TW201609096A - α-同型異構體選擇性磷脂醯肌醇3-激酶抑制劑的劑量療法 - Google Patents
α-同型異構體選擇性磷脂醯肌醇3-激酶抑制劑的劑量療法 Download PDFInfo
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Abstract
本發明係關於治療或預防有需要之患者之增殖性疾病之方法,其係藉由經口投與治療有效量之式(I)之α-同型異構體選擇性磷脂醯肌醇3-激酶抑制劑化合物或其醫藥上可接受之鹽至少兩個連續5天週期來達成,其中在該等連續5天週期之間約兩天至約三天之時段內並不向該患者投與該化合物;該式(I)化合物或其醫藥上可接受之鹽用以製造根據該劑量療法投與之用於治療或預防增殖性疾病之醫藥之用途;包括根據該劑量療法投與該式(I)化合物或其醫藥上可接受之鹽之治療性療法;及其相關醫藥組合物及包裝。
Description
本發明係關於治療或預防有需要之患者之增殖性疾病之方法,其係藉由經口投與治療有效量之式(I)之α-同型異構體選擇性磷脂醯肌醇3-激酶抑制劑化合物或其醫藥上可接受之鹽至少兩個連續5天週期來達成,其中在該等連續5天週期之間約兩天至約三天之時段內並不向該患者投與該化合物或其醫藥上可接受之鹽;該式(I)化合物或其醫藥上可接受之鹽用以製造根據該劑量療法投與之用於治療或預防增殖性疾病之醫藥之用途;包括根據該劑量療法投與該式(I)化合物或其醫藥上可接受之鹽之治療性療法;及其相關醫藥組合物及包裝。
磷脂醯肌醇3-激酶(「PI-3激酶」或「PI3K」)包括脂質激酶家族,該等脂質激酶催化磷酸酯轉移至肌醇脂質之D-3'位置以產生磷酸肌醇-3-磷酸酯(「PIP」)、磷酸肌醇-3,4-二磷酸酯(「PIP2」)及磷酸肌醇-3,4,5-三磷酸酯(「PIP3」),該等PIP、PIP2及PIP3進而藉由經常在質膜處使含有普列克底物蛋白同源(pleckstrin-homology)、FYVE、Phox及其他磷脂結合結構域之蛋白質對接至多種信號傳導複合物而在信號傳導級聯中用作第二信使(Vanhaesebroeck等人,Annu.Rev.Biochem 70:535(2001);Katso等人,Annu.Rev.Cell Dev.Biol.17:615(2001))。人類細胞含有三種編碼IA類PI3K酶之催化p110亞單
位(α、β、δ同型異構體)之基因(PIK3CA、PIK3CB及PIK3CD)。該等催化p110α、p110β及p110δ亞單位與可為p85α、p55α、p50α、p85β或p55γ之調控亞單位組成型相關。p110α及p110β表現於大部分組織中。1B類PI3K具有一個家族成員,亦即由與兩個調控亞單位p101或p84之一相關之催化p110γ亞單位構成的異源二聚體(Fruman等人,Annu Rev.Biochem.67:481(1998);Suire等人,Curr.Biol.15:566(2005))。p85/55/50亞單位之模塊化結構域包含在特定序列文本中於活化受體及胞質酪胺酸激酶上結合磷酸酪胺酸殘基之Src同源(SH2)結構域,從而使1A類PI3K活化並定位。在一些情況下,由結合肽及非肽配體之多種譜之G蛋白偶聯受體直接活化1B類以及p110β(Stephens等人,Cell 89:105(1997));Katso等人,Annu.Rev.Cell Dev.Biol.17:615-675(2001))。因此,I類PI3K之所得磷脂產物將上游受體與下游細胞活性(包含增殖、存活、趨化、細胞輸送、運動、代謝、發炎及過敏反應、轉錄及轉譯)聯繫在一起(Cantley等人,Cell 64:281(1991);Escobedo及Williams,Nature 335:85(1988);Fantl等人,Cell 69:413(1992))。
PI3K通常經由Akt活化延長存活,其異常調控係人類癌症中之最流行事件之一且已展示以多重程度發生。腫瘤阻抑基因PTEN在肌醇環之3'位處使磷酸肌醇去磷酸化且藉此拮抗PI3K活性,該基因在多種腫瘤中功能性缺失。在其他腫瘤中,p110α同型異構體PIK3CA及Akt之基因擴增,且在若干人類癌症中已顯示其基因產物之蛋白質表現有所增加。另外,已在人類癌症中闡述用於上調p85-p110複合物之p85α之突變及易位。最後,PIK3CA中活化下游信號傳導路徑之體細胞錯義突變以較大頻率闡述於各種類癌症中,包含32%之結腸直腸癌、27%之膠質母細胞瘤、25%之胃癌、36%之肝細胞癌瘤及18-40%之乳癌。(Samuels等人,Cell Cycle 3(10):1221(2004);Hartmann等人,
Acta Neuropathol.,109(6):639(June 2005);Li等人,BMC Cancer 5:29(March 2005);Lee等人,Oncogene,24(8):1477(2005);Backman等人,Cancer Biol.Ther.3(8):772-775(2004);Campbell等人,Cancer Research,64(21):7678-7681(2004);Levine等人,Clin.Cancer Res.,11(8):2875-2878(2005);及Wu等人,Breast Cancer Res.,7(5):R609-R616(2005))。PI3K(包含α同型異構體)係與人類癌症及增殖性疾病有關之最常見失調之一(Parsons等人,Nature 436:792(2005);Hennessey等人,Nature Rev.Drug Disc.4:988-1004(2005))。
(S)-吡咯啶-1,2-二甲酸2-醯胺1-({4-甲基-5-[2-(2,2,2-三氟-1,1-二甲基-乙基)-吡啶-4-基]-噻唑-2-基}-醯胺)係潛在且選擇性地靶向IA類PI3K之阿爾法(α)-同型異構體之特定2-甲醯胺環胺基脲衍生物化合物。此化合物具有下列化學結構:
(下文中之「式(I)化合物」或「化合物A」)。式(I)化合物及其醫藥上可接受之鹽、適宜調配物及其製備方法闡述於PCT申請案WO2010/029082中。
在階段I臨床試驗中,此α-同型異構體選擇性PI3K抑制劑化合物(S)-吡咯啶-1,2-二甲酸2-醯胺1-({4-甲基-5-[2-(2,2,2-三氟-1,1-二甲基-乙基)-吡啶-4-基]-噻唑-2-基}-醯胺)在患有攜載PIK3CA基因改變之晚期實體惡性腫瘤之患者之單一藥劑治療中顯示臨床效能。在劑量遞增階段,以以下方式向患者經口投與此化合物:(a)劑量介於30mg至450mg之間,每天一次(q.d.),根據持續28天之連續每日時間表;或(b)劑量介於120mg至200mg之間,每天兩次(b.i.d.),根據持續28天之
連續每日時間表,如藉由貝葉斯邏輯回歸模型(Bayesian logistic regression model)在超劑量控制下所引導。在測定最大耐受劑量(MTD)之後,實施劑量擴展階段以另外治療患有具有PIK3CA改變之頭頸癌之患者、患有具有PIK3CA改變之實體腫瘤之患者及患有PIK3CA野生型ER+/HER2-乳癌之患者。已初步證實此化合物之臨床效能。在2013年2月15日,已在以270mg/天治療之若干患者中觀察到所證實部分反應,包含患有乳癌(1名患者證實)、結腸直腸癌(1名患者證實)、子宮內膜癌(1名患者證實)及子宮頸癌(1名患者證實)之患者。(Gonzalez-Angulo等人,「Safety,pharmacokinetics,and preliminary activity of the α-specific PI3K inhibitor BYL719:results from the first-in-human study」,Presentation at 2013 ASCO Annual Meeting,2013年5月31日至6月4日舉行,Chicago,IL.)
