JP2024056686A - Drug for treating or preventing cell proliferative disorders, comprising a coumarin derivative - Google Patents
Drug for treating or preventing cell proliferative disorders, comprising a coumarin derivative Download PDFInfo
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Abstract
【課題】細胞増殖性疾患の治療又は予防用医薬を提供する。【解決手段】式(I)で表される化合物又はその薬学上許容され得る塩を有効成分として含有し、(a)前記化合物又は塩が週に2回、3週間投与され、(b)続く1週間、前記化合物又は塩の投与が休止され、(c)以後、ステップ(a)及び(b)が少なくとも1回繰り返されるように用いられる医薬を提供する。TIFF2024056686000011.tif29149【選択図】図1[Problem] To provide a medicine for treating or preventing cell proliferation diseases. [Solution] To provide a medicine containing a compound represented by formula (I) or a pharma- ceutical acceptable salt thereof as an active ingredient, the medicine being used in such a manner that (a) the compound or salt is administered twice a week for three weeks, (b) the administration of the compound or salt is suspended for the following one week, and (c) thereafter, steps (a) and (b) are repeated at least once. TIFF2024056686000011.tif29149 [Selected Figure] Figure 1
Description
特許法第30条第2項適用申請有り 刊行物:ジャーナル オブ クリニカル オンコロジー,第35巻,第15号,増刊,2017年5月20日,要旨番号2506,米国臨床腫瘍学会, ウェブページのURL:https://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.2506, https://meetinglibrary.asco.org/record/144582/abstract, 刊行物等:公開日 2017年6月3日 集会名 第53回米国臨床腫瘍学会年次総会Application for application of Article 30, Paragraph 2 of the Patent Act has been filed. Publication: Journal of Clinical Oncology, Vol. 35, No. 15, Supplement, May 20, 2017, Abstract No. 2506, American Society of Clinical Oncology, URL of web page: https://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.2506, https://meetinglibrary.asco.org/record/144582/abstract, Publication, etc.: Date of publication: June 3, 2017 Meeting name: 53rd Annual Meeting of the American Society of Clinical Oncology
本発明は、クマリン誘導体を含有する、細胞増殖性疾患、特にがんの治療又は予防用医薬に関する。 The present invention relates to a drug for treating or preventing cell proliferation disorders, particularly cancer, that contains a coumarin derivative.
下記式(I)で表される化合物(本明細書において「化合物(I)」とも言う。)及びその薬学上許容され得る塩(本明細書において単に「その塩」とも言う。)は、抗腫瘍活性等の薬理作用を有することが知られている(特許文献1又は2参照)。
化合物(I)又はその塩の用法及び用量に関しては、非小細胞肺癌、卵巣癌、子宮内膜癌、結腸・直腸癌などの固形癌の患者に対して、化合物(I)のカリウム塩を1回4mgの用量で週に2回投与することが知られている(非特許文献1参照)。 Regarding the dosage and administration of compound (I) or its salt, it is known that the potassium salt of compound (I) is administered at a dose of 4 mg twice a week to patients with solid cancers such as non-small cell lung cancer, ovarian cancer, endometrial cancer, and colorectal cancer (see Non-Patent Document 1).
上記投与レジメン(1回4mg,週2回)に従って化合物(I)又はその塩の投与を行ったところ、例えば皮疹の悪化により予定外の休薬及び/又は減量をした上で投与を継続する場合があった。 When compound (I) or a salt thereof was administered according to the above-mentioned administration regimen (4 mg once, twice a week), there were cases where administration was continued after unscheduled suspension and/or reduction due to, for example, worsening of the skin rash.
本発明は、このような事情に鑑みてなされたものであり、安全かつ長期的に実施可能な化合物(I)又はその塩の投与レジメン、及びそのような投与レジメンに基づいて用いられる細胞増殖性疾患(特にがん)の治療又は予防用医薬を提供することを目的とする。 The present invention has been made in view of the above circumstances, and aims to provide a safe and long-term administration regimen of compound (I) or a salt thereof, and a pharmaceutical for treating or preventing cell proliferative diseases (particularly cancer) that is used based on such an administration regimen.
本発明は、下記項目A1~A15に記載の医薬を提供する。
項目A1:
細胞増殖性疾患の治療又は予防用医薬であって、式(I):
で表される化合物又はその薬学上許容され得る塩を有効成分として含有し、
(a)前記化合物又は塩が週に2回、3週間投与され、
(b)続く1週間、前記化合物又は塩の投与が休止され、
(c)以後、ステップ(a)及び(b)が少なくとも1回繰り返される
ように用いられる前記医薬。
項目A2:
式(I)で表される化合物のカリウム塩を有効成分として含有する、項目A1に記載の医薬。
項目A3:
細胞増殖性疾患はがんである、項目A1又はA2に記載の医薬。
項目A4:
細胞増殖性疾患は、KRAS変異を有するがんである、項目A1~A3のいずれかに記載の医薬。
項目A5:
細胞増殖性疾患は固形癌である、項目A1~A4のいずれかに記載の医薬。
項目A6:
ステップ(a)における1回当たりの用量が3.2mgである、項目A1~A5のいずれかに記載の医薬。
項目A7:
ステップ(a)の前に、
(1)前記化合物又は塩が1回3.2mgの用量で週に2回投与され、又は
(2)
(2a)前記化合物又は塩が1回4mgの用量で週に2回、3週間投与され、
(2b)続く1週間、前記化合物又は塩の投与が休止され、
(2c)以後、ステップ(2a)及び(2b)が少なくとも1回繰り返される
ように用いられる、項目A6に記載の医薬。
項目A8:
ステップ(1)又は(2)の前に、前記化合物又は塩が1回4mgの用量で週に2回投与されるように用いられる、項目A7に記載の医薬。
項目A9:
項目A1~A5のいずれかに記載の医薬であって、
(R1)
(A)まず、前記化合物又は塩が1回4mgの用量で週に2回投与され、
(B1)次いで、前記化合物又は塩が1回3.2mgの用量で週に2回投与され、
(C)その後、
(Ca)前記化合物又は塩が1回3.2mgの用量で週に2回、3週間投与され、
(Cb)続く1週間、前記化合物又は塩の投与が休止され、
(Cc)以後、ステップ(Ca)及び(Cb)が少なくとも1回繰り返される
ように用いられるか、あるいは
(R2)
(A)まず、前記化合物又は塩が1回4mgの用量で週に2回投与され、
(B2)次いで、
(B2a)前記化合物又は塩が1回4mgの用量で週に2回、3週間投与され、
(B2b)続く1週間、前記化合物又は塩の投与が休止され、
(B2c)以後、ステップ(B2a)及び(B2b)が少なくとも1回繰り返される
ように用いられるか、あるいは
(R3)
(A)まず、前記化合物又は塩が1回4mgの用量で週に2回投与され、
(B2)次いで、
(B2a)前記化合物又は塩が1回4mgの用量で週に2回、3週間投与され、
(B2b)続く1週間、前記化合物又は塩の投与が休止され、
(B2c)以後、ステップ(B2a)及び(B2b)が少なくとも1回繰り返され、
(C)その後、
(Ca)前記化合物又は塩が1回3.2mgの用量で週に2回、3週間投与され、
(Cb)続く1週間、前記化合物又は塩の投与が休止され、
(Cc)以後、ステップ(Ca)及び(Cb)が少なくとも1回繰り返される
ように用いられる前記医薬。
項目A10:
細胞増殖性疾患は多発性骨髄腫である、項目A1~A4のいずれかに記載の医薬。
項目A11:
ステップ(a)における1回当たりの用量が4mgである、項目A10に記載の医薬。
項目A12:
細胞増殖性疾患は、NRAS変異を有するがんである、項目A10又はA11に記載の医薬。
項目A13:
デキサメタゾンと組み合わせて用いられる、項目A10~A12のいずれかに記載の医薬であって、前記化合物又は塩がデキサメタゾンの投与前、投与と同時、又は投与後に投与されるように用いられる前記医薬。
項目A14:
デキサメタゾンは1回20mgの用量で週に1回投与される、項目A13に記載の医薬。
項目A15:
前記化合物又は塩の投与は経口投与である、項目A1~A14のいずれかに記載の医薬。
The present invention provides pharmaceutical agents described in the following items A1 to A15.
Item A1:
A pharmaceutical composition for treating or preventing a cell proliferative disease, comprising a compound represented by formula (I):
or a pharma- ceutical acceptable salt thereof as an active ingredient,
(a) the compound or salt is administered twice weekly for three weeks;
(b) the administration of the compound or salt is discontinued for one week;
(c) Thereafter, steps (a) and (b) are repeated at least once.
Item A2:
The pharmaceutical agent according to item A1, which contains a potassium salt of the compound represented by formula (I) as an active ingredient.
Item A3:
The pharmaceutical agent according to item A1 or A2, wherein the cell proliferative disease is cancer.
Item A4:
The medicine according to any one of items A1 to A3, wherein the cell proliferative disease is a cancer having a KRAS mutation.
Item A5:
The medicine according to any one of items A1 to A4, wherein the cell proliferative disease is a solid cancer.
Item A6:
The pharmaceutical agent according to any one of items A1 to A5, wherein the dose per administration in step (a) is 3.2 mg.
Item A7:
Prior to step (a),
(1) the compound or salt is administered at a dose of 3.2 mg twice a week; or (2)
(2a) the compound or salt is administered at a dose of 4 mg twice a week for three weeks;
(2b) administration of the compound or salt is discontinued for one week;
The pharmaceutical agent according to item A6, wherein after (2c), steps (2a) and (2b) are repeated at least once.
