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Ū 'Z XKXQ Ꮑᕤཋˊᜓᣞእ෇ࣱย‫ܭ‬Ū ˊᜓཋƷನᡯਖ਼‫ܭ‬ఋᆔ+Ღ%Ღ᳂Ღ᳊Ღ5Ღ%TᲦGVE

14$+64#2 8'.15 241ϐဃҔၲ᧙ᡲЎ᣼Ū ဃ˳ϋЎࠋย‫ܭ‬ඥȷ‫ܭ‬᣽ႎμ៲ǪȸȈȩǸǪȫȟȎǰȩȕǣȸඥ
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マーモセットで

薬物動態試験 をやってみたいけど日本クレアで試験出来る？

メリット● 投薬量がカニクイザルに比べて約1/10量と少量で済みます。
● 採材物が血液のみの場合、
マーモセットの ご購入は不要 です。
● 1日最大採血量が2.0mLを超えなければ採血ポイントは任意にご指定可能です。
（採血部位は左右の下大静脈または下大動脈）● 被検薬を数種類混ぜたカクテル投与も可能です。
● 被検薬によっては休薬後、同じ動物で再試験が可能です。

モデルケース● マーモセット ♂ 体重300g以上 ｎ＝３頭を使用● 被検薬投与部位は後肢伏在静脈もしくは尾静脈が選択可能。
（最大投与量等はご相談ください）
経口投与でも投薬は可能です。
（採血ポイントは任意）● 投薬後、0.25、0.5、1、2、4、8、24〔時間〕で採血。
● それぞれの検体を4℃で遠心分離し、血漿100〜120μLを凍結保存。
● 24時間後採血終了後、翌日以降冷凍便にて発送。

ご注意点● 事前に弊社動物福祉委員会で承認を受けた試験に限り実施可能です。
● 臓器等の採材が必要な場合は動物をご購入して頂きます。別途ご相談ください。
● 毒性の強い被検薬の使用に関しては別途ご相談ください。
● ご提供する採材物は微量となりますので、LC-MS/MS等での測定を推奨します。
● GLP試験には対応しておりませんので、non-GLP試験での実施となります。

お問い合わせは、日本クレア（株）ホームページ内のまたは、お電話にてご連絡ください。

https://www.clea-japan.com「お問い合わせ」窓口、

東京AD部 TEL : 03-5704-7050
大阪AD部 TEL : 06-4861-7101

ਸ਼33ৰরଢ଼द৫৅औोञ঄ॺຩय़ওছঐक़५㋏
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Axcelead Drug Discovery Partners株式会社
神奈川県藤沢市村岡東二丁目26番地の1 www.axceelad.com

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௒ᅇࡣࠊࠕ᰾㓟་⸆ࡢᏳ඲ᛶࠊືែ≉ᛶ࠾ࡼࡧศᯒࠖ࠾ࡼࡧࠕ๰⸆ࡢࡓࡵࡢᑠᆺࣔࢹࣝ
ື≀ࢆά⏝ࡋࡓ⸆≀ືែホ౯ࠖࢆࢸ࣮࣐࡟ᥖࡆ࡚࠾ࡾࡲࡍࠋ๓༙࡛ࡣࠊ㏆ᖺࠊᕼᑡ⑌ᝈ
἞⒪ࡸ࣡ࢡࢳࣥ㛤Ⓨ࡟࠾࠸࡚ྎ㢌ࡍࡿ᰾㓟་⸆࡟ࡘ࠸࡚ࠊࡑࡢືែ࣭ศᯒ࠾ࡼࡧᏳ඲ᛶホ౯࡟ࡘ࠸࡚㆟ㄽࡋࡲࡍࠋᚋ༙ࡣື≀ヨ㦂ࢆࢸ࣮࣐࡜ࡋࠊᖖ࡟௜ࡁࡲ࡜࠺✀ᕪ࠾ࡼࡧࡑ
ࡢእᤄࡢၥ㢟ࢆ୰ᚰ࡟ࠊ་⸆ရࣔࢲࣜࢸ࢕࣮ࡀከᵝ໬ࡍࡿ୰࡛ᨵࡵ࡚ື≀ヨ㦂ࡢព⩏࡜㔜せᛶ࡟ࡘ࠸࡚⪃࠼ࡲࡍࠋࡇࢀࡽࡢㄢ㢟࡟ࡘ࠸࡚ࡢ᭱᪂ࡢ᝟ሗࢆඹ᭷ࡋࠊලయⓗ࡞஦౛࡟ࡘ࠸࡚ウ㆟ࡋ࡞ࡀࡽࡑࢀࡒࢀࡢၥ㢟ⅬࡸㄽⅬࡢᩚ⌮ࡀ࡛ࡁࢀࡤ࡜⪃࠼࡚࠾ࡾࡲࡍࠋཧ
ຍ⪅ⓙᵝ࡟࠾࠿ࢀࡲࡋ࡚ࡣࠊ᫝㠀άⓎ࡞ࡈ㆟ㄽࢆ㈷ࡾࡲࡍࡼ࠺ࡼࢁࡋࡃ࠾㢪࠸⏦ࡋୖࡆ
ࡲࡍࠋ
ࠝ␎Ṕࠞ
1988 ᖺி㒔኱Ꮫ⸆Ꮫ㒊༞ᴗࠊ1990 ᖺி㒔኱Ꮫ኱Ꮫ㝔⸆Ꮫ◊✲⛉ಟኈㄢ⛬ಟ஢ࠊ1991 ᖺ୰㏵㏥Ꮫࠊ1995 ᖺ༤ኈ㸦⸆Ꮫ㸧ྲྀᚓࠋ1991 ᖺி㒔኱Ꮫ⸆Ꮫ㒊ຓᡭࠊ1997 ᖺி㒔኱Ꮫ኱Ꮫ㝔⸆Ꮫ◊✲⛉ຓᩍᤵࠊ2007 ᖺ෸ᩍᤵ㸦ᨵ⛠㸧
ࠊ2016 ᖺᩍᤵࠊ⌧ᅾ࡟⮳ࡿࠋ1995 ᖺ 4 ᭶࠿ࡽ㸯ᖺ༙ࠊ༡࢝ࣜࣇ࢛ࣝࢽ࢔኱Ꮫ␃Ꮫࠋ2001 ᖺ᪥ᮏ⸆๣Ꮫ఍᪫໬ᡂ〇๣Ꮫዡບ㈹ࠊ2003 ᖺ᪥ᮏ⸆≀ືែᏛ఍ዡບ㈹ཷ㈹ࠋ
2ࡈᣵᣜ᫛࿴⸆⛉኱Ꮫ/APDD ௦⾲⌮஦ᒣᓮ ᾈྐ
 2005 ᖺ 12 ᭶ࠊ᪥ᮏ⸆≀ືែᏛ఍ (JSSX) ࠾ࡼࡧ⸆≀ືែㄯヰ఍ࡢᨭ᥼ࢆཷࡅࠊ᭷㝈㈐௵୰㛫ἲே ་⸆ရ㛤Ⓨᨭ᥼ᶵᵓ (APDD) ࡀタ❧ࡉࢀࡲࡋࡓࠋAPDD ࡣࠊ2009 ᖺ࡟୍⯡♫ᅋἲே࡜ࡋ࡚Ⓩグࡋࠊ᪥ᮏ࡛ࡣᐇ᪋ᅔ㞴࡛࠶ࡗࡓㅖ᪋⟇ࡢᐇ⌧ࢆᯝࡓࡋࠊᅜෆ◊✲⪅ࡢ๰⸆᥎㐍ᨭ᥼ࢆᅗࡗ࡚ࡁࡲࡋࡓࠋ
⫼ᬒ࡜ࡋ࡚ 1991 ᖺ௨᮶ࠊJSSX ᖺ఍ࣇ࢛࣮࣒࡛ࣛࡣࠊࣄࢺ࡟ࣛࢪ࢜࢔࢖ࢯࢺ࣮ࣉ㸦RI㸧
ᶆ㆑యࢆᢞ୚ࡍࡿヨ㦂ࡢ᫝㠀࡟ࡘ࠸࡚㆟ㄽࡀ࡞ࡉࢀࠊ2004 ᖺ࡟ࡣࣄࢺ RI ヨ㦂ࡢᐇ᪋࡟ࡣࠊἲⓗ࡟ࡶ⛉Ꮫⓗ࡟ࡶၥ㢟࡞࠸࡜ࡉࢀࡲࡋࡓࠋࡋ࠿ࡋࠊࡇࡢヨ㦂ࡢᅜෆᐇ᪋ࢆ〇⸆௻ᴗࡣぢ㏦ࡗ࡚ࡁࡓ⤒⦋ࡀ࠶ࡾࡲࡍࠋ2004 ᖺ JSSX ࡟⸆≀ືែヨ㦂᥎㐍ጤဨ఍ࡀタ⨨ࡉࢀࠊ㸱ࡘࡢㄢ㢟ᑠጤဨ఍ࠊ
ࡍ࡞ࢃࡕ 1㸧ࣄࢺ RI ヨ㦂ࡢ᥎㐍࡜ᐇ᪋ࡢࡓࡵࡢලయⓗ᪉ἲࡢ⟇ᐃࠊ
2㸧࣐࢖ࢡࣟࢻ࣮ࢬヨ㦂ࢆྵࡴ᥈⣴ⓗ᪩ᮇ⮫ᗋヨ㦂ࡢ᥎㐍ࠊ3㸧ࣂ࢖࣐࣮࣮࢜࢝ࢆά⏝ࡋࡓ PK/PD ヨ㦂ࡢ᥎㐍ࠊጤဨ఍⥶ᥦゝࢆල⌧໬ࡍࡿࡓࡵࠊᮏ APDD ࡀタ❧ࡉࢀࡲࡋࡓࠋ
2019 ᖺ࠿ࡽ JSSX ࡜ APDD ࡀྜྠ࡛ࠊ⸆≀ືែ◊✲⪅ࡀ㈉⊩࡛ࡁࡿ࣭ࡍ࡭ࡁ◊✲ෆᐜ࡟㛵ࡋ࡚┤᥋㆟ㄽࡍࡿሙ࡜ࡋ࡚ࠊJSSX-APDD ྜྠ࣮࣡ࢡࢩࣙࢵࣉࡀ㛤ጞࡉࢀࠊࡑࡢ➨භᅇࡀᮏ᪥㛤ദࡉࢀࡿ㐠ࡧ࡜࡞ࡾࡲࡋࡓࠋྜྠ࣮࣡ࢡࢩࣙࢵࣉ࡛ࡣࠊᙜึࡼࡾᑡேᩘࡢᑐ
㠃఍㆟࡜ࡋ࡚௻⏬㐠Ⴀࡋࠊ࠾ᣍࡁࡋࡓ₇⪅ࡢⓎ⾲᫬㛫࡜ཧຍ⪅ࡢⓙᵝࡢ㉁␲ࡢ᫬㛫ࡀ࡯ࡰྠࡌ࡜࠸࠺≉ᚩࢆᣢࡓࡏ࡚࠾ࡾࡲࡍࠋ2019 ᖺ 3 ᭶࠾ࡼࡧ 9 ᭶࡟㛤ദࡋࡓ➨୍ᅇ࠾ࡼࡧ
➨஧ᅇᑐ㠃఍㆟ࡣࠊᮾி㒔⏫⏣ᕷࡢ఍ሙ࡟࠾㉺ࡋ࠸ࡓࡔࡅࡿⓙᵝ࡟⤠ࡽࢀࡲࡋࡓࡀࠊ2021
ᖺ 3 ᭶ࠊ9 ᭶࠾ࡼࡧ 2022 ᖺ 3 ᭶ࡢ➨୕ᅇ̿➨஬ᅇ࢜ࣥࣛ࢖ࣥ఍㆟࡛ࡣࠊ඲ᅜ࠿ࡽᖜᗈ࠸
ⓙᵝࡢࡈཧຍࢆ࠸ࡓࡔࡁࠊ
ࢸ࣮࣐࡟ἢࡗࡓウㄽࡀ₇⪅࡜ࡢ㛫࡛ᡂࡉࢀࡲࡋࡓࠋࡇࡢ㛫 2021
ᖺ 4 ᭶࡟ࡣࠊPhase-0/Microdosing Network ࡢ➨஧ᅇ఍ྜࡶࠊ࢜ࣥࣛ࢖ࣥ఍㆟࡟࡚ APDD ࡀඹദ࠸ࡓࡋࡲࡋࡓࠋ௒ᚋࡶ₇⪅ࠊࢥ࣮ࢹ࢕ࢿ࣮ࢱ࣮࡜ཧຍ⪅ࡢⓙᵝࡢ㛫࡛ࠊ✺ࡗ㎸ࢇࡔࠊᐇࡾࡢ࠶ࡿ⸆≀ືែ◊✲ୖࡢ㆟ㄽࡢሙࢆタࡅࡓ࠸࡜ᕼᮃࡋ࡚࠾ࡾࡲࡍࠋAPDD ࡣタ❧ᙜ᫬ࡢᗈ⠊࡞┠ᶆ࡟❧ࡕ㏉ࡾࠊᡃࡀᅜࡢ๰⸆ヨ㦂㛵㐃஦ᴗࢆᨭ᥼ࡋ࡚ࡲ
࠸ࡾࡲࡍࠋᮏ᪥ࢆྵࡵࠊ௒ᚋࡢ᭱ඛ➃ࡢㅖၥ㢟࡟㛵ࡍࡿྛᡤ࡛ࡢウㄽᡂᯝࡀࡈཧຍࡢⓙᵝ࡟࠺ࡲࡃࣇ࢕࣮ࢻࣂࢵࢡࡉࢀࡿࡇ࡜ࢆ♳ᛕࡋࠊ㛤ദࡢᣵᣜ࡜ࡉࡏ࡚࠸ࡓࡔࡁࡲࡍࠋ
ͤ␎Ṕ࡜෗┿ࡣㅮ₇せ᪨࣮࣌ࢪ࡟ᥖ㍕