儘管此化合物在階段I臨床試驗中具有臨床效能,但一些以每天一次或每天兩次連續日時間表投與此化合物之患者顯示至少一種副效應或不良事件,包含但不限於高血糖症(49%之患者)、噁心(43%之患者)、食欲降低(34%之患者)、腹瀉(35%之患者)、疹及超敏性(34%之患者)、虛弱/疲勞(34%之患者)、嘔吐、口腔炎、味覺障礙及/或消化不良。(Gonzalez-Angulo等人,Presentation at the 2013 ASCO Annual Meeting,2013年5月31日至6月4日舉行,Chicago,IL.)
當前,可以如下劑量或劑量療法投與患者之強力α(α)-同型異構體選擇性PI3K抑制劑之需要未得到滿足:在臨床上有效用於治療增殖性疾病、尤其癌症,且亦減輕、減小或緩藥物解之任一已知及未知副效應(例如嚴重程度、發生率或頻率)。據信,在本發明之前任一α-同型異構體選擇性PI3K抑制劑尚未達成此需要。
本發明係關於治療或預防有需要之患者之增殖性疾病之方法,
其包括以約100mg至約450mg之日劑量向患者經口投與治療有效量之式(I)化合物:
或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期及其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於治療或預防增殖性疾病之方法,其包括第一,根據連續每日時間表經由經口投與向有需要之患者以每天約100mg至約450mg之量投與式(I)化合物或其醫藥上可接受之鹽;第二,在向該患者投與該式(I)化合物或其醫藥上可接受之鹽之後測得該具者患有選自以下之副效應:嗜中性白血球減少症、膽紅素升高、心臟毒性、不穩定型心絞痛、心肌梗塞、持續性高血壓、周邊感覺或運動神經病變/疼痛、肝臟功能障礙(例如肝損傷或肝病、天門冬胺酸轉胺酶濃度升高、丙胺酸胺基轉移酶濃度升高等)、紅血球及/或白血球計數減小、高血糖症、噁心、食欲降低、腹瀉、疹(例如斑丘疹、痤瘡樣等)及超敏性(例如擦傷敏感性增加)、光敏性、虛弱/疲勞、嘔吐、口腔炎、口腔黏膜炎、胰臟炎、味覺障礙及消化不良;及第三,將該式(I)化合物或其醫藥上可接受之鹽之投與減小至約100mg至約450mg的日劑量經由經口投與至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於減少至少一種選自以下之來自先前使用式(I)化合物或其醫藥上可接受之鹽治療之副效應之方法:嗜
中性白血球減少症、膽紅素升高、心臟毒性、不穩定型心絞痛、心肌梗塞、持續性高血壓、周邊感覺或運動神經病變/疼痛、肝臟功能障礙(例如肝損傷或肝病、天門冬胺酸轉胺酶濃度升高、丙胺酸胺基轉移酶濃度升高等)、紅血球及/或白血球計數減小、高血糖症、噁心、食欲降低、腹瀉、疹(例如斑丘疹、痤瘡樣等)及超敏性(例如擦傷敏感性增加)、光敏性、虛弱/疲勞、嘔吐、口腔炎、口腔黏膜炎、胰臟炎、味覺障礙及消化不良,其包括以約100mg至約450mg、較佳地約200mg至約400mg或更佳地約350mg至約400mg之日劑量向患者經口投與治療有效量之式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用以製造用於治療或預防增殖性疾病之醫藥之用途,其中以約100mg至約450mg該式(I)化合物或其醫藥上可接受之鹽之日劑量向有需要之患者經口投與該醫藥至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該醫藥。
在另一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用於治療或預防增殖性疾病之用途,其中以約100mg至約450mg之日劑量向有需要之患者經口投與該式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該式(I)化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於用於治療或預防有需要之患者之增殖性疾病之醫藥組合物,其包括約100mg至約450mg之量之式(I)化合物或其醫藥上可接受之鹽以及一或多種醫藥上可接受之賦形劑,
其中向患者經口投與該醫藥組合物至少兩個連續5天週期且在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與。
在另一實施例中,本發明係關於一種治療療法,其包括以約100mg至約450mg之日劑量向患者經口投與治療有效量之式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該式(I)化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於一種包裝,其包括醫藥組合物(包括日劑量為約100mg至約450mg之式(I)化合物或其醫藥上可接受之鹽以及一或多種醫藥上可接受之賦形劑)與說明之組合,該說明指示經口投與該醫藥組合物至少兩個連續5天週期且在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不投與該組合物。
圖1展示在裸小鼠(A)中以12.5、25及50mg/kg(每天一次)及在裸大鼠(B)中以12.5、25、40及80mg/kg(每天一次)經口投與化合物A之後之濃度-時間特徵。
圖2展示在裸小鼠(A)中以50mg/kg(每天一次)及在裸大鼠(B)中以40mg/kg(每天一次)經口投與化合物A之後之觀察血漿濃度與預測血漿濃度。
圖3展示在裸小鼠(A)中以6.25、12.5、25及50mg/kg(每天一次)及在裸大鼠(B)中以6.25、12.5、25、40、50及80mg/kg(每天一次)及連續日時間表經口投與化合物A之後之觀察血漿濃度與預測血漿濃度。
圖4A及4B展示在裸小鼠中以40mg/kg(每天兩次)及連續日時間
表經口投與化合物A之後PK建模研究(A)及後續重複驗證PK建模研究(B)中之觀察血漿濃度與預測血漿濃度。
圖5展示在使用化合物A治療後不同時間點於Rat1-myr P110α腫瘤中同時量測之腫瘤組織濃度及S473P-Akt抑制百分比之間之關係。
圖6展示以50mg/kg(每天一次)使用化合物A治療之Rat1-myr P110α腫瘤中之暴露(如藉由超過S473P-Akt抑制之活體內IC80之時間所量測)與抗腫瘤效能之間之關係。
圖7展示在使用各種劑量之化合物A經口(每天一次)治療之小鼠及大鼠中所觀察腫瘤PD標記物(pAkt)反應與抗腫瘤效能之間之關係。
圖8展示以6.25mg/kg至70mg/kg、連續日時間表及各種療法在裸小鼠及大鼠中經口投與化合物A之後之觀察腫瘤生長抑制與預測腫瘤生長抑制。
圖9展示在化合物A治療後於裸小鼠中以同一探針量測之血漿化合物A濃度及血漿胰島素濃度(A)或血糖濃度(B)之間之關係。
