་⸆ရ㛤Ⓨ୰ື≀࡛ㄆࡵࡽࢀࡓẘᛶࡀࣄࢺ࡛ࡶⓎࡍࡿྍ⬟ᛶࡘ࠸࡚ࡢホ౯ࡣ㸪ࡑࡢ་⸆
ရࡢ㛤Ⓨࢆ㐍ࡵࡿୖ࡛㔜せ࡞ุ᩿ᇶ‽࡞ࡿࠋ ⮫ᗋ➨ 2 ┦ヨ㦂୰ᐇࡋࡓ fasiglifam ࡢࢾ
- 44 -
ࡢᢞẘᛶヨ㦂࠾࠸࡚ࢾ≉᭷ࡢ⫢ẘᛶࡀⓎࡋࡓࠋ➨2┦ヨ㦂⤊ࡢ FDA ࡢ༠㆟
࠾࠸࡚㸪ࢾ⫢ẘᛶࡢཎᅉゎ᫂࠾ࡼࡧࣄࢺ࡛ࡢᏳᛶ㛵ࡍࡿᠱᛕࡢᡶᣔࡀ➨ 3 ┦ヨ㦂㛤ጞࡢ ᮲௳࡞ࡾ㸪ᮏྜ≀ࡢ㛤Ⓨࡣ୰᩿ࡉࢀࡓࠋ 㛤Ⓨࢆ㛤ࡉࡏࡿࡓࡵ㸪ẘᛶࡢⓎᶵᗎࢆゎ᫂ࡋ㸪
ࣄࢺ࡛ࡢᏳᇦࢆホ౯ࡋࡓࠋ MALDI–TOF MSศᯒࡢ⤖ᯝ㸪⫢⮚⌮⤌⧊᳨ᰝ࠾࠸࡚☜ㄆࡉࢀ
ࡓ⫹⟶ෆࡢ⤖ᬗᛶࡢ␗≀ࡣfasiglifam ࠾ࡼࡧ fasiglifam-G ࡀྵࡲࢀ࡚࠸ࡿࡇࡀ♧ࡉࢀࡓࠋࡉ
ࡽ㸪fasiglifam ࡢືែࢆㄪࡓ⤖ᯝ㸪ࢾ࡛ㄆࡵࡽࢀࡓ⫢ẘᛶࡣ㣬⁐ゎᗘࢆ㉸࠼ࡓ fasiglifam
࠾ࡼࡧ fasiglifam-G ࡀ⫹Ồ୰ἥࡉࢀ㸪ࡇࢀࡽࡢྜ≀ࡀ⫹⟶ෆ࡛ᯒฟࡍࡿࡇ㉳ᅉࡍࡿ
⪃࠼ࡽࢀࡓࠋࡇࡢⓎᶵᗎᇶ࡙࠸࡚⫹Ồ୰⃰ᗘࢆண ࡍࡿ PK ࣔࢹࣝࢆᵓ⠏ࡋ㸪⮫ᗋ⏝㔞࠾
ࡅࡿ⫹Ồ୰ fasiglifam ࠾ࡼࡧ fasiglifam-G ࡢ⃰ᗘࢆ᥎ᐃࡋ࡚Ᏻᇦࢆᐃ㔞ⓗホ౯ࡍࡿࡇࡀ࡛
ࡁࡓࠋᮏ◊✲ࡢᡂ⦼ࢆ FDA ༠㆟ࡋࡓ⤖ᯝ㸪ࣄࢺ࠾ࡅࡿ fasiglifam ࡢᏳᛶࡀㄆࡵࡽࢀ㸪FDA
ࡼࡾ➨ 3 ┦ヨ㦂㛤ጞࡢᢎㄆࡀᚓࡽࢀࡓࠋ ୍᪉㸪ᮏ◊✲ࡼࡾ᫂ࡽࡉࢀࡓ⫢ẘᛶࡢⓎᶵᗎ ࡣ㸪⫹Ồ୰⃰ᗘࡀ㧗ࡃ࡞ࡿ⸆࡛࠶ࢀࡤࣄࢺ࠾࠸࡚ࡶྠᵝࡢ⫢ẘᛶࡀⓎࡍࡿྍ⬟ᛶࢆ♧၀ࡋ
࡚࠸ࡿࠋᐇ㝿㸪ྜ≀ࡢ⫹Ồ୰ࡢᯒฟࡀཎᅉ࡛⫹㐨㛢ሰ࠾ࡼࡧ⫹⟶⅖ࢆⓎࡋࡓ⮫ᗋࡀ㸪 ࢭࣇ࢙࣒⣔ᢠ⏕≀㉁࡛࠶ࡿࢭࣇࢺࣜ࢟ࢯࣥࡢ⏝࡛ሗ࿌ࡉࢀ࡚࠸ࡿ (2)ࠋ ࢭࣇࢺࣜ࢟ࢯࣥࡢ
ᢞ㔞ࡣ 2 g/᪥ẚ㍑ⓗ㧗ࡃ㸪ࡲࡓ㸪ࢭࣇࢺࣜ࢟ࢯࣥࡣᢞ㔞ࡢ⣙40%ࡀ⫹Ồ୰ἥࡉࢀࡿ
ࡇࡀ▱ࡽࢀ࡚࠸ࡿ (3)ࠋ ࡋࡓࡀࡗ࡚㸪⫹Ồἥ⋡ࡀ㧗ࡃ㸪⫹Ồ୰࡛⸆≀ࡸࡑࡢ௦ㅰ≀ࡀ㧗⃰ᗘ
࡞ࡿ⸆࠾࠸࡚ࡣ⫹Ồ୰࡛ࡢᯒฟࡼࡾ fasiglifam ࡛ㄆࡵࡽࢀࡓࢾ⫢ẘᛶࡀ⮫ᗋ࠾࠸࡚
ࡶⓎࡍࡿࣜࢫࢡࡀ㧗ࡃ࡞ࡿࠋࡋࡓࡀࡗ࡚㸪ᚋ㸪ࡢྜ≀ࡢ㛤Ⓨࡣྠᵝࡢ⫢ẘᛶࡀ⮫ᗋ࡛Ⓨ
ࡍࡿྍ⬟ᛶࢆ⪃៖ࡋ࡚ᐇࡉࢀࡿࡇࡀᮃࡲࡋ࠸ࠋᮏ◊✲࡛ᵓ⠏ࡋࡓPKࣔࢹࣝࡣ㸪⫹Ồἥ㸪 ࢡࣜࣛࣥࢫ࠾ࡼࡧ⮫ᗋ⏝㔞ࡢ⾑₢୰⃰ᗘࡢሗࢆ⏝ࡋ࡚࠸ࡿࡀ㸪ࡇࢀࡽࡢሗࡀධᡭ࡛ࡁࢀ
ࡤࡢྜ≀ࡘ࠸࡚ࡶࣄࢺ⫹Ồ୰⃰ᗘࢆ᥎ᐃࡍࡿࡇࡀྍ⬟࡛࠶ࡿࠋࡇࢀࡽࡢሗࡣከࡃࡢᝈ
⪅ࡀཧຍࡍࡿ➨ 3 ┦ヨ㦂ࡲ࡛ධᡭྍ⬟࡛࠶ࡾ㸪⫢ẘᛶࡢ᭷↓㛵ࢃࡽࡎ⫹Ồ୰ࡢ⃰ᗘࢆண ࡋ㸪
⁐ゎ㝈ᗘẚ㍑ࡍࡿࡇ࡛㸪fasiglifam ࡛ㄆࡵࡽࢀࡓࢾ⫢ẘᛶࡢⓎࣜࢫࢡࡀホ౯࡛ࡁࡿࠋ ࡋ ࡓࡀࡗ࡚㸪Ⓨᶵᗎᇶ࡙࠸࡚ᵓ⠏ࡉࢀࡓᮏ◊✲ࡢPKࣔࢹࣝࡣ㸪ゎᯒࡢᑐ㇟࡞ࡗࡓ fasiglifam ࡢᏳᛶࡢᐃ㔞ⓗ࡞ホ౯ࡔࡅ࡛࡞ࡃ㸪ᚋ㛤Ⓨࡉࢀࡿྜ≀ࡢྠᵝࡢ⫢ẘᛶⓎࣜࢫࢡࡘ࠸࡚
ࡶ㔜せ࡞ሗࢆᥦ౪ࡍࡿࡇࡀ࡛ࡁࡿ⪃࠼ࡽࢀࡿࠋ
- 45 - 5.4 ࡲࡲࡵ
᥈⣴㸪㠀⮫ᗋ࠾ࡼࡧ⮫ᗋ㛤Ⓨẁ㝵࠶ࡗࡓೃ⿵ྜ≀ࡢホ౯࠾࠸࡚㸪PMx ࡢᑟධࡢ᭷⏝ᛶ
ࡘ࠸᳨࡚ドࡋࡓࠋ ➨❶࡛ࡣ㠀⮫ᗋ⸆ຠホ౯⣔ࡢ PK/PD ࣔࢹࣝゎᯒࡀ㸪ྜ≀ࡢ⸆⌮Ꮫⓗຠຊ
࠾ࡼࡧ≉ᛶࡢࡼࡾヲ⣽࡞⌮ゎࢆྍ⬟ࡋ㸪᥈⣴ẁ㝵࡛ࡢྜ≀㑅ᢥ᭷⏝࡛࠶ࡿࡇࢆ♧ࡋࡓࠋ
➨୕❶࡛ࡣࣂ࣐࣮࣮࢜࢝ࢆ⏝࠸ࡓ㠀⮫ᗋ PK/PD ࣔࢹࣝゎᯒࡀ㸪ࣂ࣐࣮࣮࢜࢝⸆ຠࡢᐃ 㔞ⓗ࡞㛵ಀࢆ᫂ࡽࡋ㸪⮫ᗋ࠾ࡅࡿ⮳㐺⏝ἲ࠾ࡼࡧ⏝㔞ࡢุᐃᇶ‽ࢆᥦ࡛ࡁࡓࡇࢆ♧ࡋ ࡓࠋ ➨ᅄ❶࡛ࡣẘᛶⓎᶵᗎࢆ⪃៖ࡋ࡚ᵓ⠏ࡋࡓ PK ࣔࢹࣝゎᯒࡼࡾẘᛶⓎ㒊࠾ࡅࡿ
⸆≀⃰ᗘࡀ᥎ᐃࡉࢀ㸪Ᏻᇦᑐࡍࡿᐃ㔞ⓗホ౯ࡀྍ⬟࡛࠶ࡿࡇࡀ♧ࡉࢀࡓࠋ௨ୖࡢ᳨ドࡼࡾ㸪
་⸆ရ㛤Ⓨࡢ PMx ࡢᑟධࡣྜ≀ࡢ⸆⌮Ꮫⓗຠຊ࠾ࡼࡧ≉ᛶࡢࡼࡾヲ⣽࡞⌮ゎ㸪⮫ᗋヨ㦂
࠾ࡅࡿ⸆ຠࡢホ౯ᇶ‽ࡢタᐃ㸪࠾ࡼࡧࣄࢺ࠾ࡅࡿ᭷ຠ⏝㔞ẘᛶ⏝㔞ࡢ㛫ࡢᏳᇦࡢ᥎ᐃࢆ
ྍ⬟ࡋ㸪ೃ⿵ྜ≀ࡢ᥈⣴㸪㠀⮫ᗋ࠾ࡼࡧ⮫ᗋ◊✲ࡢࡍ࡚ࡢ⸆ရฟ࠾ࡼࡧ㛤Ⓨẁ㝵࠾࠸
࡚㠀ᖖ᭷ຠ࡛࠶ࡿࡇࡀ♧ࡉࢀࡓࠋ ࡲࡓ㸪⸆ຠࡸẘᛶࡢ⌧㇟ㄽࡢࡳ࡛࡞ࡃ㸪PMx ࢆ⏝࠸ࡓᐃ 㔞ⓗ࡞ሗࡢྲྀᚓࡀ་⸆ရ㛤Ⓨࡢຠ⋡ᴟࡵ࡚㔜せ࡞ࡿࡇࢆ♧ࡋࡓࠋࡉࡽ㸪⸆ຠࡸᏳ
ᛶ㛵ࢃࡿせᅉࢆᩘ⌮ࣔࢹࣝࡋ࡚グ㏙ࡋ㸪ྍどࡍࡿࡇ࡛་⸆ရ㛤Ⓨ㛵ࢃࡿᵝࠎ࡞㡿ᇦࡢ
◊✲⪅㛫࡛ၥ㢟Ⅼࡸ᪂ࡓ࡞▱ぢࡢඹ᭷ࡀྍ⬟࡞ࡿᮇᚅࡉࢀࡿࠋ ࡇࢀࡽࡢࡇࡽ㸪PMx ࡢ