3ʴϕϫήϧϞʵʛ  ͺͣΌͶ    ࢃԾ ෍ٝ ઎ਫ਼‫౐ښ‬୉ָ୉ָӅ༂ָ‫ڂݜ‬Ռ-66;ʥʛ   ˽τʖϜ˾ ֫࢐ҫ༂͹҈સ੓ɼಊସಝ੓͕Γ;෾ੵ                     ϠυϪʖνʖ ߶૴ ӵਫ਼ ઎ਫ਼୊Ҳࢀ‫ࣞהڠ‬ճऀʥʲ֫࢐ҫ༂͹֋൅ಊ޴ͳ҈સ੓඲Ճʳ     Ҭ৏ ‫ي‬༦ ઎ਫ਼ ࠅཱིҫ༂඾ৱ඾Ӷਫ਼‫ॶڂݜ‬ʥʲ֫࢐ҫ༂඾͹༂෼ಊସಝ੓ͳͨ͹඲Ճʳ                     ߶૴ ӵਫ਼ ઎ਫ਼୊Ҳࢀ‫ࣞהڠ‬ճऀʥʲ֫࢐ҫ༂͹ώ΢ΨΠψϨεηघ๑ͳͨ͹ಝ௅Ͷͯ͏ͱʳ୉ᖔ կࢢ ઎ਫ਼੷ਭϟυΡΩϩ‫ࣞה‬ճऀ         ʛʀʛʀʛ ૱߻౾࿨ ʛʀʛʀʛ
ʛ  ‫ܞٵ‬ʛ   ˽τʖϜ˾ ૓༂͹ͪΌ͹ঘ‫ܗ‬Ϡυϩಊ෼Ν‫ͪ͢༽׈‬༂෼ಊସ඲Ճ          ϠυϪʖνʖ ࢃ࡜  ߔ࢛  ઎ਫ਼   দ࿪༂Ռ୉ָ$3'' ʲঘ‫ܗ‬ඉϐφྸௗྪϜʖϠιρφ༂෼େःಝ௅೼Ѵ͖Δϐφ‫ܗ‬ಊସΝߡ͓Ζʳ         ࢃ࡜  ߔ࢛  ઎ਫ਼   দ࿪༂Ռ୉ָ$3'' ʲ૓༂Ͷ͕͜Ζ LQYLYR ಊ෼υʖνཤ༽͹༙༽੓ʳࢃຌ य़ื ઎ਫ਼  ෤ీ༂඾޽‫ࣞהۂ‬ճऀ ʲඉྡজࢾ‫͖ݩ‬Δ୵ࡩదྡজࢾ‫΃ݩ‬͹‫͢ోڰ‬ʳ           ࢃీ Ҳຑ࿌ ઎ਫ਼
71$;%LRSKDUPD ‫ࣞה‬ճऀ$3'' ʛʀʛʀʛ ૱߻౾࿨ ʛʀʛʀʛ
ʛ  ͕ΚΕͶ  ࢃ࡜  ߔ࢛  ઎ਫ਼   দ࿪༂Ռ୉ָ$3'' 

