ߦኻߔࠆ PegIFN ෸߮ RBV ߩ 72 ㅳᛩਈߦࠃࠆౣᴦ≮ߩ⥃ᐥᚑ❣ߦၮߠߊᦼᓙ ᦭ല₸㧔SVR24 ₸㧦14%㧕ߣᲧߴߡ㧘޿ߕࠇߩ⟲߽᣿ࠄ߆ߦ㜞޿ߎߣ߇␜ߐࠇߚ 㧔TMC435 12 ㅳ⟲ p<0.0001㧘TMC435 24 ㅳ⟲ p=0.0001㧧HPC3004 ⹜㛎㧕ޕߥ߅㧘೨ᴦ≮ ήല଀ߦኻߒߡ㧘TMC435 ߩᛩਈᦼ㑆ࠍ 24 ㅳߦᑧ㐳ߒߡ߽㧘SVR ₸ߩะ਄ߪᦼᓙߢ߈ߥ ޿ߎߣ߇␜ໂߐࠇߚ㧔SVR12 ₸㧦TMC435 12 ㅳ⟲ 52.8%㧘TMC435 24 ㅳ⟲ 35.8%㧕ޕ

к ೋ࿁ᴦ≮଀㧘೨ᴦ≮ౣΆ଀෸߮೨ᴦ≮ήല଀ߦ TMC435 ࠍࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦࠕ࡞ࡈࠔ -2b㧔PegIFNĮ-2b㧕෸߮ RBV ߣ૬↪ߒߚߣ߈ߩ SVR12 ₸ߪ㧘TMC435 ࠍ PegIFNĮ-2a ෸߮ RBV ߣ૬↪ߒߚ࿖ౝ╙ III ⋧⹜㛎ߣᄢ߈ߥ㆑޿ߪ⹺߼ࠄࠇߥ߆ߞߚ㧔ೋ࿁ᴦ≮଀ 91.7%㧘 ೨ᴦ≮ౣΆ଀ 100%㧘೨ᴦ≮ήല଀ 38.5%㧧HPC3010 ⹜㛎㧕ޕ

к C ဳᘟᕈ⢄Ἳᖚ⠪ߦ TMC435 100 mg 1 ᣣ 1 ࿁ࠍ 12 ෶ߪ 24 ㅳ㑆ᛩਈߒߚߣ߈ߩᔋኈᕈߪ㧘 ޿ߕࠇߩⵍ㛎⠪㓸࿅㧔ೋ࿁ᴦ≮଀㧘೨ᴦ≮ౣΆ଀෸߮೨ᴦ≮ήല଀㧕ߢ߽㧘૬↪ߔࠆ PegIFN ߩ⒳㘃㧔PegIFNĮ-2a ෶ߪ PegIFNĮ-2b㧕ߦ߆߆ࠊࠄߕ㧘⦟ᅢߢ޽ࠆߣ⠨߃ࠄࠇߚޕ

5 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

ߥ߅㧘࿖ౝ㧔C215 ⹜㛎㧕ߣᶏᄖ㧔C205 ෸߮ C206 ⹜㛎㧕ߩ╙ II ⋧⹜㛎ߩ⚿ᨐࠍᲧセߒߚߣߎ ࠈ㧘ਅ⸥ߩߣ߅ࠅ㧘࿖ౝߢߩ TMC435 ߩ↪ᴺ࡮↪㊂㧔᩺㧕ࠍᡰᜬߔࠆ⚿ᨐ߇ᓧࠄࠇߡ޿ࠆ ޣ2.7.3.2.2ޤޣ2.7.6.27ޤޣ2.7.6.28ޤޣ2.7.6.29ޤޣ2.7.2.3.1.9(1)ޤޣ2.7.2.3.3.2ޤޕ к ᣣᧄੱ C ဳᘟᕈ⢄Ἳߩೋ࿁ᴦ≮ᖚ⠪㧔C215 ⹜㛎㧕ߦ TMC435 100 mg 1 ᣣ 1 ࿁ࠍ 12 ෶ߪ 24 ㅳ㑆ᛩਈߒߚߣ߈ߩ SVR12 ₸ߪ 79.2㨪92.3%㧘ᄖ࿖ੱ C ဳᘟᕈ⢄Ἳߩೋ࿁ᴦ≮ᖚ⠪ 㧔C205 ⹜㛎㧕ߦ TMC435 150 mg 1 ᣣ 1 ࿁ࠍ 12 ෶ߪ 24 ㅳ㑆ᛩਈߒߚߣ߈ߩ SVR12 ₸ߪ 80.5㨪86.1%ߢ޽ࠅ㧘ᣣᧄੱ෸߮ᄖ࿖ੱߩೋ࿁ᴦ≮ᖚ⠪ߢߩ SVR ₸ߦᄢ߈ߥ㆑޿ߪߥ޿ߣ ⠨߃ࠄࠇߚޕ

к ᣣᧄੱ C ဳᘟᕈ⢄Ἳᖚ⠪㧔C215 ⹜㛎㧕ߦ TMC435 100 mg 1 ᣣ 1 ࿁ࠍ 12 ෶ߪ 24 ㅳ㑆ᛩਈ ߒߚߣ߈ߣ㧘ᄖ࿖ੱ C ဳᘟᕈ⢄Ἳᖚ⠪㧔C205 ෸߮ C206 ⹜㛎㧕ߦ TMC435 150 mg 1 ᣣ 1 ࿁ ࠍ 12㧘24 ෶ߪ 48 ㅳ㑆ᛩਈߒߚߣ߈ߩᔋኈᕈߪ⦟ᅢߢ޽ࠆߣ⠨߃ࠄࠇߚޕ

к ᣣᧄੱ C ဳᘟᕈ⢄Ἳᖚ⠪㧔C215 ⹜㛎㧕ߦ TMC435 100 mg 1 ᣣ 1 ࿁ࠍ෻ᓳᛩਈߒߚߣ߈ߩ

Cmax ෸߮ AUC24h ߪ㧘ߘࠇߙࠇ㧘4072 ng/mL ෸߮ 60197 ng㨯h/mL ߢ޽ࠅ㧘ᄖ࿖ੱ C ဳᘟᕈ

⢄Ἳᖚ⠪㧔C205 ෸߮ C206 ⹜㛎㧕ߦ TMC435 150 mg 1 ᣣ 1 ࿁ࠍ෻ᓳᛩਈߒߚߣ߈ߩ Cmax

㧔4394 ng/mL ෸߮ 3953 ng/mL㧕෸߮ AUC24h㧔70090 ng㨯h/mL ෸߮ 59810 ng㨯h/mL㧕ߣห⒟ ᐲߢ޽ߞߚޕ

к ᣣᧄੱ C ဳᘟᕈ⢄Ἳᖚ⠪㧔C215 ⹜㛎㧕ߦ TMC435 50 mg ෶ߪ 100 mg 1 ᣣ 1 ࿁ࠍ෻ᓳᛩਈ ߒߚߣ߈ߣ㧘ᄖ࿖ੱ C ဳᘟᕈ⢄Ἳᖚ⠪ߦ TMC435 75 mg ⧯ߒߊߪ 150 mg 1 ᣣ 1 ࿁㧔C205 ⹜㛎㧕㧘෶ߪ TMC435 100 mg ⧯ߒߊߪ 150 mg 1 ᣣ 1 ࿁㧔C206 ⹜㛎㧕ࠍ෻ᓳᛩਈߒߚߣ߈

ߩ AUC24h ߣ✚ࡆ࡝࡞ࡆࡦߩࡌ࡯ࠬ࡜ࠗࡦ߆ࠄߩᦨᄢᄌൻ㊂ߩ㑐ଥߪ㘃ૃߒߡ޿ߚޕ

ᶏᄖ╙ III ⋧⹜㛎ߩਛ㑆⸃ᨆߩ⚿ᨐ߆ࠄ߽㧘ೋ࿁ᴦ≮ᖚ⠪㧔C208 ෸߮ C216 ⹜㛎㧕෸߮೨ᴦ≮ ౣΆᖚ⠪㧔HPC3007 ⹜㛎㧕ߩ޿ߕࠇߩⵍ㛎⠪㓸࿅ߢ߽㧘TMC435 150 mg ⟲ߩ SVR12 ₸ߪ㧘ࡊ࡜ ࠮ࡏ⟲ߣᲧߴߡ㧘⛔⸘ቇ⊛ߦ᦭ᗧߦ㜞޿୯߇ᓧࠄࠇ㧘ᔋኈᕈ߽⦟ᅢߢ޽ࠆߎߣ߇␜ߐࠇߡ޿ࠆ JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55 ޣ2.7.3.2.4ޤޣ2.7.6.34ޤޣ2.7.6.35ޤޣ2.7.6.36ޤޕ

1.8.2.2.2 ޡPegIFN ෸߮ RBV ߣ૬↪ߔࠆߎߣޢߩ⸳ቯᩮ᜚ ਄ㅀߩߣ߅ࠅ㧘TMC435 න೷ᛩਈ㧘ਗ߮ߦ TMC435㧘PegIFNĮ-2a ෸߮ RBV ߩ⍴ᦼ㑆૬↪ᛩਈ ߦࠃࠆ᛫࠙ࠗ࡞ࠬലᨐࠍ Genotype 1 ဳߩ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߦᬌ⸛ߒߚ C201 ⹜㛎ߩ⚿ᨐߦ ၮߠ޿ߡ㧘ߘߩᓟߩᶏᄖ⥃ᐥ⹜㛎ߢߪ㧘TMC435 ࠍ PegIFN ෸߮ RBV ߣ૬↪ᛩਈߔࠆߎߣߣߒߚ ޣ2.7.3.4.1(1)ޤޕߘߩߚ߼㧘C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߣߒߚ࿖ౝᄖߩ⥃ᐥ⹜㛎ߢߪ㧘TMC435 ࠍ PegIFN ෸߮ RBV ߣ૬↪ߒ㧘PegIFN ෸߮ RBV ߩ↪㊂ߪ㧘2 ೷૬↪≮ᴺߦ߅޿ߡᛚ⹺ߐࠇߡ޿ࠆ ߘࠇߙࠇߩᷝઃᢥᦠߦḰߓߚޣ2.7.3.4.2ޤޕ TMC435 ࠍ PegIFNĮ-2a ෸߮ RBV ߣ૬↪ᛩਈߒߚ࿖ౝ╙ III ⋧⹜㛎㧔HPC3003㧘HPC3008 ෸߮ HPC3004 ⹜㛎㧕㧘ਗ߮ߦ TMC435 ࠍ PegIFNĮ-2b ෸߮ RBV ߣ૬↪ᛩਈߒߚ࿖ౝ╙ III ⋧⹜㛎 㧔HPC3010 ⹜㛎㧕ߦࠃࠅ㧘᦭ലᕈ෸߮ᔋኈᕈ߇⏕⹺ߐࠇߚ㧔1.8.2.2.1㧕ߚ߼㧘ޡᧄ೷ߪ㧘ࡍࠣࠗ ࡦ࠲࡯ࡈࠚࡠࡦࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵ ឵߃㧕㧘෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߎߣޕޢߣߒߚޕ

6 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

1.8.3 ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕෸߮ߘߩ⸳ቯᩮ᜚

1.8.3.1 ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕 1. ᧄ೷ߩ૶↪ߦ޽ߚߞߡߪޔⴊਛ HCV RNA ߇㓁ᕈߢ޽ࠆߎߣޔ෸߮⚵❱௝෶ߪ⢄੍஻⢻ޔ ⴊዊ᧼ᢙ╬ߦࠃࠅޔᘟᕈ⢄Ἳߢ޽ࠆߎߣࠍ⏕⹺ߔࠆߎߣޕ

2. ᧂᴦ≮ᖚ⠪ߦ↪޿ࠆ႐วߪޔⴊਛ HCV RNA ㊂߇ RT-PCR ᴺߢ 5.0 Log IU/mL એ਄ߦ⋧ᒰߔ ࠆߎߣࠍ⏕⹺ߔࠆߎߣޕ

3. ࠗࡦ࠲࡯ࡈࠚࡠࡦࠍ฽߻ᴦ≮ᴺߩ߁ߜޔઁߩࡊࡠ࠹ࠕ࡯࠯㒖ኂ೷ߦࠃࠆᣢᴦ≮଀ߦኻߔࠆ ᛩਈ⚻㛎ߪߥ޿ޕߎࠇࠄߩᖚ⠪ߦኻߒߡߪޔ࠙ࠗ࡞ࠬᕈ⢄∔ᖚߩᴦ≮ߦචಽߥ⍮⼂࡮⚻㛎 ࠍᜬߟකᏧ߇೨ᴦ≮ߩ⒳㘃ޔ೨ᴦ≮ߦኻߔࠆ෻ᔕᕈޔ⠴ᕈᄌ⇣ߩ᦭ήޔᖚ⠪ߩᔋኈᕈ╬ࠍ ⠨ᘦߒߚ਄ߢޔᧄ೷ᛩਈߩนุࠍ್ᢿߔࠆߎߣޕ

1.8.3.2 ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕ߩ⸳ቯᩮ᜚

(1) ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕1 ߩ⸳ቯᩮ᜚ TMC435 ࠍ૶↪ߔࠆ೨ߦ㧘C ဳᘟᕈ⢄Ἳߩ⸻ᢿࠍⴕ߁ᔅⷐ߇޽ࠆᣦࠍᵈᗧ༐⿠ߔࠆߚ߼ߦ⸳ቯ ߒߚޕ

(2) ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕2 ߩ⸳ቯᩮ᜚ ೋ࿁ᴦ≮ᖚ⠪ߦኻߔࠆ૶↪ߪ㧘㜞࠙ࠗ࡞ࠬ㊂ߩᖚ⠪ߦ㒢ቯߐࠇߡ޿ࠆᣦࠍᵈᗧ༐⿠ߔࠆߚ߼ߦ ⸳ቯߒߚޕ

JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55 (3) ല⢻࡮ലᨐߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕3 ߩ⸳ቯᩮ᜚ ઁߩ HCV NS3/4A ࡊࡠ࠹ࠕ࡯࠯㒖ኂ೷㧘PegIFN ෸߮ RBV ߩ 3 ೷૬↪≮ᴺ߇ⴕࠊࠇߚᖚ⠪ߦ TMC435 ࠍᛩਈߒߚ⚻㛎ߪߥ޿ޕߘߩߚ߼㧘ߎࠇࠄߩᖚ⠪ߦኻߔࠆ TMC435 ᛩਈߩนุߪ㧘࠙ࠗ ࡞ࠬᕈ⢄∔ᖚߩᴦ≮ߦචಽߥ⍮⼂࡮⚻㛎ࠍᜬߟකᏧ߇㧘೨ᴦ≮ߩ⒳㘃㧘೨ᴦ≮ߦኻߔࠆ෻ᔕᕈ㧘 ⠴ᕈᄌ⇣ߩ᦭ή㧘ᖚ⠪ߩᔋኈᕈ╬ࠍ⠨ᘦߒߚ਄ߢ್ᢿߔࠆࠃ߁ߦᵈᗧ༐⿠ߔࠆߚ߼ߦ⸳ቯߒߚޕ

7 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

1.8.4 ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕෸߮ߘߩ⸳ቯᩮ᜚

1.8.4.1 ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕 1㧕 ᧄ೷ࠍන⁛ᛩਈߒߚ㓙ߩ᦭ലᕈ෸߮቟ోᕈߪ⏕┙ߒߡ޿ߥ޿ޕ

2㧕 ᧄ೷ߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆ߇ޔᦨೋߩ 12 ㅳ㑆ߪ 3 ೷૬↪ ᛩਈߒޔ⛯ߊ 12 ㅳ㑆ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߦࠃࠆ 2 ೷૬↪ᛩਈࠍታᣉ ߔࠆߎߣޕߥ߅ޔᖚ⠪ߩᴦ≮ᱧ߿⢛᥊࿃ሶޔ෸߮ೋᦼߩᴦ≮ലᨐߦᔕߓߡޔߎߩ 2 ೷૬↪ ᛩਈࠍᦝߦ 24 ㅳ㑆ᛩਈߔࠆߎߣࠍ⠨ᘦߔࠆޕߚߛߒޔᧄ೷ߣ૬↪ߔࠆ႐วޔࡍࠣࠗࡦ࠲ ࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߩ✚ᛩਈᦼ㑆ߪ 48 ㅳࠍ⿥߃ߥ޿ߎߣޕ

3㧕 ᴦ≮ਛߩ᛫࠙ࠗ࡞ࠬലᨐ߇ਇචಽߥ႐วޔ⮎೷⠴ᕈ࠙ࠗ࡞ࠬ߇಴⃻ߒߡ޿ࠆߎߣ߇޽ࠆߚ ߼ޔᴦ≮ਛᱛࠍ⠨ᘦߔࠆߎߣޕ

4㧕 ೽૞↪߿ᴦ≮ലᨐਇචಽ╬ߦࠃࠅᧄ೷ࠍਛᱛߒߚ႐วߦߪޔᧄ೷ߩᛩਈࠍౣ㐿ߒߥ޿ߎߣޕ

5㧕 ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕ޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b 㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩᛩਈ㊂ߪޔฦ⵾ຠߩᷝઃᢥᦠߦቯ߼ࠄࠇߚ↪ᴺ࡮↪㊂ ߦᓥ߁ߎߣޕ૬↪ߦ޽ߚߞߡߪޔᛩਈ㐿ᆎ೨ߦฦ⵾ຠߩᷝઃᢥᦠߦቯ߼ࠄࠇߚ⥃ᐥᬌᩏ୯ ၮḰࠍḩߚߒߡ޿ࠆߎߣࠍ⏕⹺ߔࠆߎߣޕ߹ߚޔᛩਈਛߦฦ⵾ຠߩ↪㊂⺞▵߿ᛩਈਛᱛࠍ ᔅⷐߣߔࠆ೽૞↪߇⊒⃻ߒߚ႐วߦߪޔฦ⵾ຠߩᷝઃᢥᦠࠍෳᾖߔࠆߎߣޕ

1.8.4.2 ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕ߩ⸳ቯᩮ᜚ JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55

(1) ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕1 ߩ⸳ቯᩮ᜚ ࿖ౝߢߪ㧘C ဳᘟᕈ⢄Ἳᖚ⠪ߦ TMC435 ࠍන⁛ᛩਈߒߚ⚻㛎ߪߥߊ㧘ᶏᄖߢ߽㧘TMC435 ࠍන ⁛ᛩਈߒߚߣ߈ߩ᦭ലᕈ෸߮቟ోᕈߩᚑ❣ߪ㒢ࠄࠇߡ޿ࠆߚ߼ߦ⸳ቯߒߚޕ

(2) ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕2 ߩ⸳ቯᩮ᜚ ࿖ౝ╙ III ⋧⹜㛎ߦ߅޿ߡ㧘ᄙߊߩⵍ㛎⠪߇ response-guided therapy㧔RGT㧕ၮḰߦᓥߞߡ㧘 PegIFN ෸߮ RBV ߩᛩਈࠍ 24 ㅳߢ⚳ੌߒ㨇ೋ࿁ᴦ≮଀ߢ 91.7㨪91.9%㧔HPC3003 ෸߮ HPC3010 ⹜㛎㧕㧘೨ᴦ≮ౣΆ଀ߢ 95.9㨪96.6%㧔HPC3008 ෸߮ HPC3010 ⹜㛎㧕㧘೨ᴦ≮ήല଀ߢ 73.6㨪 81.1%㧔HPC3004 ⹜㛎㧕㨉㧘ߎࠇࠄߩⵍ㛎⠪ߢߩ SVR12 ₸ߪ㧘ೋ࿁ᴦ≮଀ߢ 90.9㨪92.0%㧘೨ᴦ ≮ౣΆ଀ߢ 95.7㨪100%㧘೨ᴦ≮ήല଀ߢ߽ 48.7㨪60.5%ߢ޽ߞߚޣ2.7.3.4.2ޤޕ ߎࠇࠄߩ⚿ᨐ߆ࠄ㧘૬↪ߔࠆ PegIFN ߩ⒳㘃㧔PegIFNĮ-2a ෶ߪ PegIFNĮ-2b㧕ߦ߆߆ࠊࠄߕ㧘޿ ߕࠇߩᖚ⠪㓸࿅㧔ೋ࿁ᴦ≮ᖚ⠪㧘೨ᴦ≮ౣΆᖚ⠪෸߮೨ᴦ≮ήലᖚ⠪㧕ߦኻߒߡ߽㧘ᄙߊߩᖚ⠪ ߢ 24 ㅳߩ PegIFN ෸߮ RBV ߩᛩਈߢ SVR ߇ᓧࠄࠇࠆߣ⠨߃㧘ޡᦨೋߩ 12 ㅳ㑆ߪ 3 ೷૬↪ᛩਈ

8 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

ߒ㧘⛯ߊ 12 ㅳ㑆ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠ ࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕㧘෸߮࡝ࡃࡆ࡝ࡦߦࠃࠆ 2 ೷૬↪ᛩਈࠍታᣉߔࠆߎߣޢߣߒߚޕ ߒ߆ߒ㧘೨ᴦ≮ήല଀ߩౣΆ₸ߪ㧘ᄙߊߩⵍ㛎⠪߇ RGT ၮḰߦᓥߞߡ PegIFN ෸߮ RBV ߩᛩ ਈࠍ 24 ㅳߢ⚳ੌߒߚ HPC3004 ⹜㛎ߢ 38.6㨪51.1%ߢ޽ߞߚޕߎࠇߦኻߒߡ㧘RGT ၮḰࠍㆡ↪ߖ ߕ㧘PegIFN ෸߮ RBV ࠍ 48 ㅳᛩਈߣߒߚߣ߈ߩౣΆ₸ߪ㧘HPC3010 ⹜㛎ߩ೨ᴦ≮ήല଀ߢ 26.7%㧘C206 ⹜㛎ߩ TMC435 150 mg ⟲ߢߪ㧘೨ᴦ≮ㇱಽ෻ᔕ଀ߢ 0㨪10.0%㧘೨ᴦ≮ή෻ᔕ଀ߢ 18.2㨪41.7%ߢ޽ࠅ㧘HPC3004 ⹜㛎ࠃࠅૐ޿௑ะ߇⹺߼ࠄࠇߚޕߘߩߚ߼㧘೨ᴦ≮ήലᖚ⠪ߦኻ ߒߡߪ㧘PegIFN ෸߮ RBV ߩᛩਈࠍ 48 ㅳߣߔࠆߎߣߦࠃࠅ㧘ౣΆ₸ࠍᛥ߃㧘SVR ₸ࠍะ਄ߐߖ ࠆน⢻ᕈ߇␜ໂߐࠇߚޣ2.7.3.4.2ޤޕߐࠄߦ㧘TMC435 ߣห᭽ߦᒝജߥࡊࡠ࠹ࠕ࡯࠯㒖ኂ⮎ߢ޽ ࠆ࠹࡜ࡊ࡟ࡆ࡞ߩ☨࿖ᷝઃᢥᦠ㧔INCIVEK®USPI㧕1㧕ߢߪ㧘PegIFN ෸߮ RBV ߣߩ 3 ೷૬↪≮ᴺ ߩ㓙ߩ PegIFN ෸߮ RBV ߩᛩਈᦼ㑆ࠍ㧘೨ᴦ≮ㇱಽ෻ᔕᖚ⠪෸߮೨ᴦ≮ή෻ᔕᖚ⠪ߦኻߒߡߪ 48 ㅳߣߒߡ߅ࠅ㧘☨࿖⢄⤳ቇળߩࠟࠗ࠼࡜ࠗࡦ 2㧕ߢ߽㧘೨ᴦ≮ή෻ᔕᖚ⠪ߦኻߒߡߪ㧘PegIFN

෸߮ RBV ߩᛩਈᦼ㑆ߩ⍴❗ࠍផᅑߒߡ޿ߥ޿ޕ ৻ᣇ㧘ೋ࿁ᴦ≮ᖚ⠪෸߮೨ᴦ≮ౣΆᖚ⠪ߦኻߒߡߪ㧘࠹࡜ࡊ࡟ࡆ࡞ߣ૬↪ߔࠆ㓙ߩ PegIFN ෸ ߮ RBV ߩᛩਈᦼ㑆ࠍ㧘ᛩਈ 12 ㅳߦⴊਛ HCV RNA ߇㒶ᕈൻߒߡ߽㧘ᛩਈ 4 ㅳߦⴊਛ HCV RNA ߇㒶ᕈൻߒߡ޿ߥ޿႐วߪ㧘48 ㅳߣߔࠆߎߣࠍផᅑߒߡ޿ࠆ 2㧕ޕ߹ߚ㧘ᣣᧄ⢄⤳ቇળߩ C ဳ⢄ Ἳᴦ≮ࠟࠗ࠼࡜ࠗࡦ 3㧕ߢߪ㧘ᓥ᧪ߩ PegIFN ෸߮ RBV ߩ૬↪≮ᴺߦ㑐ߒߡ߽㧘✢⛽ൻㅴዷ଀߿ 㜞㦂ߩᅚᕈߩ႐ว㧘ౣΆ₸ࠍᛥ߃ࠆߚ߼ߦ㧘ㅢᏱ 48 ㅳߩᛩਈࠍ 72 ㅳ߹ߢᑧ㐳ߔࠆߎߣ߽ㆬᛯ⢇ ߣߒߡ޿ࠆޕߎࠇࠄߩࠟࠗ࠼࡜ࠗࡦߩ⸥タߦၮߠ߈㧘ೋ࿁ᴦ≮ᖚ⠪෸߮೨ᴦ≮ౣΆᖚ⠪ߢ߽㧘ᖚ ⠪ߩ⢛᥊࿃ሶ෸߮ೋᦼߩᴦ≮ലᨐߦᔕߓߡ㧘48 ㅳߩ PegIFN ෸߮ RBV ߩᛩਈࠍ⠨ᘦߔࠆ૛࿾߇ ޽ࠆߣ⠨߃ߚޕ એ਄㧘TMC435 ߩ⥃ᐥ⹜㛎ߩ⚿ᨐ㧘ਗ߮ߦ࠹࡜ࡊ࡟ࡆ࡞ࠍ↪޿ߚ 3 ೷૬↪≮ᴺ෸߮ᣢሽߩ PegIFN ෸߮ RBV ߩ૬↪≮ᴺߦኻߔࠆࠟࠗ࠼࡜ࠗࡦߩផᅑߦၮߠ޿ߡ㧘TMC435 ߣ૬↪ߔࠆ㓙ߩ

JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55 PegIFN ෸߮ RBV ߩᛩਈᦼ㑆ߦߟ޿ߡߪ㧘ޡᖚ⠪ߩᴦ≮ᱧ߿⢛᥊࿃ሶ㧘෸߮ೋᦼߩᴦ≮ലᨐߦᔕ ߓߡ㧘ߎߩ 2 ೷૬↪ᛩਈࠍᦝߦ 24 ㅳ㑆ᛩਈߔࠆߎߣࠍ⠨ᘦߔࠆޢߣߒߚޕ ߹ߚ㧘࿖ౝᄖߩ TMC435 ߩ⥃ᐥ⹜㛎ߢߪ㧘PegIFN ෸߮ RBV ߩᛩਈᦼ㑆ߪᦨ㐳 48 ㅳ㑆ߢ޽ߞ ߚߚ߼㧘ޡᧄ೷ߣ૬↪ߔࠆ႐ว㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪࡍࠣ ࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵߃㧕㧘෸߮࡝ࡃࡆ࡝ࡦߩ✚ᛩਈᦼ㑆ߪ 48 ㅳࠍ⿥߃ߥ ޿ߎߣޢߣߒߚޕ

(3) ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕3 ߩ⸳ቯᩮ᜚ ࿖ౝ╙ III ⋧⹜㛎ߢߪ㧘ᛩਈਛߩ᛫࠙ࠗ࡞ࠬലᨐ߇ਇචಽߢ޽ࠅ㧘SVR ࠍ㆐ᚑߔࠆน⢻ᕈ߇ૐ ޿ߣ⠨߃ࠄࠇࠆⵍ㛎⠪ߦ㧘ਇᔅⷐߥᛩਈࠍ⛮⛯ߔࠆߎߣࠍ࿁ㆱߔࠆߚ߼ߦ㧘4㧘12㧘24 ෸߮ 36 ㅳ ߦ࠙ࠗ࡞ࠬቇ⊛ਛᱛၮḰࠍ⸳ቯߒߚޕ․ߦ㧘ᒰ⹥ⵍ㛎⠪ߦࡊࡠ࠹ࠕ࡯࠯㒖ኂ⮎ߩᛩਈࠍ⛮⛯ߒ㧘 ⮎೷⠴ᕈᄌ⇣ߩ⊒⃻࡮ㅴዷ࡝ࠬࠢࠍ㜞߼ࠆߎߣࠍ㒐ߋߚ߼ߦ㧘TMC435 ߩᛩਈࠍਛᱛߔࠆၮḰࠍ 4 ෸߮ 12 ㅳߦ⸳ቯߒߚޣ2.7.3.1.2.5(4)ޤޕ ࿖ౝ╙ III ⋧⹜㛎ߢߪ㧘TMC435 ⟲ߢ࠙ࠗ࡞ࠬቇ⊛ਛᱛၮḰߦว⥌ߒߚⵍ㛎⠪ߪ 22 ଀ߢ޽ࠅ㧘 ߘߩ߁ߜ 11 ଀߇ 4 ㅳߩၮḰ㧔ⴊẏਛ HCV RNA ߇ 3.0 Log IU/mL ࠍ⿥߃ߚ႐ว㧘TMC435 ߩᛩਈ ࠍਛᱛߔࠆ㧕ߦว⥌ߒߚޕ4 ㅳએ㒠ߩ࠙ࠗ࡞ࠬቇ⊛ਛᱛၮḰߩߺߦว⥌ߒߚⵍ㛎⠪ߩ߶ߣࠎߤ

9 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

㧔8/11 ଀㧕ߪ㧘Breakthrough ଀㧔ᛩਈᦼ㑆ਛߩᦨૐ୯ߣᲧߴߡ㧘ⴊẏਛ HCV RNA ߩჇട㊂߇ 1.0 Log IU/mL ࠍ⿥߃ߚⵍ㛎⠪㧘෶ߪⴊẏਛ HCV RNA ߇ 1.2 Log IU/mL ᧂḩ෶ߪ㒶ᕈൻߣߥߞߚᓟ ߦ 2.0 Log IU/mL ࠍ⿥߃ߚⵍ㛎⠪㧕ߢ޽ߞߚޣ2.7.3.3.2.3ޤޕߎࠇࠄߩ 4 ㅳߩၮḰߦว⥌ߒߚⵍ㛎 ⠪㧔TMC435 ᛩਈࠍਛᱛߒ㧘PegIFN ෸߮ RBV ߩᛩਈࠍ⛮⛯ߒߚⵍ㛎⠪㧕෸߮ Breakthrough ଀ߪ㧘 ޿ߕࠇ߽ SVR ࠍ㆐ᚑߒߥ߆ߞߚޕ߹ߚ㧘12 ㅳߢⴊẏਛ HCV RNA ߇㒶ᕈൻߒߥ߆ߞߚⵍ㛎⠪ 20 ଀߽ SVR ࠍ㆐ᚑߒߥ߆ߞߚޣ5.3.5.1.5ޤޣ5.3.5.2.1ޤޣ5.3.5.2.2ޤޣ5.3.5.2.3ޤޕ એ਄ߩ⚿ᨐߦၮߠ޿ߡ㧘ᴦ≮ਛߩ᛫࠙ࠗ࡞ࠬലᨐ߇ਇචಽߥ႐วߪ㧘ᴦ≮ࠍ⛮⛯ߒߡ߽ SVR ࠍᓧࠄࠇࠆน⢻ᕈߪዋߥ޿ߣ⠨߃ࠄࠇࠆߚ߼㧘ޡᴦ≮ਛᱛࠍ⠨ᘦߔࠆߎߣޢߣߒߚޕ

(4) ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕4 ߩ⸳ቯᩮ᜚ ೽૞↪߿ᴦ≮ലᨐਇචಽߦࠃࠅ TMC435 ߩᛩਈࠍਛᱛߒߚᖚ⠪ߦኻߒߡ㧘TMC435 ߦࠃࠆᴦ≮ ࠍౣᐲⴕ߁ߎߣߪ㧘࡝ࠬࠢ࡮ࡌࡀࡈࠖ࠶࠻ߩⷰὐ߆ࠄᅢ߹ߒߊߥ޿ߣ⠨߃ߚߚ߼㧘⸳ቯߒߚޕ

(5) ↪ᴺ࡮↪㊂ߦ㑐ㅪߔࠆ૶↪਄ߩᵈᗧ㧔᩺㧕5 ߩ⸳ቯᩮ᜚ ࿖ౝᄖߩ⥃ᐥ⹜㛎ߢߪ㧘PegIFN ෸߮ RBV ߩ↪ᴺ࡮↪㊂㧘↪㊂⺞▵ߪ㧘ฦ⵾ຠߩᷝઃᢥᦠߦḰ ߓߡታᣉߒߚߚ߼㧘⸳ቯߒߚޕ

JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55

10 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

1.8.5 ૶↪਄ߩᵈᗧ㧔᩺㧕෸߮ߘߩ⸳ቯᩮ᜚ ૶↪਄ߩᵈᗧ㧔᩺㧕 ⸳ቯᩮ᜚ ޣ⼊๔ޤ ᧄ೷ߪ C ဳᘟᕈ⢄Ἳߦ߅ߌࠆ࠙ࠗ࡞ࠬ ᧄ೷ߪޔ࠙ࠗ࡞ࠬᕈ⢄∔ᖚߩᴦ≮ߦචಽߥ⍮⼂࡮⚻㛎ࠍᜬߟකᏧߩ߽ߣߢޔᧄ ⴊ∝ߩᡷༀࠍല⢻࡮ലᨐߣߔࠆ NS3/4A ೷ߩᛩਈ߇ㆡಾߣ್ᢿߐࠇࠆᖚ⠪ߦኻߒߡߩߺᛩਈߔࠆߎߣޕ ࠮࡝ࡦࡊࡠ࠹ࠕ࡯࠯㒖ኂ೷ߢ޽ࠆޕㆡಾ ߦ⸻ᢿߐࠇߚᖚ⠪ߦኻߒߡ૶↪ߔࠆᔅⷐ ߇޽ࠆߚ߼㧘⸳ቯߒߚޕ ޣ⑌ᔊ㧔ᰴߩᖚ⠪ߦߪᛩਈߒߥ޿ߎߣ㧕ޤ 1)ᧄ೷ߩᚑಽߦኻߒߡㆊᢅ∝ߩᣢᓔᱧߩ 1㧕ᧄ೷ߩᚑಽߦኻߒߡㆊᢅ∝ߩᣢᓔᱧߩ޽ࠆᖚ⠪ ޽ࠆᖚ⠪ߦߟ޿ߡߪ㧘ࠕ࡟࡞ࠡ࡯෻ᔕ╬ 2㧕ࠛࡈࠔࡆ࡟ࡦ࠷ޔ࡝ࡈࠔࡦࡇࠪࡦޔ࡝ࡈࠔࡉ࠴ࡦࠍᛩਈਛߩᖚ⠪㨇ޟ⋧੕૞ ߇޽ࠄࠊࠇࠆน⢻ᕈ߇޽ࠆߎߣ߆ࠄ⸳ቯ ↪ޠߩ㗄ෳᾖ㨉 ߒߚޕ 2)ߎࠇࠄ⮎೷ߣߩ૬↪ߦࠃࠅ㧘ᧄ೷ߩⴊ ẏਛỚᐲ߇⪺ߒߊૐਅߒ㧘ᧄ೷ߩലᨐ߇ චಽߦᓧࠄࠇߥ޿น⢻ᕈ߇޽ࠆߚ߼㧘⸳ ቯߒߚޕ 1㧚ᘕ㊀ᛩਈ㧔ᰴߩᖚ⠪ߦߪᘕ㊀ߦᛩਈߔࠆߎߣ㧕 1)࿖ౝ⥃ᐥ⹜㛎ߩኻ⽎ᖚ⠪෸߮ᒰ⹥੐⽎ 1㧕ⴊਛ✚ࡆ࡝࡞ࡆࡦ߇㜞୯ߩᖚ⠪㨇ⴊਛ✚ࡆ࡝࡞ࡆࡦ୯߇㜞޿ᖚ⠪ߦ߅ߌࠆ ߩ⊒⃻⁁ᴫࠍ⠨ᘦߒ⸳ቯߒߚޕ ૶↪⚻㛎߇ߥ޿ޕ߹ߚޔᧄ೷ᛩਈᤨߦⴊਛࡆ࡝࡞ࡆࡦ୯ߩ਄᣹߇ႎ๔ߐࠇߡ 2)ᄖ࿖ߩ⥃ᐥ⮎ℂ⹜㛎ᚑ❣ߦၮߠ߈⸳ቯ ޿ࠆ㧔ޟ㊀ⷐߥၮᧄ⊛ᵈᗧޠߩ㗄ෳᾖ㧕ޕ㨉 ߒߚޕ

2㧕ਛ╬ᐲએ਄ߩ⢄ᯏ⢻㓚ኂᖚ⠪㨇Cmax ෸߮ AUC ߇਄᣹ߔࠆߎߣ߇ႎ๔ߐࠇ ߡ޿ࠆ㧔ޟ⮎‛േᘒޠߩ㗄ෳᾖ㧕ޕ㨉 2㧚㊀ⷐߥၮᧄ⊛ᵈᗧ 1)Ꮐ⸥ߩ⮎೷ࠍ૬↪ߔࠆߎߣ߆ࠄ㧘ߎࠇ 1㧕ᧄ೷ߩᛩਈߪޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2 a㧔ㆮવሶ⚵឵߃㧕෶ߪ ࠄߩᷝઃᢥᦠߦၮߠ߈⸳ቯߒߚޕ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2 b㧔ㆮવሶ⚵឵߃㧕ޔ෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ 2)శ✢ㆊᢅ∝߇ႎ๔ߐࠇߡ޿ࠆߚ߼㧘శ ᛩਈߔࠆߚ߼ޔฦ⵾ຠߩᷝઃᢥᦠߦ⸥タߐࠇߡ޿ࠆ⼊๔ޔ⑌ᔊޔ૬↪⑌ᔊޔ ✢߳ߩᦑ㔺ߦ㑐ߔࠆᵈᗧ༐⿠ࠍ⸳ቯߒ ᘕ㊀ᛩਈޔ㊀ⷐߥၮᧄ⊛ᵈᗧޔ㊀ᄢߥ೽૞↪╬ߩޣ૶↪਄ߩᵈᗧޤࠍᔅߕ⏕ ߚޕ ⹺ߔࠆߎߣޕ 3)ⴊਛࡆ࡝࡞ࡆࡦ୯ߩ਄᣹߇ႎ๔ߐࠇߡ 2㧕శ✢ㆊᢅ∝߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߚ߼ޔᧄ೷ޔࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ޿ࠆߚ߼㧘ᵈᗧ༐⿠ࠍ⸳ቯߒߚޕ ࠕ࡞ࡈࠔ-2aޔ2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩ૬↪ਛߪޔㆊ೾ߥᄥ㓁శ ✢߳ߩᦑ㔺ࠍㆱߌޔశᦑ㔺ߦኻߔࠆ㒐⼔╷ࠍ⻠ߓࠆࠃ߁ᖚ⠪ߦኻߒᜰዉߔࠆ ߎߣޕ㨇ޟߘߩઁߩᵈᗧޠߩ㗄ෳᾖ㨉 3㧕ᧄ೷ᛩਈᤨߦⴊਛࡆ࡝࡞ࡆࡦ୯ߩ਄᣹߇ႎ๔ߐࠇߡ޿ࠆߩߢޔᧄ೷ᛩਈ ਛߪⴊਛࡆ࡝࡞ࡆࡦ୯ޔ⢄ᯏ⢻ᬌᩏ୯ޔᖚ⠪ߩ⁁ᘒࠍචಽߦⷰኤߒޔ⢄ᯏ⢻ ߩᖡൻ߇⹺߼ࠄࠇߚ႐วߦߪㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ 3㧚⋧੕૞↪ ᧄ೷ߩ⮎ℂ૞↪෸߮⮎‛േᘒቇ⊛૞↪㧘 ࠪࡔࡊ࡟ࡆ࡞ߪਥߦ CYP3A ߦࠃࠅઍ⻢ߐࠇࠆޕࠪࡔࡊ࡟ࡆ࡞ߪ࠻࡜ࡦࠬࡐ ᄖ࿖ߩ⥃ᐥ⮎ℂ⹜㛎ᚑ❣ߦၮߠ߈⸳ቯߒ ࡯࠲࡯㨇P ♧Ⱞ⊕㧔P-gp㧕ޔOATP1B1㨉ߩၮ⾰ߢ޽ࠅޔ߹ߚޔCYP3AޔP-gp ߚޕ ෸߮ OATP1B1 ࠍ㒖ኂߔࠆޕ㨇ޟ⮎‛േᘒޠߩ㗄ෳᾖ㨉 ࿖ౝߦ߅޿ߡ⽼ᄁߐࠇߡ޿ߥ޿⮎೷෸߮ ૬↪ߦࠃࠅᧄ೷෶ߪ૬↪⮎೷ߩⴊẏਛ෶ JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55 ߪⴊਛỚᐲߦᓇ㗀ࠍਈ߃ߥ޿ߣߐࠇߡ޿ ࠆ⮎೷ߦߟ޿ߡߪ⸥タߒߥ޿ߎߣߣߒ ߚޕ

11 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

૶↪਄ߩᵈᗧ㧔᩺㧕 ⸳ቯᩮ᜚

1㧕૬↪⑌ᔊ㧔૬↪ߒߥ޿ߎߣ㧕 ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ ࠛࡈࠔࡆ࡟ࡦ࠷ ᧄ೷ߩⴊẏਛỚᐲ߇⪺ ߎࠇࠄߩ⮎೷ߩᒝ޿ ࠬ࠻࠶ࠢ࡝ࡦ ߒߊૐਅߒޔᧄ೷ߩല CYP3A(4)⺃ዉ૞↪ߦ ࡝ࡈࠔࡦࡇࠪࡦ ᨐ߇ᷫᒙߔࠆޕ ࠃࠅޔᧄ೷ߩઍ⻢߇ଦ ࡝ࡈࠔࠫࡦ╬ ㅴߐࠇࠆޕ ࡝ࡈࠔࡉ࠴ࡦ ࡒࠦࡉ࠹ࠖࡦ

2㧕૬↪ᵈᗧ㧔૬↪ߦᵈᗧߔࠆߎߣ㧕 ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ ᒝജߥ CYP3A 㒖ኂ૞ ᧄ೷ߩⴊẏਛỚᐲ߇਄ ߎࠇࠄߩ⮎೷ߩ ↪ ᣹ߒޔ೽૞↪߇⊒⃻ߔ CYP3A 㒖ኂ૞↪ߦࠃ ࡝࠻࠽ࡆ࡞ ࠆ߅ߘࠇ߇޽ࠆߩߢޔ ࠅޔᧄ೷ߩઍ⻢߇㒖ኂ ࠳࡞࠽ࡆ࡞/࡝࠻࠽ࡆ CYP3A 㒖ኂ૞↪ߩߥ ߐࠇࠆޕ ࡞ ޿෶ߪᒙ޿⮎೷߳ߩઍ ࠢ࡜࡝ࠬࡠࡑࠗࠪࡦ ᦧࠍ⠨ᘦߔࠆߎߣޕᧄ ࠗ࠻࡜ࠦ࠽࠱࡯࡞ ೷ߣߎࠇࠄ⮎೷ࠍ૬↪ ࡏ࡝ࠦ࠽࠱࡯࡞ ߔࠆ႐วߪޔᖚ⠪ߩ⁁ ࠦࡆࠪࠬ࠲࠶࠻ࠍ฽ ᘒࠍᘕ㊀ߦⷰኤߒޔ೽ ߻⮎೷ ૞↪⊒⃻ߦචಽᵈᗧߔ