圖10展示在化合物A治療後於裸大鼠中以同一探針量測之血漿化合物A濃度與血漿胰島素濃度(A)或血糖濃度(B)之間之關係。
圖11展示裸小鼠及大鼠中在兩個連續投藥之間超過血漿高血糖症臨限值之時間分數與體重損失之間所觀察到的關聯。
圖12展示以連續日時間表使用增加劑量之化合物A經口(每天一次或每天兩次)治療之裸小鼠中之模擬效能曲線(如藉由超過S473P-Akt之IC80臨限值之時間分數所測定)及耐受性曲線(如藉由超過化合物A高血糖症臨限值之暴露持續時間所測定)。
圖13展示使用增加劑量之化合物A經口(每天一次或每天兩次)治療之裸大鼠中之模擬效能曲線(如藉由超過S473P-Akt之IC80臨限值之時間分數所測定)及耐受性曲線(如藉由超過化合物A高血糖症臨限值之暴露持續時間所測定)。
圖14展示使用化合物A以20mg/kg及替代時間表1(A)或以14mg/kg(每天一次)及連續日時間表(B)經口治療之具有Rat1-myr P110α腫瘤之裸大鼠中之模擬效能。
圖15展示使用化合物A以20mg/kg及替代時間表1(如實例1中所定義)或以14mg/kg(每天一次)及連續日時間表經口治療之裸大鼠中之模擬血漿PK特徵。
本發明係關於治療或預防有需要之患者之增殖性疾病之方法,其包括以約100mg至約450mg之日劑量向患者經口投與治療有效量之如本文所定義之式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約兩(2)天至約三(3)天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
除非另有明確說明,否則本文所用之一般術語定義為下列含義:
除非另有說明,否則術語「包括(comprising)」及「包含(包含)」在本文中係以開放性且非限制性意義使用。
除非本文另有指示或上下文明顯矛盾,否則在闡述本發明之上下文(尤其在下文申請專利範圍之上下文)中術語「一(a及an)」及「該」及類似指示物皆應解釋為涵蓋單數與複數二者。倘若化合物、鹽及諸如此類使用複數形式,則此亦意指單一化合物、鹽或諸如此類。
術語「磷脂醯肌醇3-激酶抑制劑」或「PI3K抑制劑」在本文中定義為係指靶向、降低或抑制磷脂醯肌醇3-激酶之活性之化合物。
術語「醫藥上可接受」在本文中定義為係指彼等在合理醫學判斷範圍內適於與患者之組織接觸而無過度毒性、刺激性、過敏反應及
其他問題之併發症且相應具有合理益處/風險比之化合物、材料、組合物及/或劑型。
本文所用之術語「治療(treat、treating或treatment)」包括減輕、減少或緩解患者之至少一種症狀或實現延遲增殖性病症之進展的治療或治療療法。舉例而言,治療可為諸如癌症等病症之一或若干種症狀之減退或病症之完全根除。在本發明之含義內,術語「治療」亦表示阻止、延遲發作(亦即病症臨床表現之前之時段)及/或減小病症發生或惡化之風險。
本文所用之術語「預防(prevent、preventing或prevention)」包括預防與所預防狀態、疾病或病症有關或由其引起之至少一種症狀。
術語「臨床有效」或「治療有效」係使用治療劑治療之狀態、疾病或病症之基線臨床可觀察體徵及症狀之可觀察改良。
術語「治療有效量」係足以提供使用治療劑治療之狀態、疾病或病症之基線臨床可觀察體徵及症狀之可觀察改良的量。
術語「醫藥組合物」在本文中定義為係指擬投與患者以預防或治療影響該患者之特定疾病或病狀之含有至少一種治療劑之混合物或溶液。
本文所用之片語「連續5天週期」意指在連續5天之每天期間向患者投與指定治療劑且然後在下一次向患者投與同一治療劑之前之一定時間段內並不投與。應理解,治療劑可每天以單一劑量單位或多個劑量單位投與及/或每天以單一劑量(每天一次(q.d.))或分開劑量(每天一次以上,例如每天兩次(b.i.d.))投與。
本文所用之片語「連續日時間表」意指在至少7天或未指定時間段或治療所需之較長時間之每天期間向患者投與治療劑。應理解,治療劑可每天以單一劑量單位或多個劑量單位投與及/或每天以單一劑量(每天一次(q.d.))或分開劑量(每天一次以上,例如每天兩次(b.i.d.))
投與。
本文所用之術語「天」係指一個日曆日或一個24小時時段。
術語「組合」在本文中用於係指呈一種劑量單位形式之固定組合、非固定組合或用於組合投與之部分套組,其中式(I)化合物或其醫藥上可接受之鹽及至少一種其他治療劑可同時、在同一時間獨立地或在容許組合配偶體展示協作(例如協同)效應之時間間隔內單獨投與。術語「固定組合」意指將治療劑(例如式(I)化合物或其醫藥上可接受之鹽及至少一種其他治療劑)以單一實體或劑量單位之形式同時投與患者。術語「非固定組合」或「部分套組」意指以單獨實體或劑量單位形式同時、並行或依序(無具體時間限制)將治療劑(例如式(I)化合物或其醫藥上可接受之鹽及至少一種其他治療劑)投與患者,其中該投與提供兩種治療劑在患者身體中之治療有效程度。後者亦適用於雞尾酒療法,例如投與三種或更多種治療劑。
本文所用之術語「組合投與」定義為涵蓋向單一患者投與所選治療劑,且意欲包含該等藥劑未必以相同投與途徑或同時投與之治療療法。
術語「患者」、「個體」或「溫血動物」意欲包含各種動物。個體之實例包含哺乳動物,例如人類、狗、牛、馬、豬、綿羊、山羊、貓、小鼠、兔、大鼠及轉基因非人類動物。在某些實施例中,個體係人類,例如患有腦腫瘤疾病、具有患腦腫瘤疾病之風險或可能能夠患腦腫瘤疾病之人類。尤佳之患者或溫血動物係人類。
術語「約」或「大約」通常意指在給定值或範圍之10%內、更佳地5%內。
WO2010/029082闡述特定2-甲醯胺環胺基脲衍生物,已發現其對磷脂醯肌醇3-激酶(PI3K)之α-同型異構體具有高度選擇性抑制活性。適用於本發明之α-同型異構體選擇性PI3K抑制劑係具有下列式(I)之化
合物:
(下文之「式(I)化合物」或「化合物A」)或其醫藥上可接受之鹽。式(I)化合物亦稱為化學化合物(S)-吡咯啶-1,2-二甲酸2-醯胺1-({4-甲基-5-[2-(2,2,2-三氟-1,1-二甲基-乙基)-吡啶-4-基]-噻唑-2-基}-醯胺)。式(I)化合物、其醫藥上可接受之鹽及適宜調配物闡述於PC申請案第WO2010/029082號(其全部內容以引用方式併入本文中)中且其製備方法闡述於(例如)其中之實例15中。
如本文中所使用,術語「鹽」(包含「或其鹽」或「或其鹽」)可單獨存在或以與游離式(I)化合物之混合物形式存在且較佳係醫藥上可接受之鹽。該等鹽較佳自具有鹼性氮原子之式(I)化合物與有機酸或無機酸以(例如)酸加成鹽、尤其醫藥上可接受之鹽形式形成。適宜無機酸係(例如)氫鹵酸(例如鹽酸)、硫酸或磷酸適宜有機酸係(例如)羧酸或磺酸,例如富馬酸或甲烷磺酸。出於分離或純化目的,亦可使用醫藥上不可接受之鹽,例如苦味酸鹽或高氯酸鹽。對於治療用途而言,僅使用醫藥上可接受之鹽或游離化合物(適用時呈醫藥製劑之形式),且因此該等形式係較佳的。鑒於游離形式之式(I)化合物與彼等鹽形式之間之密切關係,若適當及方便,上文及下文所提及之任一游離化合物應理解為亦係指相應鹽。式(I)化合物之鹽較佳係醫藥上可接受之鹽;業內已知形成醫藥上可接受之鹽之適宜抗衡離子。