4-66;$3'' ྜྠ࣮࣡ࢡࢩࣙࢵࣉ ➨භᅇ ࡢ㛤ദ࡟࠶ࡓࡗ࡚
᰾㓟་⸆ࡢᏳ඲ᛶࠊືែ≉ᛶ࠾ࡼࡧศᯒ
ࣔࢹ࣮ࣞࢱ࣮
➨୍୕ඹᰴᘧ఍♫ ⸆≀ືែ◊✲ᡤ㧗ⲡ ⱥ⏕
࢜ࣜࢦ᰾㓟ࢆᇶᮏ㦵᱁࡜ࡍࡿࠕ᰾㓟་⸆ရࠖࡣࠊᚑ᮶ࡢ๰⸆ᡭἲ࡛ࡣᶆⓗ࡜ࡍࡿࡢࡀ㞴ࡋ࠿ࡗࡓ㑇ఏᛶ⑌ᝈ➼࡟ᑐࡍࡿ᪂ࡋ࠸๰⸆ࣔࢲࣜࢸ࢕࡜ࡋ࡚ὀ┠ࢆ㞟ࡵ࡚࠾ࡾࠊ
㏆ᖺࠊ࢔ࣥࢳࢭࣥࢫ࡜ siRNA ࡢ᪂⸆ᢎㄆࡀຍ㏿ࡋ࡚࠸ࡿࠋᶆⓗ࡜స⏝࣓࢝ࢽࢬ࣒ࡀ᫂
☜࡛࠶ࡿࡇ࡜࡟ຍ࠼࡚ࠊಟ㣭᰾㓟ᢏ⾡ࡸ DDS ࢔ࣉ࣮ࣟࢳ࡟ࡼࡗ࡚Ᏻ඲ᛶࡸືែࡢࣉࣟ
ࣇ࢓࢖ࣝࡢไᚚࡀྍ⬟࡜࡞ࡗࡓࡇ࡜ࡀࡑࡢ⫼ᬒ࡟࠶ࡿ࡜⪃࠼ࡽࢀࡿࠋᣑ኱ࡍࡿ᰾㓟་⸆ࡢ◊✲㛤Ⓨ࡟ࡼࡗ࡚ࠊ㠀⮫ᗋ࠾ࡼࡧ⮫ᗋ࡛ࡢືែ࣭Ᏻ඲ᛶࣉࣟࣇ࢓࢖ࣝ࡟㛵ࡍࡿࢼࣞࢵࢪࡀ⵳✚ࡉࢀࡿ࡜࡜ࡶ࡟ࠊࡑࡢホ౯᪉ἲ࡟ࡘ࠸࡚ࡶ᭱㐺໬ࡉࢀ࡚ࡁ࡚࠸ࡿࠋ୍᪉
࡛ࠊᏳ඲ᛶホ౯࡟࠾ࡅࡿ✀ᕪࠊ⫢⮚௨እࡢ⤌⧊࡬ࡢࢹࣜࣂ࣮ࣜࠊ⣽⬊࡛ࣞ࣋ࣝࡢศᕸ
ᣲືࡢᐃ㔞ⓗ⌮ゎࠊin vitro ືែ࣭Ᏻ඲ᛶホ౯⣔ࡢᣑ඘࡜᭱㐺໬ࠊ௦ㅰ≀ࢆྵࡵࡓ㧗ឤᗘ࡛ሀ∼࡞ᐃ㔞ศᯒ࡞࡝ࠊࡉࡽ࡞ࡿ⌮ゎࡸᢏ⾡㐍Ṍࡀᚲせ࡞Ⅼࡶṧࡉࢀ࡚࠸ࡿࠋ
ᮏࢭࢵࢩ࡛ࣙࣥࡣࠊ᰾㓟་⸆ࡢᏳ඲ᛶࠊືែࠊࣂ࢖࢜࢔ࢼࣜࢩࢫ࡟㛵ࡋ࡚ࠊ᭱㏆ࡢࢺࣆࢵࢡࡶ஺࠼࡞ࡀࡽࠊㄢ㢟࡜ᒎᮃ࡟ࡘ࠸࡚㆟ㄽࢆ῝ࡵࡓ࠸ࠋͤ␎Ṕ࡜෗┿ࡣㅮ₇せ᪨࣮࣌ࢪ࡟ᥖ㍕

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US 1998
EU 1999

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US 2013

ApoB-100mRNA

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US 2016

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US 2016
EU 2017
JP 2017

SMN2
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๰⸆ࡢࡓࡵࡢᑠᆺࣔࢹࣝື≀ࢆά⏝ࡋࡓ⸆≀ືែホ౯ࣔࢹ࣮ࣞࢱ࣮᫛ ࿴ ⸆ ⛉ ኱ Ꮫ 㸭APDDᒣᓮ ᾈྐ
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యⓗ᪉ἲࡢ⟇ᐃ࡜ࠊ࣐࢖ࢡࣟࢻ࣮ࢬ(MD)ヨ㦂ࢆྵࡴ᥈⣴ⓗ᪩ᮇ⮫ᗋヨ㦂ࡢ᥎㐍ࡀ࠶ࡾࡲࡋࡓࠋ๰⸆᪩ᮇẁ㝵࡟࣐࢖ࢡࣟ⏝㔞ࡢ᪂⸆ೃ⿵ရࢆ┤᥋ࣄࢺ࡟ᢞ୚ࡋࠊࡑࡢ⸆≀ືែࢆ㏿ࡸ࠿࡟᫂ࡽ࠿࡟ࡍࡿ᪂ᢏ⾡ࡀୡ⏺ⓗ࡟㛤Ⓨࡉࢀ࡚࠾ࡾࡲࡍࠋ2021 ᖺ 4 ᭶࡟ࡣࠊPhase-0/Microdosing Network ࡢ➨஧ᅇ࢜ࣥࣛ࢖ࣥ఍㆟ࢆ APDD ࡀ᪥ᮏ᫬㛫ࢆࢥ࢔ࢱ࢖࣒
࡜ࡋ࡚ࠊඹദᐇ᪋࠸ࡓࡋࡲࡋࡓࠋ
㏆ᖺࠊ་⸆ೃ⿵ရࡀከᵝ࡜࡞ࡾࠊ᰾㓟་⸆࡞࡝ࡢᗈ⠊࡞᪂ศᏊࣔࢲࣜࢸ࢕᫬௦ࢆ㏄࠼ࡿ࡟࠶ࡓࡾࠊᨵࡵ࡚ື≀ᐇ㦂ࡢᐇ᪋ࢆ෌᳨ウࡍࡿࡇ࡜ࡶ㔜せ࡛࠶ࡾࡲࡍࠋࣄࢺ࡛ࡢືែ
ணࡢࡓࡵࠊṔྐⓗ࡟ࣛࢵࢺࠊ࢖ࢾࡸࢧࣝࡢά⏝ࡀ࡞ࡉࢀ࡚ࡁࡲࡋࡓࡀࠊື≀ࡢ⸆≀௦ㅰ㓝⣲࡟ࡣࣄࢺ࡜ࡢ㢧ⴭ࡞✀ᕪࡀ࠶ࡾࡲࡍࠋࡑࡢඞ᭹ࢆࡵࡊࡋࠊ᪂つື≀ࣔࢹࣝ࡜ࡋ࡚ࠊ
ࣄࢺ⫢⣽⬊⛣᳜ච␿୙඲࣐࢘ࢫࠊື≀ឡㆤࢆព㆑ࡋࡓ㣗⏝ື≀࡛࠶ࡿࣈࢱ࠿ࡽὴ⏕ࡋࡓ࣑ࢽ࠶ࡿ࠸ࡣ࣐࢖ࢡ࣑ࣟࢽࣈࢱࠊࡉࡽ࡟ࡣ⿕㦂≀㉁ࡢయ㔜ᙜࡓࡾࡢᢞ୚㸦ྜᡂ㸧㔞ࢆᑠࡉࡃ࡛ࡁࠊࣛࢵࢺྠయ㔜࡛࠶ࡿ฼Ⅼࢆࡶࡘ᪂ୡ⏺ࢨ࣐࣮ࣝࣔࢭࢵࢺࡢ฼ά⏝ࡀከ᪉㠃࠿ࡽ᳨ウࡉࢀ࡚ࡁࡲࡋࡓࠋ
ᮏ᪥ࠊ௚ࢭࢵࢩ࡛ࣙࣥࡶ㆟ㄽࡉࢀࡿࡼ࠺࡟ࠊ᰾㓟་⸆࡞࡝ࡢ᪂ศᏊࣔࢲࣜࢸ࢕᫬௦ࢆ
㏄࠼ࠊ௒ᚋࡢື≀ヨ㦂ࢆ࡝࠺ࡍࡿ࠿ࠊ┤ࡕ࡟⟅࠼ࡣ࡛࡞࠸࠿ࡶࡋࢀࡲࡏࢇࡀࠊᮏࢭࢵࢩ
࡛ࣙࣥྲྀࡾୖࡆࡲࡍࠋఏ⤫ⓗ࡞⸆≀௦ㅰ㓝⣲ࡢ≉ᚩᢕᥱ࠿ࡽࣄࢺᆺືែࢆ⪃࠼ࠊࡉࡽ࡟
ࡣࠊ㠀⮫ᗋヨ㦂࠿ࡽ᥈⣴ⓗ⮫ᗋヨ㦂࡬ࡢᶫΏࡋࢆ┠ᣦࡋࠊ〇⸆௻ᴗࡢ᭱๓⥺࡛᪂ศᏊࣔ
ࢲࣜࢸ࢕᫬௦ࡢື≀⏤᮶ࢹ࣮ࢱࡢ฼ά⏝࡟ࡘ࠸࡚ࠊⓙᵝ࡜㆟ㄽࡋ࡚࠸ࡁࡓ࠸࡜⪃࠼࡚࠸ࡲࡍࠋͤ␎Ṕ࡜෗┿ࡣㅮ₇せ᪨࣮࣌ࢪ࡟ᥖ㍕ᑠᆺ㠀ࣄࢺ㟋㛗㢮࣐࣮ࣔࢭࢵࢺ⸆≀௦ㅰ≉ᚩᢕᥱ࠿ࡽ
ࣄࢺᆺືែࢆ⪃࠼ࡿ᫛࿴⸆⛉኱Ꮫᒣᓮ ᾈྐ