Item A8:
The medicament according to item A7, wherein, prior to step (1) or (2), the compound or salt is administered at a dose of 4 mg twice a week.
Item A9:
The pharmaceutical composition according to any one of items A1 to A5,
(R1)
(A) first, the compound or salt is administered at a dose of 4 mg twice a week;
(B1) The compound or salt is then administered twice a week at a dose of 3.2 mg;
(C) Thereafter,
(Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for three weeks;
(Cb) administration of the compound or salt is suspended for one week;
(Cc) thereafter, steps (Ca) and (Cb) are used so as to be repeated at least once, or (R2)
(A) first, the compound or salt is administered at a dose of 4 mg twice a week;
(B2) Next,
(B2a) the compound or salt is administered at a dose of 4 mg twice a week for three weeks;
(B2b) administration of the compound or salt is suspended for one week;
(B2c) thereafter, steps (B2a) and (B2b) are used repeated at least once, or (R3)
(A) first, the compound or salt is administered at a dose of 4 mg twice a week;
(B2) Next,
(B2a) the compound or salt is administered at a dose of 4 mg twice a week for three weeks;
(B2b) administration of the compound or salt is suspended for one week;
After (B2c), steps (B2a) and (B2b) are repeated at least once,
(C) Thereafter,
(Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for three weeks;
(Cb) administration of the compound or salt is suspended for one week;
(Cc) The pharmaceutical composition according to the present invention, wherein steps (Ca) and (Cb) are repeated at least once after (Cc).
Item A10:
The pharmaceutical agent according to any one of items A1 to A4, wherein the cell proliferative disease is multiple myeloma.
Item A11:
The pharmaceutical agent according to item A10, wherein the dose per administration in step (a) is 4 mg.
Item A12:
The pharmaceutical agent according to item A10 or A11, wherein the cell proliferative disease is a cancer having an NRAS mutation.
Item A13:
The medicament according to any one of items A10 to A12, which is used in combination with dexamethasone, wherein the compound or salt is administered before, simultaneously with, or after administration of dexamethasone.
Item A14:
The medicament according to item A13, wherein dexamethasone is administered at a dose of 20 mg once a week.
Item A15:
The medicament according to any one of items A1 to A14, wherein the compound or salt is administered orally.
本発明の医薬は、化合物(I)又はその塩からなるものであってもよいし、他の成分をさらに含む医薬組成物であってもよい。 The medicine of the present invention may consist of compound (I) or a salt thereof, or may be a pharmaceutical composition further containing other ingredients.
本発明により、また、下記項目A16及びA17に記載の医薬が提供される。
項目A16:
式(I):
で表される化合物又はその薬学上許容され得る塩を有効成分として含有する、細胞増殖性疾患の治療又は予防用医薬であって、
(i)前記医薬を収容するための容器、及び
(ii)
(a)前記化合物又は塩が週に2回、3週間投与され、
(b)続く1週間、前記化合物又は塩の投与が休止され、
(c)以後、ステップ(a)及び(b)が少なくとも1回繰り返される
ように前記医薬を用いるための指示
とともにパッケージ化された前記医薬。
項目A17:
前記医薬は項目A1~A15のいずれかに記載の医薬であり、
前記指示は、当該医薬に対応する所定の投与レジメンに従って前記化合物又は塩が投与されるように前記医薬を用いるための指示である、
項目A16に記載の医薬。
The present invention also provides the pharmaceutical agents described in Items A16 and A17 below.
Item A16:
Formula (I):
or a pharma- ceutical agent for treating or preventing a cell proliferative disease, comprising, as an active ingredient, a compound represented by the formula:
(i) a container for containing the medicament; and (ii)
(a) the compound or salt is administered twice weekly for three weeks;
(b) the administration of the compound or salt is discontinued for one week;
(c) said medicament packaged together with instructions for using said medicament such that steps (a) and (b) are thereafter repeated at least one time.
Item A17:
The medicine is a medicine according to any one of items A1 to A15,
the instructions are for using the medicament such that the compound or salt is administered according to a predetermined dosing regimen corresponding to that medicament;
The medicament according to item A16.
本発明により、また、下記項目B1~B15に記載の方法が提供される。
項目B1:
細胞増殖性疾患の治療又は予防のための方法であって、
(a)式(I):
で表される化合物又はその薬学上許容され得る塩を週に2回、3週間投与し、
(b)続く1週間、前記化合物又は塩の投与を休止し、
(c)以後、ステップ(a)及び(b)を少なくとも1回繰り返す
ことを含む前記方法。
項目B2:
式(I)で表される化合物のカリウム塩が投与される、項目B1に記載の方法。
項目B3:
細胞増殖性疾患はがんである、項目B1又はB2に記載の方法。
項目B4:
細胞増殖性疾患は、KRAS変異を有するがんである、項目B1~B3のいずれかに記載の方法。
項目B5:
細胞増殖性疾患は固形癌である、項目B1~B4のいずれかに記載の方法。
項目B6:
ステップ(a)における1回当たりの用量が3.2mgである、項目B1~B5のいずれかに記載の方法。
項目B7:
ステップ(a)の前に、
(1)前記化合物又は塩を1回3.2mgの用量で週に2回投与し、又は
(2)
(2a)前記化合物又は塩を1回4mgの用量で週に2回、3週間投与し、
(2b)続く1週間、前記化合物又は塩の投与を休止し、
(2c)以後、ステップ(2a)及び(2b)を少なくとも1回繰り返す
ことを含む、項目B6に記載の方法。
項目B8:
ステップ(1)又は(2)の前に、前記化合物又は塩を1回4mgの用量で週に2回投与することを含む、項目B7に記載の方法。
項目B9:
項目B1~B5のいずれかに記載の方法であって、
(R1)
(A)まず、前記化合物又は塩を1回4mgの用量で週に2回投与し、
(B1)次いで、前記化合物又は塩を1回3.2mgの用量で週に2回投与し、
(C)その後、
(Ca)前記化合物又は塩を1回3.2mgの用量で週に2回、3週間投与し、
(Cb)続く1週間、前記化合物又は塩の投与を休止し、
(Cc)以後、ステップ(Ca)及び(Cb)を少なくとも1回繰り返す
ことを含むか、あるいは
(R2)
(A)まず、前記化合物又は塩を1回4mgの用量で週に2回投与し、
(B2)次いで、
(B2a)前記化合物又は塩を1回4mgの用量で週に2回、3週間投与し、
(B2b)続く1週間、前記化合物又は塩の投与を休止し、
(B2c)以後、ステップ(B2a)及び(B2b)を少なくとも1回繰り返す
ことを含むか、あるいは
(R3)
(A)まず、前記化合物又は塩を1回4mgの用量で週に2回投与し、
(B2)次いで、
(B2a)前記化合物又は塩を1回4mgの用量で週に2回、3週間投与し、
(B2b)続く1週間、前記化合物又は塩の投与を休止し、
(B2c)以後、ステップ(B2a)及び(B2b)を少なくとも1回繰り返し、
(C)その後、
(Ca)前記化合物又は塩を1回3.2mgの用量で週に2回、3週間投与し、
(Cb)続く1週間、前記化合物又は塩の投与を休止し、
(Cc)以後、ステップ(Ca)及び(Cb)を少なくとも1回繰り返す
ことを含む前記方法。
項目B10:
細胞増殖性疾患は多発性骨髄腫である、項目B1~B4のいずれかに記載の方法。
項目B11:
ステップ(a)における1回当たりの用量が4mgである、項目B10に記載の方法。
項目B12:
細胞増殖性疾患は、NRAS変異を有するがんである、項目B10又はB11に記載の方法。
項目B13:
前記化合物又は塩がデキサメタゾンと組み合わせて用いられる、項目B10~B12のいずれかに記載の方法であって、前記化合物又は塩をデキサメタゾンの投与前、投与と同時、又は投与後に投与することを含む前記方法。
項目B14:
デキサメタゾンは1回20mgの用量で週に1回投与される、項目B13に記載の方法。
項目B15:
前記化合物又は塩の投与は経口投与である、項目B1~B14のいずれかに記載の方法。
The present invention also provides the methods described in Items B1 to B15 below.
Item B1:
A method for treating or preventing a cell proliferative disorder, comprising:
(a) Formula (I):
or a pharma- ceutical acceptable salt thereof is administered twice a week for three weeks;
(b) then withdrawing administration of the compound or salt for one week;
(c) thereafter repeating steps (a) and (b) at least once.
Item B2:
The method according to claim B1, wherein a potassium salt of the compound of formula (I) is administered.
Item B3:
The method according to paragraph B1 or B2, wherein the cell proliferative disorder is cancer.
Item B4:
The method according to any one of items B1 to B3, wherein the cell proliferative disease is a cancer having a KRAS mutation.
Item B5:
The method according to any of paragraphs B1 to B4, wherein the cell proliferative disorder is a solid cancer.
Item B6:
The method according to any one of items B1 to B5, wherein the dose in step (a) is 3.2 mg.
Item B7:
Prior to step (a),
(1) administering the compound or salt at a dose of 3.2 mg twice a week; or (2)
(2a) administering the compound or salt at a dose of 4 mg twice a week for three weeks;
(2b) subsequently withdrawing administration of the compound or salt for one week;
The method according to claim B6, further comprising repeating steps (2a) and (2b) at least once after step (2c).
Item B8:
The method according to claim B7, comprising administering the compound or salt at a dose of 4 mg twice a week prior to step (1) or (2).