╬ ࠆߎߣޕ ᧄ೷ 200mg 1 ᣣ 1 ࿁ߣ ࡝࠻࠽ࡆ࡞ 100mg 1 ᣣ 2 ࿁ࠍ૬↪ߒߚߣ߈ޔ ᧄ೷ߩ AUC ߇ 7.2 ୚ߦ ਄᣹ߒߚޕ ᧄ೷ 50mg 1 ᣣ 1 ࿁ߣ ࠳࡞࠽ࡆ࡞/࡝࠻࠽ࡆ࡞ 800mg/100mg 1 ᣣ 1 ࿁ ࠍ૬↪ߒߚߣ߈ޔᧄ೷ 150mg1 ᣣ 1 ࿁න⁛ᛩ ਈߒߚߣ߈ߣᲧߒߡޔ ᧄ೷ߩ AUC ߇ 2.6 ୚ߦ ਄᣹ߒߚޕ ࡒ࡞ࠢࠪࠬ࡞㧔ࡑ࡝ࠕ ᧄ೷ߩⴊẏਛỚᐲ߇਄ ࠕࠩࡒ㧕฽᦭㘩ຠ ᣹ߒޔ೽૞↪߇⊒⃻ߔ ࠆ߅ߘࠇ߇޽ࠆߩߢޔ ᖚ⠪ߩ⁁ᘒࠍᘕ㊀ߦⷰ ኤߒޔ೽૞↪⊒⃻ߦච ಽᵈᗧߔࠆߎߣޕ ઁߩ HIV ࡊࡠ࠹ࠕ࡯࠯ ᧄ೷ߩⴊẏਛỚᐲߦᓇ ߎࠇࠄߩ⮎೷ߩ 㒖ኂ೷ 㗀ࠍ෸߷ߔ߅ߘࠇ߇޽ CYP3A 㒖ኂ૞↪෶ߪ

ࠕ࠲ࠩ࠽ࡆ࡞ ࠆޕᧄ೷ߩⴊẏਛỚᐲ ⺃ዉ૞↪ߦࠃࠅޔᧄ೷ JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55 ࡎࠬࠕࡦࡊ࡟࠽ࡆ࡞ ߇ૐਅߒᧄ೷ߩലᨐ߇ ߩઍ⻢߇㒖ኂ෶ߪଦㅴ ࡠࡇ࠽ࡆ࡞ ᷫᒙߔࠆޔ߽ߒߊߪᧄ ߐࠇࠆޕ ࠗࡦࠫ࠽ࡆ࡞ ೷ߩⴊẏਛỚᐲ߇਄᣹ ࡀ࡞ࡈࠖ࠽ࡆ࡞ ߒ೽૞↪߇⊒⃻ߔࠆ߅ ࠨࠠ࠽ࡆ࡞ ߘࠇ߇޽ࠆߩߢޔᧄ೷ ߣ૬↪ߔࠆ႐วߪචಽ ᵈᗧߔࠆߎߣޕ

12 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

૶↪਄ߩᵈᗧ㧔᩺㧕 ⸳ቯᩮ᜚

2㧕૬↪ᵈᗧ㧔૬↪ߦᵈᗧߔࠆߎߣ㧕㧔⛯߈㧕 ⮎೷ฬ╬ ⥃ᐥ∝⁁࡮ភ⟎ᣇᴺ ᯏᐨ࡮ෂ㒾࿃ሶ ઁߩ㕖࠿ࠢ࡟ࠝࠪ࠼♽ ᧄ೷ߩⴊẏਛỚᐲ߇ૐ ߎࠇࠄߩ⮎೷ߩ ㅒォ౮㉂⚛㒖ኂ೷ ਅߒޔᧄ೷ߩലᨐ߇ᷫ CYP3A(4)⺃ዉ૞↪ߦ ࠛ࠻࡜ࡆ࡝ࡦ ᒙߔࠆ߅ߘࠇ߇޽ࠆߩ ࠃࠅޔᧄ೷ߩઍ⻢߇ଦ ࡀࡆ࡜ࡇࡦ ߢޔᧄ೷ߣ૬↪ߔࠆ႐ ㅴߐࠇࠆޕ วߪචಽᵈᗧߔࠆߎ ߣޕ ࠞ࡞ࡃࡑ࠯ࡇࡦ ᧄ೷ߩⴊẏਛỚᐲ߇ૐ ࡈࠚࡁࡃ࡞ࡆ࠲࡯࡞ ਅߒޔᧄ೷ߩലᨐ߇ᷫ ࡈࠚ࠾࠻ࠗࡦ ᒙߔࠆ߅ߘࠇ߇޽ࠆߩ ߢޔᧄ೷ߣ૬↪ߔࠆ႐ วߪචಽᵈᗧߔࠆߎ ߣޕ ࠮࡛ࠗ࠙ࠝ࠻ࠡ࡝࠰࠙ ᧄ೷ߩⴊẏਛỚᐲ߇ૐ 㧔St. John’s Wortޔ࠮ࡦ ਅߒޔᧄ೷ߩലᨐ߇ᷫ ࠻࡮࡚ࠫ࡯ࡦ࠭࡮ࡢ࡯ ᒙߔࠆ߅ߘࠇ߇޽ࠆߩ ࠻㧕฽᦭㘩ຠ ߢޔᧄ೷ߣ૬↪ߔࠆ႐ วߪචಽᵈᗧߔࠆߎ ߣޕ ࠺ࠠࠨࡔ࠲࠱ࡦ㧔ోり ᧄ೷ߩⴊẏਛỚᐲ߇ૐ ᕈ㧕 ਅߒޔᧄ೷ߩലᨐ߇ᷫ ᒙߔࠆ߅ߘࠇ߇޽ࠆߩ ߢޔᧄ೷ߣ૬↪ߔࠆ႐ วߪචಽᵈᗧߔࠆߎ ߣޕ ࠛ࡝ࠬࡠࡑࠗࠪࡦ ᧄ೷෸߮ࠛ࡝ࠬࡠࡑࠗ ᧄ೷෸߮ࠛ࡝ࠬࡠࡑࠗ ࠪࡦߩⴊẏਛỚᐲ߇਄ ࠪࡦߩ CYP3A ෸߮ P- ᣹ߒޔ೽૞↪߇⊒⃻ߔ gp 㒖ኂ૞↪ߦࠃࠅޔᧄ ࠆ߅ߘࠇ߇޽ࠆߩߢޔ ೷෸߮ࠛ࡝ࠬࡠࡑࠗࠪ CYP3A 㒖ኂ૞↪ߩߥ ࡦߩઍ⻢෸߮ឃ಴߇㒖 ޿෶ߪᒙ޿⮎೷߳ߩઍ ኂߐࠇࠆޕ ᦧࠍ⠨ᘦߔࠆߎߣޕᧄ ೷ߣࠛ࡝ࠬࡠࡑࠗࠪࡦ ࠍ૬↪ߔࠆ႐วߪޔᖚ ⠪ߩ⁁ᘒࠍᘕ㊀ߦⷰኤ ߒޔ೽૞↪⊒⃻ߦචಽ ᵈᗧߔࠆߎߣޕ ᧄ೷ 150mg 1 ᣣ 1 ࿁ߣ ࠛ࡝ࠬࡠࡑࠗࠪࡦ 500mg 1 ᣣ 3 ࿁ࠍ૬↪ ߒߚߣ߈ޔᧄ೷ߩ AUC ߇ 7.5 ୚ߦ਄᣹ ߒޔࠛ࡝ࠬࡠࡑࠗࠪࡦ JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55 ߩ AUC ߪ 1.9 ୚ߦ਄᣹ ߒߚޕ ࠪࠢࡠࠬࡐ࡝ࡦ ࠪࠢࡠࠬࡐ࡝ࡦߩⴊਛ ᧄ೷ߩ CYP3A(4)㒖ኂ Ớᐲ߇਄᣹ߔࠆޕࠪࠢ ૞↪ߦࠃࠅޔߎࠇࠄߩ ࡠࠬࡐ࡝ࡦߩ↪㊂⺞▵ ⮎೷ߩઍ⻢߇㒖ኂߐࠇ ߪᔅⷐߣߒߥ޿߇ޔࠪ ࠆޕ ࠢࡠࠬࡐ࡝ࡦߩⴊਛỚ ᐲࠍࡕ࠾࠲࡝ࡦࠣߔࠆ ߎߣޕ ࠪ࡞࠺࠽ࡈࠖ࡞ ߎࠇࠄߩ⮎೷ߩⴊẏਛ ࠲࠳࡜ࡈࠖ࡞ Ớᐲ߇਄᣹ߔࠆ߅ߘࠇ ߇޽ࠆߚ߼ޔᖚ⠪ߩ⁁ ᘒࠍᘕ㊀ߦⷰኤߒޔߎ ࠇࠄߩ⮎೷ߪૐ↪㊂߆ ࠄᛩਈࠍ㐿ᆎߒޔᔅⷐ ߦᔕߓߡჇ㊂ߔࠆߎߣ ࠍ⠨ᘦߔࠆߎߣޕ ࠻࡝ࠕ࠱࡜ࡓ ࠻࡝ࠕ࠱࡜ࡓߩⴊẏਛ Ớᐲ߇਄᣹ߔࠆ߅ߘࠇ ߇޽ࠆޕᧄ೷ߣ࠻࡝ࠕ ࠱࡜ࡓࠍ૬↪ߔࠆ႐ว ߪޔᖚ⠪ߩ⁁ᘒࠍᘕ㊀ ߦⷰኤߔࠆߎߣޕ ࠕࡒࠝ࠳ࡠࡦ ߎࠇࠄߩ⮎೷ߩⴊਛỚ ࠫ࠰ࡇ࡜ࡒ࠼ ᐲ߇਄᣹ߔࠆ߅ߘࠇ߇ ࡈ࡟ࠞࠗ࠾࠼ ޽ࠆޕߎࠇࠄߩ⮎೷ߣ ࡝࠼ࠞࠗࡦ㧔ోりᕈ㧕 ૬↪ߔࠆ႐วߪޔⴊਛ ࡔࠠࠪ࡟࠴ࡦ Ớᐲࠍࡕ࠾࠲࡝ࡦࠣߔ ࡊࡠࡄࡈࠚࡁࡦ ࠆߎߣޕ ࠠ࠾ࠫࡦ

13 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

૶↪਄ߩᵈᗧ㧔᩺㧕 ⸳ቯᩮ᜚

2㧕૬↪ᵈᗧ㧔૬↪ߦᵈᗧߔࠆߎߣ㧕㧔⛯߈㧕 ࠪࡦࡃࠬ࠲࠴ࡦ ߎࠇࠄߩ⮎೷ߩⴊẏਛ ᧄ೷ߩ OATP1B1 㒖ኂ ࠕ࠻࡞ࡃࠬ࠲࠴ࡦ Ớᐲ߇਄᣹ߔࠆ߅ߘࠇ ૞↪෸߮/෶ߪ CYP3A4 ߇޽ࠆޕߎࠇࠄߩ⮎೷ 㒖ኂ૞↪ߦࠃࠅޔߎࠇ ߩ↪㊂ࠍẋჇߒޔലᨐ ࠄߩ⮎೷ߩឃ಴෸߮/෶ ࠍ⊒⃻ߔࠆᦨዊߩ↪㊂ ߪઍ⻢߇㒖ኂߐࠇࠆޕ ࠍ↪޿ޔᖚ⠪ߩ⁁ᘒࠍ ᘕ㊀ߦⷰኤߔࠆߎߣޕ ࡠࠬࡃࠬ࠲࠴ࡦ ߎࠇࠄߩ⮎೷ߩⴊẏਛ ᧄ೷ߩ OATP1B1 㒖ኂ ࡊ࡜ࡃࠬ࠲࠴ࡦ Ớᐲ߇਄᣹ߔࠆ߅ߘࠇ ૞↪ߦࠃࠅޔߎࠇࠄߩ ࡇ࠲ࡃࠬ࠲࠴ࡦ ߇޽ࠆߚ߼ޔᖚ⠪ߩ⁁ ⮎೷ߩឃ಴߇㒖ኂߐࠇ ᘒࠍᘕ㊀ߦⷰኤߒޔߎ ࠆޕ ࠇࠄߩ⮎೷ߩ↪㊂ࠍẋ Ⴧߒޔലᨐࠍ⊒⃻ߔࠆ ᦨዊߩ↪㊂ࠍ↪޿ࠆߎ ߣޕ ࠕࡓࡠࠫࡇࡦ ߎࠇࠄߩ⮎೷ߩⴊẏਛ ᧄ೷ߩ CYP3A4 㒖ኂ૞ ࡌࡊ࡝ࠫ࡞ Ớᐲ߇਄᣹ߔࠆ߅ߘࠇ ↪෸߮/෶ߪ P-gp 㒖ኂ ࠫ࡞࠴ࠕ࠯ࡓ ߇޽ࠆޕߎࠇࠄߩ⮎೷ ૞↪ߦࠃࠅޔߎࠇࠄߩ ࡈࠚࡠࠫࡇࡦ ߣ૬↪ߔࠆ႐วߪޔᖚ ⮎೷ߩઍ⻢෸߮/෶ߪឃ ࠾ࠞ࡞ࠫࡇࡦ ⠪ߩ⁁ᘒࠍᘕ㊀ߦⷰኤ ಴߇㒖ኂߐࠇࠆޕ ࠾ࡈࠚࠫࡇࡦ ߔࠆߎߣޕ

࠾࠰࡞ࠫࡇࡦ ࡌ࡜ࡄࡒ࡞ ࠫࠧࠠࠪࡦ ࠫࠧࠠࠪࡦߩⴊਛỚᐲ ᧄ೷ߩ P-gp 㒖ኂ૞↪ ߇਄᣹ߔࠆޕࠫࠧࠠࠪ ߦࠃࠅޔࠫࠧࠠࠪࡦߩ ࡦߩⴊਛỚᐲࠍࡕ࠾࠲ ឃ಴߇㒖ኂߐࠇࠆޕ ࡝ࡦࠣߒޔലᨐ߇⊒⃻ ߔࠆ↪㊂߹ߢẋჇߔࠆ ߎߣޕ ࠲ࠢࡠ࡝ࡓࠬ ࠲ࠢࡠ࡝ࡓࠬߩⴊਛỚ ᯏᐨਇ᣿ ᐲ߇ૐਅߔࠆޕ࠲ࠢࡠ ࡝ࡓࠬߩ↪㊂⺞▵ߪᔅ ⷐߣߒߥ޿߇ޔ࠲ࠢࡠ ࡝ࡓࠬߩ⮎೷ߩⴊਛỚ ᐲࠍࡕ࠾࠲࡝ࡦࠣߔࠆ ߎߣޕ

JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55

14 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

૶↪਄ߩᵈᗧ㧔᩺㧕 ⸳ቯᩮ᜚ 4㧚೽૞↪ ࿖ౝ⥃ᐥ⹜㛎㧔C215㧘HPC3003㧘 C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߦᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ 3004㧘3008 ෸߮ 3010 ⹜㛎㧕ߦ߅ߌࠆᧄ ⚵឵߃㧕෶ߪ 2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߒߚ࿖ౝ╙Τ⋧෸߮ ೷ߩ೽૞↪⊒⃻⁁ᴫࠍరߦ⸳ቯߒߚޕ߹ ╙Υ⋧⥃ᐥ⹜㛎㧔ోᛩਈᦼ㑆㧕ߦ߅ߌࠆ቟ోᕈ⹏ଔኻ⽎∝଀ 436 ଀ਛ 426 ଀ ߚ㧘㊀ᄢߥ೽૞↪ߦߟ޿ߡߪ㧘૬↪ߔࠆ 㧔97.7%㧕ߦ೽૞↪㧔⥃ᐥᬌᩏ୯⇣Ᏹࠍ฽߻㧕߇⹺߼ࠄࠇߚޕᧄ೷ߩ೽૞↪ ⮎೷ߩᷝઃᢥᦠߦ㊀ᄢߥ೽૞↪ߣߒߡ⸥ ߪޔ⊒∐ 203 ଀㧔46.6%㧕ޔߘ߁∣∝ 105 ଀㧔24.1%㧕ޔⴊਛࡆ࡝࡞ࡆࡦჇട 97 タߐࠇߡ޿ࠆ੐⽎ߩ߁ߜ࿖ౝ⥃ᐥ⹜㛎ߢ ଀㧔22.2%㧕ޔଢ⒁ 29 ଀㧔6.7%㧕ޔశ✢ㆊᢅᕈ෻ᔕ 8 ଀㧔1.8%㧕ߢ޽ߞߚޕ ߩ⊒⃻⁁ᴫࠍరߦ⸳ቯߒߚޕ 㧔↳⺧ᤨ㧕

1) ㊀ᄢߥ೽૞↪ ᧄ೷ߣࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵឵߃㧕෶ߪ 2b㧔ㆮવሶ ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߩ૬↪ߢ⹺߼ࠄࠇߚ㊀ᄢߥ೽૞↪ߪએਅߩߣ߅ࠅߢ ޽ࠆޕ (1)⽺ⴊ㧔0.2%㧕㧖㧦⽺ⴊ߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢޔቯᦼ⊛ߦⴊᶧᬌᩏࠍ ⴕ߁ߥߤⷰኤࠍචಽߦⴕ޿㧘⇣Ᏹߩ⒟ᐲ߇⪺ߒ޿႐วߦߪᛩਈߩਛᱛࠍ⠨ᘦ ߒ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎߣޕ (2)ᄙᒻ⚃᢬㧔0.2%㧕㧖㧦ᄙᒻ⚃᢬߇޽ࠄࠊࠇࠆߎߣ߇޽ࠆߩߢ㧘ⷰኤࠍචಽ ߦⴕ޿㧘∝⁁߇޽ࠄࠊࠇߚ႐วߦߪ㧘ᛩਈࠍਛᱛߒ㧘ㆡಾߥಣ⟎ࠍⴕ߁ߎ ߣޕ 㧖㧦㗫ᐲߪ 3 ೷૬↪ߒߚ࿖ౝ⥃ᐥ⹜㛎ߦ߅ߌࠆ㊀◊∝଀ࠍ␜ߔ

2) ߘߩઁߩ೽૞↪ ᧄ೷ࠍࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ̃2a㧔ㆮવሶ⚵឵߃㧕෶ߪ 2b㧔ㆮવሶ ⚵឵߃㧕෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߒߚ㓙ߩᧄ೷ߩ೽૞↪ߪએਅߩߣ߅ࠅߢ޽ ࠆޕᰴߩࠃ߁ߥ೽૞↪߇޽ࠄࠊࠇߚ႐วߦߪޔ∝⁁ߦᔕߓߡㆡಾߥಣ⟎ࠍⴕ ߁ߎߣޕ 10 %એ਄ 5%એ਄ 5%ᧂḩ 10 %ᧂḩ ⢗⣺㓚ኂ ଢ⒁ ⢄⢙㆏♽㓚ኂ ⴊਛࡆ࡝࡞ࡆࡦ Ⴧട ⊹⤏߅ࠃ߮⊹ ⊒∐ޔߘ߁∣∝ శ✢ㆊᢅᕈ෻ ਅ⚵❱㓚ኂ ᔕ ⥃ᐥᬌᩏ 㜞ࡆ࡝࡞ࡆࡦ Al-P Ⴧട ⴊ∝

5㧚㜞㦂⠪߳ߩᛩਈ 㜞㦂⠪ߦ߅ߌࠆ৻⥸⊛ߥᵈᗧ༐⿠ࠍ⸳ቯ 㜞㦂⠪ߢߪ৻⥸ߦ↢ℂᯏ⢻߇ૐਅߒߡ߅ࠅޔ߹ߚว૬∝߿૬↪⮎૶↪ߩ㗫ᐲ ߒߚޕ ߇Ⴧ߃ࠆߎߣ߆ࠄᘕ㊀ߦᛩਈߔࠆߎߣޕ 6㧚ᅧᇚޔ↥ᇚޔ᝼੃ᇚ╬߳ߩᛩਈ 1)Ꮐ⸥ߩ⮎೷ࠍ૬↪ߔࠆߎߣ߆ࠄ㧘ߎࠇ 1㧕ᧄ೷ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a ෶ߪ 2b㧔ㆮવሶ⚵឵߃㧕෸߮࡝ ࠄߩᷝઃᢥᦠߦၮߠ߈⸳ቯߒߚޕ߹ߚ㧘 JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55 ࡃࡆ࡝ࡦߣ૬↪ߔࠆߚ߼ޔᅧᇚ෶ߪᅧᆼߒߡ޿ࠆน⢻ᕈߩ޽ࠆᇚੱߦߪ૶ ᧄ೷ߩേ‛⹜㛎ߩ⚿ᨐߦၮߠ߈⸳ቯߒ ↪ߒߥ޿ߎߣޕ߹ߚޔᅧᆼߒߡ޿ߥ޿ߎߣࠍ⏕⹺ߔࠆߚ߼ޔ࡝ࡃࡆ࡝ࡦߩ ߚޕ ᷝઃᢥᦠࠍෳᾖߒޔᅧᆼᬌᩏࠍታᣉߔࠆߎߣޕ㨇࡝ࡃࡆ࡝ࡦߩേ‛ታ㛎ߢ 2)ᧄ೷ߩേ‛ታ㛎ߩ⚿ᨐߦၮߠ߈⸳ቯߒ ௅ᄸᒻᕈ෸߮⢦࡮⢝ఽ⥌ᱫ૞↪߇⹺߼ࠄࠇߡ޿ࠆޕ㨉 ߚޕ ᧄ೷ߦ߅޿ߡ࠙ࠨࠡ⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜㛎ߪታᣉߒߡ޿ߥ޿ޕ࡜࠶࠻ ⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜㛎ߦ߅޿ߡޔᦨᄢᛩਈ㊂㧔⥃ᐥᦑ㔺㊂ࠃࠅૐ޿㧕 ߢߪޔ௅ᄸᒻᕈߪ⹺߼ࠄࠇߥ߆ߞߚޕࡑ࠙ࠬ⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜㛎ߢ ߪޔᲣ૕Ქᕈ෸߮⢝ఽ૕㊀ૐ୯ࠍ઻ࠊߥ޿↪㊂㧔ᦑ㔺㊂ߣߒߡߪ⥃ᐥᦑ㔺 ㊂ߣ߶߷ห╬㧕߆ࠄޔ⢝ఽߩ㛽ᩰᄌ⇣෸߮㛽ൻㆃᑧߩ⊒↢㗫ᐲჇട߇⹺߼ ࠄࠇߚޕ࡜࠶࠻಴↢೨෸߮಴↢ᓟߩ⊒↢ߦ㑐ߔࠆ⹜㛎ߢߪޔ⥃ᐥᦑ㔺㊂ࠃ ࠅૐ޿ᦑ㔺㊂㧔Უേ‛㧕ߢޔᲣേ‛ߩ૕㊀Ⴧടᛥ೙෸߮಴↢ఽߩ⊒⢒ㆃᑧ ߇⹺߼ࠄࠇߚޕ 2㧕 ᝼੃ਛߩᇚੱߦߪޔᛩਈࠍㆱߌࠆߎߣޕ߿߻ࠍᓧߕᛩਈߔࠆ႐วߪޔ᝼੃ ࠍㆱߌߐߖࠆߎߣޕ㨇ࡅ࠻ߦ߅ߌࠆ੃᳝߳ߩ⒖ⴕߪਇ᣿ߢ޽ࠆ߇ޔ࡜࠶࠻ ߢ੃ఽ߳ߩ⒖ⴕ߇⹺߼ࠄࠇߡ޿ࠆޕ㨉 7㧚ዊఽ╬߳ߩᛩਈ ࿖ౝᄖߦ߅޿ߡዊఽ╬߳ߩ૶↪⚻㛎߇ߥ ૐ಴↢૕㊀ఽޔᣂ↢ఽޔ੃ఽޔᐜఽ෶ߪዊఽߦኻߔࠆ቟ోᕈߪ⏕┙ߒߡ޿ߥ ޿ߚ߼㧘Ꮐ⸥ߩߣ߅ࠅ⸳ቯߒߚޕ ޿ޕ㧔૶↪⚻㛎߇ߥ޿ޕ㧕

15 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

૶↪਄ߩᵈᗧ㧔᩺㧕 ⸳ቯᩮ᜚ 8㧚ㆊ㊂ᛩਈ ࿖ౝᄖߩ⥃ᐥ⹜㛎ᚑ❣ࠍరߦ⸳ቯߒߚޕ ᓽ୥ޔ∝⁁㧦 ㆊ㊂ᛩਈߦ㑐ߔࠆ࠺࡯࠲ߪ㒢ࠄࠇߡ޿ࠆޕஜᐽᚑੱߦ 1 ᣣ 1 ࿁ 400mg ࠍ 5 ᣣ㑆෻ᓳᛩਈߒߚ႐วޔ߹ߚᄖ࿖ੱߩஜᐽᚑੱߦ 600mg න࿁ᛩਈ෸߮ 1 ᣣ 1 ࿁ 400mg ࠍ 5 ᣣ㑆෻ᓳᛩਈߒߚ႐ว෶ߪ C ဳᘟᕈ⢄Ἳᖚ⠪ߦ 1 ᣣ 1 ࿁ 200mg ࠍ 4 ㅳ㑆ᛩਈߒߚ႐วߦޔ⥃ᐥ⊛ᓽ୥෸߮∝⁁ߪⷰኤߐࠇߥ߆ ߞߚޕ ಣ⟎㧦 ᧄ೷ߦኻߔࠆ․೎ߥ⸃Ქ೷ߪߥ޿ޕㆊ㊂ᛩਈߒߚ႐วߦߪޔࡃࠗ࠲࡞ࠨ ࠗࡦ෸߮⥃ᐥ∝⁁ߩⷰኤ߿ᶖൻ▤㒰ᨴߥߤ৻⥸⊛ߥᡰᜬ≮ᴺࠍⴕ߁ޕᧄ ೷ߪⴊẏⰮ⊕⚿ว₸߇㜞޿ߚ߼ޔㅘᨆߢࠪࡔࡊ࡟ࡆ࡞߇㒰෰ߐࠇࠆน⢻ ᕈߪૐ޿ޕ 9㧚ㆡ↪਄ߩᵈᗧ ৻⥸⊛ߥᵈᗧ੐㗄ߣߒߡ⸳ቯߒߚޕ ⮎೷੤ઃᤨ㧦PTP ൮ⵝߩ⮎೷ߪ PTP ࠪ࡯࠻߆ࠄขࠅ಴ߒߡ᦯↪ߔࠆࠃ߁ߦᜰ ዉߔࠆߎߣޕ㨇PTP ࠪ࡯࠻ߩ⺋㘶ߦࠃࠅޔ⎬޿㍈ⷺㇱ߇㘩㆏☼⤑߳ೝ౉ߒޔ ᦝߦߪ⓫ሹࠍ⿠ߎߒߡ❑㓒ᵢἻ╬ߩ㊀◊ߥว૬∝ࠍ૬⊒ߔࠆߎߣ߇ႎ๔ߐࠇ ߡ޿ࠆޕ㨉 10㧚ߘߩઁߩᵈᗧ ᧄ೷ߩ in vitro ⹜㛎ߢߩ⚿ᨐࠍరߦ⸳ቯ ᧄ೷ߪ in vitro ⹜㛎ߢశᲥᕈࠍ␜ߒߚߣߩႎ๔߇޽ࠆޕ ߒߚޕ

JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55

16 TMC435 1.8 ᷝઃᢥᦠ㧔᩺㧕

ෳ⠨ᢥ₂

1㧕 INCIVEKTM (telaprevir) Film Coated Tablets, for oral use. HIGHLIGHTS OF PRESCRIBING INFORMATION. Vertex Pharmaceuticals Incorporated, Revised: 12/2012.

2㧕 Ghany MG, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011 Oct; 54(4):1433-44.

3㧕 ᣣᧄ⢄⤳ቇળ ⢄Ἳ⸻≮ࠟࠗ࠼࡜ࠗࡦ૞ᚑᆔຬળ✬. C ဳ⢄Ἳᴦ≮ࠟࠗ࠼࡜ࠗࡦ㧔╙ 1 㧕. 2012.

JEDI_DEV00 \ 0900fde9804051bc 3.16 2013-09-03 14:55

17 TMC435 1.9 ৻⥸⊛ฬ⒓ߦଥࠆᢥᦠ

1.9 ৻⥸⊛ฬ⒓ߦଥࠆᢥᦠ

1.9.1 JAN ࠪࡔࡊ࡟ࡆ࡞ߪ㧘ᐔᚑ 25 ᐕ 8 ᦬ 23 ᣣ㧘࿖㓙৻⥸ฬ㧔INN㧕ߦ෼タߐࠇߚຠ⋡ߣߒߡᧄ㇌ߦ߅ ߌࠆක⮎ຠ৻⥸⊛ฬ⒓㧔JAN㧕߇ㅢ⍮ߐࠇߚޕ

JAN:㧔ᣣᧄฬ㧕ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ   㧔⧷ ฬ㧕Simeprevir Sodium

ൻቇฬ㧦 㧔ᣣᧄฬ㧕

(䉲䉪䊨䊒䊨䊏䊦䉴䊦䊐䉤䊆䊦)[(2R,3aR,10Z,11aS,12aR,14aR)-2-({7-䊜䊃䉨䉲-8-䊜䉼䊦-2-[4-(1-䊜䉼䊦䉣䉼䊦)- 1,3-䉼䉝䉹䊷䊦-2-䉟䊦]䉨䊉䊥䊮-4-䉟䊦}䉥䉨䉲)-5-䊜䉼䊦-4,14-䉳䉥䉨䉸- 1,2,3,3a,4,5,6,7,8,9,11a,12,12a,13,14,14a-䊓䉨䉰䊂䉦䊍䊄䊨䉲䉪䊨䊕䊮䉺[c]䉲䉪䊨䊒䊨䊌[g][1,6]䉳䉝䉱䉲䉪䊨䊁䊃 䊤䊂䉲䊮-12a-䉦䊦䊗䊆䊦]䉝䉱䊆䊄䊅䊃䊥䉡䊛

㧔⧷ฬ㧕 Monosodium (cyclopropylsulfonyl)[(2R,3aR,10Z,11aS,12aR,14aR)-2-({7-methoxy-8-methyl-2-[4-(1- methylethyl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo- 1,2,3,3a,4,5,6,7,8,9,11a,12,12a,13,14,14a- hexadecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a-carbonyl]azanide

JEDI_DEV00 \ 0900fde980403933 2.3 2013-08-29 11:54

1.9.2 INN simeprevir (Recommended INN List 67, WHO Drug Information, p.85, Vol.26, No.1, 2012 ߦ෼タ)

1 TMC435 1.9 ৻⥸⊛ฬ⒓ߦଥࠆᢥᦠ

1.9.3 ᭴ㅧᑼ

O CH O S O 3 CH O NNa 3 O H N N H CH H 3 H O N H S CH3

N O CH 3

JEDI_DEV00 \ 0900fde980403933 2.3 2013-08-29 11:54

2 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

International Nonproprietary Names for Pharmaceutical Substances (INN)

RECOMMENDED International Nonproprietary Names: List 67

Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances [Off. Rec. Wld Health Org., 1955, 60, 3 (Resolution EB15.R7); 1969, 173, 10 (Resolution EB43.R9); Resolution EB115.R4 (EB115/2005/REC/1)], the following names are selected as Recommended International Nonproprietary Names. The inclusion of a name in the lists of Recommended International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy. Lists of Proposed (1–105) and Recommended (1–66) International Nonproprietary Names can be found in Cumulative List No. 14, 2011 (available in CD-ROM only).

Dénominations communes internationales des Substances pharmaceutiques (DCI)

Dénominations communes internationales RECOMMANDÉES: Liste 67

Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org. mond. Santé, 1955, 60, 3 (résolution EB15.R7); 1969, 173, 10 (résolution EB43.R9); résolution EB115.R4 (EB115/2005/REC/1)] les dénominations ci-dessous sont choisies par l’Organisation mondiale de la Santé en tant que dénominations communes internationales recommandées. L’inclusion d’une dénomination dans les listes de DCI recommandées n’implique aucune recommandation en vue de l’utilisation de la substance correspondante en médecine ou en pharmacie. On trouvera d’autres listes de Dénominations communes internationales proposées (1–105) et recommandées (1–66) dans la Liste récapitulative No. 14, 2011 (disponible sur CD-ROM seulement).

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI)

Denominaciones Comunes Internacionales RECOMENDADAS: Lista 67

De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (Resolución EB15.R7); 1969, 173, 10 (Resolución EB43.R9); Résolution EB115.R4 (EB115/2005/REC/1) EB115.R4 (EB115/2005/REC/1)], se comunica por el presente anuncio que las denominaciones que a continuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas. La inclusión de una denominación en las listas de las Denominaciones Comunes Recomendadas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia. Las listas de Denominaciones Comunes Internacionales Propuestas (1–105) y Recomendadas (1–66) se encuentran reunidas en Cumulative List No. 14, 2011 (disponible sólo en CD-ROM).

45 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

Latin, English, French, Spanish: Recommended INN Chemical name or description; Molecular formula; Graphic formula

DCI Recommandée Nom chimique ou description; Formule brute; Formule développée

DCI Recomendada Nombre químico o descripción; Fórmula molecular; Fórmula desarrollada

abexinostatum abexinostat 3-[(dimethylamino)methyl]-N-{2-[4- (hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide

abexinostat 3-[(diméthylamino)méthyl]-N-{2-[4- (hydroxycarbamoyl)phénoxy]éthyl}-1-benzofurane-2-carboxamide

abexinostat 3-[(dimetilamino)metil]-N-{2-[4-(hidroxicarbamoil)fenoxi]etil}- 1-benzofuran-2-carboxamida

C21H23N3O5

O OH O N H H N O H3C N O H3C

amilomotidum # amilomotide virus like particle of bacteriophage Q-beta coat protein that is coupled to multiple copies of human beta-amyloid1-6 peptide fragment; reaction products of bacteriophage Q-beta coat protein with human beta-amyloid protein-(1-6)-peptidylglycylglycyl-L-cysteine and 3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-N-{6-[(2,5-dioxopyrrolidin- 1-yl)oxy]-6-oxohexyl}propanamide

amilomotide pseudo-particule virale de la capside du phage Q-bêta couplée à plusieurs copies du fragment 1-6 de la protéine bêta-amyloïde humaine; produit obtenu par réaction de la protéine de capside du phage Q-bêta avec la protéine bêta-amyloïde humaine- (1-6)peptidylglycylglycyl-L-cystéine et le 3-(2,5-dioxo-2,5-dihydro- 1H-pyrrole-1-yl)-N-{6-[(2,5-dioxopyrrolidin-1-yl)oxy]- 6-oxohexyl}propanamide

amilomotida pseudo-particula viral de cápsida del fago Q-beta acoplada a múltiples copias del fragmento 1-6 de la proteína beta-amiloide humana; producto obtenido por reacción de la proteína de cápsida del fago Q-beta con la proteína beta-amiloide humana- (1-6)peptidilglicilglicil-L-cisteína y el 3-(2,5-dioxo-2,5-dihidro- 1H-pirrol-1-il)-N-{6-[(2,5-dioxopirrolidin-1-il)oxi]- 6-oxohexil}propanamida

46 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

Heavy chain / Chaîne lourde / Cadena pesada AKLETVTLGN IGKDGKQTLV LNPRGVNPTN GVASLSQAGA VPALEKRVTV 50 SVSQPSRNRK NYKVQVKIQN PTACTANGSC DPSVTRQAYA DVTFSFTQYS 100 TDEERAFVRT ELAALLASPL LIDAIDQLNP AY 132

Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro 74-80

Modified residues / Résidus modifiés / Residuos modificados H A H CH3 K 1 2-13-16-46-60-63-67 H NCOH R N CO2H R NH 2 2 H O O

N N C H O O R = H or / ou / ó or / ou / ó O O N N C H * O O H S H and epimer at C* et l'épimère en C* HAsp Ala Glu Phe Arg His Gly Gly N CO2H H y el epímero al C*

anivamersenum anivamersen 2'-O-methylcytidylyl-(3'ĺ5')-2'-O-methylguanylyl-(3'ĺ5')-2'-O- methylcytidylyl-(3'ĺ5')-2'-O-methylguanylyl-(3'ĺ5')-2'-O- methylguanylyl-(3'ĺ5')-2'-O-methyluridylyl-(3'ĺ5')-2'-O- methyladenylyl-(3'ĺ5')-2'-O-methyluridylyl-(3'ĺ5')-2'-O- methyladenylyl-(3'ĺ5')-2'-O-methylguanylyl-(3'ĺ5')-2'-O- methyluridylyl-(3'ĺ5')-2'-O-methylcytidylyl-(3'ĺ5')-2'-O- methylcytidylyl-(3'ĺ5')-2'-O-methyladenylyl-(3'ĺ5')-2'-O- methylcytidine

anivamersen 2'-O-méthylcytidylyl-(3'ĺ5')-2'-O-méthylguanylyl-(3'ĺ5')-2'-O- méthylcytidylyl-(3'ĺ5')-2'-O-méthylguanylyl-(3'ĺ5')-2'-O- méthylguanylyl-(3'ĺ5')-2'-O-méthyluridylyl-(3'ĺ5')-2'-O- méthyladénylyl-(3'ĺ5')-2'-O-méthyluridylyl-(3'ĺ5')-2'-O- méthyladénylyl-(3'ĺ5')-2'-O-méthylguanylyl-(3'ĺ5')-2'-O- méthyluridylyl-(3'ĺ5')-2'-O-méthylcytidylyl-(3'ĺ5')-2'-O- méthylcytidylyl-(3'ĺ5')-2'-O-méthyladénylyl-(3'ĺ5')-2'-O- méthylcytidine

anivamersén 2'-O-metilcitidilil-(3'ĺ5')-2'-O-metilguanilil-(3'ĺ5')-2'-O-metilcitidilil- (3'ĺ5')-2'-O-metilguanilil-(3'ĺ5')-2'-O-metilguanilil-(3'ĺ5')-2'-O- metiluridilil-(3'ĺ5')-2'-O-metiladenilil-(3'ĺ5')-2'-O-metiluridilil-(3'ĺ5')- 2'-O-metiladenilil-(3'ĺ5')-2'-O-metilguanilil-(3'ĺ5')-2'-O-metiluridilil- (3'ĺ5')-2'-O-metilcitidilil-(3'ĺ5')-2'-O-metilcitidilil-(3'ĺ5')-2'-O- metiladenilil-(3'ĺ5')-2'-O-metilctidina

C157H208N56O103P14

(3'-5')-mC-mG-mC-mG-mG-mU-mA-mU-mA-mG-mU-mC-mC-mA-mC

47 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

asunaprevirum asunaprevir tert-butyl {(2S)-1-[(2S,4R)-4-({7-chloro-4-methoxyisoquinolin- 1-yl}oxy)-2-({(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]- 2-ethenylcyclopropyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2-yl}carbamate

asunaprévir (2S)-1-[(2S,4R)-4-({7-chloro-4-méthoxyisoquinolin-1-yl}oxy)- 2-({(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]- 2-éthènylcyclopropyl}carbamoyl)pyrrolidin-1-yl]-3,3-diméthyl- 1-oxobutan-2-yl}carbamate de tert-butyle

asunaprevir {(2S)-1-[(2S,4R)-4-({7-cloro-4-metoxiisoquinolin-1-il}oxi)-2-({(1R,2S)- 1-[(ciclopropanosulfonil)carbamoil]- 2-etenilciclopropil}carbamoil)pirrolidin-1-il]-3,3-dimetil-1-oxobutan- 2-il}carbamato de terc-butilo

C35H46ClN5O9S

O O S O NH O H OCH3 N H2C N H H H O N O O H3C CH3 CH3 H3C O N CH3 H H Cl CH3

atecegatranum metoxilum atecegatran metoxil (2S)-1-{(2R)-2-[3-chloro-5-(difluoromethoxy)phenyl]- 2-hydroxyacetyl}-N-({4-[(Z)-N'- methoxycarbamimidoyl]phenyl}methyl)azetidine-2-carboxamide

atécégatran métoxil (2S)-1-{(2R)-2-[3-chloro-5-(difluorométhoxy)phényl]- 2-hydroxyacétyl}-N-({4-[(Z)-N'- méthoxycarbamimidoyl]phényl}méthyl)azétidine-2-carboxamide

atecegatrán metoxilo (2S)-1-{(2R)-2-[3-cloro-5-(difluorometoxi)fenil]-2-hidroxiacetil}- N-({4-[(Z)-N'-metoxicarbamimidoil]fenil}metil)azetidina- 2-carboxamida

C22H23ClF2N4O5

H3CO N

H2N H OH H N N Cl H O O

O F

F

48 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

avagacestatum avagacestat (2R)-2-(4-chloro-N-{[2-fluoro-4-(1,2,4-oxadiazol- 3-yl)phenyl]methyl}benzenesulfonamido)-5,5,5-trifluoropentanamide

avagacestat (2R)-2-(4-chloro-N-{[2-fluoro-4-(1,2,4-oxadiazol- 3-yl)phényl]méthyl}benzenesulfonamido)-5,5,5-trifluoropentanamide

avagacestat (2R)-2-(4-cloro-N-{[2-fluoro-4-(1,2,4-oxadiazol- 3-yl)fenil]metil}bencenosulfonamido)-5,5,5-trifluoropentanamida

C20H17ClF4N4O4S

Cl O N O N O S

N CF3 H F O NH2

besifovirum besifovir [({1-[(2-amino-9H-purin- 9-yl)methyl]cyclopropyl}oxy)methyl]phosphonic acid

bésifovir acide [({1-[(2-amino-9H-purin- 9-yl)méthyl]cyclopropyl}oxy)méthyl]phosphonique

besifovir ácido [({1-[(2-amino-9H-purin-9-il)metil]ciclopropil}oxi)metil]fosfónico

C10H14N5O4P

N O N OH P OH N O H2N N

bitopertinum bitopertin {4-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}[5- (methanesulfonyl)-2-{[(2S)-1,1,1-trifluoropropan- 2-yl]oxy}phenyl]methanone

bitopertine {4-[3-fluoro-5-(trifluorométhyl)pyridin-2-yl]pipérazin-1-yl}[5- (méthanesulfonyl)-2-{[(2S)-1,1,1-trifluoropropan- 2-yl]oxy}phényl]méthanone

bitopertina {4-[3-fluoro-5-(trifluorometil)piridin-2-il]piperazin-1-il}[5- (metanosulfonil)-2-{[(2S)-1,1,1-trifluoropropan- 2-il]oxy}fenil]metanona