式(I)化合物先前已顯示強力且選擇性抑制PI3K之α-同型異構體,包含(例如)PC申請案第WO2010/029082號之實例A及C。與先前已知PI3K抑制劑相比,式(I)化合物在細胞分析中較PI3K之β-同型異構
體(IC50為1.212μmol/L)、δ-同型異構體(IC50為0.077μmol/L)及γ-同型異構體(IC50為1.097μmol/L)更強力地抑制α-同型異構體(IC50為0.008μmol/L)且缺乏針對Vps34、mTOR、DNA-PK及ATR之抑制活性。另外,式(I)化合物針對PI3K之野生型α-同型異構體、PI3K之E545K突變體α-同型異構體及PI3K之H1047R突變體α-同型異構體展示抑制活性。
可以約100mg/天至約450mg/天之劑量將式(I)化合物或其醫藥上可接受之鹽經口投與有需要之人類患者。術語「日劑量」係指在任一單一天中投與具體患者之治療劑之總劑量量。在其他實施例中,可以約200mg/天至約400mg/天或約240mg/天至約400mg/天或約300mg/天至約400mg/天或約350mg/天至約400mg/天之日劑量將式(I)化合物投與患者。在一較佳實施例中,以約350mg/天至約400mg/天之日劑量將式(I)化合物投與人類患者。
可以單一劑量(每天一次(q.d.))或分開劑量(每天一次以上,例如每天兩次(b.i.d.))將日劑量投與患者。在一實施例中,每天一次(q.d.)投與日劑量。在另一實施例中,每天兩次(b.i.d.)投與日劑量。
可以構成日劑量之單一劑量單位或多個劑量單位量將日劑量投與患者。
根據本發明之劑量療法,以約100mg至約450mg之日劑量向有需要之患者經口投與式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。較佳地,在一個連續5天週期與其隨後連續5天週期之間約2天內並不投與化合物或其醫藥上可接受之鹽。
在一實施例中,以約100mg至約450mg、較佳地約350mg至約400mg之日劑量每天一次(q.d.)向有需要之患者經口投與式(I)化合物
或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,以約100mg至約450mg、較佳地約350mg至約400mg之日劑量每天兩次((b.i.d.)向有需要之患者經口投與式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
應理解,另一選擇為,可相對於式(I)化合物或其醫藥上可接受之鹽之實際投與時間來定義本發明之劑量療法。
在一實施例中,以約100mg至約450mg、較佳地約350mg至約400mg之日劑量每天一次(q.d.)向有需要之患者經口投與式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期中該化合物或其醫藥上可接受之鹽之最後一次投與與其隨後連續5天週期中該化合物或其醫藥上可接受之鹽之第一次投與間約3天時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,以約100mg至約450mg、較佳地約350mg至約400mg之日劑量每天兩次(b.i.d.)向有需要之患者經口投與式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期中該化合物或其醫藥上可接受之鹽之最後一次投與與其隨後連續5天週期中該化合物或其醫藥上可接受之鹽之第一次投與間約2.5天時段內並不投與該化合物或其醫藥上可接受之鹽。
可藉由根據本發明之劑量療法投與式(I)化合物或其醫藥上可接受之鹽來治療或預防的增殖性疾病尤其係彼等藉由PI3K之α-同型異構體介導者。應理解,本發明之一實施例包含治療增殖性疾病且本發明之另一實施例包含預防增殖性疾病。
可根據本發明治療或預防之增殖性疾病之實例包含癌症、真性紅細胞增多症、原發性血小板增多症、髓樣化生之骨髓纖維化、哮喘、COPD、ARDS、呂弗勒氏症候群(Loffler's syndrome)、嗜伊紅球肺炎、寄生性(特定而言後生動物)感染(包含特發性嗜伊紅球增多症)、支氣管肺曲黴菌病、結節性多動脈炎(包含丘-施二氏症候群(Churg-Strauss syndrome))、嗜伊紅球肉芽腫病、由藥物反應引發之影響氣道之嗜伊紅球相關病症、牛皮癬、接觸性皮炎、特應性皮炎、斑禿、多形紅斑、皰疹樣皮炎、硬皮病、白斑症、超敏性脈管炎、蕁麻疹、大皰性類天皰瘡、紅斑狼瘡、天皰瘡、獲得性大皰性表皮鬆解、自體免疫血液病症(例如溶血性貧血、再生障礙性貧血、純紅血球貧血及特發性血小板減少症)、全身性紅斑狼瘡、多軟骨炎、硬皮病、韋格納氏肉芽腫病(Wegener granulomatosis)、皮肌炎、慢性活動型肝炎、重症肌無力、史蒂文斯-約翰遜症候群(Steven-Johnson syndrome)、特發性口炎性腹瀉、自體免疫發炎性腸病(例如潰瘍性結腸炎及克羅恩氏病(Crohn's disease))、內分泌眼病、格雷夫斯氏病(Grave's disease)、結節病、肺泡炎、慢性超敏性肺炎、多發性硬化、原發性膽汁性肝硬變、葡萄膜炎(前葡萄膜炎及後葡萄膜炎)、間質肺纖維化、牛皮癬關節炎、腎小球腎炎、心血管疾病、動脈粥樣硬化、高血壓、深部靜脈血栓形成、中風、心肌梗塞、不穩定型心絞痛、血栓栓塞、肺栓塞、溶血栓性疾病、急性動脈缺血、周邊血栓形成性阻塞及冠脈疾病、再灌注損傷、視網膜病變(例如糖尿病性視網膜病變或高壓氧誘導之視網膜病變)及特徵在於眼內壓升高或眼房水分泌之病狀(例如青光眼)。
較佳地,增殖性疾病係癌症。術語「癌症」係指較佳地藉由PI3K之α-同型異構體介導之腫瘤及/或癌細胞生長。特定而言,該等化合物可用於治療癌症,包含(例如)肉瘤、肺癌、支氣管癌、前列腺
癌、乳癌(包含散發性乳癌及考登病(Cowden disease)受害者)、胰臟癌、胃腸癌、結腸癌、直腸癌、結腸癌瘤、結腸直腸腺瘤、甲狀腺癌、肝癌、肝內膽管癌、肝細胞癌、腎上腺癌、胃癌(stomach cancer、gastric cancer)、神經膠質瘤、膠質母細胞瘤、子宮內膜癌、黑素瘤、腎癌、腎盂癌、膀胱癌、子宮體癌、子宮頸癌、陰道癌、卵巢癌、多發性骨髓瘤、食管癌、白血病、急性骨髓性白血病、慢性骨髓性白血病、淋巴細胞性白血病、髓樣白血病、腦癌、口腔癌及咽癌、喉癌、小腸癌、非何潔金氏淋巴瘤(non-Hodgkin lymphoma)、黑素瘤、結腸絨毛腺瘤、贅瘤形成、上皮性贅瘤形成、淋巴瘤、乳房癌瘤、基細胞癌瘤、鱗狀細胞癌瘤、光線性角化病、頭頸癌、真性紅細胞增多症、原發性血小板增多症、髓樣化生之骨髓纖維化及瓦爾登斯特倫氏病(Waldenstroem disease)。