Item B9:
The method according to any one of Items B1 to B5,
(R1)
(A) first administering the compound or salt at a dose of 4 mg twice a week;
(B1) then administering the compound or salt at a dose of 3.2 mg twice a week;
(C) Thereafter,
(Ca) administering the compound or salt at a dose of 3.2 mg twice a week for three weeks;
(Cb) then withdrawing administration of the compound or salt for one week;
(Cc) thereafter, repeating steps (Ca) and (Cb) at least once; or (R2)
(A) first administering the compound or salt at a dose of 4 mg twice a week;
(B2) Next,
(B2a) administering the compound or salt at a dose of 4 mg twice a week for three weeks;
(B2b) then withdrawing administration of the compound or salt for one week;
(B2c) thereafter, repeating steps (B2a) and (B2b) at least once; or (R3).
(A) first administering the compound or salt at a dose of 4 mg twice a week;
(B2) Next,
(B2a) administering the compound or salt at a dose of 4 mg twice a week for three weeks;
(B2b) then withdrawing administration of the compound or salt for one week;
(B2c) After that, steps (B2a) and (B2b) are repeated at least once,
(C) Thereafter,
(Ca) administering the compound or salt at a dose of 3.2 mg twice a week for three weeks;
(Cb) then withdrawing administration of the compound or salt for one week;
After (Cc), the method further comprises repeating steps (Ca) and (Cb) at least once.
Item B10:
The method according to any of paragraphs B1 to B4, wherein the cell proliferative disorder is multiple myeloma.
Item B11:
The method according to item B10, wherein the dose in step (a) is 4 mg per administration.
Item B12:
The method according to item B10 or B11, wherein the cell proliferative disease is a cancer having an NRAS mutation.
Item B13:
The method according to any of items B10 to B12, wherein the compound or salt is used in combination with dexamethasone, the method comprising administering the compound or salt before, simultaneously with, or after administration of dexamethasone.
Item B14:
The method according to claim B13, wherein the dexamethasone is administered at a dose of 20 mg once a week.
Item B15:
The method according to any of items B1-B14, wherein the administration of the compound or salt is oral administration.
本発明により、また、下記項目C1~C15に記載の使用が提供される。
項目C1:
細胞増殖性疾患の治療又は予防用医薬の製造のための、式(I):
で表される化合物又はその薬学上許容され得る塩の使用であって、
前記医薬は、
(a)前記化合物又は塩が週に2回、3週間投与され、
(b)続く1週間、前記化合物又は塩の投与が休止され、
(c)以後、ステップ(a)及び(b)が少なくとも1回繰り返される
ように用いられる、前記使用。
項目C2:
式(I)で表される化合物のカリウム塩の使用である、項目C1に記載の使用。
項目C3:
細胞増殖性疾患はがんである、項目C1又はC2に記載の使用。
項目C4:
細胞増殖性疾患は、KRAS変異を有するがんである、項目C1~C3のいずれかに記載の使用。
項目C5:
細胞増殖性疾患は固形癌である、項目C1~C4のいずれかに記載の使用。
項目C6:
ステップ(a)における1回当たりの用量が3.2mgである、項目C1~C5のいずれかに記載の使用。
項目C7:
前記医薬は、ステップ(a)の前に、
(1)前記化合物又は塩が1回3.2mgの用量で週に2回投与され、又は
(2)
(2a)前記化合物又は塩が1回4mgの用量で週に2回、3週間投与され、
(2b)続く1週間、前記化合物又は塩の投与が休止され、
(2c)以後、ステップ(2a)及び(2b)が少なくとも1回繰り返される
ように用いられる、項目C6に記載の使用。
項目C8:
前記医薬は、ステップ(1)又は(2)の前に、前記化合物又は塩が1回4mgの用量で週に2回投与されるように用いられる、項目C7に記載の使用。
項目C9:
項目C1~C5のいずれかに記載の使用であって、
(R1)前記医薬は、
(A)まず、前記化合物又は塩が1回4mgの用量で週に2回投与され、
(B1)次いで、前記化合物又は塩が1回3.2mgの用量で週に2回投与され、
(C)その後、
(Ca)前記化合物又は塩が1回3.2mgの用量で週に2回、3週間投与され、
(Cb)続く1週間、前記化合物又は塩の投与が休止され、
(Cc)以後、ステップ(Ca)及び(Cb)が少なくとも1回繰り返される
ように用いられるか、あるいは
(R2)前記医薬は、
(A)まず、前記化合物又は塩が1回4mgの用量で週に2回投与され、
(B2)次いで、
(B2a)前記化合物又は塩が1回4mgの用量で週に2回、3週間投与され、
(B2b)続く1週間、前記化合物又は塩の投与が休止され、
(B2c)以後、ステップ(B2a)及び(B2b)が少なくとも1回繰り返される
ように用いられるか、あるいは
(R3)前記医薬は、
(A)まず、前記化合物又は塩が1回4mgの用量で週に2回投与され、
(B2)次いで、
(B2a)前記化合物又は塩が1回4mgの用量で週に2回、3週間投与され、
(B2b)続く1週間、前記化合物又は塩の投与が休止され、
(B2c)以後、ステップ(B2a)及び(B2b)が少なくとも1回繰り返され、
(C)その後、
(Ca)前記化合物又は塩が1回3.2mgの用量で週に2回、3週間投与され、
(Cb)続く1週間、前記化合物又は塩の投与が休止され、
(Cc)以後、ステップ(Ca)及び(Cb)が少なくとも1回繰り返される
ように用いられる、前記使用。
項目C10:
細胞増殖性疾患は多発性骨髄腫である、項目C1~C4のいずれかに記載の使用。
項目C11:
ステップ(a)における1回当たりの用量が4mgである、項目C10に記載の使用。
項目C12:
細胞増殖性疾患は、NRAS変異を有するがんである、項目C10又はC11に記載の使用。
項目C13:
前記医薬がデキサメタゾンと組み合わせて用いられる、項目C10~C12のいずれかに記載の使用であって、前記化合物又は塩がデキサメタゾンの投与前、投与と同時、又は投与後に投与されるように用いられる前記使用。
項目C14:
デキサメタゾンは1回20mgの用量で週に1回投与される、項目C13に記載の使用。
項目C15:
前記化合物又は塩の投与は経口投与である、項目C1~C14のいずれかに記載の使用。
The present invention also provides the uses described in items C1 to C15 below.
Item C1:
For the manufacture of a medicament for treating or preventing a cell proliferative disease,
or a pharma- ceutically acceptable salt thereof,
The medicine is
(a) the compound or salt is administered twice weekly for three weeks;
(b) the administration of the compound or salt is discontinued for one week;
(c) Thereafter, steps (a) and (b) are repeated at least once.
Item C2:
The use according to item C1, which is the use of a potassium salt of the compound represented by formula (I).
Item C3:
The use according to item C1 or C2, wherein the cell proliferative disorder is cancer.
Item C4:
The use according to any of items C1 to C3, wherein the cell proliferative disease is a cancer with a KRAS mutation.
Item C5:
The use according to any of paragraphs C1 to C4, wherein the cell proliferative disorder is a solid cancer.
Item C6:
The use according to any one of items C1 to C5, wherein the dose in step (a) is 3.2 mg per administration.
Item C7:
The medicament, prior to step (a),
(1) the compound or salt is administered at a dose of 3.2 mg twice a week; or (2)
(2a) the compound or salt is administered at a dose of 4 mg twice a week for three weeks;
(2b) administration of the compound or salt is discontinued for one week;
The use according to item C6, wherein after (2c), steps (2a) and (2b) are repeated at least once.
Item C8:
The use according to item C7, wherein the medicament is used such that, prior to step (1) or (2), the compound or salt is administered at a dose of 4 mg twice a week.
Item C9:
The use according to any one of items C1 to C5,
(R1) The medicine is
(A) first, the compound or salt is administered at a dose of 4 mg twice a week;
(B1) The compound or salt is then administered twice a week at a dose of 3.2 mg;
(C) Thereafter,
(Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for three weeks;
(Cb) administration of the compound or salt is suspended for one week;
(Cc) thereafter, steps (Ca) and (Cb) are repeated at least once, or (R2) the medicament is
(A) first, the compound or salt is administered at a dose of 4 mg twice a week;
(B2) Next,
(B2a) the compound or salt is administered at a dose of 4 mg twice a week for three weeks;
(B2b) administration of the compound or salt is suspended for one week;
(B2c) thereafter, steps (B2a) and (B2b) are repeated at least once, or (R3) the medicament is
(A) first, the compound or salt is administered at a dose of 4 mg twice a week;
(B2) Next,
(B2a) the compound or salt is administered at a dose of 4 mg twice a week for three weeks;
(B2b) administration of the compound or salt is suspended for one week;
After (B2c), steps (B2a) and (B2b) are repeated at least once,
(C) Thereafter,
(Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for three weeks;
(Cb) administration of the compound or salt is suspended for one week;
(Cc) After that, steps (Ca) and (Cb) are repeated at least once.
Item C10:
The use according to any of paragraphs C1 to C4, wherein the cell proliferative disorder is multiple myeloma.
Item C11:
The use according to item C10, wherein the dose in step (a) is 4 mg per administration.
Item C12:
The use according to item C10 or C11, wherein the cell proliferative disease is a cancer with an NRAS mutation.
Item C13:
The use according to any of items C10 to C12, wherein the medicament is used in combination with dexamethasone, wherein the compound or salt is administered before, simultaneously with, or after administration of dexamethasone.
Item C14:
The use according to item C13, wherein dexamethasone is administered at a dose of 20 mg once a week.
Item C15:
The use according to any of items C1 to C14, wherein the administration of the compound or salt is oral administration.