⏝ࡣ་⸆ရ㛤Ⓨࡢຠ⋡ࢆಁ㐍ࡋ㸪ࡉࡽ㸪་⸆ရࡢ᭷ຠᛶࡸᏳᛶࡢᐃ㔞ⓗゎ㔘ࢆࡋ࡚㸪 ࡑࡢᡂຌ☜⋡ࡢྥୖࡁࡃ㈉⊩ࡍࡿࡶࡢ⪃࠼ࡽࢀࡿࠋ
- 46 -
ㅰ ㅰ㎡
ᮏ✏ࢆ⤊࠼ࡿ࠶ࡓࡾ㸪⤊ጞࡈᣦᑟ㸪ࡈ㠴᧡ࢆ㈷ࡾࡲࡋࡓᮾி㎰ᕤᏛ㎰Ꮫ㒊⋇་Ꮫ⛉⋇
་⸆⌮Ꮫ◊✲ᐊ బࠎᮌ୍ᩍᤵ῝ࡃឤㅰ࠸ࡓࡋࡲࡍࠋࡲࡓ㸪ㄽᩥࡢᇳ➹㝿ࡋ㸪ከࡃ ࡢࡈຓゝ㈗㔜࡞ࡈ♧၀ࢆ㈷ࡾࡲࡋࡓ㸪ᖏᗈ␆⏘Ꮫ ▼᫂ᩍᤵ㸪ᮾி㎰ᕤᏛ ⏣୰▱
ᕫᩍᤵ㸪ᒾᡭᏛ బ⸨ὒᩍᤵ㸪ᒱ㜧Ꮫ ᾏ㔝ᖺᘯᩍᤵ㸪ᚰࡽឤㅰ⏦ࡋୖࡆࡲࡍࠋ ᮏ✏ࢆ㐙⾜ࡍࡿ࠶ࡓࡾ㸪⤊ጞ⇕ᚰ࡞ࡈᣦᑟࡈຓゝࢆ࠸ࡓࡔ࠸ࡓ Axcelead Drug
Discovery Partnersᰴᘧ♫ ࢥࣥࢧࣝࢸࣥࢢ ࢩࢽࢥࣥࢧࣝࢱࣥࢺ ⏣ᕝྜྷᙪ༤ኈᚰࡼ
ࡾᚚ♩ࢆ⏦ࡋୖࡆࡲࡍࠋ ࡲࡓ㸪ᮏ◊✲ࡢᶵࢆ࠼࡚ࡃࡔࡉࡾ㸪ࡈ㧗㓄ࢆ㈷ࡾࡲࡋࡓ
Axcelead Drug Discovery Partnersᰴᘧ♫ 㠀⮫ᗋ㛤Ⓨ࣊ࢵࢻ ᮅ᪥▱༤ኈཌࡃᚚ♩⏦ࡋୖ
ࡆࡲࡍࠋ ࡲࡓ㸪ᮏ◊✲ࢆ㐙⾜ࡍࡿ࠶ࡓࡾ㸪ࡈᣦᑟ࡞ࡽࡧࡈ㠴᧡ࢆ㈷ࡾࡲࡋࡓ࢝ࣜࣇ࢛
ࣝࢽᏛࢧࣥࣇࣛࣥࢩࢫࢥᰯ Leslie Z. Benetᩍᤵ㸪࣓ࣜ࢝㣗ရ་⸆ရᒁ ་⸆ရホ౯◊
✲ࢭࣥࢱ࣮ Lping Pan༤ኈ㸪⟃ἼᏛ ⏕⎔ቃ⣔ ▼ᕝ㤶ຓᩍᤵ㸪ᮾிᏛ ⏘Ꮫ㐃ᦠᮏ㒊 ࢹࣞࢡࢱ࣮ ᮾᲄⱥ᫂༤ኈ㸪ᰴᘧ♫ࢿࣔࢺ࣭ࢧ࢚ࣥࢫ ᖖົྲྀ⥾ᙺ ㅖᶫ㞝༤ኈ㸪Ṋ
⏣⸆ရᕤᴗᰴᘧ♫ ࣇ࣮࣐ࢩ࣮ࣗࢸ࢝ࣝࢧ࢚ࣥࢫᖍ㒊ဨ ㏆⸨Ꮥᾈ༤ኈ㸪ྠ♫ࣜ
ࢧ࣮ࢳ ᖍ◊✲ဨ ᯇஂ༤ኈ㸪ྠᖍ◊✲ဨ Ᏺᒇඃ༤ኈ㸪ྠᖍ◊✲ဨ ᐑᮏ┿⣖Ặ㸪
ྠ♫᪥ᮏ࢜ࣥࢥࣟࢪ࣮ᴗ㒊 ㄢ㛗௦⌮ ᳃㑳⏕༤ኈ㸪Axcelead Drug Discovery Partnersᰴᘧ
♫ ࢥࣥࢧࣝࢸࣥࢢ ࢩࢽࢥࣥࢧࣝࢱࣥࢺ ⚟ⱥኵ༤ኈ㸪 ྠࢩࢽࢥࣥࢧࣝࢱࣥࢺ
⚟⏣ⰋẶ㸪ྠ♫་⸆᥈⣴◊✲ ᰘ⏣᪩ᬛ㞝Ặᚰࡽឤㅰ࠸ࡓࡋࡲࡍࠋ
ࡲ ࡓ 㸪 ᮏ ◊ ✲ ࡢ ゎ ᯒ 㛵 ࡋ ࡲ ࡋ ࡚ ከ ࡃ ࡢ ࡈ ຓ ゝ ࢆ 㡬 ࡁ ࡲ ࡋ ࡓ 㸪Leiden Advanced Pharmacokinetics & Pharmacodynamics(LAP&P) Consultant ࡢ Joost DeJongh ༤ኈᚰࡽឤ ㅰ⏦ࡋୖࡆࡲࡍࠋ
- 47 -
せ せ᪨
་⸆ရ㛤Ⓨ࠾ࡅࡿ᥈⣴ẁ㝵࡛ࡢೃ⿵ྜ≀ࡢ㑅ᢥࡸḟ┦ࡢ⛣⾜㛵ࡍࡿពᛮỴᐃࡣ㸪 㛤Ⓨ㈝ࡢ㧗㦐ࡸ➇தࡢ⃭ࢆ⫼ᬒࡑࡢ⢭ᗘࡢྥୖࡀồࡵࡽࢀ࡚࠸ࡿࠋ ⸆≀ືែ (PK) ࣔ ࢹࣜࣥࢢ࠾ࡼࡧ PK/⸆ຊᏛ (PD) ࣔࢹࣜࣥࢢ➼ࡢࣇ࣮࣐ࢥ࣓ࢺࣜࢡࢫ (PMx) ⥲⛠ࡉࢀ
ࡿᡭἲࡣ⸆≀ືែ㸪ែ㐍⾜㸪⒪ຠᯝ➼ࢆᐃ㔞ⓗᢅ࠸㸪⃰ᗘ᥎⛣ࡸ⸆ຠࡢண ࢆྍ⬟
ࡍࡿࡇࡽ㸪ሗ㔞ᐩࢇࡔពᛮỴᐃࢆᨭࡍࡿᢏ⾡ࡋ࡚ㄆ㆑ࡉࢀࡘࡘ࠶ࡿ (➨1❶)ࠋ ᮏ◊✲࡛ࡣ㠀⮫ᗋ᥈⣴ẁ㝵࠾ࡅࡿ⸆ຠࡢᐃ㔞ⓗ࡞ẚ㍑㸪㠀⮫ᗋࡽ⮫ᗋࡢᶫΏࡋ◊✲
࠾ࡅࡿ⮫ᗋ⮳㐺⏝ἲ࣭⏝㔞ุ᩿ᇶ‽ࡢタᐃ㸪࠾ࡼࡧ⮫ᗋẁ㝵࠾ࡅࡿ᭷ຠ⏝㔞ẘᛶⓎ⌧
ࡢ㛫ࡢᏳᇦࡢᐃ㔞ⓗホ౯ PMx ࢆᑟධࡋ㸪་⸆ရ㛤Ⓨ࠾ࡅࡿ PMx ᑟධࡢ᭷⏝ᛶ
ࡘ࠸᳨࡚ドࡋࡓࠋ
➨ 2 ❶࡛ࡣ᥈⣴ẁ㝵࠶ࡗࡓ๓❧⭢ࡀࢇ⒪ೃ⿵⸆ TAK-448 ࢦ࣮ࣝࢻࢫࢱࣥࢲ࣮ࢻ
ࡋ࡚⮫ᗋ࡛⏝ࡉࢀ࡚࠸ࡿ࣮ࣜࣗࣉࣟࣞࣜࣥ㓑㓟ሷ (TAP-144) ࡢ in vivo ᢸ⒴ࣛࢵࢺࣔ
ࢹࣝ࠾ࡅࡿᢠ⭘⒆άᛶࢆ PK/PD ࣔࢹࣝࡼࡾᐃ㔞ⓗ≉ᚩ࡙ࡅࡓࠋ ୧ྜ≀ࡶࢸࢫ ࢺࢫࢸࣟࣥ࡞ࡢࣥࢻࣟࢤࣥ࣍ࣝࣔࣥศἪࡢࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࢆច㉳ࡍࡿࡇ࡛
ࡑࢀࡽ࣍ࣝࣔࣥ౫ᏑⓗቑṪࡍࡿ๓❧⭢ࡀࢇࡢቑṪࢆᢚไࡍࡿ⪃࠼ࡽࢀ࡚࠸ࡿࠋ In vivo 㠀⮫ᗋ⸆ຠホ౯ࡣ⮫ᗋࡢ๓❧⭢ࡀࢇࢆᫎࡍࡿࡓࡵ㸪࣍ࣝࣔࣥᢚไᑐࡋ࡚⪏ᛶࢆ᭷ࡍ
ࡿ vertebral̺cancer of the prostate (VCaP) ⣽⬊ࢆ⛣᳜ࡋࡓࣛࢵࢺࢆ⏝࠸࡚ᐇࡋࡓࠋ
TAK-448 ࡣ TAP-144 ẚ࡚ᙉ࠸ᢠ⭘⒆ຠᯝࢆ♧ࡋࡓࡀ㸪㧗⏝㔞࠾ࡅࡿࣛࢵࢺ⾑₢୰ࡢࢸࢫ
ࢺࢫࢸࣟࣥࡢᢚไࡣ୧ྜ≀࡛ྠ➼࡛࠶ࡾ㸪࠸ࡎࢀࡢྜ≀ࡶཤໃࣞ࣋ࣝࡲ࡛ᢚไࡉࢀ࡚
࠸ࡓࠋࡋࡓࡀࡗ࡚㸪༢⣧࡞ࢸࢫࢺࢫࢸࣟࣥศἪᢚไ⬟ຊࡢẚ㍑࡛ࡣ୧ྜ≀ࡢᢠ⭘⒆ຠᯝࡣ ẚ㍑ྍ⬟⪃࠼ࡽࢀࡓࠋ ࡇࡢࡼ࠺࡞≧ἣ࡛୧ྜ≀ࡢᢠ⭘⒆ຠᯝࡢᕪࢆㄝ᫂ࡍࡿࡓࡵ
PK/PD ࣔࢹࣜࣥࢢࡢᡭἲࢆ㐺⏝ࡋ㸪ࡑࢀࡽ⸆⌮Ꮫⓗຠຊ࠾ࡼࡧ≉ᛶࢆẚ㍑ࡋࡓࠋࡑࡢ⤖ᯝ㸪