་⸆ೃ⿵⸆≀ࡢ⸆≀ືែᏛⓗホ౯࡟ࡣࠊ௦ㅰࡢ✀ᕪࡢᑠࡉ࠸ື≀✀ࡢ㑅ᢥࡀ㔜せ࡛࠶ࡿ 1)ࠋ₇⪅ࡣࠊᅜࡢ㟋㛗㢮ࣔࢹࣝࡢᬑཬࣉࣟࢪ࢙ࢡ࡟ཧ⏬ࡋࠊP450 㑇ఏᏊከᆺࡀ࠶ࡿ࣐
࣮ࣔࢭࢵࢺࡢపศᏊ⸆≀ࡢ⃰ᗘ᥎⛣ࢹ࣮ࢱࢆά⏝ࡋࡓࣄࢺᆺືែࡢ◊✲ࢆᐇ᪋ࡋࡓ 2)ࠋ
⸆≀ࢆྵࡴ⾑ὶࡀ⫢⮚࡟㐠ࡤࢀࡿ㏿ᗘ㸦⫢⾑ὶ㔞 Qhࠊᩥ⊩್ࢆ᥇⏝㸧ࡣࠊ⏕⌮Ꮫⓗ⸆≀ືែࣔࢹࣝ࡟࠾࠸࡚ࠊ㔜せ࡞⏕యഃࡢࢩࢫࢸ࣒ࣃ࣓࣮ࣛࢱ࡜࡞ࡿࠋ࣐࢘ࢫࠊࣛࢵࢺࠊ
࣐࣮ࣔࢭࢵࢺࠊ࢝ࢽࢡ࢖ࢨࣝࠊ࢖ࢾࠊ࣑ࢽࣈࢱ࡜ࣄࢺࡢ⫢⾑ὶ㔞 Qh ࡣື≀య㔜ࡸ⫢ᐜ✚ Vh ࡜ẚ౛㛵ಀ࡟࠶ࡗࡓࠋ⸆≀⾑୰⃰ᗘ᥎⛣ࢆᣦᶆ࡜ࡋࡓ⠊ᅖ࡟࠾࠸࡚ࠊ࣐࣮ࣔࢭࢵ
ࢺࡣࣄࢺᆺ⪁㱋ࣔࢹࣝື≀࡜ࡋ࡚┦ᛂࡋ࠸≉ᚩࢆᣢࡘࡇ࡜ࡀ᥎ᐹࡉࢀࡓࠋ࣐࣮ࣔࢭࢵࢺ
ࡢ࣡ࣝࣇ࢓ࣜࣥࡸ࣓࢜ࣉࣛࢰ࣮ࣝࡢ⾑୰⃰ᗘࢹ࣮ࢱࢆ෌⌧ࡍࡿື≀ PBPK ࣔࢹࣝ⏝⫢ࢡࣜ࢔ࣛࣥࢫ㸦⫢௦ㅰᾘኻ㸧್ࡣࠊ⸆≀௦ㅰ㓝⣲㑇ఏᏊከᆺ࡟ᛂࡌ࡚ኚືࡋࡓ 3)ࠋ
௨ୖࠊ㠀ࣄࢺ㟋㛗㢮ࣔࢹࣝࢆά⏝ࡋࡓࣄࢺᆺືែ◊✲ࡢྲྀ⤌ࡳࡢ୍➃ࢆ⤂௓ࡍࡿࠋ1)

Uno Y, Uehara S, Yamazaki H. Drug-oxidizing and conjugating non-cytochrome P450 (non-P450)
enzymes in cynomolgus monkeys and common marmosets as preclinical models for humans. Biochem
Pharmacol, 197, 114887 (2022).

2)

Uehara S, Uno Y, Yamazaki H. The marmoset cytochrome P450 superfamily: Sequence/phylogenetic
analyses, genomic structure, and catalytic function. Biochem Pharmacol, 171, 113721 (2020).

3)

Uno Y, Uehara S, Yamazaki H. Genetic polymorphisms of drug-metabolizing cytochrome P450 enzymes
in cynomolgus and rhesus monkeys and common marmosets in preclinical studies for humans. Biochem
Pharmacol, 153, 184-195 (2018).

>␎Ṕ@᫛࿴⸆⛉኱Ꮫ ⸆≀ືែᏛ◊✲ᐊ ᩍᤵᒱ⸆኱ࠊ኱㜰ᗓබ⾨◊ࠊVanderbilt ኱ࠊ㔠኱⸆ ࡜໭኱⸆㸦2001 ᖺ 7 ᭶㸧ࢆ⤒࡚ࠊ2005 ᖺ 4 ᭶ࡼࡾ⌧⫋ࠋJSSX ⌮஦ࠊJSSX FellowࠋAPDD ⥲ົ⌮஦(2010-18 ᖺ)ࠊ௦⾲⌮஦㸦➨ 4 ௦ࠊ2018 ᖺ 7 ᭶-㸧ࠋHuman1
Minipig

Dog
Monkey0.1

Marmoset
Rat

0.001

Mouse

0.1

1

10

100

Human

100
Minipig

Marmoset
Rat

1

Uehara S, Uno Y, Yamazaki H. 2020. The marmoset
cytochrome P450 superfamily: Sequence/phylogenetic
analyses, genomic structure, and catalytic function

Mouse
0.001 0.01

BW, kg0.1

1P450 2C19ࡢ㑇ఏⓗከᆺ࡜⸆≀యෆືែከᆺ

10

Hepatic volume, Vh, L
Mouse

Parameter࣐࣮ࣔࢭࢵࢺࢩࢺࢡ࣒ࣟP450ࡢ⥙⨶ⓗゎᯒ᫛࿴⸆኱ᒣᓮᾈྐ
2013.04 - 2018.03

Dog
Monkey10

Rat

Marmoset

Cynomolgu

10000

Dog

Minipig

Humans

Body weight, BW, Kg

0.025

Hepatic volume, Vh, L

0.25

0.35

5.0

10

14.2

70

0.00085 0.0085

0.015

0.15

0.3

0.24

1.5

13.1

0

31.1

96.6

200

25

500

1500

Hepatic blood flow rate, Qh,
0.16 0.853
1.5
Yamazaki et al., Chem. Res. Toxicol.,1903-1911 (2016)L/h
1.0 29,10
10Urine volume, Vu, mL/day