C21H20F7N3O4S

O O O S H3C N F N O H N CF3 CF3 H3C

49 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

blosozumabum # blosozumab immunoglobulin G4-kappa, anti-[Homo sapiens SOST (sclerostin)], humanized monoclonal antibody; gamma4 heavy chain (1-444) [humanized VH (Homo sapiens IGHV1-24*01 (85.70%) -(IGHD)-IGHJ4*01 L123>T (113)) [8.8.11] (1- 118) -Homo sapiens IGHG4*01 hinge S10>P (226), CH3 K120>del (119-444)], (132-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-13*02 (84.00%) - IGKJ1*01 Q120>G (100)) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (224-224":227-227")-bisdisulfide dimer

blosozumab immunoglobuline G4-kappa, anti-[Homo sapiens SOST (sclérostine)], anticorps monoclonal humanisé; chaîne lourde gamma4 (1-444) [VH humanisé (Homo sapiens IGHV1-24*01 (85.70%) -(IGHD)-IGHJ4*01 L123>T (113)) [8.8.11] (1- 118) -Homo sapiens IGHG4*01 charnière S10>P (226), CH3 K120>del (119-444)], (132-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1-13*02 (84.00%) -IGKJ1*01 Q120>G (100)) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (224-224":227-227")-bisdisulfure

blosozumab inmunoglobulina G4-kappa, anti-[Homo sapiens SOST (esclerostina)], anticuerpo monoclonal humanizado; cadena pesada gamma4 (1-444) [VH humanizada (Homo sapiens IGHV1-24*01 (85.70%) -(IGHD)-IGHJ4*01 L123>T (113)) [8.8.11] (1- 118) -Homo sapiens IGHG4*01 bisagra S10>P (226), CH3 K120>del (119-444)], (132-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizada (Homo sapiens IGKV1-13*02 (84.00%) - IGKJ1*01 Q120>G (100)) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (224-224":227-227")-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGAE VKKPGASVKV SCKVSGFPIK DTFQHWVRQA PGKGLEWMGW 50 SDPEIGDTEY ASKFQGRVTM TEDTSTDTAY MELSSLRSED TAVYYCATGD 100 TTYKFDFWGQ GTTVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY 150 FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTKTYT 200 CNVDHKPSNT KVDKRVESKY GPPCPPCPAP EFLGGPSVFL FPPKPKDTLM 250 ISRTPEVTCV VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTYRV 300 VSVLTVLHQD WLNGKEYKCK VSNKGLPSSI EKTISKAKGQ PREPQVYTLP 350 PSQEEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG 400 SFFLYSRLTV DKSRWQEGNV FSCSVMHEAL HNHYTQKSLS LSLG 444 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCKASQDVH TAVAWYQQKP GKAPKLLIYW 50 ASTRWTGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSDYPWTFGG 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 145-201 259-319 365-423 22''-96'' 145''-201'' 259''-319'' 365''-423'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 132-214' 132''-214''' Inter-H-H 224-224'' 227-227''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 295, 295''

50 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

brodalumabum # brodalumab immunoglobulin G2-kappa, anti-[Homo sapiens IL17RA (interleukin 17 receptor A, CD217)], Homo sapiens monoclonal antibody; gamma2 heavy chain (1-442) [Homo sapiens VH (IGHV1-18*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -Homo sapiens IGHG2*01 (117-442)], (130-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV1-15*01 (93.70%) - IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (218-218":219-219":222-222":225-225")-tetrakisdisulfide dimer

brodalumab immunoglobuline G2-kappa, anti-[Homo sapiens IL17RA (récepteur A de l'interleukine 17, CD217)], Homo sapiens anticorps monoclonal; chaîne lourde gamma2 (1-442) [Homo sapiens VH (IGHV1-18*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -Homo sapiens IGHG2*01 (117-442)], (130-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-15*01 (93.70%) - IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (218-218":219-219":222-222":225-225")-tétrakisdisulfure

brodalumab inmunoglobulina G2-kappa, anti-[IL17RA (receptor A de la interleukina 17 de Homo sapiens, CD217)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma2 (1-442) [Homo sapiens VH (IGHV1-18*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -Homo sapiens IGHG2*01 (117-442)], (130-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-15*01 (93.70%) - IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (218-218":219-219":222-222":225-225")-tetrakisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGAE VKKPGASVKV SCKASGYTFT RYGISWVRQA PGQGLEWMGW 50 ISTYSGNTNY AQKLQGRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARRQ 100 LYFDYWGQGT LVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP 150 EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS NFGTQTYTCN 200 VDHKPSNTKV DKTVERKCCV ECPPCPAPPV AGPSVFLFPP KPKDTLMISR 250 TPEVTCVVVD VSHEDPEVQF NWYVDGVEVH NAKTKPREEQ FNSTFRVVSV 300 LTVVHQDWLN GKEYKCKVSN KGLPAPIEKT ISKTKGQPRE PQVYTLPPSR 350 EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PMLDSDGSFF 400 LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP GK 442 Light chain / Chaîne légère / Cadena ligera EIVMTQSPAT LSVSPGERAT LSCRASQSVS SNLAWFQQKP GQAPRPLIYD 50 ASTRATGVPA RFSGSGSGTD FTLTISSLQS EDFAVYYCQQ YDNWPLTFGG 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 143-199 256-316 362-420 22''-96'' 143''-199'' 256''-316'' 362''-420'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 130-214' 130''-214''' Inter-H-H 218-218'' 219-219'' 222-222'' 225-225''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 292, 292''

cabozantinibum cabozantinib N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}- N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

cabozantinib N-{4-[(6,7-diméthoxyquinoléin-4-yl)oxy]phényl}- N'-(4-fluorophényl)cyclopropane-1,1-dicarboxamide

cabozantinib N-{4-[(6,7-dimetoxiquinolin-4-il)oxi]fenil}- N'-(4-fluorofenil)ciclopropano-1,1-dicarboxamida

51 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

C28H24FN3O5

H3CO N

H3CO O F O O

N N H H

calaspargasum pegolum # calaspargase pegol pegylated Escherichia coli asparaginase; [27-alanine,64-aspartic acid,252-threonine,263-asparagine]- L-asparaginase 2 (EC 3.5.1.1, L-asparagine amidohydrolase II) Escherichia coli (strain K12) tetramer Į4, carbamates with Į-carboxy- Ȧ-methoxypoly(oxyethylene)

calaspargase pégol asparaginase d'Escherichia coli pégylée; carbamates entre le tétramère Į4 de [27-alanine,64-acide aspartique,252-thréonine,263-asparagine]-L-asparaginase 2 (EC 3.5.1.1, L-asparagine amidohydrolase II) d'Escherichia coli (souche K12) et le Į-carboxy-Ȧ-méthoxypoly(oxyéthylène)

calaspargasa pegol asparaginasa de Escherichia coli pegilada; carbamatos entre el tetrámero Į4 de [27-alanina,64-ácido aspártico,252-treonina,263-asparagina]-L-asparaginasa 2 (EC 3.5.1.1, L-asparagina amidohidrolasa II) de Escherichia coli (cepa K12) y el Į-carboxi-Ȧ-metoxipoli(oxietileno)

C1516H2423N415O492S8 (peptide monomer)

Monomer / Monomère / Monómero

LPNITILATG GTIAGGGDSA TKSNYTAGKV GVENLVNAVP QLKDIANVKG 50 EQVVNIGSQD MNDDVWLTLA KKINTDCDKT DGFVITHGTD TMEETAYFLD 100 LTVKCDKPVV MVGAMRPSTS MSADGPFNLY NAVVTAADKA SANRGVLVVM 150 NDTVLDGRDV TKTNTTDVAT FKSVNYGPLG YIHNGKIDYQ RTPARKHTSD 200 TPFDVSKLNE LPKVGIVYNY ANASDLPAKA LVDAGYDGIV SAGVGNGNLY 250 KTVFDTLATA AKNGTAVVRS SRVPTGATTQ DAEVDDAKYG FVASGTLNPQ 300 KARVLLQLAL TQTKDPQQIQ QIFNQY 326 approximately 9 residues are pegylated out of 23 (1 L and 22 K) environ 9 résidus sur 23 (1 L et 22 K) sont pegylés aproximadamente están pegilados 9 restos de 23 ( 1L y 22K)

L K 1 22-29-43-49-71-72-79-104-107-139-162-172- 186-196-207-213-229-251-262-288-301-314

CH3 H H3C O O H O H2NCO2H O H3C O N n H H3C O N CO2H n H n # 112 n # 112

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 77-105 77'-105' 77'''-105''' 77''''-105''''

52 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

cantuzumabum ravtansinum # cantuzumab ravtansine immunoglobulin G1-kappa, anti-[Homo sapiens MUC1 sialylated carbohydrate, tumour-associated (CA242, cancer antigen 242)], humanized monoclonal antibody conjugated to maytansinoid DM4; gamma1 heavy chain (1-449) [humanized VH (Homo sapiens IGHV7-4-1*02 (76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T (114)) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222- 219')-disulfide with kappa light chain (1'-219') [humanized V-KAPPA (Homo sapiens IGKV2-28*01 (82.00%) -IGKJ3*01 V124>L (109), D125>E (110), I126>L (111)) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (228-228":231-231")-bisdisulfide dimer ; conjugated, on an average of 3 to 4 lysyl, to maytansinoid DM4 [N2'-deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine] via the reducible SPDB linker [N-succinimidyl 4-(2- pyridyldithio)butanoate] For the ravtansine part, please refer to the document "INN for pharmaceutical substances: Names for radicals, groups and others"*

cantuzumab ravtansine immunoglobuline G1-kappa, anti-[Homo sapiens glycane sialylé de MUC1, associé à des tumeurs (CA242, antigène du cancer 242)], anticorps monoclonal humanisé conjugué au maytansinoïde DM4; chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiens IGHV7-4-1*02 (76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T (114)) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222- 219')-disulfure avec la chaîne légère kappa (1'-219') [V-KAPPA humanisé (Homo sapiens IGKV2-28*01 (82.00%) -IGKJ3*01 V124>L (109), D125>E (110), I126>L (111)) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (228-228":231-231")-bisdisulfure; conjugué, sur 3 à 4 lysyl en moyenne, au maytansinoïde DM4 [N2'- déacétyl-N2'-(4-mercapto-4-méthyl-1-oxopentyl)-maytansine] via le linker SPDB réductible [4-(2-pyridyldithio)butanoate de N- succinimidyle] Pour la partie ravtansine, veuillez vous référer au document "INN for pharmaceutical substances: Names for radicals, groups and others"*.

cantuzumab ravtansina inmunoglobulina G1-kappa, anti-[Homo sapiens glicano sialilo de MUC1, asociado al tumor (CA242, antígeno del cancer 242)] anticuerpo monoclonal humanizado conjugado con el maitansinoide DM4; cadena pesada gamma1 (1-449) [VH humanizada (Homo sapiens IGHV7-4-1*02 (76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T (114)) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222- 219')-disulfuro con la cadena ligera kappa (1'-219') [V-KAPPA humanizada (Homo sapiens IGKV2-28*01 (82.00%) -IGKJ3*01 V124>L (109), D125>E (110), I126>L (111)) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (228-228":231-231")- bisdisulfuro; conjugado, en 3-4 grupos lisil por término medio, con el maitansinoide DM4 [N2'-desacetil-N2'-(4-mercapto-4-metil-1- oxopentil)-maitansina] mediante el conector SPDB reducible [N-4-(2- piridilditio)butanoato de succinimidilo] Para la fracción ravtansina, se ruega referirse al documento "INN for pharmaceutical substances: Names for radicals, groups and others"*.

53 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGAE VKKPGETVKI SCKASDYTFT YYGMNWVKQA PGQGLKWMGW 50 IDTTTGEPTY AQKFQGRIAF SLETSASTAY LQIKSLKSED TATYFCARRG 100 PYNWYFDVWG QGTTVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera DIVMTQSPLS VPVTPGEPVS ISCRSSKSLL HSNGNTYLYW FLQRPGQSPQ 50 LLIYRMSNLV SGVPDRFSGS GSGTAFTLRI SRVEAEDVGV YYCLQHLEYP 100 FTFGPGTKLE LKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-93' 139'-199' 23'''-93''' 139'''-199''' Inter-H-L 222-219' 222''-219''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

ceftolozanum ceftolozane (6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl- 1H-pyrazol-2-ium-2-yl)methyl]-7-[(2Z)-2-(5-amino-1,2,4-thiadiazol- 3-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetamido]-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

ceftolozane (6R,7R)-3-[(5-amino-4-{[(2-aminoéthyl)carbamoyl]amino}-1-méthyl- 1H-pyrazol-2-ium-2-yl)méthyl]-7-[(2Z)-2-(5-amino-1,2,4-thiadiazol- 3-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acétamido]-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ène-2-carboxylate

ceftolozano (6R,7R)-3-[(5-amino-4-{[(2-aminoetil)carbamoil]amino}-1-metil- 1H-pirazol-2-io-2-il)metil]-7-[(2Z)-2-(5-amino-1,2,4-tiadiazol-3-il)- 2-{[(2-carboxipropan-2-il)oxo]imino}acetamido]-8-oxo-5-tia- 1-azabiciclo[4.2.0]oct-2-eno-2-carboxilato

C23H30N12O8S2

H3C CO2H NH2 H3C CO2 O O O NH N N N H NH N N N S H C S H H 3 N O NH2

H2N

cenderitidum cenderitide natriuretic peptide receptor type B (NPR-B) agonist; human C-type natriuretic peptide-(32-53)-peptide (CNP-22) fusion protein with eastern green mamba (Dendroaspis angusticeps) natriuretic peptide-(24-38)-peptide

54 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

cendéritide agoniste du récepteur du peptide natriurétique de type B; peptide natriurétique de type-C humain-(32-53)-peptide (CNP-22) protéine de fusion avec le peptide natriurétique de Dendroaspis angusticeps (mamba vert)-(24-38)-peptide

cenderitida agonista del receptor del péptido natriurético de tipo B; péptido natriurético de tipo-C humano-(32-53)-péptido (CNP-22) proteína de fusión con el péptido natriurético de Dendroaspis angusticeps (mamba vert)-(24-38)-péptido

C158H263N49O50S3

GLSKGCFGLK LDRIGSMSGL GCPSLRDPRP NAPSTSA 37 Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro 6-22

cepeginterferonum alfa-2b # cepeginterferon alfa-2b pegylated human interferon alpha-2b; N2.1-{4-[Ȧ-methoxypoly(oxyethylene)]butyl}-human interferon alpha- 2b

cépeginterféron alfa-2b interféron alpha-2b humain pégylé; N2.1-{4-[Ȧ-méthoxypoly(oxyéthylène)]butyl}-interféron alpha-2b humain

cepeginterferón alfa-2b interferón alfa-2b humano pegilado; N2.1-{4-[Ȧ-metoxipoli(oxietileno)]butil}-interferón alfa-2b humano

C865H1359N229O256S9 [C2H4O]n

CDLPQTHSLG SRRTLMLLAQ MRRISLFSCL KDRHDFGFPQ EEFGNQFQKA 50 ETIPVLHEMI QQIFNLFSTK DSSAAWDETL LDKFYTELYQ QLNDLEACVI 100 QGVGVTETPL MKEDSILAVR KYFQRITLYL KEKKYSPCAW EVVRAEIMRS 150 FSLSTNLQES LRSKE 165

Disulfide bridges location / Positions des ponts disulfure / Posiciones de los puentes disulfuro 1-98 29-138

Modified residue / Résidu modifié / Residuo modificado H O N CO2H C H C O 1 3 n HS H n # 450

conberceptum # conbercept fusion protein for immune applications (FPIA) comprising Homo sapiens FLT1 (fms-related tyrosine kinase 1, vascular endothelial growth factor receptor 1, VEGFR1, vascular permeability factor receptor, tyrosine-protein kinase FRT) fragment, fused with Homo sapiens KDR (kinase insert domain receptor, vascular endothelial growth factor receptor 2, VEGFR2, protein-tyrosine kinase receptor FLK1, CD309) fragment, fused with Homo sapiens immunoglobulin G1 Fc fragment; FLT1, 132-232 precursor fragment (1-101) -KDR, 227-421 precursor fragment (102-296) -glycyl-prolyl-glycyl (297-299) -gamma1 chain H-CH2-CH3 fragment (300-526) [Homo sapiens IGHG1*03 hinge 6-15 P13>L (307) (300-309), CH2 (310-419), CH3-CH-S (420-526)]; (305-305':308-308')-bisdisulfide dimer

55 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

conbercept protéine de fusion pour applications immunitaires (FPIA) comprenant un fragment d'Homo sapiens FLT1 (tyrosine kinase 1 apparentée au fms, récepteur 1 du facteur de croissance de l'endothélium vasculaire, VEGFR1, récepteur du facteur de perméabilité vasculaire, tyrosine-protéine kinase FRT), fusionné à un fragment d'Homo sapiens KDR (récepteur à domaine kinase, récepteur 2 du facteur de croissance de l'endothélium vasculaire, VEGFR2, récepteur tyrosine-protéine kinase FLK1, CD309), fusionné au fragment Fc de l'Homo sapiens immunoglobuline G1; FLT1, fragment 132-232 du précurseur (1-101) -KDR, fragment 227-421 du précurseur (102-296) - glycyl-prolyl-glycyl (297-299) - fragment H-CH2-CH3 de la chaîne gamma1 (300-526) [Homo sapiens IGHG1*03 charnière 6-15 P13>L (307) (300-309), CH2 (310-419), CH3-CH-S (420-526)]; dimère (305-305':308-308')- bisdisulfure

conbercept proteína de fusión para aplicaciones inmunitarias (FPIA) que comprende un fragmento de FLT1 de Homo sapiens (tirosina kinasa 1 relacionada con fms, receptor 1 del factor de crecimiento del endotelio vascular, VEGFR1, receptor del factor de permeabilidad vascular, tirosina-protein kinasa FRT), fusionada a un fragmento de KDR de Homo sapiens (receptor con dominio kinasa, receptor 2 del factor de crecimiento del endotelio vascular, VEGFR2, receptor tirosina-protein kinasa FLK1, CD309), fusionado al fragmento Fc de la inmunoglobulina G1 de Homo sapiens; FLT1, fragmento 132-232 de precursor (1-101) -KDR, fragmento 227-421 del precursor (102-296) - glicil-prolil-glicil (297-299) - fragmento H-CH2-CH3 de la cadena gamma1 (300-526) [Homo sapiens IGHG1*03 bisagra 6-15 P13>L (307) (300-309), CH2 (310- 419), CH3-CH-S (420-526)]; dímero (305-305':308-308')-bisdisulfuro

Fused chain / chaine fusionnée / cadena fusionada GRPFVEMYSE IPEIIHMTEG RELVIPCRVT SPNITVTLKK FPLDTLIPDG 50 KRIIWDSRKG FIISNATYKE IGLLTCEATV NGHLYKTNYL THRQTNTIID 100 VVLSPSHGIE LSVGEKLVLN CTARTELNVG IDFNWEYPSS KHQHKKLVNR 150 DLKTQSGSEM KKFLSTLTID GVTRSDQGLY TCAASSGLMT KKNSTFVRVH 200 EKPFVAFGSG MESLVEATVG ERVRIPAKYL GYPPPEIKWY KNGIPLESNH 250 TIKAGHVLTI MEVSERDTGN YTVILTNPIS KEKQSHVVSL VVYVPPGPGD 300 KTHTCPLCPA PELLGGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSHEDP 350 EVKFNWYVDG VEVHNAKTKP REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC 400 KVSNKALPAP IEKTISKAKG QPREPQVYTL PPSRDELTKN QVSLTCLVKG 450 FYPSDIAVEW ESNGQPENNY KATPPVLDSD GSFFLYSKLT VDKSRWQQGN 500 VFSCSVMHEA LHNHYTQKSL SLSPGK 526 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-chain 27-76 121-182 340-400 446-504 27'-76' 121'-182' 340'-400' 446'-504' Inter-chains 305-305' 308-308'

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 376, 376'

crenezumabum # crenezumab immunoglobulin G4-kappa, anti-[Homo sapiens amyloid beta (Abeta) peptides Aȕ42 and Aȕ40)], humanized monoclonal antibody; gamma4 heavy chain (1-438) [humanized VH (Homo sapiens IGHV3-23*04 (89.70%) -(IGHD)-IGHJ4*01 L123>T (107) [8.8.5] (1-112) -Homo sapiens IGHG4*01 hinge S10>P (220) (113-438)], (126-219')-disulfide with kappa light chain (1'-219') [humanized V-KAPPA (Homo sapiens IGKV2D-29*02 (86.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (218- 218":221-221")-bisdisulfide dimer

56 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

crénezumab immunoglobuline G4-kappa, anti-[Homo sapiens peptides bêta- amyloïdes (Abêta) Aȕ42 et Aȕ40)], anticorps monoclonal humanisé; chaîne lourde gamma4 (1-438) [VH humanisé (Homo sapiens IGHV3-23*04 (89.70%) -(IGHD)-IGHJ4*01 L123>T (107) [8.8.5] (1-112) -Homo sapiens IGHG4*01 charnière S10>P (220) (113- 438)], (126-219')-disulfure avec la chaîne légère kappa (1'-219') [V-KAPPA humanisé (Homo sapiens IGKV2D-29*02 (86.00%) - IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (218-218":221-221")-bisdisulfure

crenezumab inmunoglobulina G4-kappa, anti-[péptidos beta-amiloides (Abeta) Aȕ42 y Aȕ40 de Homo sapiens)], anticuerpo monoclonal humanizado; cadena pesada gamma4 (1-438) [VH humanizada (Homo sapiens IGHV3-23*04 (89.70%) -(IGHD)-IGHJ4*01 L123>T (107) [8.8.5] (1- 112) -Homo sapiens IGHG4*01 bisagra S10>P (220) (113-438)], (126-219')-disulfuro con la cadena ligera kappa (1'-219') [V-KAPPA humanizada (Homo sapiens IGKV2D-29*02 (86.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (218- 218":221-221")-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFTFS SYGMSWVRQA PGKGLELVAS 50 INSNGGSTYY PDSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCASGD 100 YWGQGTTVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT 150 VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT KTYTCNVDHK 200 PSNTKVDKRV ESKYGPPCPP CPAPEFLGGP SVFLFPPKPK DTLMISRTPE 250 VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS TYRVVSVLTV 300 LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV YTLPPSQEEM 350 TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS 400 RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLG 438 Light chain / Chaîne légère / Cadena ligera DIVMTQSPLS LPVTPGEPAS ISCRSSQSLV YSNGDTYLHW YLQKPGQSPQ 50 LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHVP 100 WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 139-195 253-313 359-417 22''-96'' 139''-195'' 253''-313'' 359''-417'' Intra-L 23'-93' 139'-199' 23'''-93''' 139'''-199''' Inter-H-L 126-219' 126''-219''' Inter-H-H 218-218'' 221-221''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 289, 289''

crenolanibum crenolanib 1-(2-{5-[(3-methyloxetan-3-yl)methoxy]-1H-benzimidazol- 1-yl}quinolin-8-yl)piperidin-4-amine

crénolanib 1-(2-{5-[(3-méthyloxétan-3-yl)méthoxy]-1H-benzimidazol- 1-yl}quinoléin-8-yl)pipéridin-4-amine

crenolanib 1-(2-{5-[(3-metiloxetan-3-il)metoxi]-1H-benzoimidazol-1-il}quinolin- 8-il)piperidin-4-amina

57 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

C26H29N5O2

CH 3 O

O N N N N

NH2

dabrafenibum dabrafenib N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]- 2-fluorophenyl}-2,6-difluorobenzenesulfonamide

dabrafénib N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]- 2-fluorophényl}-2,6-difluorobenzènesulfonamide

dabrafenib N-{3-[5-(2-aminopirimidin-4-il)-2-terc-butil-1,3-tiazol-4-il]- 2-fluorofenil}-2,6-difluorobencenosulfonamido

C23H20F3N5O2S2

NH2 N N F F S H CH N 3 S N CH F OO H3C 3

daclatasvirum daclatasvir dimethyl N,N'-([1,1'-biphenyl]-4,4'-diylbis{1H-imidazole-5,2-diyl- [(2S)-pyrrolidine-2,1-diyl][(1S)-3-methyl-1-oxobutane- 1,2-diyl]})dicarbamate

daclatasvir N,N'-([1,1'-biphényl]-4,4'-diylbis{1H-imidazole-5,2-diyl- [(2S)-pyrrolidine-2,1-diyl][(1S)-3-méthyl-1-oxobutane- 1,2-diyl]})dicarbamate de diméthyle

daclatasvir N,N'-([1,1'-bifenil]-4,4'-diilbis{1H-imidazol-5,2-diil-[(2S)-pirrolidina- 2,1-diil][(1S)-3-metil-1-oxobutano-1,2-diil]})dicarbamato de dimetilo

C40H50N8O6

CH3

O O N O CH3 H N H NH N H H C CH3 3 H N HN H N H CH3 ON O O

CH3

58 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

dalanterceptum # dalantercept fusion protein for immune applications (FPIA) comprising Homo sapiens ACVRL1 (activin A receptor type II-like 1, activin receptor- like kinase 1, ALK1, ALK-1, serine/threonine-protein kinase receptor R3, SKR3, transforming growth factor-beta superfamily receptor type I, TGF-B superfamily receptor type I, TSR-I, HHT2, ORW2) fragment, fused with Homo sapiens immunoglobulin G1 Fc fragment; ACVR2L1, 22-120 precursor fragment (1-99) -threonyl-triglycyl (100- 103) -gamma1 chain H-CH2-CH3 fragment (104-328) [Homo sapiens IGHG1*03 hinge 8-15 (104-111), CH2 L1.3>A (115), G1>A (118), A115>V (211) (112-221), CH3 S85.3>P (284) (222-328)]; (107-107':110-110')-bisdisulfide dimer

dalantercept protéine de fusion pour applications immunitaires (FPIA) comprenant un fragment d'Homo sapiens ACVRL1 (récepteur 1 de type II-like de l'activine A, kinase 1 apparentée au récepteur de l'activine, ALK1, ALK-1, récepteur R3 de type sérine/thréonine-protéine kinase, SKR3, récepteur de type I de la superfamille du facteur de croissance transformant bêta, récepteur de type I de la superfamille du TGF-B, TSR-I, HHT2, ORW2), fusionné au fragment Fc de l'Homo sapiens immunoglobuline G1; ACVR2L1, fragment 22-120 du précurseur (1-99) -thréonyl-triglycyl (100-103) -fragment H-CH2-CH3 de la chaîne gamma1 (104-328) [Homo sapiens IGHG1*03 charnière 8-15 (104-111), CH2 L1.3>A (115), G1>A (118), A115>V (211) (112-221), CH3 S85.3>P (284) (222-328)]; dimère (107-107':110-110')-bisdisulfure

dalantercept proteína de fusión para aplicaciones inmunitarias (FPIA) que comprende un fragmento de ACVRL1 de Homo sapiens (receptor 1 de tipo II-like de la activina A, kinasa 1 relacionada con el receptor de la activina, ALK1, ALK-1, receptor R3 de tipo serina/treonina- proteinkinasa, SKR3, receptor de tipo I de la superfamilia del factor de crecimiento transformador beta, receptor de tipo I de la superfamilia del TGF-B, TSR-I, HHT2, ORW2), fusionada con el fragmento Fc de la inmunoglobulina G1 de Homo sapiens; ACVR2L1, fragmento 22-120 del precursor (1-99) -treonil-triglicil (100-103) -fragmento H-CH2-CH3 de la cadena gamma1 (104-328) [Homo sapiens IGHG1*03 bisagra 8-15 (104-111), CH2 L1.3>A (115), G1>A (118), A115>V (211) (112-221), CH3 S85.3>P (284) (222-328)]; dímero (107-107':110-110')-bisdisulfuro

Fused chain / chaine fusionnée / cadena fusionada DPVKPSRGPL VTCTCESPHC KGPTCRGAWC TVVLVREEGR HPQEHRGCGN 50 LHRELCRGRP TEFVNHYCCD SHLCNHNVSL VLEATQPPSE QPGTDGQLAT 100 GGGTHTCPPC PAPEALGAPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE 150 DPEVKFNWYV DGVEVHNAKT KPREEQYNST YRVVSVLTVL HQDWLNGKEY 200 KCKVSNKALP VPIEKTISKA KGQPREPQVY TLPPSREEMT KNQVSLTCLV 250 KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGPFFLYSK LTVDKSRWQQ 300 GNVFSCSVMH EALHNHYTQK SLSLSPGK 328 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-chain 13-30 15-20 25-48 56-68 69-74 142-202 248-306 13'-30' 15'-20' 25'-48' 56'-68' 69'-74' 142'-202' 248'-306' Inter-chains 107-107' 110-110'

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 77, 178, 77', 178'

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dasolampanelum dasolampanel (3S,4aS,6S,8aR)-6-[3-chloro-2-(1H-tetrazol-5-yl)phenoxy]- decahydroisoquinoline-3-carboxylic acid

dasolampanel acide (3S,4aS,6S,8aR)-6-[3-chloro-2-(1H-tétrazol- 5-yl)phénoxy]décahydroisoquinoléine-3-carboxylique

dasolampanel ácido (3S,4aS,6S,8aR)-6-[3-cloro-2-(1H-tetrazol-5-il)fenoxi]- decahidroisoquinolina-3-carboxilico

C17H20ClN5O3

H NH

Cl O CO2H H H H N NH NN

delanzomibum delanzomib {(1R)-1-[(2S,3R)-3-hydroxy-2-(6-phenylpyridine- 2-carboxamido)butanamido]-3-methylbutyl}boronic acid

délanzomib acide {(1R)-1-[(2S,3R)-3-hydroxy-2-(6-phénylpyridine- 2-carboxamido)butanamido]-3-méthylbutyl}boronique

delanzomib ácido {(1R)-1-[(2S,3R)-3-hidroxi-2-(6-fenilpiridina- 2-carboxamido)butanamido]-3-metilbutil}borónico

C21H28BN3O5

HO CH3 O H OH H H N N B N OH H H O CH3

CH3

delcasertibum delcasertib human immunodeficiency virus 1 protein Tat-(46-57)-peptide (1ĺ1')- disulfide with L-cysteinyl-[mouse protein kinase C delta type-(8-17)- peptide]

delcasertib protéine Tat du virus 1 de l'immunodéficience humaine-(46-57)- peptide (1ĺ1')-disulfure avec le L-cystéinyl-(protéine kinase C type delta de souris-(8-17)-peptide

delcasertib proteína Tat del virus 1 de la inmunodeficiencia humana-(46-57)- péptido (1ĺ1')-disulfuro con la L-cisteinil-[proteína kinasa C tipo delta de ratón-(8-17)-péptido]

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C120H199N45O34S2

A chain / Chaîne A / Cadena A CYGRKKRRQR RR 12 Light chain / Chaîne légère / Cadena ligera CSFNSYELGS L 11' Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro 1-1'

dolutegravirum dolutegravir (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl- 6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1- b][1,3]oxazine-9-carboxamide

dolutégravir (4R,12aS)-N-[(2,4-difluorophényl)méthyl]-7-hydroxy-4-méthyl- 6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1- b][1,3]oxazine-9-carboxamide

dolutegravir (4R,12aS)-N-[(2,4-difluorofenil)metil]-7-hidroxi-4-metil-6,8-dioxo- 3,4,6,8,12,12a-hexahidro-2H-pirido[1',2':4,5]pirazino[2,1- b][1,3]oxazina-9-carboxamida

C20H19F2N3O5

O OH H CH3 O F F N H N N O H O

encaleretum encaleret 2ƍ-{(1R)-1-[(2R)-3-{[1-(4-chloro-3-fluorophenyl)-2-methylpropan- 2-yl]amino}-2-hydroxypropoxy]ethyl}-3-methyl[1,1ƍ-biphenyl]- 4-carboxylic acid

encaléret acide 2ƍ-{(1R)-1-[(2R)-3-{[1-(4-chloro-3-fluorophényl)- 2-méthylpropan-2-yl]amino}-2-hydroxypropoxy]éthyl}-3-méthyl[1,1ƍ- biphényl]-4-carboxylique

encaleret ácido 2ƍ-{(1R)-1-[(2R)-3-{[1-(4-cloro-3-fluorofenil)-2-metilpropan- 2-yl]amino}-2-hidroxipropoxi]etil}-3-metil[1,1ƍ-bifenil]-4-carboxílico

C29H33ClFNO4

Cl CH3 H3C CH3 H F N O CO2H H CH3 HOH

61 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

epelsibanum epelsiban (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin- 3-yl)-2-(morpholin-4-yl)-2-oxoethyl]-6-[(2S)-butan-2-yl]piperazine- 2,5-dione

épelsiban (3R,6R)-3-(2,3-dihydro-1H-indén-2-yl)-1-[(1R)-1-(2,6-diméthylpyridin- 3-yl)-2-(morpholin-4-yl)-2-oxoéthyl]-6-[(2S)-butan-2-yl]pipérazine- 2,5-dione

epelsibán (3R,6R)-3-(2,3-dihidro-1H-inden-2-il)-1-[(1R)-1-(2,6-dimetilpiridin- 3-il)-2-(morfolin-4-il)-2-oxoetil]-6-[(2S)-butan-2-il]piperazina-2,5-diona

C30H38N4O4

CH3 CH O H 3

HN H O N N H O H O

H3C N CH3

etoxybamidum etoxybamide 4-hydroxy-N-(2-hydroxyethyl)butanamide

étoxybamide 4-hydroxy-N-(2-hydroxyéthyl)butanamide

etoxibamida 4-hidroxi-N-(2-hidroxietil)butanamida

C6H13NO3

O HO OH N H

evacetrapibum evacetrapib (1r,4r)-4-({(5S)-5-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(2-methyl- 2H-tetrazol-5-yl)amino]-7,9-dimethyl-2,3,4,5-tetrahydro- 1H-1-benzazepin-1-yl}methyl)cyclohexane-1-carboxylic acid

évacétrapib acide (1r,4r)-4-({(5S)-5-[{[3,5-bis(trifluorométhyl)phényl]méthyl}(2- méthyl-2H-tétrazol-5-yl)amino]-7,9-diméthyl-2,3,4,5-tétrahydro- 1H-benzazépin-1-yl}méthyl)cyclohexane-1-carboxylique

evacetrapib ácido (1r,4r)-4-({(5S)-5-[{[3,5-bis(trifluorometil)fenil]metil}(2-metil- 2H-tetrazol-5-il)amino]-7,9-dimetil-2,3,4,5-tetrahidro- 1H-1-benzazepin-1-il}metil)ciclohexano-1-carboxílico

62 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

C31H36F6N6O2

H3C CH3

N H H H F3C N CO2H

N N

CF3 NN CH3

exeporfinii chloridum exeporfinium chloride 3,3'-(21H,23H-porphyrin-5,15-diylbis{[(4,1-phenylene)oxy]- N,N,N-trimethylpropan-1-aminium}) dichloride

chlorure d'exéporfinium dichlorure de 3,3'-[21H,23H-porphyrin-5,15-diylbis(4,1- phénylèneoxy)]bis[N,N,N-triméthylpropan-1-aminium]

cloruro de exeporfinio dicloruro de 3,3'-(21H,23H-porfirin-5,15-diilbis{[(4,1-fenileno)oxi]- N,N,N-trimetilpropan-1-aminium})

C44H50Cl2N6O2

O

Cl N H CH3 N H3C H3C N N CH3 N CH3 H H3C N Cl

O

fabomotizolum fabomotizole 5-ethoxy-2-{[2-(morpholin-4-yl)ethyl]sulfanyl}-1H-benzimidazole

fabomotizole 5-éthoxy-2-{[2-(morpholin-4-yl)éthyl]sulfanyl}-1H-benzimidazole

fabomotizol 5-etoxi-2-{[2-(morfolin-4-il)etil]sulfanil}-1H-benzoimidazol

C15H21N3O2S

O NH O H C 3 N N S

faciniclinum facinicline N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1H-indazole-3-carboxamide

facinicline N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1H-indazole-3-carboxamide

faciniclina N-[(3S)-1-azabiciclo[2.2.2]octan-3-il]-1H-indazol-3-carboxamida

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C15H18N4O

N O H N H N NH

fiboflaponum fiboflapon 3-{3-(tert-butylsulfanyl)-1-{[4-(6-ethoxypyridin-3-yl)phenyl]methyl}- 5-[(5-methylpyridin-2-yl)methoxy]-1H-indol-2-yl}- 2,2-dimethylpropanoic acid

fiboflapon acide 3-{3-(tert-butylsulfanyl)-1-{[4-(6-éthoxypyridin- 3-yl)phényl]méthyl}-5-[(5-méthylpyridin-2-yl)méthoxy]-1H-indol-2-yl}- 2,2-diméthylpropanoïque

fiboflapón ácido 3-{3-(terc-butilsulfanil)-1-{[4-(6-etoxipiridin-3-il)fenil]metil}- 5-[(5-metilpiridin-2-il)metoxi]-1H-indol-2-yl}-2,2-dimetilpropanoico

C38H43N3O4S

H3C O N

CH3 H3C N CO2H

N O S H3C CH3 CH3 H3C

ficlatuzumabum # ficlatuzumab immunoglobulin G1-kappa, anti-[Homo sapiens HGF (hepatocyte growth factor, scatter factor, SF, hepatopoeitin A)], humanized monoclonal antibody; gamma1 heavy chain (1-448) [humanized VH (Homo sapiens IGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01 V124>L (114)) [8.8.11] (1-118) -Homo sapiens IGHG1*03 (119-448)], (221-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV4-1*01 (73.30%) -IGKJ2*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (227-227":230-230")-bisdisulfide dimer

ficlatuzumab immunoglobuline G1-kappa, anti-[Homo sapiens HGF (facteur de croissance de l'hépatocyte, facteur dispersant, SF, hépatopoïétine A)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-448) [VH humanisé (Homo sapiens IGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01 V124>L (114)) [8.8.11] (1-118) -Homo sapiens IGHG1*03 (119-448)], (221-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV4-1*01 (73.30%) -IGKJ2*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (227-227":230-230")- bisdisulfure

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ficlatuzumab inmunoglobulina G1-kappa, anti-[HGF de Homo sapiens (factor de crecimiento del hepatocito, factor dispersante, SF, hepatopoyetina A)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-448) [VH humanizado (Homo sapiens IGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01 V124>L (114)) [8.8.11] (1-118) -Homo sapiens IGHG1*03 (119-448)], (221-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizada (Homo sapiens IGKV4-1*01 (73.30%) -IGKJ2*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (227-227":230-230")- bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQPGAE VKKPGTSVKL SCKASGYTFT TYWMHWVRQA PGQGLEWIGE 50 INPTNGHTNY NQKFQGRATL TVDKSTSTAY MELSSLRSED TAVYYCARNY 100 VGSIFDYWGQ GTLLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150 FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200 CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250 TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300 YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350 TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400 SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK 448 Light chain / Chaîne légère / Cadena ligera DIVMTQSPDS LAMSLGERVT LNCKASENVV SYVSWYQQKP GQSPKLLIYG 50 ASNRESGVPD RFSGSGSATD FTLTISSVQA EDVADYHCGQ SYNYPYTFGQ 100 GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 145-201 262-322 368-426 22''-96'' 145''-201'' 262''-322'' 368''-426'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 221-214' 221''-214''' Inter-H-H 227-227'' 230-230''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 298, 298''

galeteronum galeterone 17-(1H-benzimidazol-1-yl)androsta-5,16-dien-3ȕ-ol

galétérone 17-(1H-benzimidazol-1-yl)androsta-5,16-dién-3ȕ-ol

galeterona 17-(1H-benzoimidazol-1-il)androsta-5,16-dien-3ȕ-ol

C26H32N2O N

N CH3

CH3 H

H H HO H

ganetespibum ganetespib 5-[2,4-dihydroxy-5-(propan-2-yl)phenyl]-4-(1-methyl-1H-indol-5-yl)- 2,4-dihydro-3H-1,2,4-triazol-3-one

ganétespib 5-[2,4-dihydroxy-5-(propan-2-yl)phényl]-4-(1-méthyl-1H-indol-5-yl)- 2,4-dihydro-3H-1,2,4-triazol-3-one

ganetespib 5-[2,4-dihidroxi-5-(propan-2-il)fenil]-4-(1-metil-1H-indol-5-il)- 2,4-dihidro-3H-1,2,4-triazol-3-ona

65 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

C20H20N4O3

H3C N

O

CH3 N NH

H3C N

HO OH

indatuximabum ravtansinum # indatuximab ravtansine immunoglobulin G4-kappa, anti-[Homo sapiens SDC1 (syndecan-1, CD138)], chimeric monoclonal antibody conjugated to maytansinoid DM4; gamma4 heavy chain (1-449) [Mus musculus VH (IGHV1-9*01 - (IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG4*01 (123- 449)], (136-214')-disulfide with kappa light chain (1'-214') [Mus musculus V-KAPPA (IGKV10-94*01 -IGKJ1*01) [6.3.9] (1'-107') - Homo sapiens IGKC*01 (108'-214')]; (228-228'':231-231'')- bisdisulfide dimer; conjugated, on an average of 3 to 4 lysyl, to maytansinoid DM4 [N2'-deacetyl-N2'-(4-mercapto-4-methyl- 1-oxopentyl)-maytansine] via the reducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio)butanoate] For the ravtansine part, please refer to the document "INN for pharmaceutical substances: Names for radicals, groups and others"*

indatuximab ravtansine immunoglobuline G4-kappa, anti-[Homo sapiens SDC1 (syndecan-1, CD138)], anticorps monoclonal chimérique conjugué au maytansinoïde DM4; chaîne lourde gamma4 (1-449) [Mus musculus VH (IGHV1-9*01 - (IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG4*01 (123- 449)], (136-214')-disulfure avec la chaîne légère kappa (1'-214') [Mus musculus V-KAPPA (IGKV10-94*01 -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (228-228":231-231")- bisdisulfure; conjugué, sur 3 à 4 lysyl en moyenne, au maytansinoïde DM4 [N2'-déacétyl-N2'-(4-mercapto-4-méthyl- 1-oxopentyl)-maytansine] via le linker SPDB réductible [4-(2-pyridyldithio)butanoate de N-succinimidyle] Pour la partie ravtansine, veuillez vous référer au document "INN for pharmaceutical substances: Names for radicals, groups and others"*.

indatuximab ravtansina inmunoglobulina G4-kappa, anti-[SDC1 de Homo sapiens (sindecán- 1, CD138)], anticuerpo monoclonal quimérico conjugado con el maitansinoide DM4; cadena pesada gamma4 (1-449) [Mus musculus VH (IGHV1-9*01 - (IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG4*01 (123- 449)], (136-214')-disulfuro con la cadena ligera kappa (1'-214') [Mus musculus V-KAPPA (IGKV10-94*01 -IGKJ1*01) [6.3.9] (1'-107') - Homo sapiens IGKC*01 (108'-214')]; dímero (228-228":231-231")- bisdisulfuro; conjugado, en 3-4 grupos lisil por término medio con el maitansinoide DM4 [N2'-desacetil-N2'-(4-mercapto-4-metil- 1-oxopentil)-maitansina] mediante el espaciador SPDB reducible [4-(2-piridilditio)butanoato de N-succinimidilo] Para la fracción ravtansina, se ruega referirse al documento "INN for pharmaceutical substances: Names for radicals, groups and others"*

66 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

Heavy chain / Chaîne lourde / Cadena pesada QVQLQQSGSE LMMPGASVKI SCKATGYTFS NYWIEWVKQR PGHGLEWIGE 50 ILPGTGRTIY NEKFKGKATF TADISSNTVQ MQLSSLTSED SAVYYCARRD 100 YYGNFYYAMD YWGQGTSVTV SSASTKGPSV FPLAPCSRST SESTAALGCL 150 VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT 200 KTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV 350 YTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 449 Light chain / Chaîne légère / Cadena ligera DIQMTQSTSS LSASLGDRVT ISCSASQGIN NYLNWYQQKP DGTVELLIYY 50 TSTLQSGVPS RFSGSGSGTD YSLTISNLEP EDIGTYYCQQ YSKLPRTFGG 100 GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 149-205 263-323 369-437 22''-96'' 149''-205'' 263''-323'' 369''-437'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 136-214' 136''-214''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

iofolastatum (123I) iofolastat (123I) N-{[(1S)-1-carboxy-5-{[(4- 123 ( I)iodophenyl)methyl]amino}pentyl]carbamoyl}-L-glutamic acid

iofolastat (123I) acide N-{[(1S)-1-carboxy-5-{[(4- 123 ( I)iodophényl)méthyl]amino}pentyl]carbamoyl}-L-glutamique

iofolastat (123I) ácido N-{[(1S)-1-carboxi-5-{[(4- 123 ( I)iodofenil)metil]amino}pentil]carbamoil}-L-glutámico