藉由PI3K之α亞單位介導之增殖性疾病可包含彼等展示以下情形者:PI3Kα之過度表現或擴增、PIK3CA之體細胞突變或PTEN之種系突變或體細胞突變或用於上調p85-p110複合物之p85 α之突變及移位。在一較佳實施例中,癌症係藉由PI3K之α同型異構體介導之腫瘤及/或癌性生長。
在一實施例中,增殖性疾病係選自以下之癌症:肺癌、支氣管癌、前列腺癌、乳癌(包含散發性乳癌及考登病受害者)、結腸癌、直腸癌、結腸癌瘤、結腸直腸腺瘤、胰臟癌、胃腸癌、肝細胞癌、胃癌(stomach cancer、gastric cancer)、卵巢癌、鱗狀細胞癌瘤及頭頸癌。
在另一實施例中,增殖性疾病係選自乳房癌、結腸癌、直腸癌、結腸癌瘤、結腸直腸腺瘤、子宮內膜癌及子宮頸癌之癌症。
在另一實施例中,增殖性疾病係選自肺癌、乳癌(包含散發性乳癌及考登病受害者)、胃癌、卵巢癌及頭頸癌之癌症。
在另一實施例中,本發明係關於藉由根據本發明之劑量療法投
與式(I)化合物或其醫藥上可接受之鹽來治療癌症。
據信,將經口投與之式(I)之此強力α-同型異構體選擇性PI3K抑制劑化合物或其醫藥上可接受之鹽的投藥自(a)日劑量為每日約100mg至約450mg根據連續每日時間表減小至(b)日劑量為約100mg至約450mg且經至少兩個連續5天週期(其中在該等連續5天週期之間約2天至約3天之時段內並不投與該化合物)會有效治療或預防增殖性疾病,同時減輕、減小或緩解任一副效應之嚴重程度、發生率及/或頻率。此尤其適於治療或預防癌症。
可藉由本發明之劑量療法減輕、減小或緩解之該等副效應之實例包含但不限於嗜中性白血球減少症、膽紅素升高、心臟毒性、不穩定型心絞痛、心肌梗塞、持續性高血壓、周邊感覺或運動神經病變/疼痛、肝臟功能障礙(例如肝損傷或肝病、天門冬胺酸轉胺酶濃度升高、丙胺酸胺基轉移酶濃度升高等)、紅血球及/或白血球計數減小、高血糖症、噁心、食欲降低、腹瀉、疹(例如斑丘疹、痤瘡樣等)及超敏性(例如擦傷敏感性增加)、光敏性、虛弱/疲勞、嘔吐、口腔炎、口腔黏膜炎、胰臟炎、味覺障礙及消化不良。熟習此項技術者應理解如何使用經歷或先前知識及/或藉由參照標準副效應評級凖則來評價患有增殖性疾病之患者之該等副效應,例如藉由使用不良事件之NCI常用術語凖則(NCI Common Terminology Criteria for Adverse Events)4.03版(網站位於:http://evs.nci.nih.gov/ftp1/CTCAE/About.html)(其全部內容以引用方式併入本文中)來評價該患者。
在一較佳實施例中,藉由本發明之劑量療法減輕、減小或緩解之副效應係選自以下之病狀:高血糖症、噁心、食欲降低、腹瀉、疹(例如斑丘疹、痤瘡樣等)及超敏性(例如擦傷敏感性增加)、光敏性、虛弱/疲勞、嘔吐、口腔炎、口腔黏膜炎、味覺障礙及消化不良。更佳地,藉由本發明之劑量療法減輕、減小或緩解之副效應係高血糖
症。
藉由已確立測試模型可展示,本發明之劑量療法得到上文所闡述之有益效應。熟習此項技術者完全能夠選擇相關測試模型來證實該等有益效應。可(例如)在臨床研究、動物研究或基本上如下文所闡述之測試程序中證實式(I)化合物或其醫藥上可接受之鹽之藥理學活性。
特定而言,適宜臨床研究係(例如)患有增殖性疾病(包含(例如)腫瘤疾病,例如乳癌)之患者中之開放標記、劑量遞增研究,其中根據本發明之劑量療法向該患者經口投與式(I)化合物。較佳地,將患者分配至不同組,其中根據連續每日時間表向至少一個組投與式(I)化合物且根據本發明之劑量療法向至少一個組投與式(I)化合物。特定而言,該等研究證實了治療劑之效能及其對於現有或潛在副效應之影響。可經由該等研究之結果(其由此為熟習此項技術者所習知)來直接測定對增殖性疾病之有益效應。特定而言,該等研究可適於比較使用治療劑之連續日時間表及本發明之投藥時間表之效應。每一患者可每天一次或每天一次以上(例如兩次)接收式(I)化合物或其醫藥上可接受之鹽之劑量。可在該等研究中(例如在12、18或24週之後)藉由每6週評估症狀評分及/或腫瘤大小量測來測定治療效能。
根據本發明,較佳地以醫藥組合物之形式來使用或投與式(I)化合物或其醫藥上可接受之鹽,該等醫藥組合物含有治療有效量之式(I)化合物或其醫藥上可接受之鹽以及一或多種適於經口投與之醫藥上可接受之賦形劑。醫藥組合物可包括約100mg至約450mg之量之擬以單一劑量單位投與之式(I)化合物或其醫藥上可接受之鹽。另一選擇為,醫藥組合物可包括如下量之式(I)化合物或其醫藥上可接受之鹽:其細分成多個劑量單位且投與約100mg至約450mg式(I)化合物或其醫藥上可接受之鹽之日劑量。
可以本身已知適於經口投與哺乳動物(溫血動物,包含人類)之方
式來製備本發明中所使用之醫藥組合物。用於經口投與之醫藥組合物可包含(例如)彼等呈劑量單位形式者,例如糖包衣錠劑、錠劑、膠囊、藥囊及另外安瓿(ampoule)。若為另外指示,則該等形式係以本身已知之方式(例如藉助習用混合、製粒、糖包衣、溶解或凍乾製程)來製備。應瞭解,含於個別劑量或劑量單位中之活性成份之量無需本身構成治療有效量,此乃因所需有效量可藉由投與複數個劑量單位來達成。
新穎醫藥組合物可含有(例如)約10%至約100%、較佳地約20%至約60%之活性成份。
在製備用於口服劑量單位形式之組合物時,可採用任一常用醫藥上可接受之賦形劑,例如水、二醇、油、醇、矯味劑、防腐劑、著色劑;或在口服固體製劑(例如粉末、膠囊及錠劑)之情形下諸如以下等賦形劑:澱粉、糖、微晶纖維素、稀釋劑、製粒劑、潤滑劑、黏合劑、崩解劑及諸如此類,其中固體口服製劑優於液體製劑。因錠劑及膠囊易於投與,故其代表最有利之口服劑量單元形式,在該情形下,顯然可採用固體醫藥載劑。
熟習此項技術者藉由常規實驗即可針對劑量單位形式之特定期望性質來選擇上述賦形劑中之一或多者而無需任何過多工作量。所用各賦形劑之量可在業內習用範圍內變化。下列皆以引用方式併入本文中之參考文獻揭示用於調配口服劑型之技術及賦形劑。(參見The Handbook of Pharmaceutical Excipients,第4版,Rowe等人編輯,American Pharmaceuticals Association(2003);及Remington:the Science and Practice of Pharmacy,第20版,Gennaro編輯,Lippincott Williams & Wilkins(2003)。)
醫藥上可接受之崩解劑之實例包含但不限於澱粉;黏土;纖維素;海藻酸鹽;樹膠;交聯聚合物,例如交聯聚乙烯基吡咯啶酮或交
聚維酮(例如來自International Specialty Products(Wayne,NJ)之POLYPLASDONE XL);交聯羧甲基纖維素鈉或交聯羧甲纖維素鈉(例如來自FMC之AC-DI-SOL);及交聯羧甲基纖維素鈣;大豆多糖;及瓜爾膠(guar gum)。崩解劑可以組合物之約0重量%至約10重量%之量存在。在一實施例中,崩解劑以組合物之約0.1重量%至約5重量%之量存在。