୧ྜ≀ࡢ⸆ຠࡀヲ⣽ゎ᫂ࡉࢀ㸪TAK-448 ࡣ TAP-144 ẚ࡚⣙ 80 ಸᙉࡃ࣍ࣝࣔࣥ౫ Ꮡⓗ࡞ᢚไάᛶࢆ᭷ࡍࡿࡇࡀ᫂ࡽ࡞ࡗࡓࠋ ࡉࡽ TAK-448 ࡢᢠ⭘⒆ຠᯝࡀⓎࡉ
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ࢀࡿᮇࡣ᪩ࡃ㸪ࡑࡢຠᯝࡣ⪏ᛶࡀ㐍ࡴ๓Ⓨࡉࢀࡿࡀ㸪TAP-144 ࡢᢠ⭘⒆ຠᯝࡢⓎ
ࡣ㐜ࡃ㸪⪏ᛶࡀ࠶ࡿ⛬ᗘ㐍ࢇࡔᚋⓎࡉࢀࡿࡇࡀ♧၀ࡉࢀࡓࠋ
➨ 3 ❶࡛ࡣᢠࡀࢇࡋ࡚ぢฟࡉࢀࡓ࣊ࢵࢪ࣍ࢵࢢࢩࢢࢼࣝఏ㐩⤒㊰㜼ᐖ⸆ TAK-441 ࡢ⮫ᗋ࠾ࡅࡿ⮳㐺⏝ἲ࣭⏝㔞ࡢุᐃᇶ‽ࢆタᐃࡍࡿࡇࢆ┠ⓗࡋ㸪 in vivo ᢸ⒴࣐࢘ࢫ
ࣔࢹࣝ࠾ࡅࡿࣂ࣐࣮࣮࢜࢝ᢠ⭘⒆άᛶࡢᐃ㔞ⓗ࡞㛵ಀࢆ PK/PD ࣔࢹࣝࢆ⏝࠸࡚
ゎᯒࡋࡓࠋ ࣂ࣐࣮࣮࢜࢝ࡣ࣊ࢵࢪ࣍ࢵࢢࢩࢢࢼࣝఏ㐩⤒㊰ࡢୗὶ⨨ࡍࡿ㌿ᅉᏊ
Gli1 ࡢ mRNA ࡢⓎ⌧㔞ࡋࡓࠋ In vivo 㠀⮫ᗋ⸆ຠホ౯⣔࡛ᚓࡽࢀࡓ⭘⒆య✚㸪Gli1
mRNA Ⓨ⌧㔞࠾ࡼࡧ⾑₢୰⸆≀⃰ᗘࢹ࣮ࢱࢆ⏝࠸࡚ PK/PD ࣔࢹ࡛ࣝゎᯒࡋࡓ⤖ᯝ㸪⭘⒆
ቑṪࢆ 90% ᢚไࡉࡏࡿࡓࡵᚲせ࡞⭘⒆୰ Gli1 mRNA Ⓨ⌧ᢚไ⋡ࡣ 94%࡛࠶ࡿࡇࡀ
♧ࡉࢀࡓࠋ ࡇࡢࣂ࣐࣮࣮࢜࢝ᢠ⭘⒆ຠᯝࡢ㛵ಀࢆ⮫ᗋヨ㦂࡛ᛂ⏝ࡍࡿࡓࡵ㸪Gli1
mRNA ࡀⓎ⌧ࡋ࡚࠸ࡿ⓶୰ࡢ Gli1 mRNA Ⓨ⌧ᢚไ⋡ࡘ࠸࡚ࡶ PK/PD ࣔࢹࣝゎᯒࡋ
ࡓ⤖ᯝ㸪⓶୰ Gli1 mRNA Ⓨ⌧ᢚไ⋡ࡢኚືࡣ⭘⒆୰ࡢࡑࢀ㠀ᖖ㢮ఝࡍࡿࡇࡀศ
ࡗࡓࠋࡇࢀࡽࡢࡇࡽ㸪Gli1 mRNA Ⓨ⌧ᢚไ⋡ࡣ TAK-441 ࡢ⸆⌮ຠᯝ ᐃࡢࡓࡵࡢࣂ
࣐࣮࣮࢜࢝࡞ࡾ࠼ࡿࡇ㸪ࡉࡽ㸪⓶୰ Gli1 mRNA Ⓨ⌧ᢚไ⋡ࢆ⭘⒆⤌⧊ࡢ௦᭰ࣂ
࣐࣮࣮࢜࢝ࡋ࡚⏝࡛ࡁࡿࡇࡀ♧၀ࡉࢀࡓࠋ ࡇࡢࣂ࣐࣮࣮࢜࢝ᢠ⭘⒆άᛶࡢ㛵 ಀࡣ⮫ᗋヨ㦂࡛ࡶ☜ㄆࡉࢀ㸪⓶୰ Gli1 mRNA Ⓨ⌧㔞ࡣ࣊ࢵࢪ࣍ࢵࢢࢩࢢࢼࣝఏ㐩⤒㊰㜼 ᐖ⸆ࡢ⭘⒆ቑṪᢚไຠᯝࢆண ࡍࡿ᭷⏝࡞ࣂ࣐࣮࣮࡛࢜࢝࠶ࡿㄆ㆑ࡉࢀࡓࠋ
➨4❶࡛ࡣ⮫ᗋ㛤Ⓨẁ㝵࠶ࡗࡓ 2 ᆺ⢾ᒀ⒪⸆ fasiglifam ࡢ᭷ຠ⏝㔞⫢ẘᛶⓎ⌧
ࡢ㛫ࡢᏳᇦࡢ᥎ᐃࢆ┠ⓗࡋࡓࠋ ⮫ᗋ➨2┦ヨ㦂୰ᐇࡋࡓࢾࡢᢞẘᛶヨ 㦂࠾࠸࡚ࢾ≉᭷ࡢ⫢ẘᛶࡀⓎࡋࡓࠋ ⫢ẘᛶࢆⓎࡋࡓಶయࡢ⫢⮚⌮⤌⧊᳨ᰝ࠾
࠸࡚㛛⬦/㛛⬦࿘ᅖ⫗ⱆ⭘ᛶ⅖ࡀぢࡽࢀ㸪ᙧᡂࡉࢀࡓ⫗ⱆ୰㢛⢏≧␗≀ࡢᏑᅾࡀ☜ㄆࡉ
ࢀࡓࡀ㸪ࡇࡢ⌧㇟ࡣࣛࢵࢺ࡛ࡣㄆࡵࡽࢀ࡞ࡗࡓࠋࡇࡢ␗≀ࢆ㉁㔞ศᯒἲ࡛ศᯒࡋࡓ⤖ᯝ㸪
fasiglifam ཬࡧࡑࡢࢢࣝࢡࣟࣥ㓟ᢪྜయ (fasiglifam-G) ࡀྵࡲࢀ࡚࠸ࡿࡇࡀ♧ࡉࢀࡓࠋ
Fasiglifam ࡢືែヨ㦂ࡢ⤖ᯝ㸪ࢾ⫹Ồ୰ fasiglifam ࠾ࡼࡧ fasiglifam-G ⃰ᗘࡣࣛࢵࢺẚ
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ࡿ᫂ࡽ㧗ࡃ㸪ࢾ⫹Ồ୰࠾ࡅࡿࡇࢀࡽࡢྜ≀ࡢ⃰ᗘࡣ㣬⁐ゎᗘࢆ㉸࠼࡚࠸
ࡓࠋࡇࢀࡽࡢᡂ⦼ࡼࡾ㸪fasiglifam ࡢᢞ࡛ㄆࡵࡽࢀࡓࢾ⫢ẘᛶࡣ㣬⁐ゎᗘࢆ㉸࠼
ࡓ fasiglifam ࠾ࡼࡧ fasiglifam-G ࡀ⫹Ồ୰ἥࡉࢀ㸪ᙧᡂࡉࢀࡓ⤖ᬗࡀ⅖ࢆ㉳ࡇࡋ࡚
⏕ࡌࡓ⪃࠼ࡽࢀࡓࠋࡑࡇ࡛㸪ࣄࢺࡢ⮫ᗋ⏝㔞 (50 mg) ࠾ࡅࡿ⫹Ồ୰ fasiglifam ⃰ᗘࢆ
PK ࣔࢹࣝゎᯒ࡛ண ࡋࡓ⤖ᯝ㸪㝈⏺⁐ゎᗘࡢ࠾ࡼࡑ 20 ศࡢ 1 ⛬ᗘపࡃ㸪fasiglifam-G ࡢ⃰ᗘࡶ⁐ゎ㝈ᗘࢆ㉸࠼࡞࠸ࡇࡀ᥎ᐃࡉࢀ㸪ࣄࢺ⫹Ồ୰࠾࠸࡚ࡣ fasiglifam ࠾ࡼࡧ
fasiglifam-G ࡀᯒฟࡋ㸪ࢾ࡛ㄆࡵࡽࢀࡓ⫢ẘᛶࡀࣄࢺ࡛Ⓨࡍࡿྍ⬟ᛶࡣ㠀ᖖప࠸⪃
࠼ࡽࢀࡓࠋ
௨ୖࡢ⤖ᯝࡽ㸪་⸆ရ㛤Ⓨࡢ PMx ࡢᑟධࡣྜ≀ࡢ⸆⌮Ꮫⓗຠຊ࠾ࡼࡧ≉ᛶࡢࡼࡾ
ヲ⣽࡞⌮ゎ㸪⮫ᗋ⮳㐺⏝ἲ࣭⏝㔞ุ᩿ᇶ‽ࡢタᐃ㸪࠾ࡼࡧࣄࢺ࠾ࡅࡿ᭷ຠ⏝㔞ẘᛶ⏝㔞
ࡢ㛫ࡢᏳᇦࡢ᥎ᐃࢆྍ⬟ࡋ㸪ೃ⿵ྜ≀ࡢ᥈⣴ࠊᶫΏࡋ◊✲ࠊ⮫ᗋࡢࡍ࡚ࡢ㛤Ⓨẁ 㝵࠾࠸࡚㠀ᖖ᭷ຠ࡛࠶ࡿࡇࡀ♧ࡉࢀࡓࠋ
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Abstract