123 C19H26 IN3O7

NH CO2H

H O H

123 HO2CNN CO2H I H H

irdabisantum irdabisant 6-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyridazin-3(2H)- one

irdabisant 6-(4-{3-[(2R)-2-méthylpyrrolidin-1-yl]propoxy}phényl)pyridazin-3(2H)- one

irdabisant 6-(4-{3-[(2R)-2-metilpirrolidin-1-il]propoxi}fenil)piridazin-3(2H)-ona

C18H23N3O2

H N O N

N O

CH3 H

67 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

ixekizumabum # ixekizumab immunoglobulin G4-kappa, anti-[Homo sapiens IL17A (interleukin 17A, IL-17A)], humanized monoclonal antibody; gamma4 heavy chain (1-445) [humanized VH (Homo sapiens IGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG4*01 hinge S10>P (227), CH3 K130>del (120-445)], (133-219')-disulfide with kappa light chain (1'-219') [humanized V-KAPPA (Homo sapiens IGKV2D-29*02 (89.00%) -IGKJ2*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (225- 225":228-228")-bisdisulfide dimer

ixékizumab immunoglobuline G4-kappa, anti-[Homo sapiens IL17A (interleukine 17A, IL-17A)], anticorps monoclonal humanisé; chaîne lourde gamma4 (1-445) [VH humanisé (Homo sapiens IGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG4*01 charnière S10>P (227), CH3 K130>del (120- 445)], (133-219')-disulfure avec la chaîne légère kappa (1'-219') [V-KAPPA humanisé (Homo sapiens IGKV2D-29*02 (89.00%) - IGKJ2*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (225-225":228-228")-bisdisulfure

ixekizumab inmunoglobulina G4-kappa, anti-[Homo sapiens IL17A (interleukina 17A, IL-17A)], anticuerpo monoclonal humanizado; cadena pesada gamma4 (1-445) [VH humanizada (Homo sapiens IGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG4*01 bisagra S10>P (227), CH3 K130>del (120-445)], (133-219')-disulfuro con la cadena ligera kappa (1'-219') [V-KAPPA humanizada (Homo sapiens IGKV2D-29*02 (89.00%) -IGKJ2*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (225- 225":228-228")-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGAE VKKPGSSVKV SCKASGYSFT DYHIHWVRQA PGQGLEWMGV 50 INPMYGTTDY NQRFKGRVTI TADESTSTAY MELSSLRSED TAVYYCARYD 100 YFTGTGVYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY 200 TCNVDHKPSN TKVDKRVESK YGPPCPPCPA PEFLGGPSVF LFPPKPKDTL 250 MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR 300 VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL 350 PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD 400 GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLG 445 Light chain / Chaîne légère / Cadena ligera DIVMTQTPLS LSVTPGQPAS ISCRSSRSLV HSRGNTYLHW YLQKPGQSPQ 50 LLIYKVSNRF IGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHLP 100 FTFGQGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 260-320 366-424 22''-96'' 146''-202'' 260''-320'' 366''-424'' Intra-L 23'-93' 139'-199' 23'''-93''' 139'''-199''' Inter-H-L 133-219' 133''-219''' Inter-H-H 225-225'' 228-228''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 296, 296''

ladarixinum ladarixin 4-[(2R)-1-oxo-1-(methanesulfonamido)propan-2-yl]phenyl trifluoromethanesulfonate

ladarixine trifluorométhanesulfonate de 4-[(2R)-1-oxo- 1-(méthanesulfonamido)propan-2-yl]phényle

68 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

ladarixina trifluoromethanesulfonato de 4-[(2R)-1-oxo- 1-(metanosulfonamido)propan-2-il]fenil

C11H12F3NO6S2

H CH 3 H N CH3 O O S S O OO F3C O

lenomorelinum lenomorelin O3.26-octanoylhuman appetite-regulating hormone (growth hormone- releasing peptide) precursor (protein M46)-(24-51)-peptide (ghrelin- 28-C8)

lénomoréline O3.26-octanoylprécurseur de l'hormone humaine de régulation de l'appétit (précurseur du peptide de libération d'hormone de croissance, protéine M46)-(24-51)-peptide (ghréline-28-C8)

lenomorelina O3.26-octanoilprecursor de la hormona humana de regulación del apetito (precursor del péptido de liberación de hormona del crecimiento, proteína M46)-(24-51)-péptido (ghrelina-28-C8)

C149H249N47O42

GSSFLSPEHQ RVQQRKESKK PPAKLQPR 28 Modified residue / Résidu modifié / Residuo modificado S O 3 O-octanoyl-L-seryl H O CH3 O-octanoyl-L-séryl O-octanoil-L-serilo N C H O

lesinuradum lesinurad 2-{[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}acetic acid

lésinurad acide 2-{[5-bromo-4-(4-cyclopropylnaphtalén-1-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}acétique

lesinurad ácido 2-{[5-bromo-4-(4-ciclopropilnaftalen-1-il)-4H-1,2,4-triazol- 3-il]sulfanil}acético

C17H14BrN3O2S

Br N N N CO H S 2

69 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

lexibulinum lexibulin 1-ethyl-3-[2-methoxy-4-(5-methyl-4-{[(1S)-1-(pyridin- 3-yl)butyl]amino}pyrimidin-2-yl)phenyl]urea

lexibuline 1-éthyl-3-[2-méthoxy-4-(5-méthyl-4-{[(1S)-1-(pyridin- 3-yl)butyl]amino}pyrimidin-2-yl)phényl]urée

lexibulina 1-etil-3-[2-metoxi-4-(5-metil-4-{[(1S)-1-(piridin- 3-il)butil]amino}pirimidin-2-il)fenil]urea

C24H30N6O2

H3C H3C H N

N N N O H

N N CH3 H H OCH3

lipegfilgrastimum # lipegfilgrastim pegylated granulocyte colony stimulating factor; O3.133-[N5-(N-{[Ȧ-methoxypoly(oxyethylene)]carbonyl}glycyl)- Į-neuraminyl-(2ĺ6)-Į-D-galactopyranosyl]-L-methionyl- des-1-L-alanine-des-37-L-valine-des-38-L-serine-des-39-L-glutamic acid-human granulocyte colony-stimulating factor (G-CSF, pluripoietin)

lipegfilgrastim facteur de stimulation de colonie de granulocytes humain pégylé; O3.133-[N5-(N-{[Ȧ-méthoxypoly(oxyéthylène)]carbonyl}glycyl)- Į-neuraminyl-(2ĺ6)-Į-D-galactopyranosyl]-L-méthionyl- dès-1-L-alanine-dès-37-L-valine-des-38-L-sérine-dès-39-L-acide glutamique-facteur de stimulation de colonie de granulocytes humain (G-CSF, pluripoïétine)

lipegfilgrastim factor de estimulación de colonias de granulocitos humano pegilado; O3.133-[N5-(N-{[Ȧ-metoxipoli(oxietileno)]carbonil}glicil)-Į-neuraminil- (2ĺ6)-Į-D-galactopiranosil]-L-metionil-des-1-L-alanina- des-37-L-valina-des-38-L-serine-des-39-L-ácido glutámico-factor de estimulación de colonias de granulocitos humanos (G-CSF, pluripoyetina)

C864H1369N225O258S9 [C2H4O]n

M 0 TPLGPASSLP QSFLLKCLEQ VRKIQGDGAA LQEKLCATYK LCHPEELVLL 50 GHSLGIPWAP LSSCPSQALQ LAGCLSQLHS GLFLYQGLLQ ALEGISPELG 100 PTLDTLQLDV ADFATTIWQQ MEELGMAPAL QPTQGAMPAF ASAFQRRAGG 150 VLVASHLQSF LEVSYRVLRH LAQP 174

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 36-42 64-74

Modified residue / Résidu modifié / Residuo modificado T HO OH 133 CO H PEG-Gly-Neu-Gal-Thr O 2 HO H O

O CH3 HN H HO O H H3C O N OH O O N C n HO OH H O O

70 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

lorediplonum lorediplon N-{2-fluoro-5-[3-(thiophene-2-carbonyl)pyrazolo[1,5-a]pyrimidin- 7-yl]phenyl}-N-methylacetamide

lorédiplon N-{2-fluoro-5-[3-(thiophéne-2-carbonyl)pryrazolo[1,5-a]pyrimidin- 7-yl]phényl}-N-méthylacétamide

lorediplón N-{2-fluoro-5-[3-(tiofeno-2-carbonil)pirazolo[1,5-a]pirimidin-7-il]fenil}- N-metilacetamida

C20H15FN4O2S

O

S N CH3 N N

H3C N

O F

lumacaftorum lumacaftor 3-{6-[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane- 1-carboxamido]-3-methylpyridin-2-yl}benzoic acid

lumacaftor acide 3-{6-[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane- 1-carboxamido]-3-methylpyridin-2-yl}benzoïque

lumacaftor ácido 3-{6-[1-(2,2-difluoro-1,3-benzodioxol-5-il)ciclopropano- 1-carboxamido]-3-metilpiridin-2-il}benzoico

C24H18F2N2O5

H O N N F CO2H F O O CH3

lurbinectedinum lurbinectedin (1'R,6R,6aR,7R,13S,14S,16R)-8,14-dihydroxy-6',9-dimethoxy- 4,10,23-trimethyl-19-oxo-2',3',4',6,7,9',12,13,14,16-decahydro- 6aH-spiro[7,13-azano-6,16- (epithiopropanooxymethano)[1,3]dioxolo[7,8]isoquinolino[3,2- b][3]benzazocine-20,1'-pyrido[3,4-b]indol]-5-yl acetate

lurbinectédine acétate de (1'R,6R,6aR,7R,13S,14S,16R)-8,14-dihydroxy- 6',9-diméthoxy-4,10,23-triméthyl-19-oxo-2',3',4',6,7,9',12,13,14,16- décahydro-6aH-spiro[7,13-azano-6,16- (épithiopropanooxyméthano)[1,3]dioxolo[7,8]isoquinolino[3,2- b][3]benzazocine-20,1'-pyrido[3,4-b]indol]-5-yl

lurbinectedina acetato de (1'R,6R,6aR,7R,13S,14S,16R)-8,14-dihidroxi- 6',9-dimetoxi-4,10,23-trimetil-19-oxo-2',3',4',6,7,9',12,13,14,16- decahidro-16H-spiro[7,13-azano-6,16- (epitiopropanooximetano)[1,3]dioxolo[7,8]isoquinolino[3,2- b][3]benzazocina-20,1'-pirido[3,4-b]indol]-5-ilo

71 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

C41H44N4O10S

OH O H H H O N O

N CH3 H3C H S H O CH H 3 O H O N H3C OH NH

OCH3

H3CO

melphalanum flufenamidum melphalan flufenamide ethyl (2S)-2-[(2S)-2-amino-3-{4-[bis(2- chloroethyl)amino]phenyl}propanamido]- 3-(4-fluorophenyl)propanoate

melphalan flufénamide (2S)-2-[(2S)-2-amino-3-{4-[bis(2- chloroéthyl)amino]phényl}propanamido]- 3-(4-fluorophényl)propanoate d'éthyle

melfalán flufenamida (2S)-2-[(2S)-2-amino-3-{4-[bis(2-cloroetil)amino]fenil}propanamido]- 3-(4-fluorofenil)propanoato de etilo

C24H30Cl2FN3O3

Cl

N Cl H NH O 2 H N O CH3 O H

F

mericitabinum mericitabine (2'R)-2'-deoxy-2'-fluoro-2'-methyl-2',3'-bis- O-(2-methylpropanoyl)cytidine

méricitabine 3',5'-bis(2-méthylpropanoate) de (2'R)-2'-déoxy-2'-fluoro- 2'-méthylcytidine

mericitabina (2'R)-2'-desoxi-2'-fluoro-2'-metil-2',3'-bis-O-(2-metilpropanoil)citidina

72 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

C18H26FN3O6

NH2 CH3 O N H3C O O N O

H3C

CH3 O F H3C O

milciclibum milciclib N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}- 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide

milciclib N,1,4,4-tétraméthyl-8-{[4-(4-méthylpipérazin-1-yl)phényl]amino}- 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide

milciclib N,1,4,4-tetrametil-8-{[4-(4-metilpiperazin-1-il)fenil]amino}-4,5-dihidro- 1H-pirazolo[4,3-h]quinazolina-3-carboxamida

C25H32N8O

H3C N H N N H CH3 N N O N CH3 N CH3 N H3C

naldemedinum naldemedine 17-(cyclopropylmethyl)-6,7-didehydro-4,5Į-epoxy-3,6,14-trihydroxy- N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]morphinan- 7-carboxamide

naldémédine 17-(cyclopropylméthyl)-6,7-didéhydro-4,5Į-époxy-3,6,14-trihydroxy- N-[2-(3-phényl-1,2,4-oxadiazol-5-yl)propan-2-yl]morphinan- 7-carboxamide

naldemedina 17-(ciclopropilmetil)-6,7-didehidro-4,5Į-epoxi-3,6,14-trihidroxi- N-[2-(3-fenil-1,2,4-oxadiazol-5-il)propan-2-il]morfinan-7-carboxamida

C32H34N4O6

H N N HO O O N HN CH HO O OH 3 H CH3

73 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

naloxegolum naloxegol 4,5Į-epoxy-6Į-[(3,6,9,12,15,18,21-heptaoxadocosan-1-yl)oxy]- 17-(prop-2-en-1-yl)morphinan-3,14-diol

naloxégol 4,5Į-époxy-6Į-[(3,6,9,12,15,18,21-heptaoxadocosan-1-yl)oxy]- 17-(prop-2-én-1-yl)morphinane-3,14-diol

naloxegol 4,5Į-epoxi-6Į-[(3,6,9,12,15,18,21-heptaoxadocosan-1-il)oxi]- 17-(prop-2-en-1-il)morfinan-3,14-diol

C34H53NO11

CH2 H N

HO

O H HO H O O O

H3C O O O O O

narnatumabum # narnatumab immunoglobulin G1-kappa, anti-[Homo sapiens MST1R (macrophage stimulating 1 receptor, macrophage stimulating protein receptor, MSP receptor, c-met-related tyrosine kinase, protein- tyrosine kinase 8, PTK8, RON, p185-Ron, CD136)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-452) [Homo sapiens VH (IGHV3-7*01 (95.90%) -(IGHD)-IGHJ6*01 T127>I (119)) [8.8.15] (1-122) - IGHG1*03 (123-452)], (225-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) - IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (231-231'':234- 234'')-bisdisulfide dimer

narnatumab immunoglobuline G1-kappa, anti-[Homo sapiens MST1R (récepteur 1 stimulant le macrophage, récepteur de la protéine stimulant le macrophage, récepteur de la MSP, tyrosine kinase apparentée à c-met, protéine-tyrosine kinase 8, PTK8, RON, p185-Ron, CD136)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-452) [Homo sapiens VH (IGHV3-7*01 (95.90%) -(IGHD)-IGHJ6*01 T127>I (119)) [8.8.15] (1-122) - IGHG1*03 (123-452)], (225-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) - IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (231- 231'':234-234'')-bisdisulfure

narnatumab inmunoglobulina G1-kappa, anti-[Homo sapiens MST1R (receptor 1 estimulante el macrófago, receptor de la proteína estimulante el macrófago, receptor de la MSP, tirosina kinasa relacionada con c- met, proteína-tirosina kinase 8, PTK8, RON, p185-Ron, CD136)], Homo sapiens anticuerpo monoclonal; cadena pesada gamma1 (1-452) [Homo sapiens VH (IGHV3-7*01 (95.90%) -(IGHD)-IGHJ6*01 T127>I (119)) [8.8.15] (1-122) - IGHG1*03 (123-452)], (225-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) - IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (231- 231'':234-234'')-bisdisulfuro

74 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFTFS SYLMTWVRQA PGKGLEWVAN 50 IKQDGSEKYY VDSVKGRFTI SRDNAKNSLN LQMNSLRAED TAVYYCTRDG 100 YSSGRHYGMD VWGQGTTVIV SSASTKGPSV FPLAPSSKST SGGTAALGCL 150 VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT 200 QTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP 250 KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ 300 YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE 350 PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP 400 PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP 450 GK 452 Light chain / Chaîne légère / Cadena ligera EIVLTQSPAT LSLSPGERAT LSCRASQSVS RYLAWYQQKP GQAPRLLIYD 50 ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPRTFGQ 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 149-2105 266-326 372-430 22''-96'' 149''-205'' 266''-326'' 372''-430'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 225-214' 225''-214''' Inter-H-H 231-231'' 234-234''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 302, 302''

navarixinum navarixin 2-hydroxy-N,N-dimethyl-3-[(2-{[(1R)-1-(5-methylfuran- 2-yl)propyl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]benzamide

navarixine 2-hydroxy-N,N-diméthyl-3-[(2-{[(1R)-1-(5-méthylfuran- 2-yl)propyl]amino}-3,4-dioxocyclobut-1-én-1-yl)amino]benzamide

navarixina 2-hidroxi-N,N-dimetil-3-[(2-{[(1R)-1-(5-metilfuran-2-il)propil]amino}- 3,4-dioxociclobut-1-en-1-il)amino]benzamida

C21H23N3O5

H3C O O H CH3

H3C O N N N CH3 H H OH O

nelociguatum nelociguat methyl (4,6-diamino-2-{1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4- b]pyridin-3-yl}pyrimidin-5-yl)carbamate

nélociguat (4,6-diamino-2-{1-[(2-fluorophényl)méthyl]-1H-pyrazolo[3,4-b]pyridin- 3-yl}pyrimidin-5-yl)carbamate de méthyle

nelociguat (4,6-diamino-2-{1-[(2-fluorofenil)metil]-1H-pirazolo[3,4-b]piridin- 3-il}pirimidin-5-il)carbamato de metilo

75 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

C19H17FN8O2

NH2 H N O N CH3 N O F N NH N 2

N

nintedanibum nintedanib methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin- 1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo- 2,3-dihydro-1H-indole-6-carboxylate

nintédanib (3Z)-3-[({4-[N-méthyl-2-(4-méthylpipérazin- 1-yl)acétamido]phényl}amino)(phényl)méthylidène]-2-oxo- 2,3-dihydro-1H-indole-6-carboxylate de méthyle

nintedanib (3Z)-3-[({4-[N-metil-2-(4-metilpiperazin- 1-il)acetamido]fenil}amino)(fenil)metiliden]-2-oxo-2,3-dihidro- 1H-indol-6-carboxilato de metilo

C31H33N5O4

O HN H O N CH3 H3C O N N O N CH 3

nivocasanum nivocasan (5R)-N-[(2S,3S)-2-(fluoromethyl)-2-hydroxy-5-oxooxolan-3-yl]- 3-(isoquinolin-1-yl)-5-(propan-2-yl)-4,5-dihydro-1,2-oxazole- 5-carboxamide

nivocasan (5R)-N-[(2S,3S)-2-(fluorométhyl)-2-hydroxy-5-oxooxolan-3-yl]- 3-(isoquinoléin-1-yl)-5-(propan-2-yl)-4,5-dihydro-1,2-oxazole- 5-carboxamide

nivocasán (5R)-N-[(2S,3S)-2-(fluorometil)-2-hidroxi-5-oxooxolan-3-il]- 3-(isoquinolin-1-il)-5-(propan-2-il)-4,5-dihidro-1,2-oxazol- 5-carboxamida

C21H22FN3O5

O

O O F N N H H OH N O CH3 H3C

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oclacitinibum oclacitinib N-methyl{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]cyclohexyl}methanesulfonamide

oclacitinib N-méthyl[trans-4-(méthyl-7H-pyrrolo[2,3-d]pyrimidin- 4-ylamino)cyclohexyl]méthanesulfonamide

oclacitinib N-metil{trans-4-[metil(7H-pirrolo[2,3-d]pirimidin- 4-il)amino]ciclohexil}metanosulfonamida

C15H23N5O2S

CH3 N N O O

H3C S HN N N H

olcorolimusum olcorolimus (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)- 9,27-dihydroxy-3-{(1R)-1-[(1S,3R,4R)-4-hydroxy- 3-methoxycyclohexyl)propan-2-yl}-10,21-dimethoxy- 6,8,12,14,20,26-hexamethyl- 3,4,5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34ª- icosahydro-11H-23,27-epoxypyrido[2,1- c][1,4]oxaazacyclohentriacontine-1,11,28,29(31H)-tetrone

olcorolimus (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)- 9,27-dihydroxy-3-{(1R)-1-[(1S,3R,4R)-4-hydroxy- 3-méthoxycyclohexyl)propan-2-yl}-10,21-diméthoxy- 6,8,12,14,20,26-hexaméthyl- 3,4,5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34ª- icosahydro-11H-23,27-époxypyrido[2,1- c][1,4]oxaazacyclohentriacontine-1,11,28,29(31H)-tétrone

olcorolimús (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)- 9,27-dihidroxi-3-{(1R)-1-[(1S,3R,4R)-4-hidroxi- 3-metoxiciclohexil)propan-2-il}-10,21-dimetoxi-6,8,12,14,20,26- hexametil-3,4,5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34ª- icosahidro-11H-23,27-epoxipirido[2,1- c][1,4]oxaazaciclohentriacontina-1,11,28,29(31H)-tetrona

C51H81NO12

OH H H

H3CO H CH3 O H H OH H H O O H H CH N O 3 CH3 OCH3 CH3 OH H H3C H O H O CH3 H HOCH3 H3C

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ordopidinum ordopidine 1-ethyl-4-[2-fluoro-3-(methanesulfonyl)phenyl]piperidine

ordopidine 1-éthyl-4-[2-fluoro-3-(méthylsulfonyl)phényl]pipéridine

ordopidina 1-etil-4-[2-fluoro-3-(metanosulfonil)fenil]piperidina

C14H20FNO2S 871351-60-9

H3C S OO F N CH 3

ozoralizumabum # ozoralizumab immunoglobulin single chain VH-VH'-VH, trivalent bispecific anti- [Homo sapiens TNF (tumor necrosis factor, TNF superfamily member 2, TNFSF2, TNFA, TNF-alpha)] VH and anti-[Homo sapiens ALB (albumin, human serum albumin, HAS)] VH', humanized Lama glama monoclonal antibody; scVH-VH'-VH (1-363) [humanized VH (Homo sapiens IGHV3-74*01 (88.80%) -(IGHD)-IGHJ1*01 W118>R (105)) [8.8.8] (1-115) - 9-mer linker (tetraglycyl-seryl-triglycyl-seryl) (116-124) -humanized VH' (Homo sapiens IGHV3-23*04 (89.60%) -(IGHD)-IGHJ1*01 W118>S (229), G119>S (230) [8.8.8] (125-239) -9-mer linker (tetraglycyl- seryl-triglycyl-seryl) (240-248) -humanized VH (Homo sapiens IGHV3-74*01 (88.80%) -(IGHD)-IGHJ1*01 W118>R (353)(249-363)

ozoralizumab immunoglobuline single chain VH-VH'-VH, trivalente bispécifique anti-[Homo sapiens TNF (facteur de nécrose tumorale, membre 2 de la superfamille du TNF, TNFSF2, TNFA, TNF-alpha)] VH et anti- [Homo sapiens ALB (albumine, sérum albumine humaine, SAH)] VH', anticorps monoclonal de Lama glama humanisé; scVH-VH'-VH (1-363) [VH humanisé (Homo sapiens IGHV3-74*01 (88.80%) -(IGHD)-IGHJ1*01 W118>R (105)) [8.8.8] (1-115) -9-mer linker (tétraglycyl-séryl-triglycyl-séryl) (116-124) -VH' humanisé (Homo sapiens IGHV3-23*04 (89.60%) -(IGHD)-IGHJ1*01 W118>S (229), G119>S (230) [8.8.8] (125-239) -9-mer linker (tétraglycyl- séryl-triglycyl-séryl) (240-248) -VH humanisé (Homo sapiens IGHV3- 74*01 (88.80%) -(IGHD)-IGHJ1*01 W118>R (353)(249-363)

ozoralizumab inmunoglobulina de cadena sencilla VH-VH'-VH, trivalente biespecífica anti-[TNF de Homo sapiens (factor de necrosis tumoral, miembro 2 de la superfamilia del TNF, TNFSF2, TNFA, TNF-alpha)] VH y anti-[Homo sapiens ALB (albumina, albumina sérica humana SAH)] VH', anticuerpo monoclonal de Lama glama humanizado; scVH-VH'-VH (1-363) [VH humanizado (Homo sapiens IGHV3-74*01 (88.80%) -(IGHD)-IGHJ1*01 W118>R (105)) [8.8.8] (1-115) - conector nonámero (tetraglicil-seril-triglicil-seril) (116-124) -VH' humanizado (Homo sapiens IGHV3-23*04 (89.60%) -(IGHD)- IGHJ1*01 W118>S (229), G119>S (230) [8.8.8] (125-239) - espaciador nonámero (tetraglicil-seril-triglicil-seril) (240-248) -VH humanizado (Homo sapiens IGHV3-74*01 (88.80%) -(IGHD)- IGHJ1*01 W118>R (353)(249-363)

78 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

scVH-VH'-VH chain / Chaîne scVH-VH'-VH / Cadena scVH-VH'-VH EVQLVESGGG LVQPGGSLRL SCAASGFTFS DYWMYWVRQA PGKGLEWVSE 50 INTNGLITKY PDSVKGRFTI SRDNAKNTLY LQMNSLRPED TAVYYCARSP 100 SGFNRGQGTL VTVSSGGGGS GGGSEVQLVE SGGGLVQPGN SLRLSCAASG 150 FTFSSFGMSW VRQAPGKGLE WVSSISGSGS DTLYADSVKG RFTISRDNAK 200 TTLYLQMNSL RPEDTAVYYC TIGGSLSRSS QGTLVTVSSG GGGSGGGSEV 250 QLVESGGGLV QPGGSLRLSC AASGFTFSDY WMYWVRQAPG KGLEWVSEIN 300 TNGLITKYPD SVKGRFTISR DNAKNTLYLQ MNSLRPEDTA VYYCARSPSG 350 FNRGQGTLVT VSS 363 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-chain 22-96 146-220 270-34

pateclizumabum # pateclizumab immunoglobulin G1-kappa, anti-[Homo sapiens LTA (lymphotoxin alpha, TNFSF1, tumor necrosis factor superfamily member 1, LT)], humanized monoclonal antibody; gamma1 heavy chain (1-447) [humanized VH (Homo sapiens IGHV3-74*01 (76.50%) -(IGHD)-IGHJ5*01) [8.9.11] (1-118) -Homo sapiens IGHG1*03 CH1 R120>K (215), CH3 K130>del (119-447)], (221-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (88.40%) -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (227-227":230-230")- bisdisulfide dimer

patéclizumab immunoglobuline G1-kappa, anti-[Homo sapiens LTA (lymphotoxine alpha, TNFSF1, membre 1 de la superfamille du facteur de nécrose tumorale, LT)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-447) [VH humanisé (Homo sapiens IGHV3-74*01 (76.50%) -(IGHD)-IGHJ5*01) [8.9.11] (1-118) -Homo sapiens IGHG1*03 CH1 R120>K (215), CH3 K130>del (119-447)], (221-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1-39*01 (88.40%) -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (227- 227":230-230")-bisdisulfure

pateclizumab inmunoglobulina G1-kappa, anti-[LTA de Homo sapiens (linfotoxina alfa, TNFSF1, miembro 1 de la superfamilia del factor de necrosis tumoral, LT)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-447) [VH humanizada (Homo sapiens IGHV3-74*01 (76.50%) -(IGHD)-IGHJ5*01) [8.9.11] (1-118) -Homo sapiens IGHG1*03 CH1 R120>K (215), CH3 K130>del (119-447)], (221-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizada (Homo sapiens IGKV1-39*01 (88.40%) -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (227- 227":230-230")-bisdisulfuro

79 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGYTFT SYVIHWVRQA PGKGLEWVGY 50 NNPYNAGTNY NEKFKGRFTI SSDKSKNTAY LQMNSLRAED TAVYYCSRPT 100 MLPWFAYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150 FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200 CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250 TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300 YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350 TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400 SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPG 447 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCRASQAVS SAVAWYQQKP GKAPKLLIYS 50 ASHRYTGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQE SYSTPWTFGQ 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 145-201 262-322 368-426 22''-96'' 145''-201'' 262''-322'' 368''-426'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 221-214' 221''-214''' Inter-H-H 227-227'' 230-230''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 298, 298''

pegadricasum # pegadricase pegylated Urate Oxidase from Candida utilis, [198-threonine(S>T)]uricase (EC 1.7.3.3, urate oxidase) Pichia jadinii (Yeast) (Candida utilis) tetramer, 6-amino group of an average of 3 lysine residues, mostly in position 16, 19, and 85 of each monomer, are amidified with Į-(3-carboxypropanoyl)- Ȧ-methoxypoly(oxyethylene)

pégadricase urate oxidase de Candida utilis pégylée, [198-thréonine(S>T)]uricase (EC 1.7.3.3, urate oxydase) Pichia jadinii (levure) (Candida utilis), tétramère, la fonction amine en 6 de certaines lysines, en moyenne 3, principalement en positions 16, 19, et 85 de chaque monomère, sont amidifiées par le Į-(3-carboxypropanoyl)-Ȧ-méthoxypoly(oxyéthylène)

pegadricasa urato oxidasa de Candida utilis pegilada, [198-treonina(S>T)]uricasa (EC 1.7.3.3, urato oxidasa) Pichia jadinii (levadura) (Candida utilis), tetrámero, la función amina en 6 de ciertas lisinas, 3 por término medio, principalmente en las posiciones 16, 19, y 85 de cada monómero, está amidificada con Į-(3-carboxipropanoil)-Ȧ-metoxipoli(oxietileno)

Monomer / Monomère / Monómero MSTTLSSSTY GKDNVKFLKV KKDPQNPKKQ EVMEATVTCL LEGGFDTSYT 50 EADNSSIVPT DTVKNTILVL AKTTEIWPIE RFAAKLATHF VEKYSHVSGV 100 SVKIVQDRWV KYAVDGKPHD HSFIHEGGEK RITDLYYKRS GDYKLSSAIK 150 DLTVLKSTGS MFYGYNKCDF TTLQPTTDRI LSTDVDATWV WDNKKIGTVY 200 DIAKAADKGI FDNVYNQARE ITLTTFALEN SPSVQATMFN MATQILEKAC 250 SVYSVSYALP NKHYFLIDLK WKGLENDNEL FYPSPHPNGL IKCTVVRKEK 300 TKL 303 Modified residues / Résidus modifiés / Residuos modificados O K H3C O 16, 19, 85 O NH main pegylation sites n principaux sites pégylés O principios sitios pegilado H

N H O

80 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

peginterferonum lambda-1a # peginterferon lambda-1a pegylated interferon lambda-1; pegylated interleukin 29; N-{3-[Į-methylpoly(oxyethylene)oxy]propyl}-L-methionyl{[171- serine]human interleukin-29 (IFN-Ȝ-1)-(7-181)-peptide}

péginterféron lambda-1a interféron lambda-1 pégylé; interleukine-29 pégylée; N-{3-[Į-méthylpoly(oxyéthylène)oxy]propyl}-L-méthionyl{[171-sérine] interleukine-29 humaine (IFN-Ȝ-1)-(7-181)-peptide}

peginterferón lambda-1a interferón lambda-1 pegilado; interleukina-29 pegilada; N-{3-[Į-metilpoli(oxietileno)oxi]propil}-L-metionil{[171-serina] interleukina-29 humana (IFN-Ȝ-1)-(7-181)-péptido}

C875H1408N254O251S5 (C2H4O)n

MKPTT TGKGCHIGRF KSLSPQELAS FKKARDALEE SLKLKNWSCS 50 SPVFPGNWDL RLLQVRERPV ALEAELALTL KVLEAAAGPA LEDVLDQPLH 100 TLHHILSQLQ ACIQPQPTAG PRPRGRLHHW LHRLQEAPKK ESAGCLEASV 150 TFNLFRLLTR DLKYVADGNL SLRTSTHPES T 181 Modified residue / Résidu modifié / Residuo modificado CH3 S H M 1 O H3C O N n H O

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 15-112 49-145

pegnivacoginum pegnivacogin a ribonucleic acid aptamer which binds Factor XIa; ester of 2'-O-methyl-5'-O-phosphonoguanylyl-(3'ĺ5')-2'-O- methyluridylyl-(3' ĺ5')-2'-O-methylguanylyl-(3'ĺ5')-2'-O- methylguanylyl-(3'ĺ5')-2'-O-methyladenylyl-(3'ĺ5')-2'-deoxy-2'- fluorocytidylyl-(3'ĺ5')-2'-deoxy-2'-fluorouridylyl-(3'ĺ5')-2'-O- methyladenylyl-(3'ĺ5')-2'-deoxy-2'-fluorouridylyl-(3'ĺ5')-2'-O- methyladenylyl-(3'ĺ5')-2'-deoxy-2'-fluorocytidylyl-(3'ĺ5')-2'-deoxy- 2'-fluorocytidylyl-(3'ĺ5')-2'-O-methylguanylyl-(3'ĺ5')-2'-deoxy-2'- fluorocytidylyl-(3'ĺ5')-2'-O-methylguanylyl-(3'ĺ5')-2'-deoxy-2'- fluorouridylyl-(3'ĺ5')-2'-O-methyladenylyl-(3'ĺ5')-2'-O- methyladenylyl-(3'ĺ5')-2'-deoxy-2'-fluorouridylyl-(3'ĺ5')-2'-O- methylguanylyl-(3'ĺ5')-2'-deoxy-2'-fluorocytidylyl-(3'ĺ5')-2'-O- methyluridylyl-(3'ĺ5')-guanylyl-(3'ĺ5')-2'-O-methylcytidylyl-(3'ĺ5')- 2'-deoxy-2'-fluorocytidylyl-(3'ĺ5')-2'-deoxy-2'-fluorouridylyl-(3'ĺ5')- 2'-O-methylcytidylyl-(3'ĺ5')-2'-O-methylcytidylyl-(3'ĺ5')-2'-O- methyladenylyl-(3'ĺ5')-2'-O-methylcytidylyl-(3'ĺ3')-thimidine with 6-[(2,6-bis{N-[Ȧ-methoxypoly(oxyethylene)carbonyl]}- DL-lysyl)amino]hexan-1-ol

81 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

pégnivacogin acide ribonucleique aptamère se liant au Factor XIa; ester de 2'-O-méthyl-5'-O-phosphonoguanylyl-(3'ĺ5')-2'-O- méthyluridylyl-(3'ĺ5')-2'-O-méthylguanylyl-(3'ĺ5')-2'-O- méthylguanylyl-(3'ĺ5')-2'-O-méthyladénylyl-(3'ĺ5')-2'-déoxy-2'- fluorocytidylyl-(3'ĺ5')-2'-déoxy-2'-fluorouridylyl-(3'ĺ5')-2'-O- méthyladénylyl-(3'ĺ5')-2'-déoxy-2'-fluorouridylyl-(3'ĺ5')-2'-O- méthyladénylyl-(3'ĺ5')-2'-déoxy-2'-fluorocytidylyl-(3'ĺ5')-2'-déoxy- 2'-fluorocytidylyl-(3'ĺ5')-2'-O-méthylguanylyl-(3'ĺ5')-2'-déoxy-2'- fluorocytidylyl-(3'ĺ5')-2'-O-méthylguanylyl-(3'ĺ5')-2'-déoxy-2'- fluorouridylyl-(3'ĺ5')-2'-O-méthyladénylyl-(3'ĺ5')-2'-O- méthyladénylyl-(3'ĺ5')-2'-déoxy-2'-fluorouridylyl-(3'ĺ5')-2'-O- méthylguanylyl-(3'ĺ5')-2'-déoxy-2'-fluorocytidylyl-(3'ĺ5')-2'-O- méthyluridylyl-(3'ĺ5')-guanylyl-(3'ĺ5')-2'-O-méthylcytidylyl-(3'ĺ5')- 2'-déoxy-2'-fluorocytidylyl-(3'ĺ5')-2'-déoxy-2'-fluorouridylyl-(3'ĺ5')- 2'-O-méthylcytidylyl-(3'ĺ5')-2'-O-méthylcytidylyl-(3'ĺ5')-2'-O- méthyladénylyl-(3'ĺ5')-2'-O-méthylcytidylyl-(3'ĺ3')-thimidine avec 6-[(2,6-bis{N-[Ȧ-méthoxypoly(oxyéthylène)carbonyl]}- DL-lysyl)amino]hexan-1-ol

pegnivacogina aptámero de ácido ribomucléico que se une a Factor XIa; éster of 2'-O-metil-5'-O-fosfonoguanilil-(3'ĺ5')-2'-O-metiluridilil- (3'ĺ5')-2'-O-metilguanilil-(3'ĺ5')-2'-O-metilguanilil-(3'ĺ5')-2'-O- metiladenilil-(3'ĺ5')-2'-desoxi-2'-fluorocitidilil-(3'ĺ5')-2'-desoxi-2'- fluorouridilil-(3'ĺ5')-2'-O-metiladenilil-(3'ĺ5')-2'-desoxi-2'- fluorouridilil-(3'ĺ5')-2'-O-metiladenilil-(3'ĺ5')-2'-desoxi-2'- fluorocitidilil-(3'ĺ5')-2'-desoxi-2'-fluorocitidilil-(3'ĺ5')-2'-O- metilguanilil-(3'ĺ5')-2'-desoxi-2'-fluorocitidilil-(3'ĺ5')-2'-O- metilguanilil-(3'ĺ5')-2'-desoxi-2'-fluorouridilil-(3'ĺ5')-2'-O- metiladenilil-(3'ĺ5')-2'-O-metiladenilil-(3'ĺ5')-2'-desoxi-2'- fluorouridilil-(3'ĺ5')-2'-O-metilguanilil-(3'ĺ5')-2'-desoxi-2'- fluorocitidilil-(3'ĺ5')-2'-O-metiluridilil-(3'ĺ5')-guanilil-(3'ĺ5')-2'-O- metilcitidilil-(3'ĺ5')-2'-desoxi-2'-fluorocitidilil-(3'ĺ5')-2'-desoxi-2'- fluorouridilil-(3'ĺ5')-2'-O-metilcitidilil-(3'ĺ5')-2'-O-metilcitidilil-(3'ĺ5')- 2'-O-metiladenilil-(3'ĺ5')-2'-O-metilcitidilil-(3'ĺ3')-timidina con 6-[(2,6-bis{N-[Ȧ-metoxipoli(oxietileno)carbonil]}-DL-lisil)amino]hexan- 1-ol

C327H422F11N114O213P31 (C2H4O)n

(3'-5')-R-pmG-mU-mG-mG-mA-dflC-dflU-mA-dflU-mA-dflC-dflC-mG- dflC-mG-dflU-mA-mA-dflU-mG-dflC-mU-G-mC-dflC-dflU-mC-mC-mA-mC3'-3'dT Legend: dfl = 2'-deoxy-2'-fluoro ; m = 2'-O-methyl ; p (as prefix) = 5'-phosphate

R- = O O N O CH3 x + y = n H y O H H O N CH2 H3C O N x H O

pimasertibum pimasertib N-[(2S)-2,3-dihydroxypropyl]-3-[(2-fluoro- 4-iodophenyl)amino]pyridine-4-carboxamide

pimasertib N-[(2S)-2,3-dihydroxypropyl]-3-[(2-fluoro- 4-iodophényl)amino]pyridine-4-carboxamide

pimasertib N-[(2S)-2,3-dihidroxipropil]-3-[(2-fluoro-4-iodofenil)amino]piridina- 4-carboxamida

82 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

C15H15FIN3O3

N F I

N H HO N O H HOH

recoflavonum recoflavone {[2-(3,4-dimethoxyphenyl)-5-methoxy-4-oxo-4H-chromen- 7-yl]oxy}acetic acid

récoflavone acide {[2-(3,4-diméthoxyphényl)-5-méthoxy-4-oxo-4H-chromen- 7-yl]oxy}acétique

recoflavona ácido {[2-(3,4-dimetoxifenil)-5-metoxi-4-oxo-4H-cromen- 7-il]oxi}acético

C20H18O8

OCH3

OCH3

HO2C O O

OCH3 O

rucaparibum rucaparib 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro- 6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one

rucaparib 8-fluoro-2-{4-[(méthylamino)méthyl]phényl}-1,3,4,5-tétrahydro- 6H-pyrrolo[4,3,2-ef][2]benzazépin-6-one

rucaparib 8-fluoro-2-{4-[(metilamino)metil]fenil}-1,3,4,5-tetrahidro- 6H-pirrolo[4,3,2-ef][2]benzazepin-6-ona

C19H18FN3O

H F N

HN CH3

O N H

safotibantum safotibant N-{[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl}-2-{2-[(4-methoxy- 2,6-dimethylbenzenesulfonyl)(methyl)amino]ethoxy}- N-methylacetamide

safotibant N-{[4-(4,5-dihydro-1H-imidazol-2-yl)phényl]méthyl}-2-{2-[(4-méthoxy- 2,6-diméthylbenzènesulfonyl)(méthyl)amino]éthoxy}- N-méthylacétamide

83 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

safotibant N-{[4-(4,5-dihidro-1H-imidazol-2-il)fenil]metil}-2-{2-[(4-metoxi- 2,6-dimetilbencenosulfonil)(metil)amino]etoxi}-N-metilacetamido

C25H34N4O5S

N

H3CO CH3 CH CH N 3 3 H N N S O OO CH3 O

selepressinum selepressin vasopressin type 1a (V1a) receptor agonist; [2-L-phenylalanine,3-L-isoleucine,4-(6-oxo-L-lysine),8-[5-N-(propan- 2-yl)-L-ornithine]]human vasopressin

sélépressine agoniste du récepteur de la vasopressine type 1a (V1a); [2-L-phénylalanine,3-L-isoleucine,4-(6-oxo-L-lysine),8-[5-N-(propan- 2-yl)-L-ornithine]]vasopressine humaine

selepresina agonista del receptor de la vasopresina tipo 1ª (V1a); [2-L-fenillalanina,3-L-isoleucina,4-(6-oxo-L-lisina),8-[5-N-(propan- 2-yl)-L-ornitina]]vasopresina humana

C46H73N13O11S2

CH3 H2N H3C HN O H H

HCys Phe Ile N Asn Cys Pro N Gly NH2 H H O O

sepantronii bromidum sepantronium bromide 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-[(pyrazin-2-yl)methyl]- 4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide

bromure de sépantronium bromure de 1-(2-méthoxyéthyl)-2-méthyl-4,9-dioxo-3-[(pyrazin- 2-yl)méthyl]-4,9-dihydro-1H-naphto[2,3-d]imidazolium

bromuro de sepantronio bromuro de 2-metil-1-(2-metoxietil)-4,9-dioxo-3-[(pirazin-2-il)metil]- 4,9-dihidro-1H-nafto[2,3-d]imidazolio

C20H19BrN4O3

O O CH3 N

CH3 Br N N O N

84 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

serelaxinum serelaxin human relaxin 2 (relaxin H2)

sérélaxine rélaxine 2 humaine (rélaxine H2)

serelaxina relaxina 2 humana (relaxina H2)

C256H408N74O74S8

B chain / Chaîne B / Cadena B DSWMEEVIKL CGRELVRAQI AICGMSTWS 29

A chain / Chaîne A / Cadena A QLYSALANKC CHVGCTKRSL ARFC 24'