醫藥上可接受之黏合劑之實例包含但不限於澱粉;纖維素及其衍生物,例如微晶纖維素(例如來自FMC(Philadelphia,PA)之AVICEL PH)、羥丙基纖維素、羥乙基纖維素及來自Dow Chemical公司(Midland,MI)之羥丙基甲基纖維素METHOCEL;蔗糖;右旋糖;玉米糖漿;多糖;及明膠。黏合劑可以組合物之約0重量%至約50重量%(例如2-20重量%)之量存在。
醫藥上可接受之潤滑劑及醫藥上可接受之滑動劑之實例包含但不限於膠體二氧化矽、三矽酸鎂、澱粉、滑石粉、磷酸鈣、硬脂酸鎂、硬脂酸鋁、硬脂酸鈣、碳酸鎂、氧化鎂、聚乙二醇、粉狀纖維素及微晶纖維素。潤滑劑可以組合物之約0重量%至約10重量%之量存在。在一實施例中,潤滑劑可以組合物之約0.1重量%至約1.5重量%之量存在。滑動劑可以約0.1重量%至約10重量%之量存在。
醫藥上可接受之填充劑及醫藥上可接受之稀釋劑之實例包含但不限於粉糖、可壓縮糖、葡聚糖黏合劑、糊精、右旋糖、乳糖、甘露醇、微晶纖維素、粉狀纖維素、山梨醇、蔗糖及滑石粉。填充劑及/或稀釋劑(例如)可以組合物之約0重量%至約80重量%之量存在。
含有式(I)化合物或其醫藥上可接受之鹽之劑量單位形式可呈包封於膠囊(例如明膠膠囊)內側之微錠劑之形式。為此,可使用用於醫藥調配物中之明膠膠囊,例如稱為CAPSUGEL之硬明膠膠囊(可自Pfizer獲得)。
醫藥上可接受之崩解劑之實例包含但不限於澱粉;黏土;纖維素;海藻酸鹽;樹膠;交聯聚合物,例如交聯聚乙烯基吡咯啶酮或交聚維酮(例如來自International Specialty Products(Wayne,NJ)之POLYPLASDONE XL);交聯羧甲基纖維素鈉或交聯羧甲纖維素鈉(例如來自FMC之AC-DI-SOL);及交聯羧甲基纖維素鈣;大豆多糖;及瓜爾膠。崩解劑可以組合物之約0重量%至約10重量%之量存在。在一實施例中,崩解劑以組合物之約0.1重量%至約5重量%之量存在。
醫藥上可接受之黏合劑之實例包含但不限於澱粉;纖維素及其衍生物,例如微晶纖維素(例如來自FMC(Philadelphia,PA)之AVICEL PH)、羥丙基纖維素、羥乙基纖維素及來自Dow Chemical公司(Midland,MI)之羥丙基甲基纖維素METHOCEL;蔗糖;右旋糖;玉米糖漿;多糖;及明膠。黏合劑可以組合物之約0重量%至約50重量%(例如2-20重量%)之量存在。
醫藥上可接受之潤滑劑及醫藥上可接受之滑動劑之實例包含但不限於膠體二氧化矽、三矽酸鎂、澱粉、滑石粉、磷酸鈣、硬脂酸鎂、硬脂酸鋁、硬脂酸鈣、碳酸鎂、氧化鎂、聚乙二醇、粉狀纖維素、硬脂基富馬酸鈉及微晶纖維素。潤滑劑可以組合物之約0重量%至約10重量%之量存在。在一實施例中,潤滑劑可以組合物之約0.1重量%至約1.5重量%之量存在。滑動劑可以約0.1重量%至約10重量%之量存在。
醫藥上可接受之填充劑及醫藥上可接受之稀釋劑之實例包含但不限於粉糖、可壓縮糖、葡聚糖黏合劑、糊精、右旋糖、乳糖、甘露醇、微晶纖維素、粉狀纖維素、山梨醇、蔗糖及滑石粉。填充劑及/或稀釋劑(例如)可以組合物之約0重量%至約80重量%之量存在。
在一實施例中,本發明係關於用於治療或預防有需要之患者之增殖性疾病之醫藥組合物,其包括約100mg至約450mg之量之式(I)化
合物或其醫藥上可接受之鹽以及一或多種醫藥上可接受之賦形劑,其中向患者經口投與該醫藥組合物至少兩個連續5天週期且在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與。
在一實施例中,本發明係關於治療或預防有需要之患者之增殖性疾病之方法,其包括以約100mg至約450mg、較佳地約200mg至約400mg或更佳地約350mg至約400mg之日劑量向患者經口投與治療有效量之式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。較佳地,在一個連續5天週期與其隨後連續5天週期之間約2天內並不投與化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於治療或預防有需要之患者之增殖性疾病之方法,其包括以約100mg至約450mg之日劑量每天一次(q.d.)向患者經口投與治療有效量之式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於治療或預防有需要之患者之增殖性疾病之方法,其包括以約100mg至約450mg之日劑量每天兩次(b.i.d.)向患者經口投與治療有效量之式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於治療或預防有需要之患者之增殖性疾病之方法,其包括以約100mg至約450mg之日劑量每天一次
(q.d.)向患者經口投與治療有效量之式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期中該化合物或其醫藥上可接受之鹽之最後一次投與與其隨後連續5天週期中該化合物或其醫藥上可接受之鹽之第一次投與間約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於治療或預防有需要之患者之增殖性疾病之方法,其包括以約100mg至約450mg、較佳地約350mg至約400mg之日劑量每天兩次(b.i.d.)向患者經口投與治療有效量之式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期中該化合物或其醫藥上可接受之鹽之最後一次投與與其隨後連續5天週期中該化合物或其醫藥上可接受之鹽之第一次投與間約2.5天之時段內並不投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於根據本文之劑量療法治療或預防增殖性疾病之方法,其中以兩個或更多個該連續5天週期投與式(I)化合物或其醫藥上可接受之鹽直至減輕、減小或緩解該患者之至少一種副效應之嚴重程度、發生率或頻率為止。
在另一實施例中,本發明係關於根據本文之劑量療法治療或預防增殖性疾病之方法,其中以兩個或更多個該連續5天週期投與式(I)化合物或其醫藥上可接受之鹽直至疾病進展為止。
在另一實施例中,本發明係關於治療或預防增殖性疾病之方法,其包括第一,根據連續每日時間表經由經口投與向有需要之患者以每天約100mg至約450mg之量投與式(I)化合物或其醫藥上可接受之鹽;第二,在向該患者投與該式(I)化合物或其醫藥上可接受之鹽之後測得該患者具有選自以下之副效應:嗜中性白血球減少症、膽紅素升高、心臟毒性、不穩定型心絞痛、心肌梗塞、持續性高血壓、周邊感覺或運動神經病變/疼痛、肝臟功能障礙(例如肝損傷或肝病、天門冬