Against the background of intensified competition in drug discovery as well as the fact that research and development of new medicine incurs enormous fees, improve the quality of decision-making during drug development such as candidate selection and go/no-go decisions has been required.
Pharmacometrics (PMx) such as Pharmacokinetics (PK) modeling and Pharmacokinetics /Pharmacodynamics (PK/PD) modeling is a method to quantitatively describe and predict drug exposure, disease progression and therapeutic effect, etc. PMx has been recognized to support informative decision-making in drug development. Applying PMx for the non-clinical exploration stage to quantitatively evaluate the drug efficacy, transrational stage to support appropriate dose selection, and clinical stage to investigate the safety margin, I examined usefulness of PMx in drug development.
In chapter 2, the potency of anti-tumor effects of TAK-448 (novel metastin/kisspeptin analog) and TAP-144 (known as leuprorelin acetate, considered a gold standard therapy for prostate cancer) in the in vivo rat xenograft model was quantitatively characterized by PK/PD model. Both compounds are considered to suppress hormone dependent prostate cancer growth by down-regulating secretion of androgen hormones such as testosterone. Vertebral̺Cancer of the Prostate (VCaP) cell line, which is characterized by resistance to hormone suppression, was selected for the xenograft model to reflect the clinical characteristics of prostate tumor. Although TAK-448 showed a stronger antitumor effect than TAP-144 in vivo rat xenograft model, the suppression of testosterone in rat plasma at high doses was similar between the two compounds, and the levels were profoundly inhibited comparable to the castrated level in both compounds. Therefore, it was considered that the difference in anti-tumor effect between the two compounds could not be explained only by comparing the ability to suppress testosterone secretion. To explain the difference in anti-tumor effect, PK/PD modeling was applied to compare their pharmacological efficacy and properties. As a result, it became possible to compare the