本発明において使用される投与レジメンは、一定の休止期間を含むサイクルを繰り返すことを含むものであり、副作用を抑制し、かつ薬効を維持しつつ、化合物(I)又はその塩を長期的に投与することを可能とする。また、患者への負担を抑制しつつ、細胞増殖性疾患、特にがんを治療又は予防することを可能とする。 The administration regimen used in the present invention involves repeating a cycle including a certain rest period, which makes it possible to administer compound (I) or a salt thereof for a long period of time while suppressing side effects and maintaining efficacy. It also makes it possible to treat or prevent cell proliferative diseases, particularly cancer, while suppressing the burden on the patient.
本発明により、安全かつ長期的に実施可能な化合物(I)又はその塩の投与レジメン、及びそのような投与レジメンに基づいて用いられる細胞増殖性疾患(特にがん)の治療又は予防用医薬が提供される。 The present invention provides a safe and long-term dosing regimen for compound (I) or a salt thereof, and a pharmaceutical for treating or preventing a cell proliferative disease (particularly cancer) that is used based on such a dosing regimen.
以下、本発明の例示的な実施形態を説明する。 The following describes an exemplary embodiment of the present invention.
化合物(I)及びその塩は、WO2007/091736又はWO2013/035754に記載の方法により製造することができる。 Compound (I) and its salts can be prepared by the methods described in WO2007/091736 or WO2013/035754.
本発明で使用される有効成分としては化合物(I)の薬学上許容され得る塩が好ましい。そのような塩としては、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、リン酸塩等の無機酸塩;メタンスルホン酸塩、ベンゼンスルホン酸、トルエンスルホン酸塩等のスルホン酸塩;ギ酸塩、酢酸塩、シュウ酸塩、マレイン酸塩、フマル酸塩、クエン酸塩、リンゴ酸塩、コハク酸塩、マロン酸塩、グルコン酸塩、マンデル酸塩、安息香酸塩、サリチル酸塩、フルオロ酢酸塩、トリフルオロ酢酸塩、酒石酸塩、プロピオン酸塩、グルタル酸塩等のカルボン酸塩;リチウム塩、ナトリウム塩、カリウム塩、セシウム塩、ルビジウム塩等のアルカリ金属塩;マグネシウム塩、カルシウム塩等のアルカリ土類金属塩;アンモニウム塩、アルキルアンモニウム塩、ジアルキルアンモニウム塩、トリアルキルアンモニウム塩、テトラアルキルアンモニウム塩等のアンモニウム塩等が挙げられる。中でも、リチウム塩、ナトリウム塩、カリウム塩、セシウム塩、ルビジウム塩等のアルカリ金属塩が好ましく、ナトリウム塩及びカリウム塩がより好ましく、カリウム塩が特に好ましい。化合物(I)のカリウム塩の具体例としては、例えば下記式(Ia)で表される塩が挙げられる。
本発明の医薬又は方法によって治療又は予防される細胞増殖性疾患としては、がん、リウマチ及び炎症が挙げられ、好ましくはがんである。 Cell proliferation diseases that can be treated or prevented by the pharmaceutical or method of the present invention include cancer, rheumatism, and inflammation, and preferably cancer.
がんとしては、例えば、白血病(急性骨髄性白血病、急性リンパ性白血病、慢性骨髄性白血病、慢性リンパ性白血病等)、悪性リンパ腫(ホジキン病、非ホジキンリンパ腫等)、多発性骨髄腫、及び骨髄異形成症候群等の血液及びリンパのがん、脳腫瘍及び神経膠腫等の中枢神経系のがん、並びに頭頚部癌(咽頭癌、喉頭癌、舌癌等)、食道癌、胃癌、大腸癌(盲腸癌、結腸癌、直腸癌等)、肺癌(小細胞癌、非小細胞癌等)、甲状腺癌、乳癌、胆のう癌、膵癌、肝臓癌、前立腺癌、卵巣癌、子宮癌(子宮内膜癌、子宮頸癌等)、精巣癌、腎細胞癌、膀胱癌、腎盂・尿管癌、悪性黒色腫及び皮膚癌(基底細胞癌、有棘細胞癌、乳房外パジェット病、メルケル細胞癌、汗腺癌(例えば、アポクリン腺癌又はエクリン腺癌)、脂腺癌、毛包上皮腫等)等の固形癌が挙げられる。血液又はリンパのがんとしては多発性骨髄腫が好ましい。固形癌としては、例えば、卵巣癌、乳癌、子宮癌、大腸癌及び肺癌が好ましく、非小細胞肺癌が特に好ましい。がんとしては、多発性骨髄腫及び固形癌が好ましく、多発性骨髄腫及び非小細胞肺癌が特に好ましい。 Examples of cancer include leukemia (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's disease, non-Hodgkin's lymphoma, etc.), multiple myeloma, myelodysplastic syndrome, and other blood and lymphatic cancers, brain tumors, gliomas, and other central nervous system cancers, as well as head and neck cancers (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, stomach cancer, and colorectal cancer (appendiculoma, colon cancer, rectal cancer). etc.), lung cancer (small cell carcinoma, non-small cell carcinoma, etc.), thyroid cancer, breast cancer, gallbladder cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (endometrial cancer, cervical cancer, etc.), testicular cancer, renal cell carcinoma, bladder cancer, renal pelvis/ureter cancer, malignant melanoma, and skin cancer (basal cell carcinoma, squamous cell carcinoma, extramammary Paget's disease, Merkel cell carcinoma, sweat gland carcinoma (e.g., apocrine gland carcinoma or eccrine gland carcinoma), sebaceous gland carcinoma, trichoepithelioma, etc.). As a blood or lymphatic cancer, multiple myeloma is preferred. As a solid cancer, for example, ovarian cancer, breast cancer, uterine cancer, colon cancer, and lung cancer are preferred, and non-small cell lung cancer is particularly preferred. As a cancer, multiple myeloma and solid cancer are preferred, and multiple myeloma and non-small cell lung cancer are particularly preferred.
がんは、遺伝子変異を有していても、遺伝子変異を有していなくても、又はそのいずれであるかが不明であってもよいが、遺伝子変異を有するものが好ましい。変異が生じる遺伝子としては、例えば、EGFR、FGFR、ALK、ROS1、PI3K、BRAF、HRAS、KRAS及びNRASが挙げられる。がんとしては、KRAS変異及び/又はNRAS変異を有するものが好ましく、KRAS変異及びNRAS変異を有する多発性骨髄腫並びにKRAS変異を有する固形癌(特に非小細胞肺癌)が特に好ましい。遺伝子変異を有するがんとしては例えばHRAS変異アポクリン腺癌も好ましい。 The cancer may have a genetic mutation, may not have a genetic mutation, or may be unknown, but preferably has a genetic mutation. Examples of genes that may be mutated include EGFR, FGFR, ALK, ROS1, PI3K, BRAF, HRAS, KRAS, and NRAS. The cancer is preferably one that has a KRAS mutation and/or NRAS mutation, and is particularly preferably multiple myeloma with a KRAS mutation and multiple myeloma with a KRAS mutation, and solid cancer (particularly non-small cell lung cancer) with a KRAS mutation. Another preferred example of a cancer that has a genetic mutation is HRAS-mutated apocrine adenocarcinoma.
化合物(I)又はその塩が投与される対象は動物であり、好ましくは哺乳動物(例えば、マウス、ラット、ウサギ、イヌ、サル(例えばカニクイザル)、及びヒト)であり、特に好ましくはヒトである。ヒトは、成人(18歳以上)であってもよいし、小児(18歳未満)であってもよい。小児は、好ましくは例えば生後6か月以上である。 The subject to which compound (I) or a salt thereof is administered is an animal, preferably a mammal (e.g., mouse, rat, rabbit, dog, monkey (e.g., cynomolgus monkey), and human), and particularly preferably a human. The human may be an adult (18 years of age or older) or a child (under 18 years of age). The child is preferably, for example, 6 months of age or older.
対象への投与方法としては、例えば、経口投与、直腸投与、静脈内投与、筋肉内投与、皮下投与、槽内投与、膣内投与、腹腔内投与、膀胱内投与、吸入投与等の全身投与、及び軟膏剤、ゲル剤、クリーム剤等による局所投与が挙げられるが、経口投与が好ましい。 Methods of administration to a subject include systemic administration such as oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intracisternal administration, intravaginal administration, intraperitoneal administration, intravesical administration, and inhalation administration, as well as local administration using ointments, gels, creams, etc., with oral administration being preferred.
化合物(I)又はその塩は、通常、一定の製剤(剤形)に製剤化して用いられる。そのような製剤としては、例えば、錠剤、カプセル剤、顆粒剤、散剤、細粒剤、丸剤、並びに水性又は非水性の溶液及び懸濁液が挙げられる。溶液及び懸濁液は、個々の用量に小分けするのに適した容器に充填して保管することができる。 Compound (I) or a salt thereof is usually formulated into a certain preparation (dosage form) for use. Such preparations include, for example, tablets, capsules, granules, powders, fine granules, pills, and aqueous or non-aqueous solutions and suspensions. The solutions and suspensions can be filled and stored in containers suitable for subdivision into individual doses.
上記の各種製剤は、化合物(I)又はその塩と薬剤学的に許容され得る添加剤とを混和して、周知の方法で製造することができる。そのような添加剤としては、賦形剤、滑沢剤(コーティング剤)、結合剤、崩壊剤、安定剤、矯味矯臭剤、基剤、分散剤、希釈剤、界面活性剤、乳化剤等が挙げられる。 The above-mentioned various preparations can be produced by mixing compound (I) or a salt thereof with pharma- ceutically acceptable additives in a known manner. Such additives include excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, emulsifiers, etc.