胺酸轉胺酶濃度升高、丙胺酸胺基轉移酶濃度升高等)、紅血球及/或白血球計數減小、高血糖症、噁心、食欲降低、腹瀉、疹(例如斑丘疹、痤瘡樣等)及超敏性(例如擦傷敏感性增加)、光敏性、虛弱/疲勞、嘔吐、口腔炎、口腔黏膜炎、胰臟炎、味覺障礙及消化不良;及第三,將該式(I)化合物或其醫藥上可接受之鹽之投與減小至約100mg至約450mg的日劑量經由經口投與至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於減少至少一種選自以下之來自先前使用式(I)化合物或其醫藥上可接受之鹽治療之副效應之方法:嗜中性白血球減少症、膽紅素升高、心臟毒性、不穩定型心絞痛、心肌梗塞、持續性高血壓、周邊感覺或運動神經病變/疼痛、肝臟功能障礙(例如肝損傷或肝病、天門冬胺酸轉胺酶濃度升高、丙胺酸胺基轉移酶濃度升高等)、紅血球及/或白血球計數減小、高血糖症、噁心、食欲降低、腹瀉、疹(例如斑丘疹、痤瘡樣等)及超敏性(例如擦傷敏感性增加)、光敏性、虛弱/疲勞、嘔吐、口腔炎、口腔黏膜炎、胰臟炎、味覺障礙及消化不良,其包括以約100mg至約450mg、較佳地約200mg至約400mg或更佳地約350mg至約400mg之日劑量向患者經口投與治療有效量之式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
另外,本發明包含根據上文針對本發明所揭示之任一其他實施例來治療或預防增殖性病症之方法。
在一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用以製造用於治療或預防增殖性疾病之醫藥之用途,其中以約100mg至約450mg、較佳地約200mg至約400mg或更佳地約350mg至約
400mg該式(I)化合物或其醫藥上可接受之鹽之日劑量向有需要之患者經口投與該醫藥至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該醫藥。
在另一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用以製造用於治療或預防增殖性疾病之醫藥之用途,其中以約100mg至約450mg之日劑量向有需要之患者每天一次(q.d.)經口投與該醫藥至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用以製造用於治療或預防增殖性疾病之醫藥之用途,其中以約100mg至約450mg之日劑量向有需要之患者每天兩次(b.i.d.)經口投與該醫藥至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用以製造用於治療或預防增殖性疾病之醫藥之用途,其中以約100mg至約450mg之日劑量向有需要之患者每天一次(q.d.)經口投與該醫藥至少兩個連續5天週期,其中在一個連續5天週期中該化合物或其醫藥上可接受之鹽之最後一次投與與其隨後連續5天週期中該化合物或其醫藥上可接受之鹽之第一次投與間約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用以製造用於治療或預防增殖性疾病之醫藥之用途,其中以約100mg至約450mg之日劑量向有需要之患者每天兩次(b.i.d.)經口投與
該醫藥至少兩個連續5天週期,其中在一個連續5天週期中該化合物或其醫藥上可接受之鹽之最後一次投與與其隨後連續5天週期中該化合物或其醫藥上可接受之鹽之第一次投與間約2.5天之時段內並不投與該化合物或其醫藥上可接受之鹽。
在另一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用以製造用於治療或預防增殖性疾病之醫藥之用途,其中根據本文之劑量療法經口投與該醫藥,其中以兩個或更多個該連續5天週期投與式(I)化合物或其醫藥上可接受之鹽直至減輕、減小或緩解該患者之至少一種副效應之嚴重程度、發生率或頻率為止。
在另一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用以製造用於治療或預防增殖性疾病之醫藥之用途,其中根據本文之劑量療法經口投與該醫藥,其中以兩個或更多個該連續5天週期投與式(I)化合物或其醫藥上可接受之鹽直至疾病進展為止。
在另一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用以製造用於治療或預防增殖性疾病之醫藥之用途,其中首先以約100mg至約450mg日劑量之量根據連續每日時間表經口投與該醫藥且隨後將投與量減小至經口投與約100mg至約450mg日劑量至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該化合物或其醫藥上可接受之鹽。
另外,本發明包含式(I)化合物或其醫藥上可接受之鹽之任一用途,其用以根據上文針對本發明所揭示之治療方法或任一實施例來製造用於治療或預防增殖性疾病之醫藥。
在一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用於治療或預防增殖性疾病之用途,其中以約100mg至約450mg之日劑量向有需要之患者經口投與該式(I)化合物或其醫藥上可接受之鹽
至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該式(I)化合物或其醫藥上可接受之鹽。
另外,本發明包含根據上文針對本發明所揭示之治療方法、製造醫藥之用途或任一實施例式(I)化合物或其醫藥上可接受之鹽之任一用途。
本發明另外係關於一種治療療法,其包括以約100mg至約450mg之日劑量向有需要之患者經口投與治療有效量之式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該式(I)化合物或其醫藥上可接受之鹽。
本發明另外係關於與至少一種其他治療劑組合投與以用於治療或預防增殖性疾病之式(I)化合物或其醫藥上可接受之鹽,其中以約100mg至約450mg之日劑量投與式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該式(I)化合物或其醫藥上可接受之鹽。
適用於本發明之治療劑包含但不限於激酶抑制劑、抗雌激素、抗雄激素、其他抑制劑、癌症化學治療藥物、烷基化藥劑、螯合劑、生物反應改質劑、癌症疫苗、用於反義療法之藥劑。實例陳述如下:
A.激酶抑制劑,包含表皮生長因子受體(EGFR)激酶抑制劑,例如小分子喹唑啉,例如吉非替尼(gefitinib)(US 5457105、US 5616582及US 5770599)、ZD-6474(WO 01/32651)、埃羅替尼(erlotinib)(Tarceva®,US 5,747,498及WO 96/30347)及拉帕替尼(lapatinib)(US 6,727,256及WO 02/02552)及西妥昔單抗(cetuximab);血管內皮生長因子受體(VEGFR)激酶抑制劑,包含SU-11248(WO 01/60814)、SU