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differences in the efficacy between the two compounds in detail. The model demonstrated that TAK-448 has about 80 times stronger hormone-dependent inhibitory activity than TAP-144. In addition, the onset of the decrease in tumor volume by hormone inhibition of TAK-448 was faster than that of TAP-144 and the completion of the resistance acquisition.
In chapter 3, to set criteria for clinically appropriate dosing regimen, quantitative relationship between biomarker response and anti-tumor effect of TAK-441 (hedgehog inhibitor) in vivo mouse xenograft model was investigated by PK/PD model. Expression level of mRNA of Gli1, which is transcription factor and is downstream of the hedgehog signaling pathway, was selected as a biomarker.
The results of PK/PD modeling using data of plasma drug concentrations, Gli1 mRNA levels and tumor size in the xenograft model indicated that a >94% inhibition of Gli1 mRNA expression in the tumor would be required to sufficiently inhibit (>90%) hedgehog-related tumor growth. Usefulness of Gli1 mRNA response in the surrogate tissue of skin as a biomarker was also investigated by PK/PD
modeling to support the dosing regimen selection in the clinic. As a result, the modeling works suggested that Gli1 mRNA expression in the skin as well as tumor could be a useful biomarker for predicting the antitumor effect of hedgehog inhibitors. The relationship between this biomarker response and antitumor activity was also confirmed in clinical trials, and the expression level of Gli1 mRNA in the skin was recognized as a useful biomarker for predicting the tumor growth inhibitory effect of hedgehog signaling pathway inhibitors.