賦形剤としては、例えば、デンプン(デンプン、バレイショデンプン、トウモロコシデンプン等)、乳糖、結晶セルロース、及びリン酸水素カルシウムが挙げられる。 Examples of excipients include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and calcium hydrogen phosphate.
滑沢剤(コーティング剤)としては、例えば、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、セラック、タルク、カルナウバロウ、及びパラフィンが挙げられる。 Lubricants (coating agents) include, for example, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, shellac, talc, carnauba wax, and paraffin.
結合剤としては、例えば、ポリビニルピロリドン及びマクロゴールの他、上記賦形剤と同様の化合物が挙げられる。 Examples of binders include polyvinylpyrrolidone and macrogol, as well as compounds similar to the excipients listed above.
崩壊剤としては、例えば、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、架橋ポリビニルピロリドン等、化学修飾されたデンプン類及びセルロース類の他、上記賦形剤と同様の化合物が挙げられる。 Disintegrants include, for example, croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and other chemically modified starches and celluloses, as well as compounds similar to the excipients listed above.
安定剤としては、例えば、メチルパラベン、プロピルパラベン等のパラオキシ安息香酸エステル類;塩化ベンザルコニウム;フェノール、クレゾール等のフェノール類;チメロサール;デヒドロ酢酸;及びソルビン酸が挙げられる。 Examples of stabilizers include paraoxybenzoic acid esters such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
矯味矯臭剤としては、例えば、通常使用される、甘味料、酸味料、香料等が挙げられる。 Flavors and flavorings include, for example, commonly used sweeteners, acidulants, fragrances, etc.
基剤としては、例えば、豚脂等の脂肪類;オリーブ油、ゴマ油等の植物油;ステアリルアルコール、セタノール等の高級アルコール類;動物油;ラノリン酸;ワセリン;パラフィン;ベントナイト;グリセリン;及びグリコール油が挙げられる。 Examples of bases include fats such as lard; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetanol; animal oils; lanolin; petrolatum; paraffin; bentonite; glycerin; and glycolic oil.
分散剤としては、例えば、セルロース誘導体(アラビアゴム、トラガント、メチルセルロース等)、ステアリン酸ポリエステル類、セスキオレイン酸ソルビタン、モノステアリン酸アルミニウム、アルギン酸ナトリウム、ポリソルベート類、及びソルビタン脂肪酸エステル類が挙げられる。 Examples of dispersants include cellulose derivatives (gum arabic, tragacanth, methylcellulose, etc.), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters.
液剤における溶媒又は希釈剤としては、例えば、フェノール、クロロクレゾール、精製水、及び蒸留水が挙げられる。 Solvents or diluents in liquid formulations include, for example, phenol, chlorocresol, purified water, and distilled water.
界面活性剤又は乳化剤としては、例えば、ポリソルベート80、ステアリン酸ポリオキシル40、及びラウロマクロゴールが挙げられる。 Surfactants or emulsifiers include, for example, polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.
製剤中の化合物(I)又はその塩の好ましい含有割合は剤形に応じて異なるが、一般に、製剤の全重量に対して0.01~100重量%である。 The preferred content of compound (I) or a salt thereof in the formulation varies depending on the dosage form, but is generally 0.01 to 100% by weight based on the total weight of the formulation.
製剤中の化合物(I)又はその塩の含有量は、予定される用量に応じて適宜設定され得る。好ましい含有量は、例えば0.01mg~10mgであり、製剤がカプセル剤の場合は例えば0.1mg~4mgである。さらに好ましい含有量としては例えば0.8mgが挙げられる。 The content of compound (I) or a salt thereof in the formulation can be appropriately set according to the intended dose. A preferred content is, for example, 0.01 mg to 10 mg, and when the formulation is a capsule, for example, it is 0.1 mg to 4 mg. A more preferred content is, for example, 0.8 mg.
本発明で使用される投与レジメンでは、化合物(I)又はその塩が次のように投与される。
(a)化合物(I)又はその塩が週に2回、3週間投与され、
(b)続く1週間、化合物(I)又はその塩の投与が休止され、
(c)以後、ステップ(a)及び(b)が少なくとも1回繰り返される。
In the dosing regimen used in the present invention, Compound (I) or a salt thereof is administered as follows.
(a) compound (I) or a salt thereof is administered twice a week for three weeks;
(b) the administration of compound (I) or a salt thereof is suspended for one week;
(c) Thereafter, steps (a) and (b) are repeated at least once.
本発明において、「週に2回」投与されるとは、1週間の期間内に、化合物(I)又はその塩が2回投与されることを意味する。投与は、同日に2回行ってもよいし、1日に1回、異なる日(連続する日であり得る。)に行ってもよいが、異なる日に行うのが好ましい。投与間隔ができるだけ均等になるように、すなわち、3~4日の投与間隔で化合物(I)又はその塩が投与されるように、例えば、当該期間の1及び4日目に又は3及び6日目に投与を行うのがさらに好ましい。1週間の期間は、例えば、月曜日に開始されてもよいし、水曜日に開始されてもよい。2回の投与が異なる日に行われる場合、各回の投与はどの時刻に行ってもよいが、ほぼ同じ時刻(例えば朝食後)に行うのが好ましい。 In the present invention, administration "twice a week" means that compound (I) or a salt thereof is administered twice within a one-week period. The administration may be twice on the same day, or once a day on different days (which may be consecutive days), but is preferably administered on different days. It is more preferable to administer compound (I) or a salt thereof, for example, on the first and fourth days or the third and sixth days of the period, so that the administration intervals are as even as possible, i.e., so that compound (I) or a salt thereof is administered at an administration interval of 3 to 4 days. The one-week period may start, for example, on Monday or Wednesday. When the two administrations are administered on different days, each administration may be administered at any time, but is preferably administered at approximately the same time (e.g., after breakfast).
1回当たりの化合物(I)又はその塩の用量は、好ましくは3.2mg又は4mgである。がんが多発性骨髄腫である場合は4mgが好ましく、がんが固形癌(特に非小細胞肺癌)である場合は3.2mg又は4mgが好ましい。 The dose of compound (I) or a salt thereof per administration is preferably 3.2 mg or 4 mg. When the cancer is multiple myeloma, 4 mg is preferred, and when the cancer is a solid cancer (particularly non-small cell lung cancer), 3.2 mg or 4 mg is preferred.
ステップ(a)及び(b)からなる4週間のサイクルは、例えば、2回(8週間)~60回(約4年8か月間)繰り返され、より具体的には、例えば8回(32週間)又は18回(72週間)繰り返される。繰り返すサイクル数が一旦決定されたとしても、サイクル数は、対象の状態等に応じて、医師又は獣医師の判断に基づいて変更され得る。また、対象の状態等に応じて、医師又は獣医師の判断に基づいて、サイクルの途中で投与を中止することもできる。 The 4-week cycle consisting of steps (a) and (b) is repeated, for example, 2 times (8 weeks) to 60 times (approximately 4 years and 8 months), and more specifically, for example, 8 times (32 weeks) or 18 times (72 weeks). Even if the number of cycles to be repeated is once determined, the number of cycles may be changed based on the judgment of a physician or veterinarian depending on the subject's condition, etc. Furthermore, administration may be discontinued midway through a cycle based on the judgment of a physician or veterinarian depending on the subject's condition, etc.
一実施形態では、ステップ(a)の前に、
(1)化合物(I)又はその塩が1回3.2mgの用量で週に2回投与され、又は
(2)
(2a)化合物(I)又はその塩が1回4mgの用量で週に2回、3週間投与され、
(2b)続く1週間、化合物(I)又はその塩の投与が休止され、
(2c)以後、ステップ(2a)及び(2b)が少なくとも1回繰り返される。
さらに、場合により、ステップ(1)又は(2)の前に、
(3)化合物(I)又はその塩が1回4mgの用量で週に2回投与される。
In one embodiment, prior to step (a),
(1) Compound (I) or a salt thereof is administered at a dose of 3.2 mg twice a week, or (2)
(2a) Compound (I) or a salt thereof is administered at a dose of 4 mg twice a week for three weeks;
(2b) the administration of compound (I) or a salt thereof is suspended for one week;
(2c) After that, steps (2a) and (2b) are repeated at least once.
Further, optionally, prior to step (1) or (2),
(3) Compound (I) or a salt thereof is administered at a dose of 4 mg twice a week.
この実施形態の投与レジメンに基づいて治療又は予防される細胞増殖性疾患としては、固形癌が好ましく、非小細胞肺癌が特に好ましい。 The cell proliferative disease to be treated or prevented based on the administration regimen of this embodiment is preferably a solid cancer, and particularly preferably non-small cell lung cancer.
ステップ(1)では、4週間の投与を1サイクルとして、当該サイクルが通常、2回(8週間)~30回(約2年4か月間)繰り返され、好ましくは例えば13回(52週間)繰り返される。 In step (1), one cycle consists of four weeks of administration, and the cycle is usually repeated 2 times (8 weeks) to 30 times (approximately 2 years and 4 months), and preferably 13 times (52 weeks), for example.
ステップ(3)では、4週間の投与を1サイクルとして、当該サイクルが通常、2回(8週間)~30回(約2年4か月間)繰り返され、好ましくは例えば8回(32週間)繰り返される。 In step (3), one cycle is a four-week administration, and the cycle is usually repeated two (eight weeks) to 30 times (approximately two years and four months), and preferably, for example, eight times (32 weeks).
ステップ(1)及び(3)では、繰り返すサイクル数が一旦決定されたとしても、サイクル数は、対象の状態等に応じて、医師又は獣医師の判断に基づいて変更され得る。また、対象の状態等に応じて、医師又は獣医師の判断に基づいて、サイクルの途中で投与を中止することもできる。 In steps (1) and (3), even if the number of cycles to be repeated is once determined, the number of cycles may be changed based on the judgment of a physician or veterinarian depending on the subject's condition, etc. Furthermore, administration may be discontinued midway through a cycle based on the judgment of a physician or veterinarian depending on the subject's condition, etc.