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 10'-15' 11-11' 23-24'

Modified residue / Résidu modifié / Residuo modificado

Q H 1' CO H N 2 L-pyroglutamic acid O H

seridopidinum seridopidine 1-ethyl-4-[3-fluoro-5-(methanesulfonyl)phenyl]piperidine

séridopidine 1-éthyl-4-[3-fluoro-5-(méthylsulfonyl)phényl]pipéridine

seridopidina 1-etil-4-[3-fluoro-5-(metanosulfonil)fenil]piperidina

C14H20FNO2S

F

H3C S OO N CH 3

simeprevirum simeprevir (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropanesulfonyl)- 2-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin- 4-yl}oxy)-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a- tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine- 12a(1H)-carboxamide

siméprévir (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropanesulfonyl)- 2-({7-méthoxy-8-méthyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinoléin- 4-yl}oxy)-5-méthyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a- tétradécahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotétradécine- 12a(1H)-carboxamide

simeprevir (2R,3aR,10Z,11aS,12aR,14aR)-N-(ciclopropanosulfonil)- 2-({7-metoxi-8-metil-2-[4-(propan-2-il)-1,3-tiazol-2-il]quinolin-4-il}oxi)- 5-metil-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a- tetradecahidrociclopenta[c]ciclopropa[g][1,6]diazaciclotetradecina- 12a(1H)-carboxamida

85 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

C38H47N5O7S2

O OCH O S 3 CH O NH 3 O H N N H H N CH3 H O H S CH3 N O CH3

siponimodum siponimod 1-({4-[(1E)-1-({[4-cyclohexyl- 3-(trifluoromethyl)phenyl]methoxy}imino)ethyl]- 2-ethylphenyl}methyl)azetidine-3-carboxylic acid

siponimod acide 1-({4-[(1E)-1-({[4-cyclohexyl- 3-(trifluorométhyl)phényl]méthoxy}imino)éthyl]- 2-éthylphényl}méthyl)azétidine-3-carboxylique

siponimod ácido 1-({4-[(1E)-1-({[4-ciclohexil- 3-(trifluorometil)fenil]metoxi}imino)etil]-2-etilfenil}metil)azetidina- 3-carboxílico

C29H35F3N2O3

N N O CO2H

CH3 CH3

CF 3

sirukumabum # sirukumab immunoglobulin G1-kappa, anti-[Homo sapiens IL6 (interleukin 6, IL-6)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-449) [Homo sapiens VH (IGHV3-7*01 (87.80%) -(IGHD)-IGHJ6*01) [8.8.12] (1-119) -IGHG1*01 (120-449)], (222-213')-disulfide with kappa light chain (1'-213') [Homo sapiens V-KAPPA (IGKV3-11*01 (87.40%) -IGKJ4*01) [5.3.9] (1'-107') - IGKC*01 (107'-213')]; (228-231'':228-231'')-bisdisulfide dimer

sirukumab immunoglobuline G1-kappa, anti-[Homo sapiens IL6 (interleukine 6, IL-6)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-449) [Homo sapiens VH (IGHV3-7*01 (87.80%) -(IGHD)-IGHJ6*01) [8.8.12] (1-119) -IGHG1*01 (120-449)], (222-213')-disulfure avec la chaîne légère kappa (1'-213') [Homo sapiens V-KAPPA (IGKV3-11*01 (87.40%) -IGKJ4*01) [5.3.9] (1'- 107') -IGKC*01 (107'-213')]; dimère (228-228'':231-231'')-bisdisulfure

86 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

sirukumab inmunoglobulina G1-kappa, anti-[IL6 de Homo sapiens (interleukina 6, IL-6)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-449) [Homo sapiens VH (IGHV3-7*01 (87.80%) -(IGHD)-IGHJ6*01) [8.8.12] (1-119) -IGHG1*01 (120-449)], (222-213')-disulfuro con la cadena ligera kappa (1'-213') [Homo sapiens V-KAPPA (IGKV3-11*01 (87.40%) -IGKJ4*01) [5.3.9] (1'- 107') -IGKC*01 (107'-213')]; dímero (228-228'':231-231'')-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFTFS PFAMSWVRQA PGKGLEWVAK 50 ISPGGSWTYY SDTVTGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARQL 100 WGYYALDIWG QGTTVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera EIVLTQSPAT LSLSPGERAT LSCSASISVS YMYWYQQKPG QAPRLLIYDM 50 SNLASGIPAR FSGSGSGTDF TLTISSLEPE DFAVYYCMQW SGYPYTFGGG 100 TKVEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150 NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200 SSPVTKSFNR GEC 213 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-87' 133'-193' 23'''-87''' 133'''-193''' Inter-H-L 222-213' 222''-213''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

solithromycinum solithromycin (3aR,4R,7S,9R,10R,11R,13R,15R,15aR)-1-{4-[4-(3-aminophenyl)- 1H-1,2,3-triazol-1-yl]butyl}-4-ethyl-7-fluoro-11-methoxy- 3ª,7,9,11,13,15-hexamethyl-10-{[trideoxy-(dimethylamino)- ȕ-D-hexopyranosyl]oxy}octahydro-2H-oxacyclotetradecino[4,3- b][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetraone

solithromycine (3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-1-{4-[4-(3-aminophényl)- 1H-1,2,3-triazol-1-yl]butyl}-4-éthyl-7-fluoro-11-méthoxy- 3a,7,9,11,13,15-hexaméthyl-10-{[3,4,6-tridéoxy-3-(diméthylamino)- ȕ-D-xylo-hexopyranosyl]oxy}octahydro-2H-oxacyclotétradécino[4,3- d]oxazole-2,6,8,14(1H,7H,9H)-tétrone

solitromicina (3aR,4R,7S,9R,10R,11R,13R,15R,15aR)-1-{4-[4-(3-aminofenil)- 1H-1,2,3-triazol-1-il]butil}-4-etil-7-fluoro-3ª,7,9,11,13,15-hexametil- 11-metoxi-10-{[tridesoxi-(dimetilamino)- ȕ-D-hexopiranosil]oxi}octahidro-2H-oxaciclotetradecino[4,3- b][1,3]oxazol-2,6,8,14(1H,7H,9H)-tetraona

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C43H65FN6O10 760981-83-7

O H N H 2 CH3 N H3C N N H CH3 H3CO H H3C O N O H3C H O O O H CH3 H CH3 O O H3C N OH FCH CH3 3

spriferminum # sprifermin L-methionyl[human fibroblast growth factor 18 (FGF-18, zFGF5)- (1-169)-peptide

sprifermine L-méthionyl[facteur 18 de croissance du fibroblaste humain (FGF-18, zFGF5)-(1-169)-peptide]

esprifermina L-metionil[factor 18 de crecimiento de fibroblastos humanos (FGF- 18, zFGF5)-(1-169)-péptido]

C876H1396N258O256S6

M EENVDFRIHV ENQTRARDDV SRKQLRLYQL YSRTSGKHIQ VLGRRISARG 50 EDGDKYAQLL VETDTFGSQV RIKGKETEFY LCMNRKGKLV GKPDGTSKEC 100 VFIEKVLENN YTALMSAKYS GWYVGFTKKG RPRKGPKTRE NQQDVHFMKR 150 YPKGQPELQK PFKYTTVTK 169 Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro 82-100

suvorexantum suvorexant [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5- methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone

suvorexant [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-méthyl-1,4-diazépan-1-yl][5- méthyl-2-(2H-1,2,3-triazol-2-yl)phényl]méthanone

suvorexant [(7R)-4-(5-cloro-1,3-benzoxazol-2-il)-7-metil-1,4-diazepan-1-il][5- metil-2-(2H-1,2,3-triazol-2-il)fenil]metanona

C23H23ClN6O2

CH3 O H N N O Cl N N N N

H3C

88 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

tabalumabum # tabalumab immunoglobulin G4-kappa, anti-[Homo sapiens TNFSF13B (tumor necrosis factor superfamily member 13B, BAFF, THANK, TALL-1, TALL1, BLYS, BLyS, B cell activating factor, B lymphocyte stimulator, CD257)], Homo sapiens monoclonal antibody; gamma4 heavy chain (1-450) [Homo sapiens VH (IGHV4-34*01 (100.00%) -(IGHD)-IGHJ4*01) [8.7.17] (1-123) -IGHG4*01 hinge S10>P (231) (124-450)], (137-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (97.90%) - IGKJ1*01) [6.3.9] (1'-107') -IGKC*05 (108'-214')]; (229-229'':232- 232'')-bisdisulfide dimer

tabalumab immunoglobuline G4-kappa, anti-[Homo sapiens TNFSF13B (membre 13B de la superfamille du facteur de nécrose tumorale, BAFF, THANK, TALL-1, TALL1, BLYS, BLyS, facteur d'activation des cellules B, stimulateur des lymphocytes B, CD257)], Homo sapiens anticorps monoclonal; chaîne lourde gamma4 (1-450) [Homo sapiens VH (IGHV4-34*01 (100.00%) -(IGHD)-IGHJ4*01) [8.7.17] (1-123) -IGHG4*01 charnière S10>P (231) (124-450)], (137-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (97.90%) - IGKJ1*01) [6.3.9] (1'-107') -IGKC*05 (108'-214')]; dimère (229- 229'':232-232'')-bisdisulfure

tabalumab inmunoglobulina G4-kappa, anti-[TNFSF13B de Homo sapiens (miembro 13B de la superfamilia del factor de necrosis tumoral, BAFF, THANK, TALL-1, TALL1, BLYS, BLyS, factor de activación de células B, estimulante de linfocitos B, CD257)], Homo sapiens anticuerpo monoclonal; cadena pesada gamma4 (1-450) [VH de Homo sapiens (IGHV4- 34*01 (100.00%) -(IGHD)-IGHJ4*01) [8.7.17] (1-123) -IGHG4*01 bisagra S10>P (231) (124-450)], (137-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (97.90%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*05 (108'-214')]; dímero (229-229'':232-232'')-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QVQLQQWGAG LLKPSETLSL TCAVYGGSFS GYYWSWIRQP PGKGLEWIGE 50 INHSGSTNYN PSLKSRVTIS VDTSKNQFSL KLSSVTAADT AVYYCARGYY 100 DILTGYYYYF DYWGQGTLVT VSSASTKGPS VFPLAPCSRS TSESTAALGC 150 LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG 200 TKTYTCNVDH KPSNTKVDKR VESKYGPPCP PCPAPEFLGG PSVFLFPPKP 250 KDTLMISRTP EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQFN 300 STYRVVSVLT VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ 350 VYTLPPSQEE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400 LDSDGSFFLY SRLTVDKSRW QEGNVFSCSV MHEALHNHYT QKSLSLSLGK 450 Light chain / Chaîne légère / Cadena ligera EIVLTQSPAT LSLSPGERAT LSCRASQSVS RYLAWYQQKP GQAPRLLIYD 50 ASNRATGIPA RFSGSGSGTD STLTISSLEP EDFAVYYCQQ RSNWPRTFGQ 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSNTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-95 150-206 264-324 370-428 22''-95'' 150''-206'' 264''-324'' 370''-428'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 137-214' 137''-214''' Inter-H-H 229-229'' 232-232''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 300, 300''

89 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

tefinostatum tefinostat cyclopentyl (2S)-2-[({4-[8-(hydroxyamino)- 8-oxooctanamido]phenyl}methyl)amino]-2-phenylacetate

téfinostat (2S)-2-[({4-[8-(hydroxyamino)- 8-oxooctanamido]phényl}methyl)amino]-2-phénylacétate de cyclopentyle

tefinostat (2S)-2-[({4-[8-(hidroxiamino)-8-oxooctanamido]fenil}metil)amino]- 2-fenilacetato de ciclopentilo

C28H37N3O5

H O N O H H O N N OH H O

tofacitinibum tofacitinib 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

tofacitinib 3-{(3R,4R)-4-méthyl-3-[méthyl(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]pipéridin-1-yl}-3-oxopropanenitrile

tofacitinib 3-{(3R,4R)-4-metil-3-[metil(7H-pirrolo[2,3-d]pirimidin- 4-il)amino]piperidin-1-il}-3-oxopropanonitrilo

C16H20N6O

H3C N N H N HN N CN H CH3 O

trametinibum trametinib N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl- 2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- 1(2H)-yl}phenyl)acetamide

tramétinib N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophényl)amino]-6,8-diméthyl- 2,4,7-trioxo-3,4,6,7-tétrahydropyrido[4,3-d]pyrimidin- 1(2H)-yl}phényl)acétamide

trametinib N-(3-{3-ciclopropil-5-[(2-fluoro-4-iodofenil)amino]-6,8-dimetil-2,4,7- trioxo-3,4,6,7-tetrahidropirido[4,3-d]pirimidin-1(2H)-il}fenil)acetamida

C26H23FIN5O4

O N O F H H H3C N N N

O N H3C CH3 I O

90 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

upamostatum upamostat ethyl 4-{(2S)-3-{3-[(E)- N'-hydroxycarbamimidoyl]phenyl}- 2-[2,3,5-tri(propan-2-yl)benzenesulfonamido]propanoyl}piperazine- 1-carboxylate

upamostat 4-{(2S)-3-{3-[(E)- N'-hydroxycarbamimidoyl]phényl}- 2-[2,3,5-tri(propan-2-yl)benzènesulfonamido]propanoyl}pipérazine- 1-carboxylate d'éthyle

upamostat 4-{(2S)-3-{3-[(E)- N'-hidroxicarbamimidoil]fenil}-2-[2,3,5-tri(propan- 2-il)bencenosulfonamido]propanoil}piperazina-1-carboxilato de etilo

C32H47N5O6S

H3C CH3

H3C CH3 O H3C O S CH3 NH OH O N O CH H 3 N N

NH2 O

vatelizumabum # vatelizumab immunoglobulin G4-kappa, anti-[Homo sapiens ITGA2 (integrin alpha 2, CD49b, GPIa, subunit of the alpha2beta1 integrin (VLA-2, collagen receptor))], humanized monoclonal antibody; gamma4 heavy chain (1-446) [humanized VH (Homo sapiens IGHV4-59*01 (79.40%) -(IGHD)-IGHJ6*01) [8.7.13] (1-119) -Homo sapiens IGHG4*01 (120-446)], (133-213')-disulfide with kappa light chain (1'-213') [humanized V-KAPPA (Homo sapiens IGKV6D-41*01 (77.90%) -IGKJ1*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'- 213')]; (225-225":228-228")-bisdisulfide dimer

vatélizumab immunoglobuline G4-kappa, anti-[Homo sapiens ITGA2 (intégrine alpha 2, CD49b, GPIa, sous-unité de l'intégrine alpha2bêta1 (VLA-2, récepteur du collagène))], anticorps monoclonal humanisé; chaîne lourde gamma4 (1-446) [VH humanisé (Homo sapiens IGHV4-59*01 (79.40%) -(IGHD)-IGHJ6*01) [8.7.13] (1-119) -Homo sapiens IGHG4*01 (120-446)], (133-213')-disulfure avec la chaîne légère kappa (1'-213') [V-KAPPA humanisé (Homo sapiens IGKV6D- 41*01 (77.90%) -IGKJ1*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; dimère (225-225":228-228")-bisdisulfure

vatelizumab inmunoglobulina G4-kappa, anti-[Homo sapiens ITGA2 (integrina alfa 2, CD49b, GPIa, subunidad de la integrina alfa2beta1 (VLA-2, receptor del colageno))], anticuerpo monoclonal humanizado; cadena pesada gamma4 (1-446) [VH humanizada (Homo sapiens IGHV4-59*01 (79.40%) -(IGHD)-IGHJ6*01) [8.7.13] (1-119) -Homo sapiens IGHG4*01 (120-446)], (133-213')-disulfuro con la cadena ligera kappa (1'-213') [V-KAPPA humanizada (Homo sapiens IGKV6D-41*01 (77.90%) -IGKJ1*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; dímero (225-225":228-228")-bisdisulfuro

91 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

Heavy chain / Chaîne lourde / Cadena pesada QVQLQESGPG LVKPSETLSL TCTVSGFSLT NYGIHWIRQP PGKGLEWLGV 50 IWARGFTNYN SALMSRLTIS KDNSKNQVSL KLSSVTAADT AVYYCARAND 100 GVYYAMDYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY 200 TCNVDHKPSN TKVDKRVESK YGPPCPSCPA PEFLGGPSVF LFPPKPKDTL 250 MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR 300 VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL 350 PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD 400 GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLGK 446 Light chain / Chaîne légère / Cadena ligera DFVMTQSPAF LSVTPGEKVT ITCSAQSSVN YIHWYQQKPD QAPKKLIYDT 50 SKLASGVPSR FSGSGSGTDY TFTISSLEAE DAATYYCQQW TTNPLTFGQG 100 TKVEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150 NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200 SSPVTKSFNR GEC 213 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-95 146-202 260-320 366-424 22''-95'' 146''-202'' 260''-320'' 366''-424'' Intra-L 23'-87' 133'-193' 23'''-87''' 133'''-193''' Inter-H-L 133-213' 133''-213''' Inter-H-H 225-225'' 228-228''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 296, 296''

* "INN for pharmaceutical substances: Names for radicals, groups & others" document available at / document disponible à / documento disponible en : http://www.who.int/medicines/services/inn/publication/en/index.html

# Electronic structure available on Mednet: http://mednet.who.int/ # Structure électronique disponible sur Mednet: http://mednet.who.int/ # Estructura electrónica disponible en Mednet: http://mednet.who.int/

92 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

AMENDMENTS TO PREVIOUS LISTS MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES MODIFICACIONES A LAS LISTAS ANTERIORES

Recommended International Non Proprietary Names (Rec. INN): List 6 (Chronicle of the WHO, December 1959, Vol. 13, No. 12) p. 468 mecamylaminum mecamylamine replace the chemical name by the following

(1RS,2SR,4SR)-N,2,3,3-tetramethylbicyclo[2.2.1]heptan-2-amine

Denominations communes internationales recommandées (DCI Rec.): Liste 6 (Chronique de l'OMS, Vol. 13, No. 12, décembre 1959) p. 488 mecamylaminum mécamylamine remplacer le nom chimique par le suivant

(1RS,2SR,4SR)-N,2,3,3-tétraméthylbicyclo[2.2.1]heptan-2-amine

Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 6 (Crónica de la OMS, Vol. 13, No. 12, diciembre de 1959) p. 501 mecamylaminum mecamilamina sustitúyase el nombre químico por el siguiente

(1RS,2SR,4SR)-N,2,3,3-tetrametilbiciclo[2.2.1]heptan-2-amina

Recommended International Non Proprietary Names (Rec. INN): List 31 (WHO Drug Information, Vol. 5, No. 3, 1991) p. 17 beraprostum beraprost replace the chemical name and the structure by the following ones

rac-4-{(1R,2R,3aS,8bS)-2-hydroxy-1-[(1E,3S,4RS)-3-hydroxy-4-methyloct- 1-en-6-ynyl]-2,3,3a,8b-tetrahydro-1H-cyclopenta[b][1]benzofuran- 5-yl}butanoic acid CO H H 2 O HO H its epimer at C* and their enantiomers H H son épimère en C* et leurs énantiomères su epímero al C* y sus enantiómeros

HO * H HCH 3 CH3

93 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

Denominations communes internationales recommandées (DCI Rec.): Liste 31 (Informations pharmaceutiques OMS, Vol. 5, No. 3, 1991) p. 18 beraprostum béraprost remplacer le nom chimique et la structure par les suivants

acide rac-4-{(1R,2R,3aS,8bS)-2-hydroxy-1-[(1E,3S,4RS)-3-hydroxy- 4-méthyloct-1-én-6-ynyl]-2,3,3a,8b-tétrahydro-1H-cyclopenta[b][1]benzofuran- 5-yl}butanoïque

CO H H 2 O HO H its epimer at C* and their enantiomers H H son épimère en C* et leurs énantiomères su epímero al C* y sus enantiómeros

HO * H HCH 3 CH3

Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 31 (Información farmacéutica OMS, Vol. 5, No. 3, 1991) p. 18 beraprostum beraprost sustitúyase el nombre químico y la estructura por los siguientes

ácido rac-4-{(1R,2R,3aS,8bS)-2-hidroxi-1-[(1E,3S,4RS)-3-hidroxi- 4-metiloct-1-en-6-inil]-2,3,3a,8b-tetrahidro-1H-ciclopenta[b][1]benzofuran- 5-il}butanoico

CO H H 2 O HO H its epimer at C* and their enantiomers H H son épimère en C* et leurs énantiomères su epímero al C* y sus enantiómeros

HO * H HCH 3 CH3

Recommended International Non Proprietary Names (Rec. INN): List 62 Denominations communes internationales recommandées (DCI Rec.): Liste 62 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 62 (WHO Drug Information, Vol. 23, No. 3, 2009) p. 250 delete/supprimer/suprimáse insert/insérer/insertese

ingenoli mebutatum ingenoli mebutas

94 WHO Drug Information, Vol. 26, No. 1, 2012 Recommended INN: List 67

Recommended International Non Proprietary Names (Rec. INN): List 63 Denominations communes internationales recommandées (DCI Rec.): Liste 63 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 63 (WHO Drug Information, Vol. 24, No. 1, 2010) p. 69 olodaterolum olodaterol replace the chemical name by the following olodatérol remplacer le nom chimique par le suivant olodaterol sustitúyase el nombre químico por el siguiente

6-hydroxy-8-[(1R)-1-hydroxy-2-{[1-(4-methoxyphenyl)-2-methylpropan- 2-yl]amino}ethyl]-2H-1,4-benzoxazin-3(4H)-one

6-hydroxy-8-[(1R)-1-hydroxy-2-{[1-(4-méthoxyphényl)-2-méthylpropan- 2-yl]amino}éthyl]-2H-1,4-benzoxazin-3(4H)-one

6-hidroxi-8-[(1R)-1-hidroxi-2-{[1-(4-metoxifenil)-2-metilpropan-2-il]amino}etil]- 2H-1,4-benzoxazin-3(4H)-ona

Recommended International Non Proprietary Names (Rec. INN): List 64 Denominations communes internationales recommandées (DCI Rec.): Liste 64 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 64 (WHO Drug Information, Vol. 24, No. 3, 2010) p. 264 condoliasum # condoliase replace the structure by the following condoliase remplacer la structure par la suivante condoliasa sustitúyase la estructura por la siguiente

ATSNPAFDPK NLMQSEIYHF AQNNPLADFS SDKNSILTLS DKRSIMGNQS 50 LLWKWKGGSS FTLHKKLIVP TDKEASKAWG RSSTPVFSFW LYNEKPIDGY 100 LTIDFGEKLI STSEAQAGFK VKLDFTGWRA VGVSLNNDLE NREMTLNATN 150 TSSDGTQDSI GRSLGAKVDS IRFKAPSNVS QGEIYIDRIM FSVDDARYQW 200 SDYQVKTRLS EPEIQFHNVK PQLPVTPENL AAIDLIRQRL INEFVGGEKE 250 TNLALEENIS KLKSDFDALN IHTLANGGTQ GRHLITDKQI IIYQPENLNS 300 QDKQLFDNYV ILGNYTTLMF NISRAYVLEK DPTQKAQLKQ MYLLMTKHLL 350 DQGFVKGSAL VTTHHWGYSS RWWYISTLLM SDALKEANLQ TQVYDSLLWY 400 SREFKSSFDM KVSADSSDLD YFNTLSRQHL ALLLLEPDDQ KRINLVNTFS 450 HYITGALTQV PPGGKDGLRP DGTAWRHEGN YPGYSFPAFK NASQLIYLLR 500 DTPFSVGESG WNNLKKAMVS AWIYSNPEVG LPLAGRHPFN SPSLKSVAQG 550 YYWLAMSAKS SPDKTLASIY LAISDKTQNE STAIFGETIT PASLPQGFYA 600 FNGGAFGIHR WQDKMVTLKA YNTNVWSSEI YNKDNRYGRY QSHGVAQIVS 650 NGSQLSQGYQ QEGWDWNRMQ GATTIHLPLK DLDSPKPHTL MQRGERGFSG 700 TSSLEGQYGM MAFDLIYPAN LERFDPNFTA KKSVLAADNH LIFIGSNINS 750 SDKNKNVETT LFQHAITPTL NTLWINGQKI ENMPYQTTLQ QGDWLIDSNG 800 NGYLITQAEK VNVSRQHQVS AENKNRQPTE GNFSSAWIDH STRPKDASYE 850 YMVFLDATPE KMGEMAQKFR ENNGLYQVLR KDKDVHIILD KLSNVTGYAF 900 YQPASIEDKW IKKVNKPAIV MTHRQKDTLI VSAVTPDLNM TRQKAATPVT 950 INVTINGKWQ SADKNSEVKY QVSGDNTELT FTSYFGIPQE IKLSPLP 997

95 Recommended INN: List 67 WHO Drug Information, Vol. 26, No. 1, 2012

Procedure and Guiding Principles / Procédure et Directives / Procedimientos y principios generales The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharmaceutical Substances will be reproduced in proposed INN lists only. Les textes de la Procédure à suivre en vue du choix de dénominations communes internationales recommandées pour les substances pharmaceutiques et des Directives générales pour la formation de dénominations communes internationales applicables aux substances pharmaceutiques seront publiés seulement dans les listes des DCI proposées. El texto de los Procedimientos de selección de denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas y de los Principios generales de orientación para formar denominaciones comunes internacionales para sustancias farmacéuticas aparece solamente en las listas de DCI propuestas.

96

⸆㣗ᑂᰝⓎ 0823 ➨ 1 ྕ ᖹᡂ 25 ᖺ 8 ᭶ 23 ᪥

ྛ㒔㐨ᗓ┴⾨⏕୺⟶㒊㸦ᒁ㸧㛗 Ẋ

ཌ⏕ປാ┬་⸆㣗ရᒁᑂᰝ⟶⌮ㄢ㛗 㸦බ༳┬␎㸧

་⸆ရࡢ୍⯡ⓗྡ⛠࡟ࡘ࠸࡚

 ᶆグ࡟ࡘ࠸࡚ࡣࠊ㺀་⸆ရࡢ୍⯡ⓗྡ⛠ࡢྲྀᢅ࠸࡟ࡘ࠸࡚㺁㸦ᖹᡂ 18 ᖺ 3 ᭶ 31 ᪥⸆ 㣗Ⓨ➨ 0331001 ྕཌ⏕ປാ┬་⸆㣗ရᒁ㛗㏻▱㸧➼࡟ࡼࡾྲྀࡾᢅࡗ࡚࠸ࡿ࡜ࡇࢁ࡛࠶ ࡿࡀࠊ௒⯡ࠊᡃࡀᅜ࡟࠾ࡅࡿ་⸆ရ୍⯡ⓗྡ⛠㸦௨ୗࠕJANࠖ࡜࠸࠺ࠋ㸧࡟ࡘ࠸࡚ࠊ ᪂ࡓ࡟ูῧࡢ࡜࠾ࡾᐃࡵࡓࡢ࡛ࠊᚚ஢▱ࡢୖࠊ㈗⟶ୗ㛵ಀᴗ⪅࡟࿘▱᪉ࡼࢁࡋࡃᚚ㓄 ៖㢪࠸ࡓ࠸ࠋ

㸦ཧ↷㸧  ᪥ᮏ་⸆ရ୍⯡ྡ⛠ࢹ࣮ࢱ࣮࣋ࢫ㸸URL http://jpdb.nihs.go.jp/jan/Default.aspx 㸦ูῧࡢ᝟ሗࡢ࠺ࡕࠊJAN ௨እࡢ᭱᪂ࡢ᝟ሗࡣࠊᙜヱࢹ࣮ࢱ࣮࣋ࢫࡢ᝟ሗ࡛ᑐᛂࡍࡿ ࡇ࡜࡜ࡋ࡚࠸ࡲࡍࠋ㸧 ูῧ

ู⾲㸯 INN ࡜ࡢᩚྜᛶࡀᅗࡽࢀࡿྍ⬟ᛶࡢ࠶ࡿࡶࡢ 㸦ᖹᡂ 18 ᖺ 3 ᭶ 31 ᪥⸆㣗ᑂᰝⓎ➨ 0331001 ྕཌ⏕ປാ┬་⸆㣗ရᒁᑂᰝ⟶⌮ㄢ㛗㏻▱࡟ ♧ࡍู⾲㸯㸧

Ⓩ㘓␒ྕ 24-3-A3  JAN㸦᪥ᮏྡ㸧㸸࣋ࢱ࢖ࣥ  JAN㸦ⱥ ྡ㸧㸸Betaine

C5H11NO2

2-(ࢺ࣓ࣜࢳࣝ࢔ࣥࣔࢽ࢜)㓑㓟

2-(Trimethylammonio)acetate

1 / 11

ู⾲㸰 INN ࡟཰㍕ࡉࢀࡓရ┠ࡢᡃࡀᅜ࡟࠾ࡅࡿ་⸆ရ୍⯡ⓗྡ⛠ 㸦ᖹᡂ 18 ᖺ 3 ᭶ 31 ᪥⸆㣗ᑂᰝⓎ➨ 0331001 ྕཌ⏕ປാ┬་⸆㣗ရᒁᑂᰝ⟶⌮ㄢ㛗㏻▱࡟ ♧ࡍู⾲㸰㸧

Ⓩ㘓␒ྕ 24-2-B7  JAN㸦᪥ᮏྡ㸧㸸࢔ࣅࣂࢡࢱ࣒ࢼࢺ࣒ࣜ࢘  JAN㸦ⱥ ྡ㸧㸸Avibactam Sodium

O H O NH N 2

N Na O S O 3 H

C7H10N3NaO6S

(1R,2S,5R)-2-࢝ࣝࣂࣔ࢖ࣝ-7-࢜࢟ࢯ-1,6-ࢪ࢔ࢨࣅࢩࢡࣟ[3.2.1]࢜ࢡࢱࣥ-6-࢖ࣝ◲㓟 ୍ࢼࢺ࣒ࣜ࢘

Monosodium (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate

2 / 11

Ⓩ㘓␒ྕ 24-2-B14  JAN㸦᪥ᮏྡ㸧㸸ࢩ࣒ࣟࣜࢫ  JAN㸦ⱥ ྡ㸧㸸Sirolimus

C51H79NO13

(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-ࢪࣄࢻࣟ࢟ ࢩ-12-{(1R)-2-[(1S,3R,4R)-4-ࣄࢻࣟ࢟ࢩ-3-࣓ࢺ࢟ࢩࢩࢡࣟ࣊࢟ࢩࣝ]-1-࣓ࢳ࢚ࣝࢳࣝ}- 19,30-ࢪ࣓ࢺ࢟ࢩ-15,17,21,23,29,35-࣊࢟ࢧ࣓ࢳࣝ-11,36-ࢪ࢜࢟ࢧ-4-࢔ࢨࢺࣜࢩࢡࣟ [30.3.1.04,9]࣊࢟ࢧࢺࣜ࢔ࢥࣥࢱ-16,24,26,28-ࢸࢺ࢚ࣛࣥ-2,3,10,14,20-࣌ࣥࢱ࢜ࣥ  (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-Dihydroxy- 12-{(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimet hoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaco nta-16,24,26,28-tetraene-2,3,10,14,20-pentaone  



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Ⓩ㘓␒ྕ 24-3-B1  JAN㸦᪥ᮏྡ㸧㸸ࢺࣞࣛࢢࣜࣉࢳࣥࢥࣁࢡ㓟ሷ  JAN㸦ⱥ ྡ㸧㸸Trelagliptin Succinate

C18H20FN5O2 • C4H6O4

2-({6-[(3R)-3-࢔࣑ࣀࣆ࣌ࣜࢪࣥ-1-࢖ࣝ]-3-࣓ࢳࣝ-2,4-ࢪ࢜࢟ࢯ-3,4-ࢪࣄࢻࣟࣆ࣑ࣜࢪ ࣥ-1(2H)-࢖ࣝ}࣓ࢳࣝ)-4-ࣇࣝ࢜ࣟ࣋ࣥࢰࢽࢺࣜࣝ ୍ࢥࣁࢡ㓟ሷ

2-({6-[(3R)-3-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl}methyl)-4-fluorobenzonitrile monosuccinate

4 / 11

Ⓩ㘓␒ྕ 24-3-B2  JAN㸦᪥ᮏྡ㸧㸸࣎ࣀࣉࣛࢨࣥࣇ࣐ࣝ㓟ሷ  JAN㸦ⱥ ྡ㸧㸸Vonoprazan Fumarate

C17H16FN3O2S㺃C4H4O4

1-[5-(2-ࣇࣝ࢜ࣟࣇ࢙ࢽࣝ)-1-(ࣆࣜࢪࣥ-3-࢖ࣝࢫࣝ࣍ࢽࣝ)-1H-ࣆ࣮ࣟࣝ-3-࢖ࣝ]-N-࣓ ࢳ࣓ࣝࢱࣥ࢔࣑ࣥ ୍ࣇ࣐ࣝ㓟ሷ

1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanami ne monofumarate 

5 / 11

Ⓩ㘓␒ྕ 24-3-B3  JAN㸦᪥ᮏྡ㸧㸸࢔ࢼࣔࣞࣜࣥሷ㓟ሷ  JAN㸦ⱥ ྡ㸧㸸Anamorelin Hydrochloride

C31H42N6O3•HCl

(3R)-3-࣋ࣥࢪࣝ-N,N’,N’-ࢺ࣓ࣜࢳࣝ-1-(2-࣓ࢳࣝ࢔ࣛࢽࣝ-D-ࢺࣜࣉࢺࣇ࢕ࣝ)ࣆ࣌ࣜࢪ ࣥ-3-࢝ࣝ࣎ࣄࢻࣛࢪࢻ ୍ሷ㓟ሷ

(3R)-3-Benzyl-N,N’,N’-trimethyl-1-(2-methylalanyl-D-tryptophyl)piperidine-3-carbo hydrazide monohydrochloride

6 / 11

Ⓩ㘓␒ྕ 24-3-B4  JAN㸦᪥ᮏྡ㸧㸸ࣈࣞࢡࢫࣆࣉࣛࢰ࣮ࣝ  JAN㸦ⱥ ྡ㸧㸸Brexpiprazole

C25H27N3O2S

7-{4-[4-(1-࣋ࣥࢰࢳ࢜ࣇ࢙ࣥ-4-࢖ࣝ)ࣆ࣌ࣛࢪࣥ-1-࢖ࣝ]ࣈࢳࣝ࢜࢟ࢩ}࢟ࣀࣜࣥ -2(1H)-࢜ࣥ

7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butyloxy}quinolin-2(1H)-one

7 / 11

Ⓩ㘓␒ྕ 24-3-B7  JAN㸦᪥ᮏྡ㸧㸸ࢳࣆࣛࢩࣝሷ㓟ሷ  JAN㸦ⱥ ྡ㸧㸸Tipiracil Hydrochloride

C9H11ClN4O2࣭HCl

5-ࢡࣟࣟ-6-[(2-࢖࣑ࣀࣆࣟࣜࢪࣥ-1-࢖ࣝ)࣓ࢳࣝ]ࣆ࣑ࣜࢪࣥ-2,4(1H,3H)-ࢪ࢜ࣥ ୍ሷ 㓟ሷ

5-Chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione monohydrochloride

8 / 11

Ⓩ㘓␒ྕ 24-3-B10  JAN㸦᪥ᮏྡ㸧㸸࢚࢝ࣛࣥࢳࢻ㸦㑇ఏᏊ⤌᥮࠼㸧  JAN㸦ⱥ ྡ㸧㸸Ecallantide(Genetical Recombination)

࢔࣑ࣀ㓟㓄ิཬࡧࢪࢫࣝࣇ࢕ࢻ⤖ྜ㸸

EAMHSFCAFK ADDGPCRAAH PRWFFNIFTR QCEEFIYGGC EGNQNRFESL

EECKKMCTRD

C305H442N88O91S8

࢚࢝ࣛࣥࢳࢻࡣ㸪㑇ఏᏊ⤌᥮࠼ࣄࢺ⤌⧊ᅉᏊ⤒㊰࢖ࣥࣄࣅࢱ࣮㢮⦕య࡛࠶ࡾ㸪ࣄࢺ⤌ ⧊ᅉᏊ⤒㊰࢖ࣥࣄࣅࢱ࣮ࡢ 20㹼79 ␒┠ࡢ࢔࣑ࣀ㓟ṧᇶ࡟ᑐᛂࡍࡿ㸬࢚࢝ࣛࣥࢳࢻࡢ 1㸪 2㸪17㸪19㸪20㸪21 ཬࡧ 23 ␒┠ࡢ࢔࣑ࣀ㓟ṧᇶࡣ㸪ࡑࢀࡒࢀ㸪Glu㸪Ala㸪Arg㸪Ala㸪 His㸪Pro ཬࡧ Trp ࡟⨨᥮ࡉࢀ࡚࠸ࡿ㸬࢚࢝ࣛࣥࢳࢻࡣ㸪60 ಶࡢ࢔࣑ࣀ㓟ṧᇶ࠿ࡽ࡞ࡿ ࣌ࣉࢳࢻ࡛࠶ࡿ㸬

Ecallantide is a recombinant human tissue factor pathway inhibitor analog corresponding to amino acid residues 20̾79 of human tissue factor pathway inhibitor. Amino acid residues of Ecallantide at positions 1, 2, 17, 19, 20, 21 and 23 are substituted by Glu, Ala, Arg, Ala, His, Pro and Trp, respectively. Ecallantide is a peptide consisting of 60 amino acid residues.