In chapter 4, the safety margin of fasiglifam, which was developed for the treatment of type 2 diabetes mellitus and was in the clinical stage, was estimated. Fasiglifam-related liver toxicity was observed in repeat-dose dog toxicity studies conducted during phase 2 clinical trials. Associated histopathological changes were characterized as portal/peri-portal granulomatous inflammation with crystal formation. The histopathological changes observed in dogs were not found in rats. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) analysis
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indicated that the crystalline material in the liver sections of affected dogs contained fasiglifam and fasiglifam glucuronide (fasiglifam-G). Pharmacokinetic studies of fasiglifam indicated that concentrations of fasiglifam and fasiglifam-G in dog bile were much higher than those in rat bile, and the concentrations of these compounds in dog bile exceeded the solubility limits of these compounds.
These results indicated that the observed hepatotoxicity seen in the dog upon repeated administration of fasiglifam is due to formation of fasiglifam and fasiglifam-G crystals in the bile leading to an inflammatory response in the liver. PK model was established to predict the concentrations of fasiglifam and fasiglifam-G in human bile at a clinical dose of 50 mg. As a result, the PK model suggested that fasiglifam concentration in human bile following proposed therapeutic dose (50 mg) would be 20-fold lower than its solubility limit, and that the concentrations of fasiglifam-G are not likely to be beyond its solubility limit. These results indicated that a sufficient margin of safety exists.