Matsumoto, Kamimura, Yamazaki et al.,Xenobiotica. 51:479-93, 2021

[S-Warfarin] inplasma, ng/mL

0.01

1A1
1A2
1B1
2A6
2B6
2C8
2C18
2C19
2C58
2C76
2D6(19)2D8⫢⾑ὶ㔞 vs య㔜

1000ࢤࣀ࣒⦅㞟ᢏ⾡ࢆ⏝࠸ࡓ Interleukin 2 receptor
subunit gamma 㑇ఏᏊࣀࢵࢡ࢔࢘ࢺ࣐࣮ࣔࢭࢵ
ࢺసฟ (⛣᳜ࢆྍ⬟࡜ࡍࡿච␿୙඲࣐࣮ࣔࢭࢵࢺࠊබ┈㈈ᅋἲேᐇ㦂ື≀୰ኸ◊✲ᡤ ࣐࣮ࣔࢭࢵࢺ◊✲㒊 Cell Stem Cell. 2016 19:12738㸧

䝬䞊䝰䝉䝑䝖⫢⾑ὶ㔞 71.4 mL/min/kg
Gabrielsson J., Hjorth S (2012) Quantitative
Pharmacology: An Introduction to
Integrative PharmacokineticPharmacodynamic Analysis, Stockholm:
Swedish Pharmaceutical Press

100

100
10

Wild-type

1

2E1
2F1
2J2
3A4(21)
3A5
3A90
4A11
4F2
4F3(3B)
4F71(11)4F12P450 2C19[p.(Phe7Leu;
Ser254Leu; Thr469Ile)]
Mutant1000

Mutant1000

Cyranoski. Nature 514(7521):151-2, 2014䝠䝖䚸䜲䝚䚸䝃䝹䚸䜴䝃䜼䚸䝷䝑䝖䚸䝬䜴䝇⫢⾑ὶ
Davies and Morris Pharm Res 10:1093-5(1993)

10
1

Wild-type

0.1

0.01

0

12

24

0

2

4

Time after oral administration, hUno, Uehara, Yamazaki. Biochem Pharmacol, 153, 184–195, 2018

40

0
3

2

GSTO1

CDNB

1-lodohexane

GSTO1

CES1

GSTO2

CDNB

1-lodohexane

GSTO2

SULT1C4

irinotecan

CES2

GSTP1

CDNB

1-lodohexane

GSTP1

SULT1E1 1-naphthol estradiol SULT1E1

FMO1

benzydamine

sulindac

FMO1

GSTS1

CDNB

1-lodohexane

GSTS1

SULT2A1 1-naphthol estradiol SULT2A1

FMO2
benzydamine

trimethylamine

FMO3

FMO4
FMO5

Human
SULT1C3

GSTT1

CDNB

1-lodohexane

GSTT1

UGT1A1

estradiol

GSTT2

UGT1A3

estradiol

FMO4

GSTT4

CDNB

1-lodohexane

GSTT4

UGT1A4FMO5

GSTT4L

CDNB

GSTZ1

UGT1A1

Homozygote
P450 2C19
p.[(Phe7Leu;
Ser254Leu;
Ile469Thr)]

serotonin UGT1A3
serotonin UGT1A4

1-lodohexane

CDNB

UGT1A5

GSTA1

CDNB

1-lodohexane

GSTA1

GSTZ1

UGT1A6

propofol

serotonin UGT1A6

GSTA2

MGST1

CDNB

1-lodohexane

MGST1

UGT1A7

propofol

serotonin UGT1A7

GSTA3

CDNB

1-lodohexane

GSTA3

MGST2

CDNB

1-lodohexane

MGST2

GSTA4

CDNB

1-lodohexane

GSTA4

MGST3

CDNB

1-lodohexane

MGST3

GSTA4L

CDNB

1-lodohexane

NAT1

Isonizidaminobenzoic acid

NAT1
NAT2

UGT2B49

GSTK1

CDNB

1-lodohexane

1-lodohexane

estradiol

SULT1A1UGT2B50UGT2B7

SULT1A2UGT2B51

UGT2B10

SULT1A3UGT2B52

UGT2B11

SULT1A4UGT2B53

UGT2B15

GSTA5
GSTK1

SULT1A1dopamine

GSTM1
GSTM2
GSTM3

CDNB

1-lodohexane

CDNB

GSTM2

1-lodohexane

SULT1A3dopamine

estradiol

Wild typeP450 2C19

GSTM3

10000

100
10
1

0

propofol

12

10000

24
E

1000
100
10
1

0

12

24

10000

B

1000
100
10
1

0

12

10000

24
F

1000
100
10
1

0

12

24

1000
100
10
1
0.1
0.01
0
1000
100
10
1
0.1
0.01
0

Time after oral administration, h

UGT1A8UGT1A9A

1000

serotonin UGT1A9Central compartment
V1, 0.36 L, Cb
CLr
Qh, 1.5 L/h

UGT1A10UGT2B4

GSTM4

CDNB

1-lodohexane

GSTM4

SULT1B1dopamine

estradiol

SULT1B1UGT2B17

GSTM5

CDNB

1-lodohexane

GSTM5

SULT1C2dopamine

estradiol

SULT1C2UGT2B28

Liver compartment
Vh, ChFaFg, 1

Ka ,3.1 h-1 CLh, 0.72-1.22
L/h
Gut compartment㑇ఏᏊከᆺ䛾Xg
ᙳ㡪䛒䜚
R-Omeprazole, 0.5 mg/kg

C

2

4
G

2

4

1000
100
10
1
0.1
0.01
0
1000
100
10
1
0.1
0.01
0

D

2

4
H

2

4

Time after oral administration, hRelationship between observed individual AUC0-4/24, p.o. values and
AUC0-4/24, p.o. values calculated using individual PBPK models
100

R-Warfarin50

r = 0.92, p < 0.01

AUC0-24, p.o., Pg h//mL

FMO3

Marmoset

AUC0-24, p.o., Pg h//mL

FMO2

Human

0
0
50
100
Predicted AUC0-24, p.o., Pg h/mL

100

S-Warfarin50

r = 0.99, p < 0.01

0
0
50
100
Predicted AUC0-24, p.o., Pg h/mL

200

R-Omeprazole100

r = 0.99, p <AUC0-4, p.o., ng h//mL

AOX1

oseltamivir

procaine[S-Omeprazole] in plasma, ng/mL

phthalazine

temocapril[R-Omeprazole] in plasma, ng/mL

Marmosetcarbazeran

CES2

AUC0-4, p.o., ng h//mL

Human

AOX1
CES1

[R-Warfarin] in plasma, ng/mL

Marmoset[S-Warfarin] in plasma, ng/mL

P450 2C19 ከᆺᛶ䜢♧䛩䝬䞊䝰䝉䝑䝖ಶయู䛾䝽䝹䝣䜯䝸䞁䛸䜸䝯䝥䝷䝌䞊䝹⾑୰⃰ᗘ᥎⛣

Typical Substrates of Non-P450 Enzymes for Marmosets

0.01
0
0
100
200
Predicted AUC0-4, p.o., ng h/mL

200

S-Omeprazole100

r = 0.99, p <
0.01
0
0
100
200
Predicted AUC0-4, p.o., ng h/mL

Kusama, Yamazaki et al. Xenobiotica. 48:1072-7, 2018

Uno, Uehara, Yamazaki. Biochem Pharmacol 197:114887, 2022

54

6 0 0 0

M

a r m

m

ic r o s o mo s e tliv e rMarmosets genotyped for polymorphic P450 2C19,
because of lacking the ortholog of human P450 2C9:P450 2C19 p.[(Phe7Leu; Ser254Leu; Thr469Ile)]

c

e s

2 0

3 0

t

u m

liv e r

R

m

,

4 0

m

5 0

6 0

in

ic r o s o m

e s
c

4’-OH

4 0 0 0

2 8 2

A

4’

5

2 0 0 0

b
0
0

1 0

2 0

3 0

t

R

,

4 0

m

10 2
10 1

5 0

in

4’-Hydroxyation rates of
diclofenac by human liver
microsomes were high to
5-hydroxyation rates.