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Ⓩ㘓␒ྕ 24-3-B16  JAN㸦᪥ᮏྡ㸧㸸ࢩࢫࢸ࢔࣑ࣥ㓇▼㓟ሷ  JAN㸦ⱥ ྡ㸧㸸Cysteamine Bitartrate

C2H7NS࣭C4H6O6

2-࢔࣑ࣀ࢚ࢱࣥࢳ࣮࢜ࣝ ୍- (2R,3R)-㓇▼㓟ሷ

2-Aminoethanethiol mono-(2R,3R)-tartrate

 

10 / 11

Ⓩ㘓␒ྕ 24-5-B14  JAN㸦᪥ᮏྡ㸧㸸ࢩ࣓ࣉࣞࣅࣝࢼࢺ࣒ࣜ࢘  JAN㸦ⱥ ྡ㸧㸸Simeprevir Sodium

O CH O S O 3 CH O NNa 3 O H N N H CH H N 3 H O H S CH3

N O

CH3

C38H46N5NaO7S2  (ࢩࢡࣟࣉࣟࣆࣝࢫࣝࣇ࢛ࢽࣝ)[(2R,3aR,10Z,11aS,12aR,14aR)-2-({7-࣓ࢺ࢟ࢩ-8-࣓ࢳ ࣝ-2-[4-(1-࣓ࢳ࢚ࣝࢳࣝ)-1,3-ࢳ࢔ࢰ࣮ࣝ-2-࢖ࣝ]࢟ࣀࣜࣥ-4-࢖ࣝ}࢜࢟ࢩ)-5-࣓ࢳࣝ-4,1 4-ࢪ࢜࢟ࢯ-1,2,3,3a,4,5,6,7,8,9,11a,12,12a,13,14,14a-࣊࢟ࢧࢹ࢝ࣄࢻࣟࢩࢡࣟ࣌ࣥࢱ [c]ࢩࢡࣟࣉࣟࣃ[g][1,6]ࢪ࢔ࢨࢩࢡࣟࢸࢺࣛࢹࢩࣥ-12a-࢝ࣝ࣎ࢽࣝ]࢔ࢨࢽࢻࢼࢺࣜ࢘ ࣒

Monosodium (cyclopropylsulfonyl)[(2R,3aR,10Z,11aS,12aR,14aR)-2-({7-methoxy-8- methyl-2-[4-(1-methylethyl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo- 1,2,3,3a,4,5,6,7,8,9,11a,12,12a,13,14,14a-hexadecahydrocyclopenta[c]cyclopropa[g] [1,6]diazacyclotetradecine-12a-carbonyl]azanide   

ͤJAN ௨እࡢ᝟ሗࡣࠊཧ⪃࡜ࡋ࡚ᥖ㍕ࡋࡲࡋࡓࠋ

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TMC435 1.10 Ქ⮎࡮഍⮎╬ߩᜰቯክᩏ⾗ᢱߩ߹ߣ߼

1.10 Ქ⮎࡮഍⮎╬ߩᜰቯክᩏ⾗ᢱߩ߹ߣ߼ Ქ⮎࡮഍⮎╬ߩᜰቯክᩏߦଥࠆ⾗ᢱߦߟ޿ߡ㧘ᧄ↳⺧ߦଥࠆౝኈࠍᰴࡍ࡯ࠫࠃࠅ␜ߔޕ

JEDI_DEV00 \ 0900fde9803ffd28 2.4 2013-08-16 09:35

1 TMC435 1.10 Ქ⮎࡮഍⮎╬ߩᜰቯክᩏ⾗ᢱߩ߹ߣ߼

ൻቇฬ࡮೎ฬ 㩿䉲䉪䊨䊒䊨䊏䊦䉴䊦䊐䉤䊆䊦㪀㪲㩿㪉㪩㪃㪊㪸㪩㪃㪈㪇㪱㪃㪈㪈㪸㪪㪃㪈㪉㪸㪩㪃㪈㪋㪸㪩㪀㪄㪉㪄㩿㫒㪎㪄䊜䊃䉨䉲㪄㪏㪄䊜䉼 䊦㪄㪉㪄㪲㪋㪄㩿㪈㪄䊜䉼䊦䉣䉼䊦㪀㪄㪈㪃㪊㪄䉼䉝䉹䊷䊦㪄㪉㪄㫐㫃㪴䉨䊉䊥䊮㪄㪋㪄䉟䊦㫔䉥䉨䉲㪀㪄㪌㪄䊜䉼䊦㪄 㪋㪃㪈㪋㪄䉳䉥䉨䉸㪄㪈㪃㪉㪃㪊㪃㪊㪸㪃㪋㪃㪌㪃㪍㪃㪎㪃㪏㪃㪐㪃㪈㪈㪸㪃㪈㪉㪃㪈㪉㪸㪃㪈㪊㪃㪈㪋㪃㪈㪋㪸㪄䊓䉨䉰䊂䉦䊍䊄䊨䉲䉪䊨䊕 䊮䉺㪲㪺㪴䉲䉪䊨䊒䊨䊌㪲㪾㪴㪲㪈㪃㪍㪴䉳䉝䉱䉲䉪䊨䊁䊃䊤䊂䉲䊮㪄㪈㪉㪸㪄䉦䊦䊗䊆䊦㪴䉝䉱䊆䊄䊅䊃䊥 䉡䊛㩷 ᭴ㅧᑼ O CH O S O 3 CH O NNa 3 O H N N H CH H 3 H O N H S CH3

N O

CH3 ല⢻࡮ലᨐ ࠮ࡠࠣ࡞࡯ࡊ 1㧔ࠫࠚࡁ࠲ࠗࡊΣ㧔1 a㧕෶ߪΤ㧔1 b㧕㧕 ߩ C ဳᘟᕈ⢄Ἳߦ ߅ߌࠆᰴߩ޿ߕࠇ߆ߩ࠙ࠗ࡞ࠬⴊ∝ߩᡷༀ 㧝㧕ⴊਛ HCV RNA ㊂߇㜞୯ߢࠗࡦ࠲࡯ࡈࠚࡠࡦ⵾೷ߩන⁛≮ᴺ㧘෶ߪ࡝ࡃ ࡆ࡝ࡦߣߩ૬↪≮ᴺߩᧂᴦ≮ᖚ⠪ 㧞㧕ࠗࡦ࠲࡯ࡈࠚࡠࡦ⵾೷ߩන⁛≮ᴺ㧘෶ߪ࡝ࡃࡆ࡝ࡦߣߩ૬↪≮ᴺߢήല ෶ߪౣΆߣߥߞߚᖚ⠪ ↪ᴺ࡮↪㊂ ㅢᏱ㧘ᚑੱߦߪࠪࡔࡊ࡟ࡆ࡞ߣߒߡ 100 mg ࠍ 1 ᣣ 1 ࿁⚻ญᛩਈߒ㧘ᛩਈᦼ 㑆ߪ 12 ㅳ㑆ߣߔࠆޕᧄ೷ߪ㧘ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2a㧔ㆮવሶ⚵ ឵߃㧕෸߮࡝ࡃࡆ࡝ࡦ㧘෶ߪࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ ࠕ࡞ࡈࠔ-2b㧔ㆮવሶ⚵឵ ߃㧕෸߮࡝ࡃࡆ࡝ࡦߣ૬↪ߔࠆߎߣޕ ഍⮎╬ߩᜰቯ

Ꮢ⽼ฬ෸߮᦭ല ࠰ࡉ࡝ࠕ࡯࠼ࠞࡊ࠮࡞ 100mg㧔1 ࠞࡊ࠮࡞ਛࠪࡔࡊ࡟ࡆ࡞ߣߒߡ 100mg ฽ ᚑಽ࡮ಽ㊂ ᦭㧕 Ქᕈ ᕆᕈᲥᕈ േ‛⒳ ᛩਈ⚻〝 ᕈ೎ ᭎⇛ߩ⥌ᱫ㊂㧔mg/kg㧕a b JEDI_DEV00 \ 0900fde9803ffd28 2.4 2013-08-16 09:35 2000< ۃۅ ࡑ࠙ࠬ ⚻ญ c 1000< ۅ ࡜࠶࠻ ⚻ญ c 320< ۃۅ ࠗ࠿ ⚻ญ c 300< ۅ ⚻ญ ࠨ࡞ c 5< ۅ 㕒⣂ౝ a : ࠪࡔࡊ࡟ࡆ࡞ߣߒߡߩ↪㊂ࠍ␜ߔޕb : 㛽㜑ዊᩭ⹜㛎ޕc : 㕖 GLP ⹜㛎

෻ᓳᛩਈᲥᕈ ᛩਈᦼ㑆 ᛩਈ㊂ a ήᲥᕈ㊂ a േ‛⒳ ᕈ೎ ਥߥᚲ⷗ a ᛩਈ⚻〝 (mg/kg/ᣣ) (mg/kg/ᣣ) ᳞߼ࠄࠇ ҈150㧦ࠦ࡟ࠬ࠹ࡠ࡯࡞Ļ, ࠕࡒ࡜࡯ ,500 ,150 ,0 ۃۅ ࡑ࠙ࠬ 3ࠞ᦬㑆 b ⚻ญ 2000/1000 ߥ߆ߞߚ ࠯Ĺ, ⢗ߩ⇣Ᏹౝኈ‛, ⢗⣺▤ߩ ⤘ḩ, ⤟⣼ᚱ⚦⢩ߩⓨ⢩ൻ࡮࠴ ࡕ࡯ࠥࡦ㗰☸ߩᷫዋ ҈500㧦૕㊀Ĺ, ⤟⤳㊀㊂Ĺ, ዊ⪲ਛᔃ ᕈ⢄⚦⢩⢈ᄢ 2000/1000㧦⢄⤳㊀㊂Ĺ, ዊ⣺☼⤑వ ┵ㇱߩ⚦⢩ߩ⣲⣘࡮ⓨ⢩ൻ ⸥ߔߴ߈ᚲ⷗ߥߒ․ 500 ,150 ,50 ,0 ۃۅ ࡜࠶࠻ 1ࠞ᦬㑆 ⚻ญ 500 ⸥ߔߴ߈ᚲ⷗ߥߒ․ 500 ,150 ,50 ,0 ۃۅ ࡜࠶࠻ 6ࠞ᦬㑆 ⚻ญ 500 30㧦☼ᶧଢ, ૕㊀Ļ, ࠦ࡟ࠬ࠹ࡠ࡯҈ 10 ,30 ,10 ,0 ۃۅ ࠗ࠿ 1ࠞ᦬㑆 ⚻ญ 90 ࡞Ļ, ALTĹ, ⢄⚦⢩უᱫ 90㧦ᵹᶘ, エଢ, ⴊଢ, ៨㙄㊂Ļ, ✚ࡆ

2 TMC435 1.10 Ქ⮎࡮഍⮎╬ߩᜰቯክᩏ⾗ᢱߩ߹ߣ߼

࡝࡞ࡆࡦĹ, ALPĹ, ASTĹ, Ȗ-GTĹ, HbĻ, HtĻ, ✚ߚࠎ⊕Ļ, ࠕ ࡞ࡉࡒࡦĻ, ∳ߖ ,45㧦エଢ, ☼ᶧଢ, ଢㅌ⦡, ᵹᶘ 15 ,15 ,5 ,0 ۃۅ ࠗ࠿ 6ࠞ᦬㑆 ⚻ญ 45 ૕㊀Ļ,࠻࡝ࠣ࡝࠮࡝࠼Ļ, ✚ࡆ࡝ ࡞ࡆࡦĹ, ALPĹ, ALTĹ, ASTĹ, ⢄ ⤳㊀㊂Ĺ, ⢄⚦⢩უᱫ, 㐷⣂ߩἻ ∝⚦⢩ᶐẢ, ࠢ࠶ࡄ࡯⚦⢩࡮ࡑ ࠢࡠࡈࠔ࡯ࠫߩⶊ⦡⦡⚛ᴉ⌕, ዊ⣺☼⤑వ┵ㇱߩ⚦⢩ߩⓨ⢩ൻ ,45㧦ᵹᶘ,エଢ,ᶧ⁁ଢ, ALTĹ, ALPĹ 15 ,15 ,5 ,0 ۃۅ ࠗ࠿ 39 ㅳ㑆 ⚻ญ 45 ⢙᳝㉄Ĺ, ࠦ࡟ࠬ࠹ࡠ࡯࡞Ļ a㧦ࠪࡔࡊ࡟ࡆ࡞ߣߒߡߩ↪㊂ࠍ␜ߔޕ b㧦ኻᾖ⟲ࠍ฽߻ో⟲ߢᱫ੢࡮ಾㄼዼᲕ଀߇ߺࠄࠇ㧘ᱫ࿃ߪᧄ⮎ߩ⢗ឃ಴ㆃᑧਗ߮ߦ ᛩਈ⵾೷ߩ㜞޿☼ᕈ෸߮ೝỗᕈߦࠃߞߡᛩਈ⵾೷߇᳇㆏ߦㅒᵹ/ๆᒁߐࠇ㧘Ἳ∝ᕈ/ უᱫᕈᄌൻ߇⺃⊒ߐࠇߚߚ߼ߣ⠨߃ࠄࠇߚޕ2000 mg/kg/ᣣ⟲ߢߪᱫ੢࡮ಾㄼዼᲕ 8 1000 mg/kg/ ଀߇㜞㗫ᐲߦߺࠄࠇߚߚ߼ᛩਈ ᣣߦ ᣣߦᷫ㊂ߒߚޕ ೽૞↪ ೽૞↪⊒⃻₸㧔⥃ᐥᬌᩏ୯⇣Ᏹᄌേࠍ฽߻㧕426㧛436 ଀㧩97.7% 㨇࿖ౝ╙ II ⋧⹜㛎 1 ⹜㛎㧔TMC435-TiDP16-C215㧕࿖ౝ╙ III ⋧⹜㛎 4 ⹜㛎 㧔TMC435-HPC3003/3004/3008/30410㧕ߩ㓸⸘㨉

೽૞↪ߩ⒳㘃 ଀ᢙ ⥃ᐥᬌᩏ୯⇣Ᏹߩ⒳㘃  ଀ᢙ ⊒∐ 203 㜞ࡆ࡝࡞ࡆࡦⴊ∝ 36 ⴊਛࡆ࡝࡞ࡆࡦჇട 97 Al-P Ⴧട 15 ߘ߁∣∝ 105 ଢ⒁ 29 శ✢ㆊᢅᕈ෻ᔕ 8

ળ␠ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑᩣᑼળ␠ ⵾೷㧦⵾ㅧ㧘ャ౉

JEDI_DEV00 \ 0900fde9803ffd28 2.4 2013-08-16 09:35

3 JEDI_DEV00 \ 0900fde9803cceb9 \ 2.6 \ 2013-02-07 15:33

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ ࠺࡯࠲෶ߪႎ๔ᦠ

 ᐕ ᦬㨪 5 FTWIUWDUVCPEG ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ  ᐕ ᦬

 ᐕ ᦬㨪 2 FTWIRTQFWEV ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ  ᐕ ᦬

# CRRGPFKEGU 㧙 㧙 ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ

1 ᐕ᦬㨪 4 TGIKQPCNKPHQTOCVKQP ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ  ᐕ ᦬ ෳ⠨ᢥ₂ ⹥ᒰ⾗ᢱߥߒ

2 JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ ⹜㛎ႎ๔ᦠ ⮎ℂ⹜㛎 ലജࠍⵣઃߌࠆ⹜㛎 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ %QET[UVCNNK\CVKQPQH6/%YKVJ*%8 ⾗ᢱ  GVCN     ,CPUUGP4& ᶏᄖ ⹏ଔ⾗ᢱ 05# 6/%%QET[UVCN #8/4 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ $KQEJGOKECNCEVKXKV[QH6/%CICKPUV*%8 GV ⾗ᢱ      ᶏᄖ ⹏ଔ⾗ᢱ 05#RTQVGCUGUCPFEGNNWNCTRTQVGCUGU CN 6/% $KQEJGO#EVKXKV[#8/4 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ $KQEJGOKECNCEVKXKV[QH6/%CICKPUV ⾗ᢱ  GVCN   ᶏᄖ ⹏ଔ⾗ᢱ JWOCPMKPCUGU 6/%%GNN-KPCUGU #8/4 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ #PVKXKTCNCEVKXKV[QH6/%KPEGNNWNCT GV      ᶏᄖ ⾗ᢱ ⹏ଔ⾗ᢱ TGRNKEQPOQFGNU CN 6/%4GRNKEQP#8/4 3 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ 6QZKEKV[CPFE[VQUVCVKECEVKXKV[QH6/% GV      ᶏᄖ ⾗ᢱ ⹏ଔ⾗ᢱ KPEGNNNKPGUCPF2$/%U CN 6/%6QZ#8/4 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ #EVKXKV[QH6/%CICKPUVFKHHGTGPV GV ⾗ᢱ      ,CPUUGP4& ᶏᄖ ⹏ଔ⾗ᢱ XKTWUGU CN 6/%1VJGT 8KTWUGU#8/4 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ 'HHGEVQH6/%QPVJGTGUVQTCVKQPQH GV  ⾗ᢱ  ᶏᄖ ⹏ଔ⾗ᢱ KPPCVGKOOWPKV[ CN   6/% +PPCVG+OOWPKV[#8/4 5GNGEVKQP'ZRGTKOGPVU9KVJ6/%KP6JTGG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ &KHHGTGPV*%8)GPQV[RG4GRNKEQP GV      ,CPUUGP4& ᶏᄖ ⾗ᢱ ⹏ଔ⾗ᢱ %QPVCKPKPI%GNN.KPGUCPFKP*%8)GPQV[RG CN 6/%+85#8/4 C,(*+PHGEVGF%GNNU #PVKXKTCNCEVKXKV[QH6/%CICKPUV*%8 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ GV  05#UKVGFKTGEVGFOWVCPVU 5&/ KPC     ,CPUUGP4& ᶏᄖ ⾗ᢱ ⹏ଔ⾗ᢱ CN VTCPUKGPVTGRNKEQPCUUC[ 6/%5&/#8/4

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ #PVKXKTCNCEVKXKV[QH6/%CICKPUV ⾗ᢱ GV  TGEQODKPCPVENKPKECNKUQNCVGUKPC     ,CPUUGP4& ᶏᄖ 6/% ⹏ଔ⾗ᢱ CN VTCPUKGPVTGRNKEQPCUUC[ %NKPKECN+UQNCVGU #8/4 'HHGEVQHKPXKVTQEQODKPCVKQPQH6/% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ YKVJQVJGTCPVK*%8CIGPVUQPCPVKXKTCN GV ⾗ᢱ      ,CPUUGP4& ᶏᄖ ⹏ଔ⾗ᢱ CEVKXKV[CPFUWRRTGUUKQPQHTGUKUVCPV CN 6/%%QODKPCVKQP TGRNKEQPEGNNEQNQPKGU #8/4 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ +PXKVTQCPVK*+8CEVKXKV[QH6/%KP  GVCN   ᶏᄖ ⾗ᢱ ⹏ଔ⾗ᢱ EQODKPCVKQPYKVJ*+8RTQVGCUGKPJKDKVQTU 6/%%QODQ*+8#8/4 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ #PVK*%8CEVKXKV[QH6/%KPEQODKPCVKQP  GVCN   ,CPUUGP4& ᶏᄖ ⾗ᢱ ⹏ଔ⾗ᢱ YKVJ*+8RTQVGCUGKPJKDKVQTU 6/%%QODQ*%8#8/4 ೽ᰴ⊛⮎ℂ⹜㛎 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ  +PXKVTQ2JCTOCEQNQI[5VWF[QH6/%   ᶏᄖ ⾗ᢱ ⹏ଔ⾗ᢱ 4 0% /&52JCTOC5GTXKEGU2JCTOC5ETGGP&CVC ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ GV  4GRQTV1P%QORQWPF6$%6/%(QT   ᶏᄖ ⾗ᢱ ⹏ଔ⾗ᢱ CN 6KDQVGE$8$# 0% ቟ోᕈ⮎ℂ⹜㛎 'HHGEVUQH,0,### ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ 6/% QPVJGOGODTCPG- EWTTGPV GV      ,,24& ᶏᄖ ⾗ᢱ ෳ⠨⾗ᢱ + KP*'4)VTCPUHGEVGF*'-EGNNU CN -T 0% EQORCTGFVQCUVGOK\QNG 'HHGEVUQH,0,### 6/% CPFQHNKFQECKPG ,0, ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ      ,,24& ᶏᄖ ⾗ᢱ ෳ⠨⾗ᢱ GVCN ### QPVJGOGODTCPG0C EWTTGPVKP%*1 0% EGNNUUVCDN[VTCPUHGEVGFYKVJJ*CE&0# 'HHGEVUQH,0,### ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ GV  6/% QPVJGKUQNCVGFURQPVCPGQWUN[     ,,24& ᶏᄖ ⾗ᢱ ෳ⠨⾗ᢱ CN DGCVKPITKIJVCVTKWOQHVJGIWKPGCRKI 0% 'NGEVTQRJ[UKQNQIKECNGHHGEVUQH,0, ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ ### 6/% KP GV      ᶏᄖ ⾗ᢱ ෳ⠨⾗ᢱ KUQNCVGF.CPIGPFQTHHRGTHWUGFTCDDKV CN 0% JGCTVU

JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24 JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ +PXKVTQGHHGEVUQH,0,###  6/% QPJWOCPRNCVGNGV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ GV  HWPEVKQPWUKPIEQNNCIGPCFGPQUKPG     ,,24& ᶏᄖ ⾗ᢱ ෳ⠨⾗ᢱ CN FKRJQURJCVGCPFCTCEJKFQPKECEKFCU 0% CIQPKUVUHQTRNCVGNGVCIITGICVKQP 'HHGEVQH,0,### ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ GV  6/% QPKPXKVTQJWOCPTGFDNQQF     ,,24& ᶏᄖ ⾗ᢱ ෳ⠨⾗ᢱ CN EGNNJGOQN[UKU 0% %CTFKQJGOQF[PCOKEECTFKQ GNGEVTQRJ[UKQNQIKECNCPFRWNOQPCT[GHHGEVU ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ  QH,0,### ̄OIMIKX     ,,24& ᶏᄖ ⾗ᢱ ෳ⠨⾗ᢱ GVCN KPOGEJCPKECNN[XGPVKNCVGFCPGUVJGVK\GF 0% FQIU 1TCN%CTFKQXCUEWNCTCPF4GURKTCVQT[5CHGV[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ GV  5VWF[YKVJ6/% ,0,### KP     ,,24& ᶏᄖ ⾗ᢱ ⹏ଔ⾗ᢱ CN VJG%QPUEKQWU$GCING&QI 0% 5KPING&QUG1TCN5CHGV[2JCTOCEQNQI[5VWF[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ GV  QH6/%KPVJG4CV/QFKHKGF+TYKP U     ,,24& ᶏᄖ ⾗ᢱ ⹏ଔ⾗ᢱ

5 CN 6GUV 0% 'HHGEVUQHVJGJGRCVKVKU%XKTWU *%8 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ␠ౝ  RTQVGCUGKPJKDKVQT6/% ,0,     ,,24& ᶏᄖ ⾗ᢱ ෳ⠨⾗ᢱ GVCN QT4 QPICUVTKEGORV[KPIKPTCVU 0% ⮎ജቇ⊛⮎‛⋧੕૞↪⹜㛎 ⹥ᒰ⾗ᢱߥߒ ⮎‛േᘒ⹜㛎 ಽᨆᴺ෸߮ࡃ࡝࠺࡯࡚ࠪࡦႎ๔ᦠ 8CNKFCVKQP HWNN QHCP.%/5/5OGVJQF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  HQTVJGFGVGTOKPCVKQPQH6/%KP     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN OQWUG'&6#RNCUOC 0% 8CNKFCVKQP HWNN QHCP.%/5/5OGVJQF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  HQTVJGFGVGTOKPCVKQPQH6/% ,0, GVCN     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ  KPTCV'&6#RNCUOC 0% 8CNKFCVKQP HWNN QHCP.%/5/5OGVJQF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  HQTVJGFGVGTOKPCVKQPQH6/%KPFQI GVCN     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ '&6#RNCUOC 0% 8CNKFCVKQP RCTVKCN QHCP.%/5/5OGVJQF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  HQTVJGFGVGTOKPCVKQPQH6/%KPFQI GVCN     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ JGRCTKPRNCUOC 0% ๆ෼

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ 5VWF[QPVJGVTCPUGRKVJGNKCNVTCPURQTVQH 6/%VJGTQNGQH2IN[EQRTQVGKP 2 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ IR KPVJGVTCPUGRKVJGNKCNVTCPURQTVQH GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 6/%CETQUU%CEQOQPQNC[GTUCPFQP CN 0% VJGRQUUKDNGKPJKDKVKQPQHJWOCP KPVGUVKPCN2IRD[6/% 2JCTOCEQMKPGVKEUVKUUWGFKUVTKDWVKQPCPF CDUQNWVGDKQCXCKNCDKNKV[KPOCNG52( 5RTCIWG&CYNG[TCVUCHVGTUKPINGQTCN ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ CFOKPKUVTCVKQPQHC8KV'62)52')  GVCN     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ UQNWVKQPQH6/%CVOIMICPF 0% CHVGTUKPINGKPVTCXGPQWUCFOKPKUVTCVKQPQH C*2Ǫ%&UQNWVKQPQH6/%CV OIMI 2JCTOCEQMKPGVKEUQH6/%KPOCNG5RTCIWG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ &CYNG[TCVUCHVGTUKPING+8CFOKPKUVTCVKQP      ,CPUUGP4& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ QHC2')UQNWVKQPQH6/%CV A CPFOIGSMI 6 2JCTOCEQMKPGVKEUCPFCDUQNWVG DKQCXCKNCDKNKV[QH6/%KPOCNG U[TKCPJCOUVGTUCHVGTUKPINGKPVTCXGPQWU ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  CFOKPKUVTCVKQPQHC*2Ǫ%&UQNWVKQP     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ QH6/%CVOIMICPFCHVGTUKPING 0% QTCNCFOKPKUVTCVKQPQHC2')UQNWVKQP QH6/%CVOIMI 2JCTOCEQMKPGVKEUCPFTGNCVKXG DKQCXCKNCDKNKV[QH6/%KPHGOCNG0GY

JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24 JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ 2JCTOCEQMKPGVKEUCPFCDUQNWVGCPFTGNCVKXG DKQCXCKNCDKNKV[KPOCNGDGCINGFQIUCHVGT UKPINGKPVTCXGPQWUCFOKPKUVTCVKQPQHCP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ CSWGQWU*2Ǫ%&UQNWVKQPQH6/%      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CVOIMICPFCHVGTUKPINGQTCN GVCN 0% CFOKPKUVTCVKQPQH6/%CUCUQNWVKQP KP2')YKVJ8KV'62)5CV OIMIKPHGFCPFHCUVGFEQPFKVKQPU 2JCTOCEQMKPGVKEUQH6/%KPOCNGDGCING ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ FQIUCHVGTUKPING+8CFOKPKUVTCVKQPQHC      ,CPUUGP4& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 2')UQNWVKQPQH6/%CVCPF A OIGSMI 'XCNWCVKQPQHVJGQTCNDKQCXCKNCDKNKV[CPF RJCTOCEQMKPGVKEUQH,0, ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  6/% KPOCNG%[PQOQNIWUOQPMG[U     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN HQNNQYKPICUKPINGQTCNCPFKPVTCXGPQWU 0% DQNWUCFOKPKUVTCVKQP 2KNQVUVWF[QPTGNCVKXGDKQCXCKNCDKNKV[ 7 CPFRJCTOCEQMKPGVKEUQH6/% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ HQNNQYKPIQTCNCFOKPKUVTCVKQPQH6/%      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CUHTGGCEKFCU0CUCNVCPFCU 0% KPRGNNGVU D[FKGVCT[CFOKZVWTGHQT FC[UVQOCNGOKEG  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 9GGM4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ GV 㧔ߩ     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ QH6/%KPVJG/QWUG CN ㊀ⶄ⸥タ㧕 0%  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ /QPVJ4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ GV 㧔ߩ     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ QH6/%KPVJG/QWUG CN ㊀ⶄ⸥タ㧕 0%  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 9GGM4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ GV 㧔ߩ     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ QH6/%KPVJG4CV CN ㊀ⶄ⸥タ㧕 0%  OQPVJ4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV 㧔ߩ QH6/%KPVJG4CVYKVJCOQPVJ     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN ㊀ⶄ⸥タ㧕 4GEQXGT[2GTKQF 0%  OQPVJ4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV 㧔 QH6/%KPVJG4CVYKVJ/QPVJ     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN ߩ㊀ⶄ⸥タ㧕 KPVGTKOMKNN 0%

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ YGGMVQZKEKV[UVWF[D[QTCNTQWVG 㧔     ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ ICXCIG KPDGCINGFQIU ߩ㊀ⶄ⸥タ㧕 0%  OQPVJ4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV 㧔 QH6/%KPVJG$GCING&QIYKVJC     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN ߩ㊀ⶄ⸥タ㧕 OQPVJ4GEQXGT[2GTKQF 0%  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ OQPVJTGRGCVGFFQUGQTCNVQZKEKV[UVWF[ 㧔 GVCN     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ QH6/%KPVJGDGCINGFQI ߩ㊀ⶄ⸥タ㧕 0%  6/%6QZKEKV[5VWF[D[1TCN)CXCIG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 㧔 #FOKPKUVTCVKQPVQ$GCING&QIUHQT9GGMU     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ ߩ㊀ⶄ⸥タ㧕 (QNNQYGFD[C9GGM4GEQXGT[2GTKQF 0% 6/%6QZKEQMKPGVKECPFGUECNCVKPI  KPVTCXGPQWUCPFQTCN D[ICXCIG FQUG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 㧔 TCPIGHKPFKPIUVWF[HQNNQYGFD[CPQTCN     ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ ߩ㊀ⶄ⸥タ㧕 QTFC[HKZGFFQUGRJCUGKPVJG 0% OCNGTJGUWUOQPMG[  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ

8 YGGM4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ GV 㧔     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ QH6/%KPVJG4CV CN ߩ㊀ⶄ⸥タ㧕 0% ಽᏓ 6KUUWGFKUVTKDWVKQPQH%6/%CU UVWFKGFD[YJQNGDQF[CWVQTCFKQITCRJ[KP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ   VJGRKIOGPVGFOCNGOKEGCHVGTUKPINGQTCN ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ   CFOKPKUVTCVKQPQH%6/%CV 0% OIMI 6KUUWGFKUVTKDWVKQPQH%6/%CU UVWFKGFD[YJQNGDQF[CWVQTCFKQITCRJ[KP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  VJGRKIOGPVGFOCNGTCVCHVGTUKPINGQTCN     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CFOKPKUVTCVKQPQH%6/%CV 0% OIMI ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  GV  6JGRNCUOCRTQVGKPDKPFKPIQH *6/%     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN KPCPKOCNUCPFOCP 0%

JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24 JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ 6JGRTQVGKPDKPFKPIQH*6/%KPRNCUOC EQNNGEVGFKPCRJCUGUKPINGFQUGQRGP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  NCDGNUGSWGPVKCNVTKCNVQKPXGUVKICVGVJG     ,CPUUGP4& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ RJCTOCEQMKPGVKEUUCHGV[CPFVQNGTCDKNKV[ A QH6/%KPUWDLGEVUYKVJOQFGTCVGN[QT UGXGTGN[KORCKTGFJGRCVKEHWPEVKQP 6JGRTQVGKPDKPFKPIQH*6/%KPRNCUOC EQNNGEVGFKPCRJCUGQRGPNCDGNVTKCN ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  VQKPXGUVKICVGVJGGHHGEVQHUGXGTGTGPCN     ,CPUUGP4& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ KORCKTOGPVQPVJGRJCTOCEQMKPGVKEUCPF (- UCHGV[QH6/% 6JGCDUQTRVKQPOGVCDQNKUOCPFGZETGVKQP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ QH%6/%KPVJGOCNG$GCINGFQI GV   ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ  CN   CHVGTCUKPINGQTCNFQUGQH %6/% 0% CVOIMI 6KUUWGFKUVTKDWVKQPCPFRNCEGPVCNVTCPUHGT QH%6/%CUUVWFKGFD[YJQNGDQF[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ

9  CWVQTCFKQITCRJ[KPVJG5RTCIWG&CYNG[TCV     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CHVGTUKPINGQTCNCFOKPKUVTCVKQPQH% 0% 6/%CVOIMI 2JCTOCEQMKPGVKEUVKUUWGFKUVTKDWVKQPCPF CDUQNWVGDKQCXCKNCDKNKV[KPOCNG52( 5RTCIWG&CYNG[TCVUCHVGTUKPINGQTCN  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ CFOKPKUVTCVKQPQHC8KV'62)52') 㧔ߩ GVCN     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ UQNWVKQPQH6/%CVOIMICPF ㊀ⶄឝタ㧕 0% CHVGTUKPINGKPVTCXGPQWUCFOKPKUVTCVKQPQH C*2Ǫ%&UQNWVKQPQH6/%CV OIMI  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 9GGM4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ GV 㧔ߩ     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ QH6/%KPVJG/QWUG CN ㊀ⶄ⸥タ㧕 0%  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 9GGM4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ GV 㧔ߩ     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ QH6/%KPVJG4CV CN ㊀ⶄ⸥タ㧕 0%  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ YGGMVQZKEKV[UVWF[D[QTCNTQWVG 㧔     ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ ICXCIG KPDGCINGFQIU ߩ㊀ⶄ⸥タ㧕 0%

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ  6/%6QZKEKV[5VWF[D[1TCN)CXCIG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 㧔 #FOKPKUVTCVKQPVQ$GCING&QIUHQT9GGMU     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ ߩ㊀ⶄ⸥タ㧕 (QNNQYGFD[C9GGM4GEQXGT[2GTKQF 0%  6/%2TGNKOKPCT[2TGCPF2QUV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 㧔 0CVCN&GXGNQROGPV5VWF[D[1TCN)CXCIG     ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ ߩ㊀ⶄ⸥タ㧕 #FOKPKUVTCVKQPVQ%&4CVU 0% ઍ⻢ 6JGKPXKVTQ OGVCDQNKUOQH6/%KP JGRCVQE[VGUCPFNKXGTUWDEGNNWNCT ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  HTCEVKQPUQHOCNGCPFHGOCNGOQWUGOCNG     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN CPFHGOCNGTCVHGOCNGTCDDKVOCNGFQI 0% OCNGE[PQOQNIWUOQPMG[CPFOCP  6JGKPXKVTQ OGVCDQNKUOQH %6/% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV   KPNKXGTOKETQUQOGUCPFJGRCVQE[VGUQH ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN   OCNGOQWUGOCNGTCVHGOCNGTCDDKVOCNG 0% FQIOCNGOQPMG[CPFJWOCP 'UVKOCVKQPQHVJGGHHGEVQH6/%QP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ VJGOGVCDQNKUOQHEQCFOKPKUVGTGFFTWIUD[ GV 10      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ VJGFGVGTOKPCVKQPQHVJG- CPF8 HQT CN O OCZ 0% 6/%KPJWOCPNKXGTOKETQUQOGU 6JGOGVCDQNKUOCPFGZETGVKQPQH% 6/%KPOCNGCPFHGOCNG5RTCIWG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  &CYNG[TCVUCHVGTUKPINGQTCN     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN CFOKPKUVTCVKQPQH%6/%CV 0% OIMI 6JGDKNKCT[GZETGVKQPQH6/%KPOCNG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  52(5RTCIWG&CYNG[TCVUCHVGTCUKPING     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN QTCNCFOKPKUVTCVKQPCVOIMI 0% .%/5KFGPVKHKECVKQPQHVJGOGVCDQNKVGUKP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  OQWUGRNCUOCCHVGTUKPINGCPFOWNVKRNG     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ QTCNCFOKPKUVTCVKQPQH6/% 0% #PKPXKVTQ UVWF[VQFGVGTOKPGVJG MKPGVKEUQH6/%OGVCDQNKUOKPJWOCP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ NKXGTOKETQUQOGUCPFVQKFGPVKH[VJG GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ OKETQUQOCNE[VQEJTQOG2KUQGP\[OGU CN 0% OGFKCVKPI6/%OGVCDQNKUO TGCEVKQP RJGPQV[RKPI

JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24 JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ #PKPXKVTQ UVWF[QPVJGFKTGEVKPJKDKVKQP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  QHVJGOGVCDQNKUOQHVJGE[VQEJTQOG2     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN RTQDGUWDUVTCVGUD[6/% 0% #PKPXKVTQUVWF[VQCUUGUUVJGRQVGPVKCN ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ QH6/%VQKPFWEG%;2GP\[OG GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CEVKXKVKGUKPET[QRTGUGTXGFJWOCP CN 0% JGRCVQE[VGU 6/%5VWF[QPVJGRQUUKDNGKPFWEVKQP CPFQTKPJKDKVKQPQHJGRCVKEFTWI OGVCDQNKUKPIGP\[OGUD[6/%KPOCNGCPF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  HGOCNG52(#NDKPQ5YKUUOKEGCHVGTQTCN GVCN     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CFOKPKUVTCVKQPD[ICXCIGHQTOQPVJUCV 0% FQUGUQHCPFOIMIDQF[ YGKIJVFC[ #UVWF[QHVJGGHHGEVUQH6/%QP UQOGJGRCVKEGP\[OGCEVKXKVKGUCHVGTQTCN ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  CFOKPKUVTCVKQPHQTQPGOQPVJCVFQUGUQH GVCN     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CPFOIMIFC[VQOCNGCPF 0% 11 HGOCNG5RTCIWG&CYNG[TCVU 6/%5VWF[QPVJGRQUUKDNGKPFWEVKQP CPFQTKPJKDKVKQPQHJGRCVKEFTWI OGVCDQNKUKPIGP\[OGUD[6/%KPOCNGCPF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  HGOCNGDGCINGFQIUCHVGTQTCN     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN CFOKPKUVTCVKQPD[ICXCIGHQTOQPVJUCV 0% FQUGUQHCPFOIMIDQF[ YGKIJVFC[ 6JGCDUQTRVKQPOGVCDQNKUOCPFGZETGVKQP   ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ QH %6/%KPVJGOCNG$GCINGFQI GV  㧔ߩ ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ  CN   ㊀ⶄឝタ㧕 CHVGTCUKPINGQTCNFQUGQH %6/% 0% CVOIMI ឃᴭ 6JGOGVCDQNKEUVCDKNKV[OGVCDQNKUOCPF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GZETGVKQPQH6/%KPVJGOCNG52( GV   ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 5RTCIWG&CYNG[TCVCHVGTCUKPINGQTCN CN   0% FQUGQH%6/%CVOIMI

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ 6JGCDUQTRVKQPOGVCDQNKUOCPFGZETGVKQP  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ QH%6/%KPVJGOCNG$GCINGFQI GV  㧔ߩ ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ  CN   ㊀ⶄឝタ㧕 CHVGTCUKPINGQTCNFQUGQH %6/% 0% CVOIMI 6JGOGVCDQNKUOCPFGZETGVKQPQH%  6/%KPOCNGCPFHGOCNG5RTCIWG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV 㧔ߩ &CYNG[TCVUCHVGTUKPINGQTCN     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN ㊀ⶄឝタ㧕 CFOKPKUVTCVKQPQH%6/%CV 0% OIMI  6JGDKNKCT[GZETGVKQPQH6/%KPOCNG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV 㧔ߩ 52(5RTCIWG&CYNG[TCVUCHVGTCUKPING     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN ㊀ⶄឝタ㧕 QTCNCFOKPKUVTCVKQPCVOIMI 0% ⮎‛േᘒቇ⊛⮎‛⋧੕૞↪㧔㕖⥃ᐥ㧕 #PKPXKVTQ UVWF[QPVJGKPJKDKVQT[GHHGEV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  QH6/%QPVJGOGVCDQNKUOQH     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN RQVGPVKCNEQOGFKECVKQP 0% 2JCTOCEQMKPGVKEUQH6/%CPFDQQUVKPI ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 12 GHHGEVQH4KVQPCXKTKPHGFOCNGDGCING      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ FQIUCHVGTUKPINGQTCNCFOKPKUVTCVKQPQH 0% 6/%CVCRRTQZKOCVGN[CPFOIMI ߘߩઁߩ⮎‛േᘒ⹜㛎 #PKPXKVTQ UVWF[QPVJGKPJKDKVKQPQH ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 7)6#OGFKCVGFDKNKTWDKPINWEWTQPKFCVKQP GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ D[6/%CPF4KDCXKTKPKPJWOCPNKXGT CN 0% OKETQUQOGU +PXKVTQ UVWF[QPVJGWRVCMGVTCPURQTVQH 6/%KPTCVCPFJWOCPJGRCVQE[VGUVJG GHHGEVQHTKVQPCXKTTKHCORKEKPCPF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  E[ENQURQTKP#QP6/%WRVCMGCPFVJG     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN GHHGEVQH6/%QPJGRCVKEWRVCMGQH 0% VCWTQEJQNCVGCPFGUVTCFKQNǪ& INWEWTQPKFG +PXKVTQ UVWF[QPVJGWUGQHJWOCP UCPFYKEJEWNVWTGFJGRCVQE[VGUHQTVJG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  CUUGUUOGPVQHVJGGHHGEVQH6/%QPVJG     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN WRVCMGCPFGHHNWZQHVCWTQEJQNCVGCPF 0% GUVTCFKQNǪ&INWEWTQPKFG

JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24 JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ 6JGWRVCMGQH6/%KP*'-EGNNNKPGU ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  QXGTGZRTGUUKPIVJGVTCPURQTVGTU1#62$     ,CPUUGP4& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 1#62$1#62$QT1#62$  A 2JCTOCEQMKPGVKEUQH6/%KPVJGOCNG YKNFV[RG(8$OKEGCPFOCNG1CVRCD OKEGCHVGTUKPINGQTCNCFOKPKUVTCVKQPQHC ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ       ,CPUUGP4& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 2')HQTOWNCVKQPQH %6/%CV A OIMI YKNFV[RGCPF1CVRCD CPF OIMI 1CVRCD 6JGGHHGEVQH6/%QPVTCPURQTVQHǪ GUVTCFKQNINWEWTQPKFGCPFVCWTQEJQNCVG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  OGFKCVGFD[1#62$ 5.%1$ CPF06%2     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 5.%# KP%*1EGNNNKPGUQXGTGZRTGUUKPI 0% VJGUGVTCPURQTVGTU 5VWF[QP#$%$#DEICPF#$%%OGFKCVGF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ VTCPURQTVQH6/%KP..%2- #$%$ CPF GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ /&%-++ #DEI#$%% EGNNNKPGU CN 0% VTCPUFWEGFYKVJVJKUVTCPURQTVGT 13 #UUGUUKPIVTCPURQTVKPJKDKVKQPQH6/% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  QP#$%% /42 CPF#$%$ $5'2 WUKPI     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ KPUKFGQWVXGUKENGU 0% Ქᕈ⹜㛎 න࿁ᛩਈᲥᕈ⹜㛎 ⹥ᒰ⾗ᢱߥߒ ෻ᓳᛩਈᲥᕈ⹜㛎 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 9GGM4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ QH6/%KPVJG/QWUG CN 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ /QPVJ4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ QH6/%KPVJG/QWUG CN 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 9GGM4GRGCVGF&QUG&KGVCT[6QZKEKV[ GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ 5VWF[QH6/%KPVJG/QWUG CN 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 6/%6QZKEKV[5VWF[D[&KGVCT[      ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ #FOKPKUVTCVKQPVQ%&/KEGHQT9GGMU 0%

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ 6/%2TGNKOKPCT[6QZKEKV[5VWF[D[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  &KGVCT[#FOKPKUVTCVKQPVQ%&/KEGHQT     ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ &C[U 0% 6/%5WRRNGOGPVCT[6QZKEKV[5VWF[D[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  &KGVCT[#FOKPKUVTCVKQPVQ%&/KEGHQT     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 9GGMU 0% 5KPING&QUG1TCN6QZKEKV[5VWF[HQNNQYGF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  D[C&C[4GRGCVGF&QUG1TCN6QZKEKV[     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ CN 5VWF[KPVJG4CV VQNGTCDKNKV[UVWF[ 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 9GGM4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ QH6/%KPVJG4CV CN 0% OQPVJ4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  QH6/%KPVJG4CVYKVJCOQPVJ     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN 4GEQXGT[2GTKQF 0% OQPVJ4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  QH6/%KPVJG4CVYKVJ/QPVJ     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN KPVGTKOMKNN 0% 14 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 9GGM4GRGCVGF&QUG&KGVCT[6QZKEKV[ GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ 5VWF[QH6/%KPVJG4CV CN 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 6/%2KNQV6QZKEKV[5VWF[D[&KGVCT[      ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ #FOKPKUVTCVKQPVQ%&4CVUHQT&C[U 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 6/%6QZKEKV[5VWF[D[&KGVCT[      ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ #FOKPKUVTCVKQPVQ%&4CVUHQT9GGMU 0% 5KPING&QUG'UECNCVKQP1TCN6QZKEKV[5VWF[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ QH6/%KPVJG$GCING&QI(QNNQYGFD[ GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ C&C[4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ CN 0% 6QNGTCDKNKV[UVWF[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ YGGMVQZKEKV[UVWF[D[QTCNTQWVG      ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ ICXCIG KPDGCINGFQIU 0% OQPVJ4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  QH6/%KPVJG$GCING&QIYKVJC     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN OQPVJ4GEQXGT[2GTKQF 0%

JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24 JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ OQPVJTGRGCVGFFQUGQTCNVQZKEKV[UVWF[  GVCN     ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ QH6/%KPVJGDGCINGFQI 0% 6/%6QZKEKV[5VWF[D[1TCN)CXCIG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  #FOKPKUVTCVKQPVQ$GCING&QIUHQT9GGMU     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ (QNNQYGFD[C9GGM4GEQXGT[2GTKQF 0% 6/%6QZKEQMKPGVKECPFGUECNCVKPI KPVTCXGPQWUCPFQTCN D[ICXCIG FQUG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  TCPIGHKPFKPIUVWF[HQNNQYGFD[CPQTCN     ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ QTFC[HKZGFFQUGRJCUGKPVJG 0% OCNGTJGUWUOQPMG[ ㆮવᲥᕈ⹜㛎  +P8KVTQ ⹜㛎 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ +P8KVTQ $CEVGTKCN4GXGTUG/WVCVKQP6GUV GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ YKVJ6/%KP5CNOQPGNNCV[RJKOWTKWO CN 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ +P8KVTQ $CEVGTKCN4GXGTUG/WVCVKQP6GUV GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 15 YKVJ6/%KP5CNOQPGNNCV[RJKOWTKWO CN 0% +P8KVTQ /COOCNKCP(QTYCTF/WVCVKQP6GUV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ YKVJ.;/QWUG.[ORJQOC%GNNU 6- GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ NQEWU WUKPIVJG/KETQVKVGTo(NWEVWCVKQP CN 0% 6GEJPKSWGYKVJ6/%  +P8KXQ ⹜㛎 &GVGTOKPCVKQPCPFCUUGUUOGPVQHVJG RQVGPVKCNQH,0,###VQKPFWEG FCOCIGVQVJGEJTQOQUQOGUQTVJGOKVQVKE CRRCTCVWUKPRGTKRJGTCNDNQQF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  TGVKEWNQE[VGU OKETQPWENGWUVGUV CPF   ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ GVCN FGVGTOKPCVKQPQHU[UVGOKEGZRQUWTGVQ,0, 0% ###YJGPCFOKPKUVGTGFQPEG QTCNN[D[ICUVTKEKPVWDCVKQPVQOCNG%& OKEG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ +PXKXQ OKETQPWENGWUVGUVYKVJ6/%      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ QPDQPGOCTTQYEGNNUQHOKEG GVCN 0% ߇ࠎේᕈ⹜㛎 㐳ᦼ߇ࠎේᕈ⹜㛎 ⹥ᒰ⾗ᢱߥߒ

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ ⍴ᦼ෶ߪਛᦼ߇ࠎේᕈ⹜㛎 ⹥ᒰ⾗ᢱߥߒ ߘߩઁߩ⹜㛎 ⹥ᒰ⾗ᢱߥߒ ↢ᱺ⊒↢Ქᕈ⹜㛎 ฃ⢝⢻෸߮⌕ᐥ߹ߢߩೋᦼ⢦⊒↢ߦ㑐ߔࠆ⹜㛎 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ (GTVKNKV[UVWF[QHQTCN6/%KPVJG      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ OCNGCPFHGOCNGTCV GVCN 0% ⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜㛎 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 2KNQVQTCNFGXGNQROGPVCNVQZKEKV[UVWF[QH      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ 6/%KPVJGOQWUG GVCN 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 'ODT[Q(GVCN6QZKEKV[5VWF[D[1TCN)CXCIG GV      ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ #FOKPKUVTCVKQPVQ%&/KEG CN 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 2KNQVQTCNFGXGNQROGPVCNVQZKEKV[UVWF[QH      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ 16 6/%KPVJGTCV GVCN 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 1TCN&GXGNQROGPVCN6QZKEKV[5VWF[QH      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 6/%KPVJG4CV GVCN 0% ಴↢೨෸߮಴↢ᓟߩ⊒↢ਗ߮ߦᲣ૕ߩᯏ⢻ߦ㑐ߔࠆ⹜㛎 6/%2TGNKOKPCT[2TGCPF2QUV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  0CVCN&GXGNQROGPV5VWF[D[1TCN)CXCIG     ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ #FOKPKUVTCVKQPVQ%&4CVU 0% 6/%2TGCPF2QUV0CVCN&GXGNQROGPV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  5VWF[KPVJG%&4CVD[1TCN)CXCIG     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ #FOKPKUVTCVKQP 0% ᣂ↢ఽࠍ↪޿ߚ⹜㛎 ⹥ᒰ⾗ᢱߥߒ ዪᚲೝỗᕈ⹜㛎 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ +P8KVTQ $QXKPG%QTPGCN1RCEKV[      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ 2GTOGCDKNKV['[G+TTKVCVKQP6GUV CN 0% %[VQVQZKEKV[#UUC[+P8KVTQ YKVJ$#.$E ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 6%GNNU0GWVTCN4GF 04 6GUVYKVJ      ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 6/%FWTKPI5KOWNVCPGQWU+TTCFKCVKQP 0% YKVJ#TVKHKEKCN5WPNKIJV

JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24 JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ %[VQVQZKEKV[#UUC[+P8KVTQ YKVJ$#.$E 6%GNNU0GWVTCN4GF 04 6GUVYKVJ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  6/%KPRTGUGPEGQHCRTQVGKPUWRRNGOGPV     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ FWTKPI5KOWNVCPGQWU+TTCFKCVKQPYKVJ 0% #TVKHKEKCN5WPNKIJV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ .QECN.[ORJ0QFG#UUC[ ..0# KP/KEGYKVJ      ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 6/% 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 2TKOCT[5MKP+TTKVCVKQP5VWF[KP4CDDKVU      ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ *QWT5GOK1EENWUKXG#RRNKECVKQP 0% ߘߩઁߩᲥᕈ⹜㛎 ᛫ේᕈ⹜㛎 ⹥ᒰ⾗ᢱߥߒ ఺∉Ქᕈ⹜㛎 ⹥ᒰ⾗ᢱߥߒ Ქᕈ⊒⃻ߩᯏᐨߦ㑐ߔࠆ⹜㛎 ⹥ᒰ⾗ᢱߥߒ 17 ଐሽᕈ⹜㛎 ⹥ᒰ⾗ᢱߥߒ ઍ⻢‛ߩᲥᕈ⹜㛎 ⹥ᒰ⾗ᢱߥߒ ਇ⚐‛ߩᲥᕈ⹜㛎 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ YGGM4GRGCVGF&QUG1TCN6QZKEKV[5VWF[  GVCN     ,CPUUGP4& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ QH6/%KPVJG4CV A +P8KVTQ $CEVGTKCN4GXGTUG/WVCVKQP6GUV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  YKVJ6/%URKMGFYKVJ類縁物質F KP*     ,CPUUGP4& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ GVCN 5CNOQPGNNCV[RJKOWTKWO A * ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 6/% 類縁物質F +P8KVTQ /WVCVKQP      ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 6GUVWUKPI/QWUG.[ORJQOC.;%GNNU A +P8KVTQ $CEVGTKCN4GXGTUG/WVCVKQP6GUV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  YKVJ6/%URKMGFYKVJ類縁物質R CPF*     ,CPUUGP4& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ * CN 類縁物質H KP5CNOQPGNNCV[RJKOWTKWO A * 6/% 類縁物質H * 類縁物質R +P ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  8KVTQ /WVCVKQP6GUVWUKPI/QWUG.[ORJQOC     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ .;%GNNU A

*新薬承認情報提供時に置き換え

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ +P8KVTQ $CEVGTKCN4GXGTUG/WVCVKQP6GUV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ * GV  YKVJ6/%URKMGFYKVJ類縁物質J CPF     ,CPUUGP4& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN 類縁物質S KP* 5CNOQPGNNCV[RJKOWTKWO A * 6/% 類縁物質J 類縁物質S*  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  +P8KVTQ /WVCVKQP6GUVWUKPI/QWUG     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ .[ORJQOC.;%GNNU A +P8KVTQ $CEVGTKCN4GXGTUG/WVCVKQP6GUV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  YKVJ6/%URKMGFYKVJ類縁物質N CPF*     ,CPUUGP4& ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN 類縁物質Q KP* 5CNOQPGNNCV[RJKOWTKWO A * 6/% 類縁物質N* 類縁物質Q  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  +P8KVTQ /WVCVKQP6GUVWUKPI/QWUG     ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ .[ORJQOC.;%GNNU A ߘߩઁߩ⹜㛎 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 5GXGPFC[UTGRGCVGFFQUG6QZKEKV[5VWF[QH GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ 6/%KPVJG4CV CN 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ YGGM4GRGCVGF&QUG1TCN6QZKEKV[5VWF[ GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ 18 QH6/%KPVJG4CV CN 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ +P8KVTQ $QXKPG%QTPGCN1RCEKV[ GV      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ 2GTOGCDKNKV[+TTKVCVKQP6GUV CN 0% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 6JGE[VQVQZKEKV[QH6/%KPTCVFQI      ,,24& ᶏᄖ ␠ౝ⾗ᢱ ෳ⠨⾗ᢱ E[PQOQNIWUOQPMG[CPFJWOCPJGRCVQE[VGU 0% ෳ⠨ᢥ₂ ⮎ℂ⹜㛎 4GIWNCVKQPQHKPVGTHGTQPTGIWNCVQT[ ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ  HCEVQTD[VJGJGRCVKVKU%XKTWUUGTKPG (Q['GVCN 㧙 㧙 㧙 ₂⇟ภ㧦 㧙 RTQVGCUG5EKGPEG  +OOWPGGXCUKQPD[JGRCVKVKU%XKTWU05# ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ RTQVGCUGOGFKCVGFENGCXCIGQHVJG6QNN  .K-GVCN 㧙 㧙 㧙 ₂⇟ภ㧦 㧙 NKMGTGEGRVQTCFCRVQTRTQVGKP64+(2TQE  0CVN#ECF5EK75# *GRCVKVKU%XKTWURTQVGCUG05#ENGCXGU OKVQEJQPFTKCNCPVKXKTCNUKIPCNKPIRTQVGKP ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ  QHHVJGOKVQEJQPFTKCVQGXCFGKPPCVG .K:&GVCN 㧙 㧙 㧙 ₂⇟ภ㧦 㧙 KOOWPKV[2TQE0CVN#ECF5EK75#  

*新薬承認情報提供時に置き換え

JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24 JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ %CTFKHKUCPCFCRVQTRTQVGKPKPVJG4+)+ ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ CPVKXKTCNRCVJYC[CPFKUVCTIGVGFD[ /G[NCP'GV  㧙㧙㧙₂⇟ภ㧦 㧙 JGRCVKVKU%XKTWU0CVWTG CN   8KTCNCPFEGNNWNCTFGVGTOKPCPVUQH ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ .QJOCPP8GV  JGRCVKVKU%XKTWU40#TGRNKECVKQPKPEGNN 㧙㧙㧙₂⇟ภ㧦 㧙 CN EWNVWTG,8KTQN  'PJCPEGOGPVQHJGRCVKVKU%XKTWU40# ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ -TKGIGT0GV  TGRNKECVKQPD[EGNNEWNVWTGCFCRVKXG 㧙㧙㧙₂⇟ภ㧦 㧙 CN OWVCVKQPU,8KTQN  *KIJNKIJVUQH2TGUETKDKPI+PHQTOCVKQPHQT ® ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ  8+%64'.+5  DQEGRTGXKT %CRUWNGUHQTQTCN 㧙㧙㧙㧙₂⇟ภ㧦 㧙 WUG/GTEM5JCTR&QJOG%QTR  4GXKUGF *KIJNKIJVUQH2TGUETKDKPI+PHQTOCVKQPHQT 6/ ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ  +0%+8'-  VGNCRTGXKT (KNO%QCVGF6CDNGVU 㧙㧙㧙㧙₂⇟ภ㧦 㧙 HQTQTCNWUG8GTVGZ2JCTOCEGWVKECNU  19 +PEQTRQTCVGF4GXKUGF ⮎‛േᘒ⹜㛎 %[VQEJTQOG2OGFKCVGFOGVCDQNKUOQHVJG ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ *+8RTQVGCUGKPJKDKVQTTKVQPCXKT #$6 -WOCT)0GV ₂⇟ภ㧦  㧙㧙㧙 㧙  KPJWOCPNKXGTOKETQUQOGU, CN  2JCTOCEQN'ZR6JGT  1#62$RQN[OQTRJKUOKUCOCLQT ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ FGVGTOKPCPVQHUGTWODKNKTWDKPNGXGNDWV ₂⇟ภ㧦  PQVCUUQEKCVGFYKVJTKHCORKEKPOGFKCVGF

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ 5VTWEVWTGCPFHWPEVKQPQHVJG/42 #$%% ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ RTQVGKPCPFKVUTQNGKPFTWIFKURQUKVKQP ,GFNKVUEJM[) ₂⇟ภ㧦  㧙㧙㧙 㧙 'ZRGTV1RKP&TWI/GVCD6QZKEQN GVCN    5VTCVGIKGUHQTCDUQTRVKQPUETGGPKPIKP ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ $QJGVU*GV  FTWIFKUEQXGT[CPFFGXGNQROGPV%WTT6QR 㧙㧙㧙₂⇟ภ㧦 㧙 CN /GF%JGO  ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ ࠛࡇ࠰࡯࠼⮎‛േᘒቇ╙ ᧲੩੩ㇺᑝ ₂⇟ภ㧦  ㄞᓆ✚⋙ୃ 㧙 㧙 㧙 㧙 Ꮉᦠᐫ   Ქᕈ⹜㛎 2QUUKDNGCFXGTUGGHHGEVUQHUQ[DGCP ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ  CPVKECTEKPQIGPU,0WVT  .KGPGT+' 㧙 㧙 㧙 ₂⇟ภ㧦 㧙 5WRRN 55  'HHGEVUQHECOQUVCVCU[PVJGVKERTQVGCUG ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ KPJKDKVQTQPGPFQETKPGCPFGZQETKPG /WNNGT/-GV  㧙㧙㧙₂⇟ภ㧦 㧙 RCPETGCUQHVJGTCV,0WVT CN 20     2TQVGKPUDWVPQVCOKPQCEKFU ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ ECTDQJ[FTCVGUQTHCVUUVKOWNCVG .KFFNG4#GV  㧙㧙㧙₂⇟ภ㧦 㧙 EJQNGE[UVQMKPKPUGETGVKQPKPVJGTCV#O, CN  2J[UKQN 2V ) /QTRJQOGVTKEUVWF[QHVJGTCVGZQETKPG ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ RCPETGCUCHVGTFKXGTUKQPQHDKNGCPF -CUJKOC-GV  㧙㧙㧙₂⇟ภ㧦 㧙 RCPETGCVKELWKEGHTQOVJGKPVGUVKPG CN  )CUVTQGPVGTQNQI[   %CNEKWOFGRGPFGPVGP\[OGCEVKXCVKQPCPF ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ XCEWQNGHQTOCVKQPKPVJGCRKECNITCPWNCT 4CTCV[/GV  㧙㧙㧙₂⇟ภ㧦 㧙 TGIKQPQHRCPETGCVKECEKPCTEGNNU2TQE CN  0CVN#ECF5EK   㨬ࡍࠟࠪࠬ⊹ਅᵈǴIࡍࠟࠪࠬ⊹ਅᵈǴI ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦࠕ࡞ࡈࠔC ㆮવሶ⚵឵  㧙㧙㧙㧙₂⇟ภ㧦 㧙 ߃ ߦ㑐ߔࠆክᩏႎ๔ᦠ㨭ⴡ⎇⊒╙ภ  ᐕ᦬ᣣ

JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24 JEDI_DEV00 \ 0900fde9803ce5ac \ 1.7 \ 2013-02-13 11:24

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ 㨬ࡍࠣࠗࡦ࠻ࡠࡦ⊹ਅᵈ↪ǴIO.↪ห ǴIO.↪หǴIO.↪ࡍࠣࠗࡦ࠲࡯ ࡈࠚࡠࡦࠕ࡞ࡈࠔD ㆮવሶ⚵឵߃ ࡟ࡌ࠻࡯ ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ ࡞ࠞࡊ࠮࡞OI࡝ࡃࡆ࡝ࡦ෸߮ࠗࡦ࠻ࡠࡦ#  㧙㧙㧙㧙₂⇟ภ㧦 㧙 ᵈ኿↪หหࠗࡦ࠲࡯ࡈࠚࡠࡦࠕ  ࡞ࡈࠔD ㆮવሶ⚵឵߃ ߦ㑐ߔࠆክᩏႎ๔ ᦠ㨭⁛┙ⴕ᡽ᴺੱක⮎ຠක≮ᯏེ✚วᯏ ᭴ᐕ᦬ᣣ 㨬ࠦࡍࠟࠬ㍤OI࡝ࡃࡆ࡝ࡦ෸߮ࡍࠟࠪࠬ⊹ ਅᵈǴIหǴIࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦࠕ ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ  ࡞ࡈࠔC ㆮવሶ⚵឵߃ ߦ㑐ߔࠆክᩏႎ๔ 㧙㧙㧙㧙₂⇟ภ㧦 㧙 ᦠ㨭⁛┙ⴕ᡽ᴺੱක⮎ຠක≮ᯏེ✚วᯏ  ᭴ᐕ᦬ᣣ 㨬࡟ࡌ࠻࡯࡞ࠞࡊ࠮࡞OI࡝ࡃࡆ࡝ࡦ෸߮ࠗ ឝタ㗄⇟ภ෸߮ෳ⠨ᢥ ࡦ࠻ࡠࡦ#ᵈ኿↪หหࠗࡦ࠲࡯  㧙㧙㧙㧙₂⇟ภ㧦 㧙 ࡈࠚࡠࡦࠕ࡞ࡈࠔD ㆮવሶ⚵឵߃ ߦ㑐ߔࠆ  ክᩏႎ๔ᦠ㨭ⴡ⎇⊒╙ภᐕ᦬ᣣ 21

22 JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ ో⥃ᐥ⹜㛎৻ⷩ⴫ ⥃ᐥ⹜㛎ႎ๔ᦠ ↢‛⮎೷ቇ⹜㛎ႎ๔ᦠ ࡃࠗࠝࠕࡌࠗ࡜ࡆ࡝࠹ࠖ㧔$#㧕⹜㛎ႎ๔ᦠ ⹥ᒰ⾗ᢱߥߒ Ყセ$#⹜㛎෸߮↢‛ቇ⊛ห╬ᕈ㧔$'㧕⹜㛎ႎ๔ᦠ #UKPINGFQUGQRGPNCDGNTCPFQOK\GF VYQYC[ETQUUQXGTUVWF[VQCUUGUUVJG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ TGNCVKXGDKQCXCKNCDKNKV[QH6/%OI ᐕ᦬ᣣ -4KVQWGV ␠ౝ⾗ᢱ  IKXGPCUVJG2JCUG+++HQTOWNCVKQP ) 㨪ᐕ᦬ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ⹜㛎⇟ภ㧦 EQORCTGFVQVJG2JCUG++HQTOWNCVKQP ᣣ 6/%*2% ( WPFGTHCUVGFCPFHGFEQPFKVKQPUKP ,CRCPGUGJGCNVJ[CFWNVOCNGUWDLGEVU 2JCUG+QRGPNCDGNYC[ETQUUQXGTVTKCN ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ KPJGCNVJ[XQNWPVGGTUVQEQORCTGVJGQTCN ᐕ᦬ᣣ ␠ౝ⾗ᢱ DKQCXCKNCDKNKV[QHCUKPINGFQUGQH 48GTNQGUGV  㨪ᐕ᦬ ࡌ࡞ࠡ࡯ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ 6/%HQTOWNCVGFCUCUQNWVKQPVQVJCV CN ᣣ 6/%6K&2 QHCUKPINGFQUGKPVCMGQH6/% 23 % HQTOWNCVGFCUFKHHGTGPVECRUWNGU 2JCUG+QRGPNCDGNYC[ETQUUQXGTVTKCN KPJGCNVJ[UWDLGEVUVQEQORCTGVJG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ DKQCXCKNCDKNKV[QHCUKPINGQTCNFQUGQH ᐕ᦬ᣣ ␠ౝ⾗ᢱ 48GTNQGUGV  6/%HQTOWNCVGFCUFKHHGTGPVUQNKF 㨪ᐕ᦬ ࡌ࡞ࠡ࡯ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ CN HQTOWNCVKQPUVQVJCVQHCUKPINGQTCNFQUG ᣣ 6/%6K&2 QH6/%HQTOWNCVGFCUCRQYFGTDNGPF % ECRUWNG #2JCUG+QRGPNCDGNTCPFQOK\GFUKPING FQUGETQUUQXGTUVWF[KPJGCNVJ[UWDLGEVU ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ᐕ᦬ᣣ VQCUUGUUVJGTGNCVKXGDKQCXCKNCDKNKV[QH )&G5OGFV ␠ౝ⾗ᢱ  㨪ᐕ᦬ ࡌ࡞ࠡ࡯ ᶏᄖ ෳ⠨⾗ᢱ 6/%HQNNQYKPICFOKPKUVTCVKQPQH GVCN ⹜㛎⇟ภ㧦 ᣣ RQVGPVKCN2JCUG+++HQTOWNCVKQPUEQORCTGF 6/%6K&2% VQVJG2JCUG++DECRUWNG #UKPINGFQUGQRGPNCDGNTCPFQOK\GF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ VYQYC[ETQUUQXGTUVWF[VQCUUGUUVJG -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  GHHGEVQHHQQFQPVJGRJCTOCEQMKPGVKEUQH ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 6/%KP,CRCPGUGJGCNVJ[CFWNVOCNG 6/%*2% UWDLGEVU

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ #2JCUG+QRGPNCDGNTCPFQOK\GFUKPING FQUGRCPGNETQUUQXGTVTKCNKPJGCNVJ[ UWDLGEVUVQCUUGUUVJGTGNCVKXG DKQCXCKNCDKNKV[QH6/%HQNNQYKPI ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ CFOKPKUVTCVKQPQHVJG*2/%ECRUWNG /$GWOQPV ᐕ᦬ᣣ ␠ౝ⾗ᢱ  HQTOWNCVKQPEQORCTGFVQVJGIGNCVKP ࡌ࡞ࠡ࡯ ᶏᄖ ෳ⠨⾗ᢱ /CWXKGNGVCN 㨪ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ECRUWNGHQTOWNCVKQPCPFVQCUUGUUVJG 6/%6K&2% GHHGEVQHFKHHGTGPVOGCNV[RGUQPVJG DKQCXCKNCDKNKV[QH6/%HQNNQYKPI CFOKPKUVTCVKQPQHVJG*2/%QTIGNCVKP 6/%HQTOWNCVKQP #2JCUG+QRGPNCDGNTCPFQOK\GFUKPING FQUGETQUUQXGTUVWF[KPJGCNVJ[UWDLGEVU VQCUUGUUVJGTGNCVKXGDKQCXCKNCDKNKV[QH ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 6/%HQNNQYKPICFOKPKUVTCVKQPQH )&G5OGFV ᐕ᦬ᣣ ␠ౝ⾗ᢱ  RQVGPVKCN2JCUG+++HQTOWNCVKQPUEQORCTGF ࡌ࡞ࠡ࡯ ᶏᄖ ෳ⠨⾗ᢱ GVCN 㨪ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 VQVJG2JCUG++DECRUWNGCPFVQCUUGUUVJG 6/%6K&2% GHHGEVQHHQQFQPVJGDKQCXCKNCDKNKV[QH 24 6/%HQNNQYKPICFOKPKUVTCVKQPQH6/% HQTOWNCVGFCUVJG2JCUG++DECRUWNG +P8KVTQ㧙+P8KXQߩ㑐ㅪࠍᬌ⸛ߒߚ⹜㛎ႎ๔ᦠ ⹥ᒰ⾗ᢱߥߒ ↢‛ቇ⊛෸߮ℂൻቇ⊛ಽᨆᴺᬌ⸛ႎ๔ᦠ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 8CNKFCVKQP HWNN QHCP.%/5/5OGVJQF ␠ౝ⾗ᢱ -$KLPGPUGV ᐕ᦬ᣣ  HQTVJGFGVGTOKPCVKQPQH6/%KP ࡌ࡞ࠡ࡯ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ CN 㧔ႎ๔ᣣ㧕 JWOCP'&6#RNCUOC 6/%6K&2 0% $# ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ␠ౝ⾗ᢱ 8CNKFCVKQPQHCP.%/5/5OGVJQFHQTVJG  ᐕ ᦬ ᣣ ⹜㛎⇟ภ㧦  FGVGTOKPCVKQPQH6/%KPJWOCP'&6# ࠝ࡜ࡦ࠳ ᶏᄖ ෳ⠨⾗ᢱ 㧔ႎ๔ᣣ㧕 RNCOUCUCORNGU GVCN ,,2'. $$# ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 8CNKFCVKQP RCTVKCN QHCP.%/5/5OGVJQF GV ᐕ᦬ᣣ ␠ౝ⾗ᢱ  HQTVJGFGVGTOKPCVKQPQH,0, ਛ࿖ ᶏᄖ ෳ⠨⾗ᢱ CN 㧔ႎ๔ᣣ㧕 ⹜㛎⇟ภ㧦 6/% KPJWOCP'&6#RNCUOC 5*,4$# ࡅ࠻↢૕⹜ᢱࠍ↪޿ߚ⮎‛േᘒ㑐ㅪߩ⹜㛎ႎ๔ᦠ

JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21 JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ ⴊẏⰮ⊕⚿ว⹜㛎ႎ๔ᦠ  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ   ᐕ ᦬㨪 㧔ߩ 6JGRNCUOCRTQVGKPDKPFKPIQH *6/% ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ GVCN  ᐕ ᦬ ㊀ⶄ⸥タ㧕 KPCPKOCNUCPFOCP 0% 6JGRTQVGKPDKPFKPIQH*6/%KPRNCUOC  EQNNGEVGFKPCRJCUGUKPINGFQUGQRGP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  ᐕ ᦬㨪 㧔ߩ NCDGNUGSWGPVKCNVTKCNVQKPXGUVKICVGVJG ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ  ᐕ ᦬ ㊀ⶄ⸥タ㧕 RJCTOCEQMKPGVKEUUCHGV[CPFVQNGTCDKNKV[ A QH6/%KPUWDLGEVUYKVJOQFGTCVGN[QT UGXGTGN[KORCKTGFJGRCVKEHWPEVKQP 6JGRTQVGKPDKPFKPIQH*6/%KPRNCUOC  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ EQNNGEVGFKPCRJCUGQRGPNCDGNVTKCN  ᐕ ᦬㨪 㧔ߩ ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ VQKPXGUVKICVGVJGGHHGEVQHUGXGTGTGPCN  ᐕ ᦬ ㊀ⶄ⸥タ㧕 KORCKTOGPVQPVJGRJCTOCEQMKPGVKEUCPF (- UCHGV[QH6/% ⢄ઍ⻢෸߮⮎‛⋧੕૞↪⹜㛎ႎ๔ᦠ 'UVKOCVKQPQHVJGGHHGEVQH6/%QP  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ

25 VJGOGVCDQNKUOQHEQCFOKPKUVGTGFFTWIUD[ GV ᐕ᦬㨪 㧔ߩ ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ VJGFGVGTOKPCVKQPQHVJG- CPF8 HQT CN  ᐕ ᦬ ㊀ⶄ⸥タ㧕 O OCZ 0% 6/%KPJWOCPNKXGTOKETQUQOGU #PKPXKVTQ UVWF[VQFGVGTOKPGVJG MKPGVKEUQH6/%OGVCDQNKUOKPJWOCP  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ NKXGTOKETQUQOGUCPFVQKFGPVKH[VJG GV  ᐕ ᦬㨪 㧔ߩ ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ OKETQUQOCNE[VQEJTQOG2KUQGP\[OGU CN ᐕ᦬ ㊀ⶄ⸥タ㧕 0% OGFKCVKPI6/%OGVCDQNKUO TGCEVKQP RJGPQV[RKPI  #PKPXKVTQ UVWF[QPVJGFKTGEVKPJKDKVKQP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  ᐕ ᦬㨪 㧔ߩ QHVJGOGVCDQNKUOQHVJGE[VQEJTQOG2 ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN ᐕ᦬ ㊀ⶄ⸥タ㧕 RTQDGUWDUVTCVGUD[6/% 0% #PKPXKVTQ UVWF[QPVJGKPJKDKVKQPQH  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 7)6#OGFKCVGFDKNKTWDKPINWEWTQPKFCVKQP GV  ᐕ ᦬㨪 㧔ߩ ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ D[6/%CPF4KDCXKTKPKPJWOCPNKXGT CN ᐕ᦬ ㊀ⶄ⸥タ㧕 0% OKETQUQOGU #PKPXKVTQUVWF[VQCUUGUUVJGRQVGPVKCN  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ QH6/%VQKPFWEG%;2GP\[OG GV  ᐕ ᦬㨪 㧔ߩ ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CEVKXKVKGUKPET[QRTGUGTXGFJWOCP CN  ᐕ ᦬ ㊀ⶄ⸥タ㧕 0% JGRCVQE[VGU

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ  #PKPXKVTQ UVWF[QPVJGKPJKDKVQT[GHHGEV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  ᐕ ᦬㨪 㧔ߩ QH6/%QPVJGOGVCDQNKUOQH ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN  ᐕ ᦬ ㊀ⶄ⸥タ㧕 RQVGPVKCNEQOGFKECVKQP 0% ઁߩࡅ࠻↢૕⹜ᢱࠍ↪޿ߚ⹜㛎ႎ๔ᦠ 5VWF[QPVJGVTCPUGRKVJGNKCNVTCPURQTVQH 6/%VJGTQNGQH2IN[EQRTQVGKP 2  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ IR KPVJGVTCPUGRKVJGNKCNVTCPURQTVQH GV  ᐕ ᦬㨪 㧔ߩ ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ 6/%CETQUU%CEQOQPQNC[GTUCPFQP CN  ᐕ ᦬ ㊀ⶄ⸥タ㧕 0% VJGRQUUKDNGKPJKDKVKQPQHJWOCP KPVGUVKPCN2IRD[6/% +PXKVTQ UVWF[QPVJGWRVCMGVTCPURQTVQH 6/%KPTCVCPFJWOCPJGRCVQE[VGUVJG  GHHGEVQHTKVQPCXKTTKHCORKEKPCPF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ,GV  ᐕ ᦬㨪 㧔ߩ E[ENQURQTKP#QP6/%WRVCMGCPFVJG ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN  ᐕ ᦬ ㊀ⶄ⸥タ㧕 GHHGEVQH6/%QPJGRCVKEWRVCMGQH 0% VCWTQEJQNCVGCPFGUVTCFKQNǪ& INWEWTQPKFG +PXKVTQ UVWF[QPVJGWUGQHJWOCP 26  UCPFYKEJEWNVWTGFJGRCVQE[VGUHQTVJG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GV  ᐕ ᦬㨪 㧔ߩ CUUGUUOGPVQHVJGGHHGEVQH6/%QPVJG ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ CN  ᐕ ᦬ ㊀ⶄ⸥タ㧕 WRVCMGCPFGHHNWZQHVCWTQEJQNCVGCPF 0% GUVTCFKQNǪ&INWEWTQPKFG  6JGWRVCMGQH6/%KP*'-EGNNNKPGU ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  ᐕ ᦬㨪 㧔ߩ QXGTGZRTGUUKPIVJGVTCPURQTVGTU1#62$ ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ  ᐕ ᦬ ㊀ⶄ⸥タ㧕 1#62$1#62$QT1#62$  A 6JGGHHGEVQH6/%QPVTCPURQTVQHǪ  GUVTCFKQNINWEWTQPKFGCPFVCWTQEJQNCVG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  ᐕ ᦬㨪 㧔ߩ OGFKCVGFD[1#62$ 5.%1$ CPF06%2 ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ ᐕ᦬ ㊀ⶄ⸥タ㧕 5.%# KP%*1EGNNNKPGUQXGTGZRTGUUKPI 0% VJGUGVTCPURQTVGTU 5VWF[QP#$%$#DEICPF#$%%OGFKCVGF  ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ VTCPURQTVQH6/%KP..%2- #$%$ CPF GV  ᐕ ᦬㨪 㧔ߩ ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ /&%-++ #DEI#$%% EGNNNKPGU CN ᐕ᦬ ㊀ⶄ⸥タ㧕 0% VTCPUFWEGFYKVJVJKUVTCPURQTVGT  #UUGUUKPIVTCPURQTVKPJKDKVKQPQH6/% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  ᐕ ᦬㨪 㧔ߩ QP#$%% /42 CPF#$%$ $5'2 WUKPI ࡌ࡞ࠡ࡯ ᶏᄖ ␠ౝ⾗ᢱ ⹏ଔ⾗ᢱ ᐕ᦬ ㊀ⶄ⸥タ㧕 KPUKFGQWVXGUKENGU 0% ⥃ᐥ⮎‛േᘒ㧔2-㧕⹜㛎ႎ๔ᦠ ஜᐽⵍ㛎⠪ߦ߅ߌࠆ2-෸߮ೋᦼᔋኈᕈ⹜㛎ႎ๔ᦠ

JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21 JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ 2JCUG+FQWDNGDNKPFTCPFQOK\GF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ RNCEGDQEQPVTQNNGFVTKCNVQGZCOKPGVJG ᐕ᦬ᣣ ␠ౝ⾗ᢱ UCHGV[VQNGTCDKNKV[CPFRNCUOC 48GTNQGUGV  㨪ᐕ᦬ ☨࿖ ᶏᄖ ⹜㛎⇟ภ㧦 ⹏ଔ⾗ᢱ RJCTOCEQMKPGVKEUQHCUEGPFKPIQTCNFQUGU CN ᣣ 6/%6K&2 QH6/%CHVGTUKPINGCPFTGRGCVGF % FQUKPIKPJGCNVJ[,CRCPGUGOCNGUWDLGEVU 2JCUG+FQWDNGDNKPFTCPFQOK\GF RNCEGDQEQPVTQNNGFVTKCNKPJGCNVJ[ UWDLGEVUVQGZCOKPGVJGUCHGV[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ VQNGTCDKNKV[CPFRJCTOCEQMKPGVKEUQH ᐕ᦬ᣣ ␠ౝ⾗ᢱ 48GTNQGUGV  KPETGCUKPIQTCNFQUGUQH6/%CHVGT 㨪ᐕ᦬ ࠝ࡜ࡦ࠳ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ CN UKPINGCPFTGRGCVGFFQUKPIHQNNQYGFD[CP ᣣ 6/%6K&2 QRGPNCDGNTGRGCVGFFQUKPIUGUUKQPKP % *%8IGPQV[RGKPHGEVGFRCVKGPVU PQP RNCEGDQEQPVTQNNGF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ #2JCUG+QRGPNCDGNVTKCNVQ ᐕ᦬ᣣ ␠ౝ⾗ᢱ EJCTCEVGTK\GVJGCDUQTRVKQPOGVCDQNKUO 48GTNQGUGV  㨪ᐕ᦬ ࡌ࡞ࠡ࡯ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ 27 CPFGZETGVKQPQH%6/%CHVGTC CN ᣣ 6/%6K&2 UKPINGFQUGKPJGCNVJ[OCNGXQNWPVGGTU % ᖚ⠪ߦ߅ߌࠆ2-෸߮ೋᦼᔋኈᕈ⹜㛎ႎ๔ᦠ #2JCUG++TCPFQOK\GFQRGPNCDGNUVWF[ KP,CRCPVQKPXGUVKICVGVJGGHHKECE[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  UCHGV[CPFRJCTOCEQMKPGVKEUQH6/%CU -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ 㧔ߩ RCTVQHCVTGCVOGPVTGIKOGPKPENWFKPI ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ㊀ⶄ⸥タ㧕 RGIKPVGTHGTQPCNHCCCPFTKDCXKTKPKP 6/%6K&2% VTGCVOGPVPC°XGIGPQV[RGEJTQPKE JGRCVKVKU%UWDLGEVU #2JCUG+++TCPFQOK\GFFQWDNGDNKPF RNCEGDQEQPVTQNNGFVTKCNKP,CRCPVQ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ KPXGUVKICVGVJGGHHKECE[CPFUCHGV[QH  ᐕ᦬ᣣ ␠ౝ⾗ᢱ 6/%XURNCEGDQCURCTVQHCVTGCVOGPV -4KVQWGV 㧔 㨪ᐕ᦬ᣣ ᣣᧄ ࿖ౝ ⹜㛎⇟ภ㧦 ⹏ଔ⾗ᢱ TGIKOGPKPENWFKPIRGIKPVGTHGTQPCNHCC CN ߩ㊀ⶄ⸥タ㧕 㧔⛮⛯ਛ㧕 6/%*2% CPFTKDCXKTKPKPVTGCVOGPVPC°XGIGPQV[RG 㧔584㧕 JGRCVKVKU%KPHGEVGFUWDLGEVU584 +PVGTKO#PCN[UKU

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ #2JCUG+++TCPFQOK\GFFQWDNGDNKPF RNCEGDQEQPVTQNNGFVTKCNKP,CRCPVQ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  KPXGUVKICVGVJGGHHKECE[CPFUCHGV[QH ᐕ᦬ᣣ -4KVQWGV ␠ౝ⾗ᢱ 㧔 6/%XURNCEGDQCURCTVQHCVTGCVOGPV 㨪ᐕ᦬ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ⹜㛎⇟ภ㧦 ߩ㊀ⶄ⸥タ㧕 TGIKOGPKPENWFKPIRGIKPVGTHGTQPCNHCC ᣣ 6/%*2% CPFTKDCXKTKPKPVTGCVOGPVPC°XGIGPQV[RG JGRCVKVKU%KPHGEVGFUWDLGEVU #2JCUG+++QRGPNCDGNVTKCNKP,CRCPVQ KPXGUVKICVGVJGGHHKECE[CPFUCHGV[QH ᐕ᦬ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  6/%CURCTVQHCVTGCVOGPVTGIKOGP -4KVQWGV 㨪ᐕ᦬ ␠ౝ⾗ᢱ 㧔ߩ KPENWFKPIRGIKPVGTHGTQPCNHCCCPF ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᣣ ⹜㛎⇟ภ㧦 ㊀ⶄ⸥タ㧕 TKDCXKTKPKPIGPQV[RGJGRCVKVKU% 6/%*2% KPHGEVGFUWDLGEVUYJQTGNCRUGFCHVGT RTGXKQWU+(0DCUGFVJGTCR[ #2JCUG+++TCPFQOK\GFQRGPNCDGNVYQ CTOVTKCNKP,CRCPVQKPXGUVKICVGVJG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GHHKECE[CPFUCHGV[QH6/%CURCTVQHC  ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ VTGCVOGPVTGIKOGPKPENWFKPIRGIKPVGTHGTQP -4KVQWGV 28 㧔 ᐕ᦬ᣣ ᣣᧄ ࿖ౝ ⹜㛎⇟ภ㧦 ⹏ଔ⾗ᢱ CNHCCCPFTKDCXKTKPKP*GRCVKVKU% CN ߩ㊀ⶄ⸥タ㧕 㧔⛮⛯ਛ㧕 6/%*2% IGPQV[RGKPHGEVGFUWDLGEVUYJQHCKNGFVQ 㧔584㧕 TGURQPFVQRTGXKQWU+(0DCUGFVJGTCR[ 584+PVGTKO#PCN[UKU #2JCUG+++TCPFQOK\GFQRGPNCDGNVYQ CTOVTKCNKP,CRCPVQKPXGUVKICVGVJG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  GHHKECE[CPFUCHGV[QH6/%CURCTVQHC -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ 㧔 VTGCVOGPVTGIKOGPKPENWFKPIRGIKPVGTHGTQP ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ߩ㊀ⶄ⸥タ㧕 CNHCCCPFTKDCXKTKPKP*GRCVKVKU% 6/%*2% IGPQV[RGKPHGEVGFUWDLGEVUYJQHCKNGFVQ TGURQPFVQRTGXKQWU+(0DCUGFVJGTCR[ #RJCUG+++QRGPNCDGNUVWF[KP,CRCPVQ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ CUUGUUVJGGHHKECE[CPFUCHGV[QH6/%  ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ CURCTVQHCVTGCVOGPVTGIKOGPKPENWFKPI -4KVQWGV 㧔 ᐕ᦬ᣣ ᣣᧄ ࿖ౝ ⹜㛎⇟ภ㧦 ⹏ଔ⾗ᢱ RGIKPVGTHGTQPCNHCDCPFTKDCXKTKPKP CN ߩ㊀ⶄ⸥タ㧕 㧔⛮⛯ਛ㧕 6/%*2% *GRCVKVKU%IGPQV[RGKPHGEVGFUWDLGEVU 㧔584㧕 584+PVGTKO#PCN[UKU

JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21 JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ #RJCUG+++QRGPNCDGNUVWF[KP,CRCPVQ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  CUUGUUVJGGHHKECE[CPFUCHGV[QH6/% -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ 㧔 CURCTVQHCVTGCVOGPVTGIKOGPKPENWFKPI ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ߩ㊀ⶄ⸥タ㧕 RGIKPVGTHGTQPCNHCDCPFTKDCXKTKPKP 6/%*2% *GRCVKVKU%IGPQV[RGKPHGEVGFUWDLGEVU 2JCUG+FQWDNGDNKPFTCPFQOK\GF RNCEGDQEQPVTQNNGFVTKCNKPJGCNVJ[ UWDLGEVUVQGZCOKPGVJGUCHGV[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  VQNGTCDKNKV[CPFRJCTOCEQMKPGVKEUQH ᐕ᦬ᣣ ␠ౝ⾗ᢱ 48GTNQGUGV 㧔ߩ KPETGCUKPIQTCNFQUGUQH6/%CHVGT 㨪ᐕ᦬ ࠝ࡜ࡦ࠳ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ CN ㊀ⶄ⸥タ㧕 UKPINGCPFTGRGCVGFFQUKPIHQNNQYGFD[CP ᣣ 6/%6K&2 QRGPNCDGNTGRGCVGFFQUKPIUGUUKQPKP % *%8IGPQV[RGKPHGEVGFRCVKGPVU PQP RNCEGDQEQPVTQNNGF #FQWDNGDNKPFTCPFQOK\GFRNCEGDQ EQPVTQNNGFVTKCNKP)GPQV[RG*GRCVKVKU% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  UWDLGEVUVQGXCNWCVGVJGGCTN[GHHKECE[ ᐕ᦬ᣣ ࡌ࡞ࠡ࡯㧘࠼ࠗ࠷㧘 ␠ౝ⾗ᢱ )&G5OGFV 㧔ߩ UCHGV[VQNGTCDKNKV[CPFRJCTOCEQMKPGVKEU 㨪ᐕ᦬ ࡈ࡜ࡦࠬ㧘⧷࿖㧘ࠝ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ 29 GVCN ㊀ⶄ⸥タ㧕 QH6/%HQNNQYKPITGRGCVGFFQUGUCPF ᣣ ࡜ࡦ࠳㧘ࡐ࡯࡜ࡦ࠼ 6/%6K&2 YKVJQTYKVJQWVRGI[NCVGFKPVGTHGTQPCPF % TKDCXKTKP ࠝ࡯ࠬ࠻࡜࡝ࠕ㧘 #2JCUG++DTCPFQOK\GFFQWDNGDNKPF ࠾ࡘ࡯ࠫ࡯࡜ࡦ࠼㧘 RNCEGDQEQPVTQNNGFVTKCNVQKPXGUVKICVG ࠞ࠽࠳㧘ࠝ࡯ࠬ࠻࡝ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  VJGGHHKECE[VQNGTCDKNKV[UCHGV[CPF ᐕ᦬ᣣ ࠕ㧘ࡌ࡞ࠡ࡯㧘࠼ࠗ /$GWOQPV ␠ౝ⾗ᢱ 㧔ߩ RJCTOCEQMKPGVKEUQH6/%CURCTVQHC 㨪ᐕ᦬ ࠷㧘ࠬࡍࠗࡦ㧘ࡈ࡜ ᶏᄖ ෳ⠨⾗ᢱ /CWXKGNGVCN ⹜㛎⇟ภ㧦 ㊀ⶄ⸥タ㧕 VTGCVOGPVTGIKOGPKPENWFKPIRGIKPVGTHGTQP ᣣ ࡦࠬ㧘ࡐ࡯࡜ࡦ࠼㧘 6/%6K&2% CNHCCCPFTKDCXKTKPKPVTGCVOGPVPC°XG ࡠࠪࠕ㧘ࡁ࡞࠙ࠚ IGPQV[RGJGRCVKVKU%KPHGEVGFUWDLGEVU ࠗ㧘࠺ࡦࡑ࡯ࠢ㧘☨ ࿖ ࡠࠪࠕ㧘ࡈ࡜ࡦࠬ㧘 #2JCUG++DTCPFQOK\GFFQWDNGDNKPF ࠼ࠗ࠷㧘ࡐ࡯࡜ࡦ RNCEGDQEQPVTQNNGFVTKCNVQKPXGUVKICVG ࠼㧘ࠗࠬ࡜ࠛ࡞㧘ࡌ VJGGHHKECE[VQNGTCDKNKV[UCHGV[CPF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  ᐕ᦬ᣣ ࡞ࠡ࡯㧘⧷࿖㧘ࠝ࡯ RJCTOCEQMKPGVKEUQH6/%CURCTVQHC /$GWOQPV ␠ౝ⾗ᢱ 㧔ߩ 㨪ᐕ᦬ ࠬ࠻࡝ࠕ㧘ࡐ࡞࠻ࠟ ᶏᄖ ෳ⠨⾗ᢱ VTGCVOGPVTGIKOGPKPENWFKPI2GI+(0CCCPF /CWXKGNGVCN ⹜㛎⇟ภ㧦 ㊀ⶄ⸥タ㧕 ᣣ ࡞㧘ࡁ࡞࠙ࠚࠗ㧘☨ TKDCXKTKPKP*%8IGPQV[RGPQPTGURQPFGTU 6/%6K&2% ࿖㧘ࠞ࠽࠳㧘ࠝ࡯ࠬ CPFTGNCRUGTUHQNNQYKPICVNGCUVEQWTUG ࠻࡜࡝ࠕ㧘࠾ࡘ࡯ QH2GI+(0CCDCPF4$8VJGTCR[ ࠫ࡯࡜ࡦ࠼

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ #2JCUG+++TCPFQOK\GFFQWDNGDNKPF ࠝ࡯ࠬ࠻࡜࡝ࠕ㧘 RNCEGDQEQPVTQNNGFUVWF[VQKPXGUVKICVG ࠾ࡘ࡯ࠫ࡯࡜ࡦ࠼㧘 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ VJGGHHKECE[UCHGV[CPFVQNGTCDKNKV[QH ࠼ࠗ࠷㧘ࠗ࠲࡝ࠕ㧘  ᐕ᦬ᣣ ␠ౝ⾗ᢱ 6/%XURNCEGDQCURCTVQHCVTGCVOGPV /$GWOQPV ࡞࡯ࡑ࠾ࠕ㧘ࡠࠪࠕ 㧔 㨪ᐕ᦬ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ TGIKOGPKPENWFKPIRGIKPVGTHGTQP CCPF /CWXKGNGVCN ㅪ㇌㧘ࠬࡍࠗࡦ㧘࠙ ߩ㊀ⶄ⸥タ㧕 Į ᣣ㧔⛮⛯ਛ㧕 6/%6K&2% ࠢ࡜ࠗ࠽㧘⧷࿖㧘ࠞ TKDCXKTKPKPVTGCVOGPVPC°XGIGPQV[RG 㧔9㧕 JGRCVKVKU%KPHGEVGFUWDLGEVU2TKOCT[ ࠽࠳㧘ࡔࠠࠪࠦ㧘ࡊ #PCN[UKU ࠛ࡞࠻࡝ࠦ㧘☨࿖ #2JCUG+++TCPFQOK\GFFQWDNGDNKPF ࠝ࡯ࠬ࠻࡝ࠕ㧘ࡌ࡞ RNCEGDQEQPVTQNNGFUVWF[VQKPXGUVKICVG ࠡ࡯㧘ࡉ࡞ࠟ࡝ࠕ㧘 VJGGHHKECE[UCHGV[CPFVQNGTCDKNKV[QH ࡈ࡜ࡦࠬ㧘࠼ࠗ࠷㧘 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 6/%XGTUWURNCEGDQCURCTVQHC  ᐕ᦬ᣣ ࠝ࡜ࡦ࠳㧘ࡐ࡯࡜ࡦ ␠ౝ⾗ᢱ VTGCVOGPVTGIKOGPKPENWFKPIRGIKPVGTHGTQP /$GWOQPV 㧔 㨪ᐕ᦬ ࠼㧘ࡐ࡞࠻ࠟ࡞㧘ࠬ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ ĮC 2GICU[Uo CPFTKDCXKTKP %QRGIWUo /CWXKGNGVCN ߩ㊀ⶄ⸥タ㧕 ᣣ㧔⛮⛯ਛ㧕 ࡠࡃࠠࠕ㧘ࠬࡍࠗ 6/%6K&2% QTRGIKPVGTHGTQPĮD 2GI+PVTQPo CPF ࡦ㧘࠻࡞ࠦ㧘☨࿖㧘 㧔9㧕 TKDCXKTKP 4GDGVQNo KPVTGCVOGPVPC°XG ࠕ࡞࠯ࡦ࠴ࡦ㧘ࡉ࡜ IGPQV[RGJGRCVKVKU%KPHGEVGFUWDLGEVU ࠫ࡞