These studies indicated that the introduction of PMx into drug development enables better understanding of the pharmacological properties, setting quantitative criteria for appropriate clinical dosing regimen and estimation of safety margin for clinical dose, and that PMx is extremely effective at all development stages, involving non-clinical exploration, translational and clinical stages.
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ᘬ
ᘬ⏝ᩥ⊩
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53. ㎷ ⏿ ၿ ⾜ (2014). GPR40/FFAR1 ࢦ ࢽ ࢫ ࢺ ࡢ ⸆ ⌮ స ⏝: ᪂ つ ⢾ ᒀ ⒪ ⸆ GPR40/FFAR1 㑅ᢥⓗࢦࢽࢫࢺFasiglifam ࡢ◊✲㛤Ⓨ. ᪥⸆⌮ㄅ 144, 59-63.
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- 60 -
ᅗ ᅗ⾲
Figure 1-1. Concentration-effect curve with hysteresis. Hysteresis loops suggest that there is a time lag in the relationship between the measured drug concentration and the observed drug effect. In the presence of hysteresis, two different drug concentrations correspond to one drug effect or one drug concentration corresponds to two drug effects. To collapse hysteresis and to simplify the concentration-effect relationship, PK-PD modeling approaches have been used.
- 61 -
Table 2-1 Parameter estimates for tumor growth in intact and castration groups
RSE, relative standard error.
Parameter Definition Value RSE (%)
Population mean
TV0 (mm3) Tumor volume at day 0 7050 4.55
L (mm3/day) Zero-order tumor growth rate 631 8.4
kap (day-1) First-order tumor loss rate 0.00881 14.5
TRmax Maximum effect of resistance 0.85 7.58
ET50 (day) Time corresponding to 50% of TRmax 18.3 12.8
Ȗ Hill coefficient describing steepness of
the time - response relationship 3.43 4.02
TV0 0.156 28.8
L 0.159 42.1
kap 0.822 61.7
TV0 x L 0.116 31
5HVLGXDOYDULDELOLW\į2)
Proportional error 0.0037 15.7
,QWHULQGLYLGXDOYDULDELOLW\Ȧ2)
- 62 - Table 2-2 PD parameter estimates for the PK/PD model
RSE, relative standard error.
Estimate RSE(%) Estimate RSE(%)
kout (day-1) First-order constant for the loss
of transduction response 0.218 27.2 1.91 30.3
Emax Maximum inhibition of the
transduction response 1 fixed 1 fixed
EC50 (pg/mL) Drug concentration
corresponding to 50% of Emax 132 14.2 1.74 18.3
5HVLGXDOYDULDELOLW\į2)
Proportional error 0.00685 12.6 0.0054 14.8
Parameters TAP-144-SR TAK-448-SR
Population mean
Definition
- 63 -
Figure 2-1. Scheme for the PK models for TAK-448 and TAP-144. The PK profiles of sustained-release formulations of TAK-448 and TAP-144 were described by a two-compartment model with two processes of absorption: an immediate first-order input describing the initial rapid increase in the plasma concentration levels, and a slow first-order input to account for the prolonged release from the sustained-release formulations. A1, A2, A3 and A4 denote the amount of drug in plasma, peripheral, immediately absorbed skin and sustained release skin compartments, respectively. The PK model variables included the elimination rate constant (kel), volume of distribution in the plasma compartment (V), intercompartment transfer rate constants (k12 and k21), absorption rate constants for immediate-release (kIR) and sustained-release (kSR), bioavailability from the site of immediate-release (F3) and sustained-release (F4). Cp indicates concentrations of the drugs in plasma.
- 64 -
Figure 2-2. Scheme of the PK/PD models for TAK-448 and TAP-144 administrated to rats bearing VCaP xenograft tumors. HDE448 and HDE144 are hormone-dependent drug effects of TAK-448 and TAP-144, respectively. TV is the tumor volume. TR is the signal in the transduction compartment. L and kap represent the zero-order tumor growth rate constant and the first-order tumor loss rate constant, respectively. kin denotes the zero-order rate constant for production of the transduction response, and kout defines the first-order constant for the loss of the transduction response. Plus (+), minus (-), and cross (×) signs indicate stimulation, inhibition, and complete inhibition, respectively.
- 65 -
Figure 2-3. Observed mean and model-predicted plasma concentrations of TAK-448 (A) and TAP-144 (B) after subcutaneous administration of TAK-448-SR (1M) and TAP-TAP-144-SR (1M). Symbols represent the observed mean ± SD for 3 animals. Lines represent the model-predicted plasma concentrations.
- 66 -
Figure 2-4. Observed and model-predicted tumor growth curves in intact and castrated individual animals. Symbols represent observed tumor volumes. Dashed and solid lines indicate the predicted tumor growth curves for populations and individuals, respectively.
0 14 28 42 56
Time (day)
0 10000 20000 30000 40000 50000
0 10000 20000 30000 40000 50000
Tumor volume (mm
3)
Intact
Castrated
- 67 -
Figure 2-5. Observed and model-predicted tumor growth curves after administration of TAK-448-SR (A) and TAP-144-SR (B). Symbols represent observed tumor volumes. Dashed and solid lines indicate the predicted tumor growth curves for populations and individuals, respectively.
0 14 28 42 56
0 14 28 42 56
Time (day)
0 10000 20000 30000 40000 50000
0 10000 20000 30000 40000 50000
Tumor volume (mm3 )
TAK-448: 0.01 mg/kg TAK-448: 0.03 mg/kg
TAK-448: 0.3 mg/kg TAK-448: 3 mg/kg
0 14 28 42 56
0 14 28 42 56
Time (day)
0 10000 20000 30000 40000 50000
0 10000 20000 30000 40000 50000
Tumor volume (mm3 )
TAP-144: 0.1 mg/kg TAP-144: 0.3 mg/kg
TAP-144: 1 mg/kg TAP-144: 10 mg/kg
(A)
(B)
- 68 -
Figure 2-6. Simulation of tumor volume at the maximum effective dose. The time profiles of the tumor volume in the TAK-448-SR and TAP-144-SR groups were simulated at sufficient effective doses of 3000 and 10,000 mg/kg, respectively, which were 1000 times higher than the maximum dose used for each drug in the xenograft study.
- 69 -
Figure 2-7. Simulated time profiles of the virtual hormone levels (red: TAK-448, green: TAP-144) and development of resistance (purple). The estimated ET50 for describing resistance development was estimated to be 18.3 days, indicating that it took several weeks for the xenograft tumor to become castration resistant. The estimated TRmax was 0.85, indicating that the resistance reduces the antitumor effect of hormone suppression by up to 85% in 56 days. The maximum inhibition of hormone level is observed within a few days after administration of TAK-448, indicating that inhibition of hormone in the TAK-448-treated group peaked much faster than ET50 (18.3 days). On the other hand, the maximum inhibition is observed around 21 days after administration of TAP-144.