また、一実施形態では、化合物(I)又はその塩が次のように投与される。
(R1)
(A)まず、化合物(I)又はその塩が1回4mgの用量で週に2回投与され、
(B1)次いで、化合物(I)又はその塩が1回3.2mgの用量で週に2回投与され、
(C)その後、
(Ca)化合物(I)又はその塩が1回3.2mgの用量で週に2回、3週間投与され、
(Cb)続く1週間、化合物(I)又はその塩の投与が休止され、
(Cc)以後、ステップ(Ca)及び(Cb)が少なくとも1回繰り返されるか、あるいは
(R2)
(A)まず、化合物(I)又はその塩が1回4mgの用量で週に2回投与され、
(B2)次いで、
(B2a)化合物(I)又はその塩が1回4mgの用量で週に2回、3週間投与され、
(B2b)続く1週間、化合物(I)又はその塩の投与が休止され、
(B2c)以後、ステップ(B2a)及び(B2b)が少なくとも1回繰り返されるか、あるいは
(R3)
(A)まず、化合物(I)又はその塩が1回4mgの用量で週に2回投与され、
(B2)次いで、
(B2a)化合物(I)又はその塩が1回4mgの用量で週に2回、3週間投与され、
(B2b)続く1週間、化合物(I)又はその塩の投与が休止され、
(B2c)以後、ステップ(B2a)及び(B2b)が少なくとも1回繰り返され、
(C)その後、
(Ca)化合物(I)又はその塩が1回3.2mgの用量で週に2回、3週間投与され、
(Cb)続く1週間、化合物(I)又はその塩の投与が休止され、
(Cc)以後、ステップ(Ca)及び(Cb)が少なくとも1回繰り返される。
(R1)~(R3)のいずれが選択されるべきかは、対象において観察された有害事象の重症度又はグレード等に応じて、例えば図3に示される投与ガイダンスに従って決定され得る。
Also, in one embodiment, compound (I) or a salt thereof is administered as follows:
(R1)
(A) First, compound (I) or a salt thereof is administered at a dose of 4 mg twice a week;
(B1) Compound (I) or a salt thereof is then administered twice a week at a dose of 3.2 mg;
(C) Thereafter,
(Ca) Compound (I) or a salt thereof is administered at a dose of 3.2 mg twice a week for three weeks;
(Cb) the administration of compound (I) or a salt thereof is suspended for one week;
After (Cc), steps (Ca) and (Cb) are repeated at least once, or (R2)
(A) First, compound (I) or a salt thereof is administered at a dose of 4 mg twice a week;
(B2) Next,
(B2a) Compound (I) or a salt thereof is administered at a dose of 4 mg twice a week for three weeks;
(B2b) the administration of compound (I) or a salt thereof is suspended for one week;
After (B2c), steps (B2a) and (B2b) are repeated at least once, or (R3)
(A) First, compound (I) or a salt thereof is administered at a dose of 4 mg twice a week;
(B2) Next,
(B2a) Compound (I) or a salt thereof is administered at a dose of 4 mg twice a week for three weeks;
(B2b) the administration of compound (I) or a salt thereof is suspended for one week;
After (B2c), steps (B2a) and (B2b) are repeated at least once,
(C) Thereafter,
(Ca) Compound (I) or a salt thereof is administered at a dose of 3.2 mg twice a week for three weeks;
(Cb) the administration of compound (I) or a salt thereof is suspended for one week;
After (Cc), steps (Ca) and (Cb) are repeated at least once.
Which of (R1) to (R3) should be selected can be determined according to the severity or grade of the adverse event observed in the subject, for example, according to the administration guidance shown in FIG.
この実施形態の投与レジメンに基づいて治療又は予防される細胞増殖性疾患としては、がんが好ましく、固形癌がより好ましい。固形癌の中では、非小細胞肺癌が好ましく、KRAS変異を有する非小細胞肺癌が特に好ましい。 The cell proliferative disease to be treated or prevented based on the administration regimen of this embodiment is preferably cancer, more preferably solid cancer. Among solid cancers, non-small cell lung cancer is preferred, and non-small cell lung cancer with a KRAS mutation is particularly preferred.
ステップ(A)では、4週間の投与を1サイクルとして、当該サイクルが通常、2回(8週間)~30回(約2年4か月間)繰り返され、好ましくは例えば13回(52週間)繰り返される。 In step (A), one cycle is a four-week administration, and the cycle is usually repeated 2 times (8 weeks) to 30 times (approximately 2 years and 4 months), and preferably 13 times (52 weeks), for example.
ステップ(B1)では、4週間の投与を1サイクルとして、当該サイクルが通常、2回(8週間)~30回(約2年4か月間)繰り返され、好ましくは例えば8回(32週間)繰り返される。 In step (B1), one cycle is a four-week administration, and the cycle is usually repeated two (eight weeks) to 30 times (approximately two years and four months), and preferably, for example, eight times (32 weeks).
ステップ(A)、(B1)、(B2)及び(C)では、繰り返すサイクル数が一旦決定されたとしても、サイクル数は、対象の状態等に応じて、医師又は獣医師の判断に基づいて変更され得る。また、対象の状態等に応じて、医師又は獣医師の判断に基づいて、サイクルの途中で投与を中止することもできる。 In steps (A), (B1), (B2), and (C), even if the number of cycles to be repeated is once determined, the number of cycles may be changed based on the judgment of a physician or veterinarian depending on the subject's condition, etc. Furthermore, administration may be discontinued midway through a cycle based on the judgment of a physician or veterinarian depending on the subject's condition, etc.
化合物(I)又はその塩は単独で又は他の薬物と組み合わせて用いられ得る。他の薬物と組み合わせて用いられる場合、他の薬物としては、例えば、制吐剤及び抗がん剤が挙げられ、抗がん剤が好ましい。抗がん剤としては、例えば、サリドマイド、レナリドミド等のサリドマイド系抗がん剤、ボルテゾミブ、イキサゾミブ等のプロテオソーム阻害剤、及びデキサメタゾン、プレドニゾロン等のステロイド系抗がん剤が挙げられる。 Compound (I) or a salt thereof may be used alone or in combination with other drugs. When used in combination with other drugs, examples of the other drugs include antiemetics and anticancer drugs, with anticancer drugs being preferred. Examples of anticancer drugs include thalidomide-based anticancer drugs such as thalidomide and lenalidomide, proteosome inhibitors such as bortezomib and ixazomib, and steroid-based anticancer drugs such as dexamethasone and prednisolone.
がんが例えば非小細胞肺癌である場合、化合物(I)又はその塩は単独で用いるのが好ましい。 When the cancer is, for example, non-small cell lung cancer, it is preferable to use compound (I) or a salt thereof alone.
化合物(I)又はその塩が他の薬物と組み合わせて多発性骨髄腫の治療に用いられる場合、他の薬物としては例えばデキサメタゾンが好ましい。デキサメタゾンは多発性骨髄腫の標準治療に含まれる薬物である。 When compound (I) or a salt thereof is used in combination with another drug for the treatment of multiple myeloma, the other drug is preferably, for example, dexamethasone. Dexamethasone is a drug included in the standard treatment for multiple myeloma.
化合物(I)又はその塩がデキサメタゾンと組み合わせて多発性骨髄腫の治療に用いられる場合、デキサメタゾンは週に1回投与されるのが好ましく、1回当たりのデキサメタゾンの用量としては例えば20mgが好ましい。 When compound (I) or a salt thereof is used in combination with dexamethasone to treat multiple myeloma, dexamethasone is preferably administered once a week, and the dose of dexamethasone per administration is preferably, for example, 20 mg.
化合物(I)又はその塩がデキサメタゾンと組み合わせて用いられる場合、それらの投与の順序及びタイミングは特に限定されず、化合物(I)又はその塩はデキサメタゾンの投与前、投与と同時又は投与後に投与され得る。例えば、ステップ(a)において、1週間の期間内に化合物(I)若しくはその塩及びデキサメタゾンが投与される場合、好ましくは、例えば、化合物(I)又はその塩は当該期間の1及び4日目に、デキサメタゾンは2日目に投与され、あるいは化合物(I)又はその塩は当該期間の3及び6日目に、デキサメタゾンは4日目に投与され、あるいは化合物(I)又はその塩は当該期間の2及び5日目に、デキサメタゾンは1日目に投与され、あるいは化合物(I)又はその塩は当該期間の4及び7日目に、デキサメタゾンは2日目に投与される。1週間の期間は、例えば、月曜日に開始されてもよいし、水曜日に開始されてもよい。各回の投与はどの時刻に行ってもよいが、ほぼ同じ時刻(例えば夕食後)に行うのが好ましい。 When compound (I) or a salt thereof is used in combination with dexamethasone, the order and timing of administration thereof are not particularly limited, and compound (I) or a salt thereof may be administered before, simultaneously with, or after administration of dexamethasone. For example, in step (a), when compound (I) or a salt thereof and dexamethasone are administered within a one-week period, preferably, for example, compound (I) or a salt thereof is administered on the first and fourth days of the period, and dexamethasone on the second day, or compound (I) or a salt thereof is administered on the third and sixth days of the period, and dexamethasone on the fourth day, or compound (I) or a salt thereof is administered on the second and fifth days of the period, and dexamethasone on the first day, or compound (I) or a salt thereof is administered on the fourth and seventh days of the period, and dexamethasone on the second day. The one-week period may start, for example, on Monday or Wednesday. Each dose can be administered at any time, but it is preferable to administer each dose at approximately the same time (e.g., after dinner).