6 0

Mutant homogyzote
for P450 2C19

10 2

5-OH

10 0

5-OH

10 1
10 0

4'-OH

10 -1

,

P V

a

a n

Area under the curve, μM h/L

1 0

H

50 mg/kg,
p.o.

4'-OH
10 -1

eto

0

Wild-type marmoset 10 3

0

4

8

0

4

8

Human
MonkeyMarmoset
Rat

300
200
100
0

am
glu inoc u phro ens nid
am ulf ea
glu ino tec u phAcr e
eto sonidn
am ulf ea
glu ino tec u phAcr e
eto sonidn
am ulf ea
glu ino tec u phro ensunidelfa
te0

6 0 0 0

10 3

Acetaminophen and its conjugatesobserved in monkeys andmarmosets

eto

b
a

400

Ac

2 8 2

A

2 0 0 0

[Diclofenac, 4'- and 5-OH-diclofenac],in plasma, Pg/mL

5-OH

,

P V

[S], 100 μM
4 0 0 0Time after oral administration, hLevels of 4′-hydroxydiclofenac and 5-hydroxydiclofenac
formed by marmoset liver microsomes were roughly
similar in the marmoset plasma samples.

Estimated log (AUC in liver ofacetaminophen)

Measured Plasma and Estimated Hepatic Concentrations of
Acetaminophen after Oral Administrations by PBPK Models

Metabolic Profiles of Diclofenac in LiverMicrosomes and Marmoset Plasma

Ac

Hepatic volume, Vh, L

10࣐࣮ࣔࢭࢵࢺ⸆≀௦ㅰᆺP450㸦᪤▱8✀࠾ࡼࡧ᪂᪂つ15✀㸧

[R-Omeprazole] inplasma, ng/mL

Hepatic blood flow rate, Qh, L/h

Mouse, Rat, Marmoset, Monkey, Dog, Minipig䛚䜘䜃䝠䝖䛾⏕⌮Ꮫⓗᩘ್

5
Human
Minipig
Marmoset4
Monkey

3

Rat

Mouse
Humanized-liver mouse

2
0
1
2
3
4
Measured log (AUC in plasma ofcysteinyl acetaminophen)

Uno, Uehara, Yamazaki. Biochem Pharmacol. 197:114887, 2022; Toda, Yamazaki et al. Xenobiotica 51 316-323, 2021

Nakanishi, Yamazaki et al., Biochem Pharmacol. 152:272-278, 2018811䝠䝖ᆺື≀䝕䞊䝍䜢ά⏝䛩䜛䝠䝖௦ㅰ䞉ືែண

Five and Six Decades After the Discovery of Cytochrome P-450

Editor: Hiroshi YamazakiISBN:
978-4-431-54991-8(Print)978-4-431-54992-5(Online)http://www.springer.com/
978-4-431-54991-8(2014)

㠀ࣄࢺ㟋㛗㢮P450㑇ఏᏊከᆺࡀほᐹࡉࢀࡿື≀యෆࢹ࣮ࢱࢆά⏝ࡋࡓࣄࢺᆺ⸆≀ືែࡢ◊✲஦౛z ࣐࣮ࣔࢭࢵࢺP450࡜non-P450㓝⣲ศᏊ✀࡟୍㒊ࣄࢺ࡜ᕪ␗ࡀㄆࡵ
ࡽࢀࡿࡶࡢࡢࠊ⥲ࡌ࡚ྠᵝࡢ㓝⣲ศᏊ✀ࢆᣢࡘz ࣐࣮ࣔࢭࢵࢺࡢ࣡ࣝࣇ࢓ࣜࣥ࡜࣓࢜ࣉࣛࢰ࣮ࣝື≀యෆࢹ࣮ࢱࢆ
෌⌧ࡍࡿ௬᝿ື≀PBPKࣔࢹࣝ⏝⫢ࢡࣜ࢔ࣛࣥࢫ್ࡣࠊື≀ P450
2C19ከᆺ࡟ᛂࡌ࡚ኚືz 䝬䞊䝰䝉䝑䝖ಶయ䝺䝧䝹䛷⸆≀䛻䜘䜛P450ㄏᑟ䜔ຍ㱋䛻䜘䜛P450άᛶపୗ䜒ほᐹ䛥䜜䜛ADVANCES IN PHARMACOLOGY
Volume 95 䠄2022䠅
Pharmacology and Toxicology of
Cytochrome P450 – 60th Anniversary
Hiroshi Yamazaki, Volume Editor
Sam J. Enna, Series Editor
https://www.elsevier.com/books/pha
rmacology-and-toxicology-ofcytochrome-p450-60thanniversary/yamazaki/978-0-32391109-2

1st Edition - August 1, 2022
11. Polymorphic cytochromes P450
in non-human primates
Uno, Uehara, Yamazaki

12

13



創薬のための小型モデル動物を活用した薬物動態評価
創薬における in vivo 動物データ利用の有用性

武田薬品工業株式会社

リサーチ

山本

薬物動態研究所俊輔

ヒト体内動態予測は、医薬品開発の成功確率を向上させるために重要な役割を担ってきた。動物実験、特にサルなど霊長類を用いた体内動態評価は、ヒトでの現象に対する多くの洞察を与える重要な位置付けにあり、特に新分子モダリティ時代を迎えた近年では、その重要性はさらに高まっている。一方で、このサルの需要の高まりによる需給バ
ランスの崩壊ひいては試験コストの高騰や、動物実験倫理の課題意識の高まりなど、その使用に付随する諸問題も議論されている。
本セッションでは、代替動物を含めた戦略的アプローチの台頭が望まれている中、新たな動物モデルとして、ヒト肝キメラマウス、ミニブタ、マーモセットの利用について、先ずは市販の低分子化合物を用いた包括的検証結果を報告する。その上で、次世代医療
モダリティの代表として核酸医薬品の体内動態予測におけるヒト肝キメラマウスおよび
マーモセットの有用性について、社内事例を交えながら議論する。

[略歴]
武田薬品工業株式会社

薬物動態研究所

主席研究員

2009 年に名古屋市立大学大学院薬学研究科博士前期課程終了
後、武田薬品工業株式会社へ入社。現在に至るまで薬物動態研究に従事。2017 年および 2019 年に日本薬物動態学会年会にてベストポスター賞受賞。2019 年から日本薬物動態学会代議員。2021 年に日本薬物動態学会にて創薬貢献奨励賞を受賞。2022 年、日本薬物動態学会第 37 回年会実行委員長。
15Right place, Right time, and Right concentration

Absorption

Distribution

創薬におけるin vivo動物データ利用の有用性
Metabolism
Elimination

Syunsuke Yamamoto on behalf of the teamDrug Metabolism & Pharmacokinetics Research Laboratories, PTS, Research
Takeda Pharmaceutical Company Limited
2022.09.02
APDD｜ AP D D|

S e p t e mb e r 2 n d 2 0 2 2

Why we need alternative animals

Be quantitative for patients✓ Data from monkeys are valuablefor predicting human pharmacokinetics.

✓ Therapeutic modality has been diversified
to balance the portfolio.

However,Mode of action◼ Not perfect◼ Ethical concerns◼ Worldwide shortage◼ Cost increase◼ Difficulties in production◼ Cross reactivity◼ Unknown distribution mechanism◼ Immunogenicity

Animal models
Modeling &Simulation

AI

PK/PD/Efficacy
without Toxicity

In vitro systems

1. Multiple options of animal model to evaluate pharmacokinetics of drug candidates
2. Applicability to new therapeutic modalities｜ AP D D｜ AP D D|

Prediction ofabsorption
profileHumanizedliver mouserat

marmosetmonkeyS e p t e mb e r 2 n d 2 0 2 2

Today’s agenda

Animals in this presentation

Mouse

|

S e p t e mb e r 2 n d 2 0 2 2

Minipig

Prediction ofsystemic PK
profilePrediction ofbrain distribution

Application to“Newtherapeuticmodality”

Human

Body weight｜ AP D D｜ AP D D|

S e p t e mb e r 2 n d 2 0 2 2

Publication list

Conclusion
Prediction ofPrediction ofabsorption
profilesystemic PK
profile✓ Prediction of human oral
absorption was difficult
based on animal data.
✓ Transdermal absorption
could be predicted basedon data from hairless rats.

|

S e p t e mb e r 2 n d 2 0 2 2

Prediction ofApplication to“Newbrain distribution

therapeutic✓ Humanized liver chimeric ✓ Kp,uu,CSF tend to be higher
mice, minipigs, andthan Kp,uu,brain in all tested
marmosets were useful tospecies.
predict human✓ PBPK model can describe
pharmacokinetics after IV.
brain distribution of drugcandidates in all tested
species.