- 70 -
Table 3-1 Pharmacokinetic parameter estimates of TAK-441 after oral and Alzet infusion administration of TAK-441
Relative standard errors (%) are shown in parentheses.
Parameter Definition Estimate
CL (L/hr/kg) Clearance 0.488 (4.16)
Vmax (mg/hr/kg) Maximum rate of absorption 15.9 (22.5)
Km (mg/kg) Dose of TAK-441 causing one-half maximum absorption rate (Vmax) 63.1 (28.1)
V (L/kg) Distribution volume 0.158 (13.7)
- 71 -
Table 3-2 Pharmacodynamic parameter estimates of TAK-441 for tumor growth after repeated oral administration of TAK-441
Relative standard errors (%) are shown in parentheses.
Parameter Definition Estimate
T0 (mm3) Initial tumor size 185 (1.47)
Kin (h-1) First-order tumor growth rate 0.0119 (12.7)
Imax_Tumor Maximum inhibition of tumor growth 0.557 (15.2)
IC50_TumorȝJP/ TAK-441 concentration that produces 50% of Imax_Tumor 0.075 (102) TG50 (mm3) Tumor size that inhibits 50% of the tumor growth rate 473 (22.4)
Ȧ7 6.24 (44.1)
Ȧ.in (%) 12.0 (47.8)
Residual variability
Proportional error % 8.5 (13.2)
Population mean
Inter-individual variability
- 72 -
Table 3-3 Pharmacodynamic parameter estimates of TAK-441 for Gli1 mRNA response after administration of TAK-441
Relative standard errors (%) are shown in parentheses.
BL, baseline response; Rout, first-order constant for the loss of the response; Imax_Gli, maximal inhibition of production of response; IC50_Gli, drug concentration producing one-half of the maximum inhibition.
BL Rout Imax_Gli IC50_Gli
% of control h-1 ȝJP/
Tumor 104 (3.38) 0.201 (0.896) 1 (fixed) 0.0457 (4.29) Skin 100 (fixed) 0.368 (7.2) 0.969 (1.48) 0.113 (7.73) Tissue
- 73 -
Figure 3-1. Observed and model-predicted plasma concentrations of TAK-441 after oral and Alzet infusion administration of TAK-441. Symbols represent observed plasma concentrations of TAK-441, and lines are modelpredicted plasma concentrations of TAK-441. bid, twice daily; po, orally; qd, daily.
- 74 -
Figure 3-2. The concentrations of TAK-441 in the tumor and skin after three days of subcutaneous infusion.
- 75 -
Figure 3-3. Observed and model-predicted tumor growth curves after repeated oral administration of TAK-441. Symbols represent observed and dashed and solid lines indicate the population predicted and individual predicted tumor growth curves, respectively.
0 128 256 384 0 128 256 384 0 128 256 384 0 128 256 384 Time (h)
0 500 1000 1500 2000
Tumor size (mm3 )
Vehicle 1 mg/kg 10 mg/kg 25 mg/kg
- 76 -
Figure 3-4. Observed and model-predicted Gli1 mRNA response in the stromal cells in the tumor after oral and Alzet infusion administration of TAK-441. Symbols represent observed Gli1 mRNA response, and lines are model-predicted Gli1 mRNA response.
- 77 -
Figure 3-5. Observed and model-predicted Gli1 mRNA response in the skin after oral and Alzet infusion administration of TAK-441. Symbols represent observed Gli1 mRNA response, and lines are model-predicted Gli1 mRNA response.
- 78 -
Figure 3-6. Relationships between PK-biomarker responses and PK-efficacy. The IC90 value for tumor growth inhibition was estimated to be 0.68 mg/ml, which corresponded to 83% inhibition of the Gli1 mRNA expression in the skin and 94% inhibition of the Gli1 mRNA expression in the tumor
- 79 -
Table 4-1 Concentrations of radioactivity in the plasma and liver after administration of a single oral dose of [14C]fasiglifam in rats and dogs
Data were obtained from one animal for each collection time.
Plasma Liver
1 4.98 18.1
8 3.32 13.8
1 237 275
8 352 341
2 5.04 10.6
8 1.84 5.08
2 315 179
8 39.0 55.3
Dog
2 200
Time (h)
Concentration of radioactivity (μg equiv./mL or g)
Rat
2 200 Species Dose
(mg/kg)
- 80 -
Table 4-2 Concentrations of total radioactivity (percentages in parentheses) for fasiglifam, and fasiglifam-G in the liver after the oral administration of [14C]fasiglifam at a dose of 200 mg/kg/day to dogs
Data at first dose and 14th dose were obtained from one animal and two animals, respectively.
2 8
Animal-1 Animal-2 Animal-1 Animal-2 Animal-1 Animal-2
244 203 224 (100%) 201 172 186 (83%) 28.2 18.5 23.3 (10%)
Animal-3 Animal-5 Animal-3 Animal-5 Animal-3 Animal-5
91.4 120 106 (100%) 55.7 84.6 70.1 (66%) 7.63 21.8 14.7 (14%)
179 (100%) 55.3 (100%)
130 (73%) 31.6 (57%)
36.1 (20%) 23.7 (43%)
14th dose
Time after dosage (h)
1st dose
Concentration (μg equiv./g)
2 8
Mean Mean Mean
Mean Mean Mean
Total 14C Fasiglifam Fasiglifam-G
- 81 -
Table 4-3 Mean levels (percentages in parentheses) of fasiglifam and its metabolites in the bile of rats and dogs during 0–24 h following a single dose of [14C]fasiglifam
Each value represents an average of two animals. Numbers in parentheses represent proportions to the total radioactivity (%).
2 mg/kg 200 mg/kg 2 mg/kg 200 mg/kg
78.2 42.0 81.4 54.1
(100.0) (100.0) (100.0) (100.0)
10.8 4.6 5.7 5.3
(13.8) (11.0) (7.0) (9.8)
LOQ LOQ LOQ 1.3
(0.0) (0.0) (0.0) (2.4)
39.4 33.1 38.8 22.5
(50.4) (78.8) (47.7) (41.6)
4.5 0.2 15.2 12.2
(5.8) (0.5) (18.7) (22.6)
23.5 4.2 21.9 13.0
(30.0) (9.7) (26.6) (23.6) M-I
Fasiglifam-G Fasiglifam-Tau
Others Compound
% of administered dose
Dog Rat
Total radioactivity Fasiglifam