化合物(I)又はその塩がデキサメタゾンと組み合わせて用いられる期間は、対象の状態等に応じて、医師又は獣医師の判断に基づいて決定され得る。また、対象の状態等に応じて、医師又は獣医師の判断に基づいて、化合物(I)若しくはその塩及びデキサメタゾンの一方又は両方の投与を中止することもできる。 The period during which compound (I) or a salt thereof is used in combination with dexamethasone can be determined based on the judgment of a physician or veterinarian depending on the condition of the subject, etc. Furthermore, administration of either or both of compound (I) or a salt thereof and dexamethasone can be discontinued based on the judgment of a physician or veterinarian depending on the condition of the subject, etc.
式(I):
で表される化合物又はその薬学上許容され得る塩を有効成分として含有する、細胞増殖性疾患の治療又は予防用医薬は、
(i)当該医薬を収容するための容器、及び
(ii)
(a)化合物(I)又はその塩が週に2回、3週間投与され、
(b)続く1週間、化合物(I)又はその塩の投与が休止され、
(c)以後、ステップ(a)及び(b)が少なくとも1回繰り返される
ように当該医薬を用いるための指示
とともにパッケージ化されていてもよい。
Formula (I):
or a pharma- ceutical acceptable salt thereof as an active ingredient,
(i) a container for containing the medicine; and (ii)
(a) compound (I) or a salt thereof is administered twice a week for three weeks;
(b) the administration of compound (I) or a salt thereof is suspended for one week;
(c) optionally packaged with instructions for using the medicament so that steps (a) and (b) are thereafter repeated at least one time.
好ましくは、例えば、パッケージ化された医薬は前述の項目A1~A15のいずれかに記載の医薬であり、上記指示は、当該医薬に対応する所定の投与レジメンに従って化合物(I)又はその塩が投与されるように当該医薬を用いるための指示である。「当該医薬に対応する所定の投与レジメン」とは、例えば、項目A9に記載の医薬の場合、項目A9に記載された投与レジメン(R1)~(R3)のいずれかを指す。 Preferably, for example, the packaged pharmaceutical is a pharmaceutical described in any one of the above items A1 to A15, and the instructions are instructions for using the pharmaceutical so that compound (I) or a salt thereof is administered according to a predetermined administration regimen corresponding to the pharmaceutical. For example, in the case of a pharmaceutical described in item A9, the "predetermined administration regimen corresponding to the pharmaceutical" refers to any one of the administration regimens (R1) to (R3) described in item A9.
パッケージ化は、例えば包装材(例えば紙箱)を用いて行われ得る。また、パッケージには、例えば、ラベル、パンフレット、又は薬学的に許容され得る緩衝材がさらに含まれ得る。 Packaging may be achieved, for example, using a wrapping material (e.g., a paper box). The package may further include, for example, a label, a pamphlet, or pharma- ceutically acceptable cushioning material.
上記(i)の容器は、例えば瓶又はPTPシートであり、例えば、ガラス、プラスチック、アルミニウム等の材料から製造され得る。好ましくは、容器には、例えば、医薬が所定の疾患の治療又は予防用であることを示す文字が印刷されているか、又はそのような文字が印刷されたラベルが貼付されている。 The container (i) above is, for example, a bottle or a PTP sheet, and may be made of a material such as glass, plastic, or aluminum. Preferably, the container has printed thereon, or has attached thereto, a label having printed thereon, characters indicating that the medicine is for the treatment or prevention of a specific disease.
上記(i)の容器は、当該医薬が収容されていてもいなくてもよいが、収容されているのが好ましい。 The container (i) above may or may not contain the medicine, but it is preferable that it does.
上記(ii)の指示は、所定の投与レジメンに基づいて当該医薬を用いるために必要な情報を含む。また、上記指示は、例えば、当該医薬の効能及び効果に関する情報をさらに含み得る。 The instructions in (ii) above include information necessary for using the medicine according to a predetermined dosing regimen. The instructions may further include, for example, information regarding the efficacy and effectiveness of the medicine.
上記(ii)の指示は、例えば文書の形態で存在し得る。上記指示を含む文書としては、例えば医薬品添付文書が挙げられる。上記指示を含む文書は、例えば、ラベルに印刷されていても、包装材(例えば紙箱)に印刷されていてもよい。また、上記指示は、例えば、紙又はプラスチックに印刷された形態であっても、CD-ROM、フラッシュメモリ等の記憶媒体に電子的に保存された形態であってもよい。 The instructions in (ii) above may be in the form of a document. An example of a document containing the instructions is a pharmaceutical package insert. The instructions may be printed on a label or on a packaging material (e.g., a paper box). The instructions may be printed on paper or plastic, or electronically stored on a storage medium such as a CD-ROM or flash memory.
以下、実施例に基づいて本発明の例示的な実施形態を説明する。 Below, an exemplary embodiment of the present invention will be described based on an example.
実施例1:
化合物(I)のカリウム塩(本実施例において「IMP」とも言う。)を、KRAS変異及びNRAS変異IgGλ型多発性骨髄腫の患者に対して、3週間の投与及びそれに続く1週間の休止(3週間投与/1週間休止)からなる4週間のサイクルで、週に2回(火曜日及び金曜日)、4mgの用量で経口投与した。IMPとデキサメタゾンの併用はしなかった。
Example 1:
The potassium salt of compound (I) (also referred to as "IMP" in this example) was orally administered at a dose of 4 mg twice a week (Tuesdays and Fridays) in a four-week cycle consisting of three weeks on followed by one week off (3 weeks on/1 week off) to patients with KRAS-mutated and NRAS-mutated IgG λ-type multiple myeloma. IMP was not administered concomitantly with dexamethasone.
患者への投与は2016年11月29日に開始した。有害事象としては、IMPに関連している可能性のある間欠性のグレード1の下痢が当初から継続的に見られた。また、IMPに関連したグレード2の発疹も生じた。患者の経過は極めて良好であり、国際骨髄腫作業部会(International Myeloma Working Group(IMWG))の基準による部分奏効(partial response)が継続的に得られた(FLCλ:325mg/L(投与開始前),161mg/L(1サイクル後),264mg/L(2サイクル後))。 The patient began treatment on November 29, 2016. Adverse events included initial and persistent intermittent grade 1 diarrhea possibly related to IMP. The patient also experienced a grade 2 rash related to IMP. The patient did extremely well and consistently achieved partial response according to the International Myeloma Working Group (IMWG) criteria (FLCλ: 325 mg/L (before treatment), 161 mg/L (after 1 cycle), 264 mg/L (after 2 cycles)).
患者は以前に下記の治療を受けていた。
・自家造血幹細胞移植
・プロテオソーム阻害剤
・免疫調節剤
・シクロホスファミド+デキサメタゾン+サリドマイド
・メルファラン
・レナリドミド
・シクロホスファミド+ボルテゾミブ
・デキサメタゾン
・脊椎T3-T12,5分割(放射線治療)
The patient had previously received the following treatments:
・Autologous hematopoietic stem cell transplantation ・Proteosome inhibitors ・Immunomodulators ・Cyclophosphamide + dexamethasone + thalidomide ・Melphalan ・Lenalidomide ・Cyclophosphamide + bortezomib ・Dexamethasone ・Spine T3-T12, 5-fraction (radiotherapy)
実施例2:
化合物(I)のカリウム塩(本実施例において「IMP」とも言う。)をKRAS変異非小細胞肺癌の患者に経口投与した。
Example 2:
The potassium salt of compound (I) (also referred to as "IMP" in this example) was orally administered to patients with KRAS-mutated non-small cell lung cancer.
患者の治療は2014年9月1日に開始した。IMPは、当初、4週間の投与からなる4週間のサイクルでの4mg週2回(4mg 4週間投与)の用量で投与した。サイクル9において、グレード3の斑点状丘疹のために、用量を4週間のサイクルでの3.2mg週2回(3.2mg 4週間投与)に減少させた。サイクル22において、グレード3の顔面皮疹のために、用量を再び減少させて3週間投与/1週間休止スケジュールでの3.2mg週2回(3.2mg 3週間投与/1週間休止)とした。これらの減量により発疹は減少してわずかグレード1となり、サイクル40の時点でもうまく抑えられていた。治療効果に関しては、固形腫瘍における効果判定基準(Response Evaluation Criteria in Solid Tumors(RECIST))1.1による部分奏効(partial response(PR))が得られ、サイクル40の時点でも維持されていた。 The patient's treatment began on September 1, 2014. IMP was initially administered at a dose of 4 mg twice weekly in 4-week cycles (4 mg 4 weeks on). In cycle 9, the dose was reduced to 3.2 mg twice weekly in 4-week cycles (3.2 mg 4 weeks on) because of a grade 3 maculopapular rash. In cycle 22, the dose was reduced again to 3.2 mg twice weekly on a 3-week on/1-week off schedule (3.2 mg 3 weeks on/1-week off) because of a grade 3 facial rash. These dose reductions reduced the rash to only grade 1 and remained well controlled as of cycle 40. Regarding the therapeutic effect, a partial response (PR) was obtained according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and this was maintained as of cycle 40.