✓ Ning Ding, Syunsuke Yamamoto et al. Drug Metab Pharmacokinet. 41:100408. (2021)✓ Syunsuke Yamamoto et al. Pharm Res. 34(11): 2415 (2017)✓ Syunsuke Yamamoto et al. Xenobiotica. 50(7):831-838. (2020)

modality”✓ Chimeric mice was utilized toevaluate ASO distribution tohuman hepatocytes.
✓ Marmosets showed goodpredictability for humanpharmacokinetics after IV.

✓ Maki Miyamoto et al. Xenobiotica. 51(1):51-60. (2021)✓ Suguru Kato et al. Drug Metab Dispos. 48(10):934-943. (2020)✓ Maki Miyamoto et al. Xenobiotica. 49(12):1379-1387. (2019)✓ Maki Miyamoto et al. Xenobiotica. 47(12):1052-1063. (2017)✓ Sho Sato et al. AAPS J. 3;23(4):81. (2021)｜ AP D D|

S e p t e mb e r 2 n d 2 0 2 2｜ AP D D

16|

S e p t e mb e r 2 n d 2 0 2 2๰⸆ࡢࡓࡵࡢᑠᆺࣔࢹࣝື≀ࢆά⏝ࡋࡓ⸆≀ືែホ౯㠀⮫ᗋヨ㦂࠿ࡽ᥈⣴ⓗ⮫ᗋヨ㦂࡬ࡢᶫΏࡋ
TNAX Biopharma ᰴᘧ఍♫ࠊ୍⯡♫ᅋἲே་⸆ရ㛤Ⓨᨭ᥼ᶵᵓᒣ⏣୍☻࿅పศᏊ๰⸆ࡢᡂຌ☜⋡ࡣప࠸ࠋཎᅉࡢ୍ࡘ࡜ࡋ࡚ᐇ㦂ື≀࡜ࣄࢺࡢ✀ᕪࡀ࠶ࡿࠋ₇⪅ࡶ◊✲ᡤ᫬௦࡟ࠊᢸᙜࣉࣟࢪ࢙ࢡࢺࡢ࡯࡜ࢇ࡝ࡣ⮫ᗋヨ㦂࡛ᾘ࠼ཤࡗࡓࠋ᣺ࡾ㏉ࡗ࡚ࡳ
ࡿ࡜ࠊPOC ࡲ࡛ࡢ᪩ᮇ⮫ᗋヨ㦂ࡢኻᩋࡢཎᅉࡣࠊ⸆≀ືែࡢ✀ᕪ࡟㉳ᅉࡋ࡚࠸ࡿ஦౛ࡀ
ከ࠿ࡗࡓࠋ⮫ᗋࡲ࡛㐍ࢇ࡛ኻᩋࡋࡓࣉࣟࢪ࢙ࢡࢺࡣࠊἑᒣࡢࣜࢯ࣮ࢫࢆᢞࡌ࡚࠸ࡿࡀᨾ
࡟᚟άࡣ㞴ࡋ࠸ࠋ◊✲ẁ㝵ࡢྍ⬟࡞㝈ࡾ᪩࠸ࢱ࢖࣑ࣥࢢ࡛ࣄࢺࡢࢹ࣮ࢱࢆྲྀᚓ࡛ࡁࢀࡤࠊ
᭱㐺໬ࡉࢀࡓࣉࣟࢪ࢙ࢡࢺࢆ⮫ᗋ㛤Ⓨ࡬ᶫΏࡋࡍࡿࡇ࡜ࡀྍ⬟࡜࡞ࡾࠊᡂຌ☜⋡ࡣྥୖࡍࡿࠋ࣐࢖ࢡࣟࢻ࣮ࢬ㸦MD㸧⮫ᗋヨ㦂ࡣࠊᴟᚤ㔞㸦᥎ᐃ⸆ຠ⏝㔞ࡢ 1/100 ௨ୗୟࡘᢞ୚㔞100 ȣg ௨ୗ㸧ࡢ་⸆ရೃ⿵໬ྜ≀㸦୺࡟పศᏊ㸧ࢆࣄࢺ࡟ᢞ୚ࡋࠊ⸆≀ືែ≉ᛶࡢⰋ࠸ࡶࡢࢆ㑅ᢥࡍࡿࡇ࡜ࢆ┠ⓗ࡟ࡋࡓ᥈⣴ⓗ⮫ᗋヨ㦂࡛࠶ࡿࠋ2008 ᖺ 6 ᭶ࠊཌ⏕ປാ┬࠿ࡽࠕMD ⮫ᗋヨ㦂ࡢᐇ᪋࡟㛵ࡍࡿ࢞࢖ࢲࣥࢫࠖࡀ㏻▱ࡉࢀࠊྠᖺ 10 ᭶ࠊAPDD ࡣ NEDO࠿ࡽ MD ࣉࣟࢪ࢙ࢡࢺ㸦PL: ᮡᒣ㞝୍ඛ⏕㸧ࢆཷクࡋࡓࠋ๓༙㒊ศ࡛ࡣࠊపศᏊ๰⸆࡟࠾ࡅࡿ MD ヨ㦂ࡢ࣏ࢪࢩࣙࢽࣥࢢ࡟ࡘ࠸࡚⤂௓ࡍࡿࠋᚋ
༙㒊ศ࡛ࡣࠊ᭱㏆ὀ┠ࡉࢀ࡚࠸ࡿ᰾㓟་⸆࡟ࡘ࠸࡚ࠊ๰⸆࡟࠾ࡅࡿ⸆≀ືែᏛⓗ࡞ㄢ㢟ࢆཧຍ⪅ࡢⓙᵝ࡜ඹ᭷ࡍࡿ࡜࡜ࡶ࡟ࠊ᪤Ꮡࡢ MD ๰⸆ᢏ⾡ࡀࡇࡢㄢ㢟࡟ᑐࡋ࡚ solutionࢆᥦ౪ฟ᮶ࡿ࠿ྰ࠿ࠊཧຍ⪅ࡢⓙᵝ࡜ពぢ஺᥮ࡋࡓ࠸ࠋ

>␎Ṕ@TNAX Biopharma ᰴᘧ఍♫ ྲྀ⥾ᙺ◊✲㛤Ⓨ㒊㛗୍⯡♫ᅋἲே་⸆ရ㛤Ⓨᶵᵓ ๪௦⾲⌮஦
1983 ᖺ 㮵ඣᓥ኱Ꮫ኱Ꮫ㝔ಟ஢ᚋࠊ⏣㎶୕⳻〇⸆ओ㸦ᪧྜྷᐩ〇⸆ओ㸧ධ♫ࠋ1983 ᖺ࠿ࡽ 2 ᖺ㛫ࠊ኱㜰኱Ꮫ་Ꮫ㒊➨୍⸆⌮Ꮫᩍᐊ◊✲⏕. 1991 ᖺ ⸆Ꮫ༤ኈ㸦⇃ᮏ኱Ꮫ㸧ࠋ2003 ᖺ බ┈㈈ᅋἲே᪥ᮏ⏕⏘ᛶᮏ㒊⤒Ⴀ࢔࢝ࢹ࣑࣮

ᢏ⾡⤒Ⴀࢥ࣮ࢫ

(MOT) ಟ஢ࠋ2007 ᖺ࠿ࡽ᪥ᮏ⸆≀ືែᏛ఍ ௦㆟ဨTrends in clinical success rates and therapeutic focus

Phase 0/microdosing consortia and history
CREAM(䡚䡚2006)
Prediction of human PK
EUMAPP(䡚2011)PEDMIC,PAMPERS(䡚2015)Phase-0/
Microdosing
Network(2013䡚present)

NEDOMicrodose
Projects(2008䡚2011)
To promote eIND in Japan

PK in children

Nat Rev Drug Discov.
Dowden H and Munro J, 18, 2019

Properties of Analytical Tools Used in Phase-0 Studies

Strategic Considerations

AMS

PET

Sensitivity

10-16 to 10-18 g/mL

10-12 to 10-14 g/mL

10-12 g/mL

PK

Yes; most sensitive

limited by radionuclide t1/2

limited by LLOQ

PD / PoM

Drug in tissue samples

Tissue access, target binding

Drug in tissue samples

Detection of
metabolites

possible with HPLC

no

Sample types

mostly plasma but any may be
used (e.g., biopsies, urine, CSF)