30 2TKOCT[ #PCN[UKU #2JCUG+++TCPFQOK\GFFQWDNGDNKPF ࠝ࡯ࠬ࠻࡜࡝ࠕ㧘 RNCEGDQEQPVTQNNGFUVWF[VQKPXGUVKICVG ࠾ࡘ࡯ࠫ࡯࡜ࡦ࠼㧘 VJGGHHKECE[UCHGV[CPFVQNGTCDKNKV[QH ࠝ࡯ࠬ࠻࡝ࠕ㧘ࡌ࡞ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  6/%XURNCEGDQCURCTVQHCVTGCVOGPV ᐕ᦬ᣣ ࠡ࡯㧘ࡈ࡜ࡦࠬ㧘࠼ /$GWOQPV ␠ౝ⾗ᢱ 㧔 TGIKOGPKPENWFKPIRGIKPVGTHGTQP CCPF 㨪ᐕ᦬ ࠗ࠷㧘ࠗ࠲࡝ࠕ㧘 ᶏᄖ ෳ⠨⾗ᢱ Į /CWXKGNGVCN ⹜㛎⇟ภ㧦 ߩ㊀ⶄ⸥タ㧕 ᣣ㧔⛮⛯ਛ㧕 ࡐ࡯࡜ࡦ࠼㧘ࡠࠪࠕ TKDCXKTKPKPJGRCVKVKU%IGPQV[RG 6/%*2%㧔9㧕 KPHGEVGFUWDLGEVUYJQTGNCRUGFCHVGT ㅪ㇌㧘ࠬࡍࠗࡦ㧘⧷ RTGXKQWUKPVGTHGTQPDCUGFVJGTCR[2TKOCT[ ࿖㧘ࠞ࠽࠳㧘ࡊࠛ࡞ #PCN[UKU ࠻࡝ࠦ㧘☨࿖ ౝ࿃ᕈⷐ࿃ࠍᬌ⸛ߒߚ2-⹜㛎ႎ๔ᦠ #2JCUG+QRGPNCDGNUGSWGPVKCNVTKCNVQ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ KPXGUVKICVGVJGRJCTOCEQMKPGVKEUUCHGV[ /$GWOQPV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  CPFVQNGTCDKNKV[QH6/%KPUWDLGEVU ☨࿖ ᶏᄖ ෳ⠨⾗ᢱ /CWXKGNGVCN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 YKVJOQFGTCVGN[QTUGXGTGN[KORCKTGF 6/%6K&2% JGRCVKEHWPEVKQP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ #2JCUG+QRGPNCDGNVTKCNVQKPXGUVKICVG /$GWOQPV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  VJGGHHGEVQHUGXGTGTGPCNKORCKTOGPVQP ࠴ࠚࠦ౒๺࿖ ᶏᄖ ෳ⠨⾗ᢱ /CWXKGNGVCN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 VJGRJCTOCEQMKPGVKEUCPFUCHGV[QH6/% 6/%6K&2% ᄖ࿃ᕈⷐ࿃ࠍᬌ⸛ߒߚ2-⹜㛎ႎ๔ᦠ

JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21 JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ 2JCUG+QRGPNCDGNVTKCNKPJGCNVJ[ UWDLGEVUVQGXCNWCVGVJGFTWIFTWI ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ KPVGTCEVKQPDGVYGGPTKVQPCXKTCVUVGCF[ ᐕ᦬ᣣ ␠ౝ⾗ᢱ 48GTNQGUGV  UVCVGCPF6/%CXKTCNRTQVGCUG 㨪ᐕ᦬ ࡌ࡞ࠡ࡯ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ CN KPJKDKVQTCICKPUVJGRCVKVKU%XKTWUCHVGT ᣣ 6/%6K&2 VJGHKTUVCPFVJGNCUVFQUGQHOWNVKRNG % FQUKPITGIKOGP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 2JCUG+QRGPNCDGNYC[ETQUUQXGTVTKCN ᐕ᦬ᣣ ␠ౝ⾗ᢱ KPJGCNVJ[UWDLGEVUVQFGVGTOKPGVJGFTWI 48GTNQGUGV  㨪ᐕ᦬ ☨࿖ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ FTWIKPVGTCEVKQPDGVYGGP6/%CPF CN ᣣ 6/%6K&2 TKHCORKPCHVGTOWNVKRNGFQUKPI % #2JCUG+QRGPNCDGNRGTKQF TCPFQOK\GFETQUUQXGTVTKCNKPJGCNVJ[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ UWDLGEVUVQCUUGUUVJGFTWIKPVGTCEVKQP )&G5OGFV ᐕ᦬ᣣ ␠ౝ⾗ᢱ  RQVGPVKCNQH6/%YKVJQTCNOKFC\QNCO ࠼ࠗ࠷ ᶏᄖ ෳ⠨⾗ᢱ GVCN 㨪ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 CPFYKVJCFTWIEQEMVCKNTGRTGUGPVCVKXGQH 6/%6K&2% %;2#%;2%%;2&%;2#CPF 31 %;2%UWDUVTCVGU #2JCUG+RCPGNQRGPNCDGN TCPFQOK\GFETQUUQXGTVTKCNKPJGCNVJ[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ UWDLGEVUVQKPXGUVKICVGVJG /$GWOQPV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ☨࿖ ᶏᄖ ෳ⠨⾗ᢱ RJCTOCEQMKPGVKEKPVGTCEVKQPDGVYGGP6/% /CWXKGNGVCN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 CPFVTCPURQTVGTUWDUVTCVGUFKIQZKPCPF 6/%6K&2% TQUWXCUVCVKP #2JCUG+RCPGNQRGPNCDGN TCPFQOK\GFETQUUQXGTVTKCNKPJGCNVJ[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ UWDLGEVUVQKPXGUVKICVGVJG ᐕ᦬ᣣ /$GWOQPV ␠ౝ⾗ᢱ  RJCTOCEQMKPGVKEKPVGTCEVKQPDGVYGGP6/% 㨪ᐕ᦬ ࡌ࡞ࠡ࡯ ᶏᄖ ෳ⠨⾗ᢱ /CWXKGNGVCN ⹜㛎⇟ภ㧦 CPFCPVKTGVTQXKTCNCIGPVU6/%CPF ᣣ 6/%6K&2% VGPQHQXKTFKUQRTQZKNHWOCTCVG 6&( CV UVGCF[UVCVG #2JCUG+QRGPNCDGNUKPINGUGSWGPEG FTWIFTWIKPVGTCEVKQPVTKCNKPUWDLGEVUQP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ UVCDNGOGVJCFQPGOCKPVGPCPEGVJGTCR[VQ )&G5OGFV ᐕ᦬ᣣ ␠ౝ⾗ᢱ  ࠞ࠽࠳ ᶏᄖ ෳ⠨⾗ᢱ KPXGUVKICVGVJGRQVGPVKCNRJCTOCEQMKPGVKE GVCN 㨪ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 KPVGTCEVKQPDGVYGGP6/%CPFOGVJCFQPG 6/%6K&2% CVUVGCF[UVCVG

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ #2JCUG+QRGPNCDGNTCPFQOK\GFYC[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ETQUUQXGTVTKCNKPJGCNVJ[UWDLGEVUVQ )&G5OGFV ᐕ᦬ᣣ ␠ౝ⾗ᢱ  KPXGUVKICVGVJGRJCTOCEQMKPGVKE ࡐ࡯࡜ࡦ࠼ ᶏᄖ ෳ⠨⾗ᢱ GVCN 㨪ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 KPVGTCEVKQPDGVYGGP6/%CPF 6/%6K&2% GUEKVCNQRTCOCVUVGCF[UVCVG #2JCUG+RCPGNQRGPNCDGN TCPFQOK\GFETQUUQXGTVTKCNKPJGCNVJ[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ UWDLGEVUVQKPXGUVKICVGVJG /$GWOQPV ᐕ᦬ᣣ ␠ౝ⾗ᢱ  ࡌ࡞ࠡ࡯ ᶏᄖ ෳ⠨⾗ᢱ RJCTOCEQMKPGVKEKPVGTCEVKQPDGVYGGP6/% /CWXKGNGVCN 㨪ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 CPF%;2#KPJKDKVQTUGT[VJTQO[EKPCPF 6/%6K&2% FCTWPCXKTTKVQPCXKT &48T #2JCUG+RCPGNQRGPNCDGN TCPFQOK\GFETQUUQXGTVTKCNKPJGCNVJ[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ᐕ᦬ᣣ UWDLGEVUVQKPXGUVKICVGVJGGHHGEVQH /$GWOQPV ␠ౝ⾗ᢱ  㨪ᐕ᦬ ࡌ࡞ࠡ࡯ ᶏᄖ ෳ⠨⾗ᢱ 6/%QPVJGRJCTOCEQMKPGVKEUQHVJG /CWXKGNGVCN ⹜㛎⇟ภ㧦 ᣣ KOOWPQUWRRTGUUCPVUE[ENQURQTKPGCPF 6/%6K&2% VCETQNKOWU #2JCUG+RCPGNQRGPNCDGN 32 TCPFQOK\GFETQUUQXGTVTKCNKPJGCNVJ[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ᐕ᦬ᣣ UWDLGEVUVQKPXGUVKICVGVJG /$GWOQPV ␠ౝ⾗ᢱ  㨪ᐕ᦬ ࠼ࠗ࠷ ᶏᄖ ෳ⠨⾗ᢱ RJCTOCEQMKPGVKEKPVGTCEVKQPDGVYGGP6/% /CWXKGNGVCN ⹜㛎⇟ภ㧦 ᣣ CPFCPVKTGVTQXKTCNCIGPVUGHCXKTGP\CPF 6/%6K&2% TCNVGITCXKTCVUVGCF[UVCVG #2JCUG+QRGPNCDGNVTKCNKPJGCNVJ[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ HGOCNGUWDLGEVUVQKPXGUVKICVGVJGGHHGEV /$GWOQPV ᐕ᦬ᣣ ␠ౝ⾗ᢱ  QH6/%CVUVGCF[UVCVGQPVJGUVGCF[ ࡌ࡞ࠡ࡯ ᶏᄖ ෳ⠨⾗ᢱ /CWXKGNGVCN 㨪ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 UVCVGRJCTOCEQMKPGVKEUQHGVJKP[NGUVTCFKQN 6/%6K&2% CPFPQTGVJKPFTQPG #2JCUG+RCPGNQRGPNCDGNUVWF[KP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ JGCNVJ[UWDLGEVUVQKPXGUVKICVGVJG ᐕ᦬ᣣ /$GWOQPV ␠ౝ⾗ᢱ  RJCTOCEQMKPGVKEKPVGTCEVKQPDGVYGGP6/% 㨪ᐕ᦬ ☨࿖ ᶏᄖ ෳ⠨⾗ᢱ /CWXKGNGVCN ⹜㛎⇟ภ㧦 CPFVJG*/)%Q#TGFWEVCUGKPJKDKVQTU ᣣ 6/%*2% CVQTXCUVCVKPCPFUKOXCUVCVKP ࡐࡇࡘ࡟࡯࡚ࠪࡦ2-⹜㛎ႎ๔ᦠ $C[GUKCP(GGFDCEM#PCN[UKUVQFGVGTOKPG KPFKXKFWCNGZRQUWTGVQ6/%KPVTKCN ᐕ᦬ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  ࠝ࡜ࡦ࠳ ᶏᄖ ⹏ଔ⾗ᢱ 6/%*2% VTGCVOGPVFWTCVKQP GVCN 㧔ႎ๔ᣣ㧕 ␠ౝ⾗ᢱ YGGMU

JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21 JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ  ᐕ ᦬ ᣣ $C[GUKCP(GGFDCEM#PCN[UKUVQFGVGTOKPG 㧔ႎ๔ᣣ㧕 KPFKXKFWCNGZRQUWTGVQ6/%KPVTKCN GV ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ   ᐕ ᦬ ᣣ ࠝ࡜ࡦ࠳ ᶏᄖ ⹏ଔ⾗ᢱ 6/%*2% VTGCVOGPVFWTCVKQPQT CN ␠ౝ⾗ᢱ 㧔ႎ๔ᣣ YGGMU #OGPFOGPV㧕 $C[GUKCP(GGFDCEM#PCN[UKUVQFGVGTOKPG GV KPFKXKFWCNGZRQUWTGVQ6/%KPVTKCN CN ᐕ᦬ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  ࠝ࡜ࡦ࠳ ᶏᄖ ⹏ଔ⾗ᢱ 6/%*2% VTGCVOGPVFWTCVKQP 㧔ႎ๔ᣣ㧕 ␠ౝ⾗ᢱ YGGMU $C[GUKCP(GGFDCEM#PCN[UKUVQFGVGTOKPG GV KPFKXKFWCNGZRQUWTGVQ6/%KPVTKCN CN ᐕ᦬ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  ࠝ࡜ࡦ࠳ ᶏᄖ ⹏ଔ⾗ᢱ 6/%*2% VTGCVOGPVFWTCVKQP 㧔ႎ๔ᣣ㧕 ␠ౝ⾗ᢱ YGGMU 2QRWNCVKQP2-OGVCCPCN[UKUKPENWFKPI GV  ᐕ ᦬ ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  EQXCTKVCVGCPCN[UKUQH6/%KPQPG2JCUG ࠝ࡜ࡦ࠳ ᶏᄖ ⹏ଔ⾗ᢱ CN 㧔ႎ๔ᣣ㧕 ␠ౝ⾗ᢱ ++CPFHQWT2JCUG+++,CRCPGUGVTKCNU 2QRWNCVKQP2JCTOCEQMKPGVKECPCN[UKUHQT

33 6/%C*%805CKPJKDKVQTCPF  ᐕ ᦬ ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  ࠝ࡜ࡦ࠳ ᶏᄖ ෳ⠨⾗ᢱ 2JCTOCEQMKPGVKE2JCTOCEQF[PCOKEOQFGNNKPI GVCN 㧔ႎ๔ᣣ㧕 ␠ౝ⾗ᢱ QHKVUGHHGEVQPDKNKTWDKP 2QRWNCVKQPRJCTOCEQMKPGVKECPCN[UKUHQT 6/%C*%805CKPJKDKVQTKP  ᐕ ᦬ ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  VTGCVOGPVPC°XGCPFVTGCVOGPVGZRGTKGPEGF ࠝ࡜ࡦ࠳ ᶏᄖ ෳ⠨⾗ᢱ GVCN 㧔ႎ๔ᣣ㧕 ␠ౝ⾗ᢱ *%8KPHGEVGFRCVKGPVU UVWFKGU6/% 6K&2%CPF6/%6K&2% #PCN[UKUQH'ZRQUWTG$KNKTWDKP ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ %QPEGPVTCVKQP4GNCVKQPUJKRHQT6/%C ᐕ᦬ᣣ ␠ౝ⾗ᢱ  /#EJKTC ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ *%805CKPJKDKVQTKP6/%6K&2% 㧔ႎ๔ᣣ㧕 ⹜㛎⇟ภ㧦 5VWF[ %2- ⥃ᐥ⮎ജቇ㧔2&㧕⹜㛎ႎ๔ᦠ ஜᐽⵍ㛎⠪ߦ߅ߌࠆ2&⹜㛎෸߮2-2&⹜㛎ႎ๔ᦠ #FQWDNGDNKPFFQWDNGFWOO[TCPFQOK\GF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ RGTKQFETQUUQXGTRNCEGDQCPF ᐕ᦬ᣣ /$GWOQPV ␠ౝ⾗ᢱ  RQUKVKXGEQPVTQNNGFUVWF[VQGXCNWCVGVJG 㨪ᐕ᦬ ⧷࿖ ᶏᄖ ⹏ଔ⾗ᢱ /CWXKGNGVCN ⹜㛎⇟ภ㧦 GHHGEVQH6/%QPVJG36EKPVGTXCNKP ᣣ 6/%6K&2% JGCNVJ[UWDLGEVU

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ #4CPFQOK\GF&QWDNG$NKPF&QWDNG&WOO[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 2NCEGDQCPF2QUKVKXG%QPVTQNNGF2JCUG+ /$GWOQPV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⧷࿖ ᶏᄖ ෳ⠨⾗ᢱ 6TKCNVQ'XCNWCVGVJG2JQVQUGPUKVK\KPI /CWXKGNGVCN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 2QVGPVKCNQH6/%KP*GCNVJ[5WDLGEVU 6/%6K&2% ᖚ⠪ߦ߅ߌࠆ2&⹜㛎෸߮2-2&⹜㛎ႎ๔ᦠ ⹥ᒰ⾗ᢱߥߒ ᦭ലᕈ෸߮቟ోᕈ⹜㛎ႎ๔ᦠ ↳⺧ߔࠆㆡᔕ∝ߦ㑐ߔࠆᲧセኻᾖ⹜㛎ႎ๔ᦠ #FQWDNGDNKPFTCPFQOK\GFRNCEGDQ EQPVTQNNGFVTKCNKP)GPQV[RG*GRCVKVKU% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ UWDLGEVUVQGXCNWCVGVJGGCTN[GHHKECE[ ᐕ᦬ᣣ ࡌ࡞ࠡ࡯㧘࠼ࠗ࠷㧘 ␠ౝ⾗ᢱ )&G5OGFV  UCHGV[VQNGTCDKNKV[CPFRJCTOCEQMKPGVKEU 㨪ᐕ᦬ ࡈ࡜ࡦࠬ㧘⧷࿖㧘ࠝ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ GVCN QH6/%HQNNQYKPITGRGCVGFFQUGUCPF ᣣ ࡜ࡦ࠳㧘ࡐ࡯࡜ࡦ࠼ 6/%6K&2 YKVJQTYKVJQWVRGI[NCVGFKPVGTHGTQPCPF % TKDCXKTKP #2JCUG++TCPFQOK\GFQRGPNCDGNUVWF[ KP,CRCPVQKPXGUVKICVGVJGGHHKECE[ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ UCHGV[CPFRJCTOCEQMKPGVKEUQH6/%CU 34 -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  RCTVQHCVTGCVOGPVTGIKOGPKPENWFKPI ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 RGIKPVGTHGTQPCNHCCCPFTKDCXKTKPKP 6/%6K&2% VTGCVOGPVPC°XGIGPQV[RGEJTQPKE JGRCVKVKU%UWDLGEVU ࠝ࡯ࠬ࠻࡜࡝ࠕ㧘 #2JCUG++DTCPFQOK\GFFQWDNGDNKPF ࠾ࡘ࡯ࠫ࡯࡜ࡦ࠼㧘 RNCEGDQEQPVTQNNGFVTKCNVQKPXGUVKICVG ࠞ࠽࠳㧘ࠝ࡯ࠬ࠻࡝ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ VJGGHHKECE[VQNGTCDKNKV[UCHGV[CPF ᐕ᦬ᣣ ࠕ㧘ࡌ࡞ࠡ࡯㧘࠼ࠗ /$GWOQPV ␠ౝ⾗ᢱ  RJCTOCEQMKPGVKEUQH6/%CURCTVQHC 㨪ᐕ᦬ ࠷㧘ࠬࡍࠗࡦ㧘ࡈ࡜ ᶏᄖ ෳ⠨⾗ᢱ /CWXKGNGVCN ⹜㛎⇟ภ㧦 VTGCVOGPVTGIKOGPKPENWFKPIRGIKPVGTHGTQP ᣣ ࡦࠬ㧘ࡐ࡯࡜ࡦ࠼㧘 6/%6K&2% CNHCCCPFTKDCXKTKPKPVTGCVOGPVPC°XG ࡠࠪࠕ㧘ࡁ࡞࠙ࠚ IGPQV[RGJGRCVKVKU%KPHGEVGFUWDLGEVU ࠗ㧘࠺ࡦࡑ࡯ࠢ㧘☨ ࿖

JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21 JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ ࡠࠪࠕ㧘ࡈ࡜ࡦࠬ㧘 #2JCUG++DTCPFQOK\GFFQWDNGDNKPF ࠼ࠗ࠷㧘ࡐ࡯࡜ࡦ RNCEGDQEQPVTQNNGFVTKCNVQKPXGUVKICVG ࠼㧘ࠗࠬ࡜ࠛ࡞㧘ࡌ VJGGHHKECE[VQNGTCDKNKV[UCHGV[CPF ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ᐕ᦬ᣣ ࡞ࠡ࡯㧘⧷࿖㧘ࠝ࡯ RJCTOCEQMKPGVKEUQH6/%CURCTVQHC /$GWOQPV ␠ౝ⾗ᢱ  㨪ᐕ᦬ ࠬ࠻࡝ࠕ㧘ࡐ࡞࠻ࠟ ᶏᄖ ෳ⠨⾗ᢱ VTGCVOGPVTGIKOGPKPENWFKPI2GI+(0CCCPF /CWXKGNGVCN ⹜㛎⇟ภ㧦 ᣣ ࡞㧘ࡁ࡞࠙ࠚࠗ㧘☨ TKDCXKTKPKP*%8IGPQV[RGPQPTGURQPFGTU 6/%6K&2% ࿖㧘ࠞ࠽࠳㧘ࠝ࡯ࠬ CPFTGNCRUGTUHQNNQYKPICVNGCUVEQWTUG ࠻࡜࡝ࠕ㧘࠾ࡘ࡯ QH2GI+(0CCDCPF4$8VJGTCR[ ࠫ࡯࡜ࡦ࠼ #2JCUG+++TCPFQOK\GFFQWDNGDNKPF RNCEGDQEQPVTQNNGFVTKCNKP,CRCPVQ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ KPXGUVKICVGVJGGHHKECE[CPFUCHGV[QH ᐕ᦬ᣣ ␠ౝ⾗ᢱ 6/%XURNCEGDQCURCTVQHCVTGCVOGPV -4KVQWGV  㨪ᐕ᦬ᣣ ᣣᧄ ࿖ౝ ⹜㛎⇟ภ㧦 ⹏ଔ⾗ᢱ TGIKOGPKPENWFKPIRGIKPVGTHGTQPCNHCC CN 㧔⛮⛯ਛ㧕 6/%*2% CPFTKDCXKTKPKPVTGCVOGPVPC°XGIGPQV[RG 㧔584㧕 JGRCVKVKU%KPHGEVGFUWDLGEVU584 +PVGTKO#PCN[UKU #2JCUG+++TCPFQOK\GFFQWDNGDNKPF 35 RNCEGDQEQPVTQNNGFVTKCNKP,CRCPVQ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ KPXGUVKICVGVJGGHHKECE[CPFUCHGV[QH ᐕ᦬ᣣ -4KVQWGV ␠ౝ⾗ᢱ  6/%XURNCEGDQCURCTVQHCVTGCVOGPV 㨪ᐕ᦬ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ⹜㛎⇟ภ㧦 TGIKOGPKPENWFKPIRGIKPVGTHGTQPCNHCC ᣣ 6/%*2% CPFTKDCXKTKPKPVTGCVOGPVPC°XGIGPQV[RG JGRCVKVKU%KPHGEVGFUWDLGEVU #2JCUG+++TCPFQOK\GFFQWDNGDNKPF ࠝ࡯ࠬ࠻࡜࡝ࠕ㧘 RNCEGDQEQPVTQNNGFUVWF[VQKPXGUVKICVG ࠾ࡘ࡯ࠫ࡯࡜ࡦ࠼㧘 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ VJGGHHKECE[UCHGV[CPFVQNGTCDKNKV[QH ࠼ࠗ࠷㧘ࠗ࠲࡝ࠕ㧘 ᐕ᦬ᣣ ␠ౝ⾗ᢱ 6/%XURNCEGDQCURCTVQHCVTGCVOGPV /$GWOQPV ࡞࡯ࡑ࠾ࠕ㧘ࡠࠪࠕ  㨪ᐕ᦬ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ TGIKOGPKPENWFKPIRGIKPVGTHGTQP CCPF /CWXKGNGVCN ㅪ㇌㧘ࠬࡍࠗࡦ㧘࠙ Į ᣣ㧔⛮⛯ਛ㧕 6/%6K&2% ࠢ࡜ࠗ࠽㧘⧷࿖㧘ࠞ TKDCXKTKPKPVTGCVOGPVPC°XGIGPQV[RG 㧔9㧕 JGRCVKVKU%KPHGEVGFUWDLGEVU2TKOCT[ ࠽࠳㧘ࡔࠠࠪࠦ㧘ࡊ #PCN[UKU ࠛ࡞࠻࡝ࠦ㧘☨࿖

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ #2JCUG+++TCPFQOK\GFFQWDNGDNKPF RNCEGDQEQPVTQNNGFUVWF[VQKPXGUVKICVG ࠝ࡯ࠬ࠻࡝ࠕ㧘ࡌ࡞ VJGGHHKECE[UCHGV[CPFVQNGTCDKNKV[QH ࠡ࡯㧘ࡉ࡞ࠟ࡝ࠕ㧘 6/%XGTUWURNCEGDQCURCTVQHC ࡈ࡜ࡦࠬ㧘࠼ࠗ࠷㧘 ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ᐕ᦬ᣣ ࠝ࡜ࡦ࠳㧘ࡐ࡯࡜ࡦ ␠ౝ⾗ᢱ VTGCVOGPVTGIKOGPKPENWFKPIRGIKPVGTHGTQP /$GWOQPV  㨪ᐕ᦬ ࠼㧘ࡐ࡞࠻ࠟ࡞㧘ࠬ ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ ĮC 2GICU[Uo CPFTKDCXKTKP %QRGIWUo /CWXKGNGVCN ᣣ㧔⛮⛯ਛ㧕 ࡠࡃࠠࠕ㧘ࠬࡍࠗ 6/%6K&2% QTRGIKPVGTHGTQPĮD 2GI+PVTQPo CPF ࡦ㧘࠻࡞ࠦ㧘☨࿖㧘 㧔9㧕 TKDCXKTKP 4GDGVQNo KPVTGCVOGPVPC°XG ࠕ࡞࠯ࡦ࠴ࡦ㧘ࡉ࡜ IGPQV[RGJGRCVKVKU%KPHGEVGFUWDLGEVU ࠫ࡞ 2TKOCT[ #PCN[UKU #2JCUG+++TCPFQOK\GFFQWDNGDNKPF ࠝ࡯ࠬ࠻࡜࡝ࠕ㧘 RNCEGDQEQPVTQNNGFUVWF[VQKPXGUVKICVG ࠾ࡘ࡯ࠫ࡯࡜ࡦ࠼㧘 VJGGHHKECE[UCHGV[CPFVQNGTCDKNKV[QH ࠝ࡯ࠬ࠻࡝ࠕ㧘ࡌ࡞ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 6/%XURNCEGDQCURCTVQHCVTGCVOGPV ᐕ᦬ᣣ ࠡ࡯㧘ࡈ࡜ࡦࠬ㧘࠼ /$GWOQPV ␠ౝ⾗ᢱ  TGIKOGPKPENWFKPIRGIKPVGTHGTQP CCPF 㨪ᐕ᦬ ࠗ࠷㧘ࠗ࠲࡝ࠕ㧘 ᶏᄖ ෳ⠨⾗ᢱ Į /CWXKGNGVCN ⹜㛎⇟ภ㧦 ᣣ㧔⛮⛯ਛ㧕 ࡐ࡯࡜ࡦ࠼㧘ࡠࠪࠕ TKDCXKTKPKPJGRCVKVKU%IGPQV[RG 6/%*2%㧔9㧕 KPHGEVGFUWDLGEVUYJQTGNCRUGFCHVGT ㅪ㇌㧘ࠬࡍࠗࡦ㧘⧷ ࿖㧘ࠞ࠽࠳㧘ࡊࠛ࡞

36 RTGXKQWUKPVGTHGTQPDCUGFVJGTCR[2TKOCT[ #PCN[UKU ࠻࡝ࠦ㧘☨࿖ 㕖ኻᾖ⹜㛎ႎ๔ᦠ #2JCUG+++QRGPNCDGNVTKCNKP,CRCPVQ KPXGUVKICVGVJGGHHKECE[CPFUCHGV[QH ᐕ᦬ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 6/%CURCTVQHCVTGCVOGPVTGIKOGP -4KVQWGV 㨪ᐕ᦬ ␠ౝ⾗ᢱ  KPENWFKPIRGIKPVGTHGTQPCNHCCCPF ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᣣ ⹜㛎⇟ภ㧦 TKDCXKTKPKPIGPQV[RGJGRCVKVKU% 6/%*2% KPHGEVGFUWDLGEVUYJQTGNCRUGFCHVGT RTGXKQWU+(0DCUGFVJGTCR[ #2JCUG+++TCPFQOK\GFQRGPNCDGNVYQ CTOVTKCNKP,CRCPVQKPXGUVKICVGVJG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GHHKECE[CPFUCHGV[QH6/%CURCTVQHC ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ VTGCVOGPVTGIKOGPKPENWFKPIRGIKPVGTHGTQP -4KVQWGV  ᐕ᦬ᣣ ᣣᧄ ࿖ౝ ⹜㛎⇟ภ㧦 ⹏ଔ⾗ᢱ CNHCCCPFTKDCXKTKPKP*GRCVKVKU% CN 㧔⛮⛯ਛ㧕 6/%*2% IGPQV[RGKPHGEVGFUWDLGEVUYJQHCKNGFVQ 㧔584㧕 TGURQPFVQRTGXKQWU+(0DCUGFVJGTCR[ 584+PVGTKO#PCN[UKU

JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21 JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ #2JCUG+++TCPFQOK\GFQRGPNCDGNVYQ CTOVTKCNKP,CRCPVQKPXGUVKICVGVJG ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ GHHKECE[CPFUCHGV[QH6/%CURCTVQHC -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  VTGCVOGPVTGIKOGPKPENWFKPIRGIKPVGTHGTQP ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 CNHCCCPFTKDCXKTKPKP*GRCVKVKU% 6/%*2% IGPQV[RGKPHGEVGFUWDLGEVUYJQHCKNGFVQ TGURQPFVQRTGXKQWU+(0DCUGFVJGTCR[ #RJCUG+++QRGPNCDGNUVWF[KP,CRCPVQ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ CUUGUUVJGGHHKECE[CPFUCHGV[QH6/% ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ CURCTVQHCVTGCVOGPVTGIKOGPKPENWFKPI -4KVQWGV  ᐕ᦬ᣣ ᣣᧄ ࿖ౝ ⹜㛎⇟ภ㧦 ⹏ଔ⾗ᢱ RGIKPVGTHGTQPCNHCDCPFTKDCXKTKPKP CN 㧔⛮⛯ਛ㧕 6/%*2% *GRCVKVKU%IGPQV[RGKPHGEVGFUWDLGEVU 㧔584㧕 584+PVGTKO#PCN[UKU #RJCUG+++QRGPNCDGNUVWF[KP,CRCPVQ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ CUUGUUVJGGHHKECE[CPFUCHGV[QH6/% -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  CURCTVQHCVTGCVOGPVTGIKOGPKPENWFKPI ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 RGIKPVGTHGTQPCNHCDCPFTKDCXKTKPKP 6/%*2% *GRCVKVKU%IGPQV[RGKPHGEVGFUWDLGEVU 37 ⶄᢙߩ⹜㛎ᚑ❣ࠍ૬ߖߡ⸃ᨆߒߚႎ๔ᦠ %QORCTKUQPQHVJGRJCTOCEQMKPGVKEUQH ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 6/%KP,CRCPGUGCPFPQP,CRCPGUG ᐕ᦬ᣣ ␠ౝ⾗ᢱ  *1VCPK ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ JGCNVJ[UWDLGEVUCPFJGRCVKVKU%XKTWU 㧔ႎ๔ᣣ㧕 ⹜㛎⇟ภ㧦 KPHGEVGFUWDLGEVU %2- ߘߩઁߩ⹜㛎ႎ๔ᦠ #UUGUUOGPVQHVJGRQVGPVKCNKPHNWGPEGQP 6/%RNCUOCGZRQUWTGQHVJGIGPGVKE ᐕ᦬ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  XCTKCVKQPKPECPFKFCVGIGPGUGPEQFKPI ,#GTUUGPU ,CPUUGP4& ᶏᄖ ෳ⠨⾗ᢱ 㧔ႎ๔ᣣ㧕 ␠ౝ⾗ᢱ RTQVGKPUYKVJMPQYPQTCUUWOGFKPXQNXGOGPV KPVJGOGVCDQNKUOQH6/% 8KTQNQI[CPCN[UKUQH6/%KPENKPKECN ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ UVWFKGU6/%%CPF6/%% ␠ౝ⾗ᢱ 6/%OQPQVJGTCR[CPF6/%KP 68GTDKPPGP  ᐕ ᦬㨪  ,CPUUGP4& ᶏᄖ ⹜㛎⇟ภ㧦 ෳ⠨⾗ᢱ EQODKPCVKQPYKVJ2GI+(04$8KPVTGCVOGPV GVCN  ᐕ ᦬ 6/%%% PC°XGCPF̄GZRGTKGPEGFIGPQV[RG #8/4 JGRCVKVKU%KPHGEVGFUWDLGEVU 8KTQNQI[CPCN[UKUQH6/%KPENKPKECN ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ UVWF[6/%%6/%KPEQODKPCVKQP .6CODW[\GT  ᐕ ᦬㨪 ␠ౝ⾗ᢱ  ,CPUUGP4& ᶏᄖ ෳ⠨⾗ᢱ YKVJ2GI+(04$8KPVTGCVOGPVPC°XG GVCN  ᐕ ᦬ ⹜㛎⇟ภ㧦 IGPQV[RGJGRCVKVKU%KPHGEVGFUWDLGEVU 6/%%#8/4

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ 8KTQNQI[CPCN[UKUQH6/%KPENKPKECN ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ UVWF[6/%%6/%KPEQODKPCVKQP '.CVJQWYGTU  ᐕ ᦬㨪 ␠ౝ⾗ᢱ  ,CPUUGP4& ᶏᄖ ෳ⠨⾗ᢱ YKVJ2GI+(04$8KPVTGCVOGPVGZRGTKGPEGF GVCN  ᐕ ᦬ ⹜㛎⇟ภ㧦 IGPQV[RGJGRCVKVKU%KPHGEVGFUWDLGEVU 6/%%#8/4 ,CPUUGP +PHGEVKQWU ᐕ᦬ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ  6/%8KTQNQI[5WOOCT[ &KUGCUGU ,CPUUGP4& ᶏᄖ ෳ⠨⾗ᢱ 㧔ႎ๔ᣣ㧕 ␠ౝ⾗ᢱ &KCIPQUVKEU $8$# Ꮢ⽼ᓟߩ૶↪⚻㛎ߦ㑐ߔࠆႎ๔ᦠ ⹥ᒰ⾗ᢱߥߒ ᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀⸥㍳ ↪㊂⸳ቯߩᩮ᜚ߣߥߞߚਥⷐߥ⹜㛎෸߮ਥⷐߥ᦭ലᕈߩᬌ⸽⹜㛎ߩ∝଀৻ⷩ⴫ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ⸥㍳ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ ↪㊂⸳ቯߩᩮ᜚ߣߥߞߚਥⷐߥ⹜㛎෸߮ਥⷐߥ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ᦭ലᕈߩᬌ⸽⹜㛎ߩ∝଀৻ⷩ⴫ 6/%6K&2% ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 38 ᐕ᦬ᣣ ⸥㍳ -4KVQWGV ␠ౝ⾗ᢱ  㨪ᐕ᦬ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ ↪㊂⸳ቯߩᩮ᜚ߣߥߞߚਥⷐߥ⹜㛎෸߮ਥⷐߥ CN ⹜㛎⇟ภ㧦 ᣣ ᦭ലᕈߩᬌ⸽⹜㛎ߩ∝଀৻ⷩ⴫ 6/%*2% ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ᐕ᦬ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ⸥㍳ -4KVQWGV 㨪ᐕ᦬ ␠ౝ⾗ᢱ  ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ ↪㊂⸳ቯߩᩮ᜚ߣߥߞߚਥⷐߥ⹜㛎෸߮ਥⷐߥ CN ᣣ ⹜㛎⇟ภ㧦 ᦭ലᕈߩᬌ⸽⹜㛎ߩ∝଀৻ⷩ⴫ 6/%*2% ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ⸥㍳ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ ↪㊂⸳ቯߩᩮ᜚ߣߥߞߚਥⷐߥ⹜㛎෸߮ਥⷐߥ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ᦭ലᕈߩᬌ⸽⹜㛎ߩ∝଀৻ⷩ⴫ 6/%*2% ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ⸥㍳ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ ↪㊂⸳ቯߩᩮ᜚ߣߥߞߚਥⷐߥ⹜㛎෸߮ਥⷐߥ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ᦭ലᕈߩᬌ⸽⹜㛎ߩ∝଀৻ⷩ⴫ 6/%*2% ታᣉߐࠇߚోߡߩ⥃ᐥ⹜㛎ߦ߅޿ߡ೽૞↪߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ᐕ᦬ᣣ -4KVQWGV ␠ౝ⾗ᢱ  ⸥㍳ 㨪ᐕ᦬ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ⹜㛎⇟ภ㧦 ೽૞↪߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ᣣ 6/%*2%

JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21 JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ೽૞↪߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%*2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ᐕ᦬ᣣ ␠ౝ⾗ᢱ 48GTNQGUGV  ⸥㍳ 㨪ᐕ᦬ ☨࿖ ᶏᄖ ⹜㛎⇟ภ㧦 ⹏ଔ⾗ᢱ CN ೽૞↪߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ᣣ 6/%6K&2 % ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ᐕ᦬ᣣ /$GWOQPV ␠ౝ⾗ᢱ  ⸥㍳ 㨪ᐕ᦬ ⧷࿖ ᶏᄖ ⹏ଔ⾗ᢱ /CWXKGNGVCN ⹜㛎⇟ภ㧦 ೽૞↪߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ᣣ 6/%6K&2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ೽૞↪߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%6K&2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 39 ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ᐕ᦬ᣣ -4KVQWGV ␠ౝ⾗ᢱ  ⸥㍳ 㨪ᐕ᦬ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ⹜㛎⇟ภ㧦 ೽૞↪߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ᣣ 6/%*2% ᐕ᦬ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV 㨪ᐕ᦬ ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᣣ ⹜㛎⇟ภ㧦 ೽૞↪߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%*2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ೽૞↪߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%*2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ೽૞↪߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%*2% ታᣉߐࠇߚోߡߩ⥃ᐥ⹜㛎ߦ߅޿ߡ㊀◊ߥ᦭ኂ੐⽎߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ㊀◊ߥ᦭ኂ੐⽎߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%6K&2%

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ᐕ᦬ᣣ -4KVQWGV ␠ౝ⾗ᢱ  ⸥㍳ 㨪ᐕ᦬ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ⹜㛎⇟ภ㧦 ㊀◊ߥ᦭ኂ੐⽎߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ᣣ 6/%*2% ᐕ᦬ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV 㨪ᐕ᦬ ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᣣ ⹜㛎⇟ภ㧦 ㊀◊ߥ᦭ኂ੐⽎߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%*2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ㊀◊ߥ᦭ኂ੐⽎߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%*2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ㊀◊ߥ᦭ኂ੐⽎߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%*2% ታᣉߐࠇߚోߡߩ⥃ᐥ⹜㛎ߦ߅޿ߡ⥃ᐥᬌᩏ୯⇣Ᏹᄌേ߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ 40 ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ᐕ᦬ᣣ -4KVQWGV ␠ౝ⾗ᢱ  ⸥㍳ 㨪ᐕ᦬ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ⹜㛎⇟ภ㧦 ⥃ᐥᬌᩏ୯⇣Ᏹᄌേ߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ᣣ 6/%*2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ⥃ᐥᬌᩏ୯⇣Ᏹᄌേ߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%*2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ᐕ᦬ᣣ ␠ౝ⾗ᢱ 48GTNQGUGV  ⸥㍳ 㨪ᐕ᦬ ☨࿖ ᶏᄖ ⹜㛎⇟ภ㧦 ⹏ଔ⾗ᢱ CN ⥃ᐥᬌᩏ୯⇣Ᏹᄌേ߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ᣣ 6/%6K&2 % ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ᐕ᦬ᣣ /$GWOQPV ␠ౝ⾗ᢱ  ⸥㍳ 㨪ᐕ᦬ ⧷࿖ ᶏᄖ ⹏ଔ⾗ᢱ /CWXKGNGVCN ⹜㛎⇟ภ㧦 ⥃ᐥᬌᩏ୯⇣Ᏹᄌേ߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ᣣ 6/%6K&2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ⥃ᐥᬌᩏ୯⇣Ᏹᄌേ߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%6K&2%

JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21 JEDI_DEV00 \ 0900fde9803e597d \ 3.4 \ 2013-05-10 14:21

⹏ଔ⾗ᢱ࡮ ᷝઃ⾗ᢱ⇟ภ ࠲ࠗ࠻࡞ ⪺⠪ ⹜㛎ታᣉᦼ㑆 ⹜㛎ታᣉ႐ᚲ ႎ⒳㘃 ឝタ⹹ ෳ⠨⾗ᢱ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ ᐕ᦬ᣣ -4KVQWGV ␠ౝ⾗ᢱ  ⸥㍳ 㨪ᐕ᦬ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ⹜㛎⇟ภ㧦 ⥃ᐥᬌᩏ୯⇣Ᏹᄌേ߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ ᣣ 6/%*2% ᐕ᦬ᣣ ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV 㨪ᐕ᦬ ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᣣ ⹜㛎⇟ภ㧦 ⥃ᐥᬌᩏ୯⇣Ᏹᄌേ߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%*2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ⥃ᐥᬌᩏ୯⇣Ᏹᄌേ߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%*2% ࡗࡦ࠮ࡦࡈࠔ࡯ࡑ ߦ㑐ߔࠆᖚ⠪࠺࡯࠲৻ⷩ⴫෸߮∝଀ -4KVQWGV ᐕ᦬ᣣ㨪 ␠ౝ⾗ᢱ  ⸥㍳ ᣣᧄ ࿖ౝ ⹏ଔ⾗ᢱ CN ᐕ᦬ᣣ ⹜㛎⇟ภ㧦 ⥃ᐥᬌᩏ୯⇣Ᏹᄌേ߇ⷰኤߐࠇߚ∝଀ߩ৻ⷩ⴫ 6/%*2% ታᣉߐࠇߚోߡߩ⥃ᐥ⹜㛎ߦ߅޿ߡⷰኤߐࠇߚ⥃ᐥᬌᩏ୯ߩᄌേࠍㆡಾߦ␜ߒߚ࿑ ⹥ᒰ⾗ᢱߥߒ 41 ෳ⠨ᢥ₂ ෳ⠨ᢥ₂৻ⷩ⴫෸߮ෳ  ෳ⠨ᢥ₂     ෳ⠨⾗ᢱ ⠨ᢥ₂ࠍᷝઃ