最初の40サイクル(約3年間)における患者の腫瘍サイズの変化を図1に示す。横軸(X軸)は治療サイクル番号を表し、縦軸(Y軸)は腫瘍サイズのベースラインからの変化率を表す。腫瘍サイズはCTスキャンを用いて測定された。4mg 4週間投与、3.2mg 4週間投与、及び3.2mg 3週間投与/1週間休止の投与スケジュールにおいて得られた最も高い効果は、それぞれ、RECIST1.1による標的病変の58%縮小、61%縮小、及び68%縮小であった。2018年4月18日(サイクル48)(3.6年目に相当)現在、IMPによる患者の治療は継続中であり、グレード2以上の発疹は観察されていない。 The change in the patient's tumor size over the first 40 cycles (approximately 3 years) is shown in Figure 1. The horizontal axis (X axis) represents the treatment cycle number, and the vertical axis (Y axis) represents the percentage change in tumor size from baseline. Tumor size was measured using CT scans. The highest efficacy obtained in the administration schedules of 4 mg for 4 weeks, 3.2 mg for 4 weeks, and 3.2 mg for 3 weeks on/1 week off was a 58%, 61%, and 68% reduction in target lesions by RECIST 1.1, respectively. As of April 18, 2018 (cycle 48) (corresponding to 3.6 years), the patient's treatment with IMP is ongoing, and no rash of grade 2 or higher has been observed.
患者は以前に下記の治療を受けていた。
・カルボプラチン/ペメトレキセド
・ペメトレキセド
・ドセタキセル
・胸膜癒着術(2012年10月)(手術)
The patient had previously received the following treatments:
Carboplatin/pemetrexed Pemetrexed Docetaxel Pleurodesis (October 2012) (surgery)
実施例3:
化合物(I)のカリウム塩(本実施例において「IMP」とも言う。)を頭皮のHRAS変異アポクリン腺癌の患者に経口投与した。頭皮のアポクリン腺癌は皮膚汗腺癌である。患者は2014年に診断され、IMPによる治療前に放射線治療と手術を2回受けていた。
Example 3:
The potassium salt of compound (I) (also referred to as "IMP" in this example) was orally administered to a patient with HRAS-mutated apocrine gland carcinoma of the scalp. Apocrine gland carcinoma of the scalp is a skin sweat gland carcinoma. The patient was diagnosed in 2014 and had undergone radiation therapy and two surgeries before treatment with IMP.
IMPによる患者の治療は、4週間のサイクルでの4mg週2回の用量で2018年1月8日に開始した。サイクル1の3週目に、グレード2のざ瘡様皮疹及びグレード2の下痢が生じたため、用量を3週間投与/1週間休止スケジュールでの4mg週2回に減少させた。ざ瘡様皮疹のグレードは、サイクル2の1日目に1、サイクル2の22日目に3、サイクル3の1日目に2であった。そのため、サイクル3の1日目の用量は3.2mgに減少させず、4mgとした。CTスキャンにより測定された患者の腫瘍サイズの変化は、固形腫瘍における効果判定基準(Response Evaluation Criteria in Solid Tumors(RECIST))1.1による部分奏効(partial response(PR))を示した(サイクル2の22日目に54%縮小、サイクル4の15日目に58%縮小)。 The patient's treatment with IMP began on January 8, 2018 at a dose of 4 mg twice weekly in 4-week cycles. During week 3 of cycle 1, the dose was reduced to 4 mg twice weekly on a 3-week on/1-week off schedule due to the development of grade 2 acneiform rash and grade 2 diarrhea. The acneiform rash was graded 1 on day 1 of cycle 2, 3 on day 22 of cycle 2, and 2 on day 1 of cycle 3. Therefore, the dose on day 1 of cycle 3 was not reduced to 3.2 mg but was instead kept at 4 mg. The change in the patient's tumor size, measured by CT scan, showed a partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (54% reduction on day 22 of cycle 2, 58% reduction on day 15 of cycle 4).
本実施例で使用された投与レジメン並びにその観察された有効性及び安全性の概要を図2に示す。本実施例で使用された投与ガイダンスを図3に示す。2018年4月30日(サイクル5の1日目)現在、IMPによる患者の治療は継続中であり、グレード2以上の発疹及び下痢は観察されていない。 The dosing regimen used in this example and its observed efficacy and safety are outlined in Figure 2. The dosing guidance used in this example is provided in Figure 3. As of April 30, 2018 (Day 1 of Cycle 5), the patient's treatment with IMP is ongoing, with no observed Grade 2 or higher rash or diarrhea.
Claims (17)
で表される化合物又はその薬学上許容され得る塩を有効成分として含有し、
(a)前記化合物又は塩が週に2回、3週間投与され、
(b)続く1週間、前記化合物又は塩の投与が休止され、
(c)以後、ステップ(a)及び(b)が少なくとも1回繰り返される
ように用いられる前記医薬。 A pharmaceutical composition for treating or preventing a cell proliferative disease, comprising a compound represented by formula (I):
or a pharma- ceutical acceptable salt thereof as an active ingredient,
(a) the compound or salt is administered twice weekly for three weeks;
(b) the administration of the compound or salt is discontinued for one week;
(c) Thereafter, steps (a) and (b) are repeated at least once.
(1)前記化合物又は塩が1回3.2mgの用量で週に2回投与され、又は
(2)
(2a)前記化合物又は塩が1回4mgの用量で週に2回、3週間投与され、
(2b)続く1週間、前記化合物又は塩の投与が休止され、
(2c)以後、ステップ(2a)及び(2b)が少なくとも1回繰り返される
ように用いられる、請求項6に記載の医薬。 Prior to step (a),
(1) the compound or salt is administered at a dose of 3.2 mg twice a week; or (2)
(2a) the compound or salt is administered at a dose of 4 mg twice a week for three weeks;
(2b) administration of the compound or salt is discontinued for one week;
The method according to claim 6, wherein after (2c), steps (2a) and (2b) are repeated at least once.
(A)まず、前記化合物又は塩が1回4mgの用量で週に2回投与され、
(B1)次いで、前記化合物又は塩が1回3.2mgの用量で週に2回投与され、
(C)その後、
(Ca)前記化合物又は塩が1回3.2mgの用量で週に2回、3週間投与され、
(Cb)続く1週間、前記化合物又は塩の投与が休止され、
(Cc)以後、ステップ(Ca)及び(Cb)が少なくとも1回繰り返される
ように用いられるか、あるいは
(A)まず、前記化合物又は塩が1回4mgの用量で週に2回投与され、
(B2)次いで、
(B2a)前記化合物又は塩が1回4mgの用量で週に2回、3週間投与され、
(B2b)続く1週間、前記化合物又は塩の投与が休止され、
(B2c)以後、ステップ(B2a)及び(B2b)が少なくとも1回繰り返される
ように用いられるか、あるいは
(A)まず、前記化合物又は塩が1回4mgの用量で週に2回投与され、
(B2)次いで、
(B2a)前記化合物又は塩が1回4mgの用量で週に2回、3週間投与され、
(B2b)続く1週間、前記化合物又は塩の投与が休止され、
(B2c)以後、ステップ(B2a)及び(B2b)が少なくとも1回繰り返され、
(C)その後、
(Ca)前記化合物又は塩が1回3.2mgの用量で週に2回、3週間投与され、
(Cb)続く1週間、前記化合物又は塩の投与が休止され、
(Cc)以後、ステップ(Ca)及び(Cb)が少なくとも1回繰り返される
ように用いられる前記医薬。 The pharmaceutical composition according to any one of claims 1 to 5,
(A) first, the compound or salt is administered at a dose of 4 mg twice a week;
(B1) The compound or salt is then administered twice a week at a dose of 3.2 mg;
(C) Thereafter,
(Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for three weeks;
(Cb) administration of the compound or salt is suspended for one week;
(Cc) thereafter, steps (Ca) and (Cb) are repeated at least once, or (A) first, the compound or salt is administered at a dose of 4 mg twice a week,
(B2) Next,
(B2a) the compound or salt is administered at a dose of 4 mg twice a week for three weeks;
(B2b) administration of the compound or salt is suspended for one week;
(B2c) Thereafter, steps (B2a) and (B2b) are repeated at least once, or (A) the compound or salt is first administered twice a week at a dose of 4 mg;
(B2) Next,
(B2a) the compound or salt is administered at a dose of 4 mg twice a week for three weeks;
(B2b) administration of the compound or salt is suspended for one week;
After (B2c), steps (B2a) and (B2b) are repeated at least once,
(C) Thereafter,
(Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for three weeks;
(Cb) administration of the compound or salt is suspended for one week;
(Cc) The pharmaceutical composition according to the present invention, wherein steps (Ca) and (Cb) are repeated at least once after (Cc).
で表される化合物又はその薬学上許容され得る塩を有効成分として含有する、細胞増殖性疾患の治療又は予防用医薬であって、
(i)前記医薬を収容するための容器、及び
(ii)
(a)前記化合物又は塩が週に2回、3週間投与され、
(b)続く1週間、前記化合物又は塩の投与が休止され、
(c)以後、ステップ(a)及び(b)が少なくとも1回繰り返される
ように前記医薬を用いるための指示
とともにパッケージ化された前記医薬。 Formula (I):
or a pharma- ceutical agent for treating or preventing a cell proliferative disease, comprising, as an active ingredient, a compound represented by the formula:
(i) a container for containing the medicament; and (ii)
(a) the compound or salt is administered twice weekly for three weeks;
(b) the administration of the compound or salt is discontinued for one week;
(c) said medicament packaged together with instructions for using said medicament such that steps (a) and (b) are thereafter repeated at least one time.
前記指示は、当該医薬に対応する所定の投与レジメンに従って前記化合物又は塩が投与されるように前記医薬を用いるための指示である、
請求項16に記載の医薬。 The medicament is a medicament according to any one of claims 1 to 15,
the instructions are for using the medicament such that the compound or salt is administered according to a predetermined dosing regimen corresponding to that medicament;
The pharmaceutical composition according to claim 16.
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