SamplevolumeTypically, 25-50 ȝ/,

Typically, 100 ȝ/-2 mL

Mostly 11C, 18F, 124I

very low

low

none

can be outsourced~ 6 facilities worldwide~ $ 400-600 k

on-site only
available in specialized centers~ $ 500-700 k

can be outsourced
commonly available~ $ 80-140 k

none

Burt et al., Nat Rev Drug Discov., 2020

Adapted from Bauer et al. 2008᰾㓟๰⸆䛾ㄢ㢟୰ศᏊ⸆䚸㧗ศᏊ⸆䚸పศᏊ⸆䛾ᕷሙᡂ㛗ᛶᕷሙつᶍ䠄2020䠅

ᡂ㛗⋡䠄2020-2030)

ᕷሙつᶍ(2030)

〇ရ౛

᰾㓟་⸆

0.45

㧗
(17%)

2.1

䝇䝢䞁䝷䝄

䝨䝥䝏䝗་⸆

3.2

୰
(8%)

4.7
(2025)

䝔䝸䝟䝷䝏䝗

ᢠయ་⸆

16

୰
(8%)

23
(2025)

䝠䝳䝭䝷
䜸䝥䝆䞊䝪

㧗ศᏊ་⸆

䝍䞁䝟䜽㉁་⸆

6.4

ప
(4%)

10

䝛䝇䝥
䜲䞁䝍䝣䜵䝻䞁〇๣

పศᏊ་⸆

పศᏊ་⸆

48
(2016)

ప(ᚤቑ䠅

55䜺䞁䚸⢾ᒀ⑓䚸⑊③἞⒪⸆ ➼

୰ศᏊ་⸆mostly plasma but any may be
used (e.g., biopsies, urine, CSF)

AMS – accelerator mass spectrometry; PET – positron emission tomography; LC-MS/MS – liquid chromatography tandem mass spectrometry; LLOQ – lower-limit of quantification;
HPLC – high performance liquid chromatography; GMP – Good Manufacturing Practices; N/A – not applicable; t1/2 – half-life

CMC – chemistry, manufacturing, and controls
GMP – good manufacturing practices

䝰䝎䝸䝔䜱possible

N/A
continuous / dynamic‘counting’N/Acontinuous / dynamic‘counting’

Mostly 14C

Radiolabeling
Radiation
exposure
Site
Availability
Study costs

LC-MS/MS

1. ᪂䛯䛺⑌ᝈཎᅉ㑇ఏᏊ䛾ゎ᫂
2. ᶆⓗ㒊఩䜈䛾㏦㐩ᐇ⌧••⣽⬊እ䛷㠀ᖖ䛻୙Ᏻᐃ䛷䛒䜛⣽⬊⭷㏱㐣ᛶ䛜ప䛔

3. 㠀⮫ᗋ䛛䜙⮫ᗋ䜈䛾እᤄᛶ••⾑₢୰⃰ᗘ䛸స⏝㒊఩⃰ᗘ䛾┦㛵ᛶ䝃䝻䝀䞊䝖᰾㓟䛸㛤Ⓨ᰾㓟䛾┦㐪༢఩䠖඙෇Arthur D. Little Japan, 2020 䠄୍㒊ᨵኚ䠅䝬䜲䜽䝻䝗䞊䝈⮫ᗋヨ㦂䛾ᐇ᪋䛻㛵䛩䜛䜺䜲䝎䞁䝇䠄⸆㣗ᑂᰝⓎ➨ 0603001ྕ䚸2008ᖺ6᭶3᪥䠅᰾㓟་⸆ရ䛾Phase 0/microdosing ヨ㦂䛾ពᚿỴᐃ

1. ᐃ⩏ཬ䜃㐺⏝⠊ᅖ••᪩ᮇ䛻MDヨ㦂䛾䝕䞊䝍䛜ḧ䛧䛔

䝬䜲䜽䝻䝗䞊䝈⮫ᗋヨ㦂䛸䛿䚸䝠䝖䛻䛚䛔䛶⸆⌮స⏝䜢Ⓨ⌧䛩䜛䛸᥎ᐃ䛥䜜䜛ᢞ୚㔞䠄௨ୗ䛂⸆ຠⓎ⌧㔞䛃䛸䛔䛖䚹䠅䛾1/100䜢㉸䛘䛺䛔⏝㔞ཪ䛿 100 μg䛾䛔䛪䜜䛛䛾ᑡ䛺䛔⏝㔞䜢䚸೺ᗣ䛺⿕㦂⪅䛻༢ᅇᢞ୚䛩䜛䛣䛸䛻䜘䜚⾜䜟䜜䜛⮫ᗋヨ㦂䜢䛔䛖䚹䠄⸆ຠⓎ⌧㔞䜘䜚䜒᭱኱↓ẘᛶ㔞䠄NOAEL)䛾䜋䛖䛜ᑡ䛺䛔ሙྜ䛻䛿䚸NOAEL䛾1/100䜢㉸䛘䛺䛔⏝㔞ཪ䛿100 μg䛾䛔䛪䜜䛛ᑡ䛺䛔⏝㔞䜢᭱㧗⏝㔞䛸䛧䛶᥇⏝䛩䜉䛝䛷䛒䜛䚹

䛔䛔䛘

䛿䛔

ᶆ‽ⓗ䛺
Phase 1 ヨ㦂᪤Ꮡ䛾䜺䜲䝗䝷䜲
䞁䛷ᐇ᪋ྍ⬟䛛ᮏ䜺䜲䝎䞁䝇䛿䚸୺䛸䛧䛶పศᏊ໬ྜ≀䜢㐺ᛂ⠊ᅖ䛸䛧䛶䛔䜛䚹䛺䛚䚸⏕≀⏤᮶〇ရཪ䛿యෆ䛷ዴఱ䛺䜛ཷᐜయ䛜㛵୚䛩䜛䛛༑ศ䛺▱ぢ䛜ᚓ䜙䜜䛶䛔䛺䛔䜒䛾䛺䛹ᚑ᮶䛾་⸆ရ䛸䛿඲䛟␗䛺䜛స⏝ᶵᗎ䛻䜘䜛⸆⌮స⏝䜢ᮇᚅ䛧䛯໬ྜ≀䜢ᢞ୚䛩䜛ሙྜ䛻䛴䛔䛶䛿䚸ಶู䛻䛭䛾Ᏻ඲ᛶ➼䛻䛴䛔䛶䛾⪃ᐹ䛜ᚲせ䛷䛒䜚䚸ᮏ䜺䜲䝎䞁䝇䜢䛭䛾䜎䜎㐺⏝䛩䜛䛣䛸䛿䛷䛝䛺䛔䚹

䛿䛔

䛔䛔䛘

೺ᗣᡂே
MD ヨ㦂

• ⿕㦂⪅䛾䝯䝸䝑䝖䚸䝕䝯䝸䝑䝖䜢⪃៖• ึᅇᢞ୚㔞䛾タᐃ᰿ᣐᝈ⪅䜺䜲䝗䝷䜲䞁䛾ಟṇ

2. ┠ⓗ•⿕㦂≀㉁䛾䝠䝖䛻䛚䛡䜛⸆≀ືែ䛻㛵䛩䜛᝟ሗ䜢་⸆ရ䛾⮫ᗋ㛤Ⓨ䛾ึᮇẁ㝵䛻ᚓ䜛஦䛷䛒䜛䚹ලయⓗ䛻䛿䚸⿕㦂≀㉁䛾྾཰䜔⾑୰ືែ䚸᤼ἥ≉ᛶ䚸䝠䝖䛻䛚䛡䜛௦ㅰ≀䝥䝻䝣䜱䝹➼䜢᫂䜙䛛䛻䛩䜛䛣䛸䚸ศᏊ䜲䝯䞊䝆䞁䜾ᢏ⾡䜢⏝䛔䛶⿕㦂≀㉁䛾యෆ䛻䛚䛡䜛ᒁᅾ䛻㛵䛩䜛᝟ሗ䜢ᚓ䜛஦䛷䛒䜛䚹

೺ᗣᡂே
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