5416(US 5,883,113及WO 99/61422)、SU 6668(US 5,883,113及WO 99/61422)、CHIR-258(US 6,605,617及US 6,774,237)、伐他拉尼(vatalanib)或PTK-787(US 6,258,812)、VEGF-Trap(WO 02/57423)、B43-染料木黃酮(WO-09606116)、芬維A胺(fenretinide)(視黃酸對-羥基苯基胺)(US 4,323,581)、IM-862(WO 02/62826)、貝伐單抗(bevacizumab)或Avastin®(WO 94/10202)、KRN-951、3-[5-(甲基磺醯基六氫吡啶甲基)-吲哚基]-喹諾酮、AG-13736及AG-13925、吡咯并[2,1-f][1,2,4]三嗪、ZK-304709、Veglin®、VMDA-3601、EG-004、CEP-701(US 5,621,100)、Cand5(WO 04/09769);Erb2酪胺酸激酶抑制劑,例如帕妥珠單抗(pertuzumab)(WO 01/00245)、曲司佐單抗(trastuzumab)及利妥昔單抗(rituximab);Akt蛋白質激酶抑制劑,例如RX-0201;蛋白質激酶C(PKC)抑制劑,例如LY-317615(WO 95/17182)及哌立福辛(perifosine)(US 2003171303);Raf/Map/MEK/Ras激酶抑制劑,包含索拉非尼(sorafenib)(BAY 43-9006)、ARQ-350RP、LErafAON、BMS-354825AMG-548、MEK162及其他揭示於WO 03/82272中者;纖維母細胞生長因子受體(FGFR)激酶抑制劑;細胞依賴性激酶(CDK)抑制劑,包含CYC-202或羅克韋汀(roscovitine)(WO 97/20842及WO 99/02162);血小板源生長因子受體(PDGFR)激酶抑制劑,例如CHIR-258、3G3 mAb、AG-13736、SU-11248及SU6668;及Bcr-Abl激酶抑制劑及融合蛋白,例如STI-571或Gleevec®(伊馬替尼(imatinib))。
B.抗雌激素:雌激素靶向劑包含選擇性雌激素受體調變劑(SERM),包含他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene);芳香酶抑制劑,包含Arimidex®或阿那曲唑(anastrozole);雌激素受體下調劑(ERD),包含Faslodex®或氟維司群(fulvestrant)。
C.抗雄激素:雄激素靶向劑,包含氟他胺(flutamide)、比卡魯胺(bicalutamide)、非那雄胺(finasteride)、胺魯米特(aminoglutethamide)、酮康唑(ketoconazole)及皮質類固醇。
D.其他抑制劑,包含蛋白質法呢基轉移酶抑制劑,包含替吡法尼(tipifarnib)或R-115777(US 2003134846及WO 97/21701)、BMS-214662、AZD-3409及FTI-277;拓撲異構酶抑制劑,包含梅爾巴隆(merbarone)及二氟替康(diflomotecan)(BN-80915);有絲分裂驅動蛋白紡錘體蛋白(KSP)抑制劑,包含SB-743921及MKI-833;蛋白酶體調變劑,例如硼替佐米(bortezomib)或Velcade®(US 5,780,454)、XL-784;環氧合酶2(COX-2)抑制劑,包含非類固醇抗發炎藥I(NSAID);來曲唑(letrozole);依西美坦(exemestane);及艾日布林(eribulin)。
E.癌症化學治療藥包含阿那曲唑(Arimidex®)、比卡魯胺(Casodex®)、硫酸博來黴素(bleomycin sulfate,Blenoxane®)、白消安(busulfan,Myleran®)、白消安注射劑(Busulfex®)、卡培他濱(capecitabine,Xeloda®)、N4-戊氧基羰基-5-去氧-5-氟胞苷、卡鉑(carboplatin,Paraplatin®)、卡莫司汀(carmustine,BiCNU®)、苯丁酸氮芥(Leukeran®)、順鉑(cisplatin,Platinol®)、克拉屈濱(cladribine,Leustatin®)、環磷醯胺(Cytoxan®或Neosar®)、阿糖胞苷(cytarabine)、胞嘧啶阿糖核苷(cytosine arabinoside,Cytosar-U®)、阿糖胞苷脂質體注射劑(DepoCyt®)、達卡巴嗪(dacarbazine,DTIC-Dome®)、更生黴素(dactinomycin)(放線菌素D(Actinomycin D),Cosmegan)、唐黴素鹽酸鹽(daunorubicin hydrochloride,Cerubidine®)、檸檬酸唐黴素脂質體注射劑(DaunoXome®)、地塞米松(dexamethasone)、多西他賽(docetaxel,Taxotere®)、多柔比星鹽酸鹽(doxorubicin hydrochloride,Adriamycin®、Rubex®)、依託泊苷
(etoposide,Vepesid®)、磷酸氟達拉濱(fludarabine phosphate,Fludara®)、5-氟尿嘧啶(5-fluorouracil,Adrucil®、Efudex®)、氟他胺(Eulexin®)、替紮他濱(tezacitibine)、吉西他濱(Gemcitabine,雙氟去氧胞苷)、羥基脲(hydroxyurea,Hydrea®)、艾達黴素(Idarubicin,Idamycin®)、異環磷醯胺(ifosfamide,IFEX®)、伊立替康(irinotecan,Camptosar®)、L-天門冬醯胺酶(ELSPAR®)、甲硫四氫葉酸鈣、美法侖(melphalan,Alkeran®)、6-巰基嘌呤(Purinethol®)、胺甲蝶呤(methotrexate,Folex®)、米托蒽醌(mitoxantrone,Novantrone®)、滅髓瘤(mylotarg)、太平洋紫杉醇(paclitaxel,Taxol®)、菲尼克斯(phoenix,釔90/MX-DTPA)、噴司他丁(pentostatin)、聚苯丙生20(polifeprosan 20)與卡莫司汀植入物(Gliadel®)、檸檬酸他莫昔芬(tamoxifen citrate,Nolvadex®)、替尼泊苷(teniposide,Vumon®)、6-硫鳥嘌呤、塞替派(thiotepa)、替拉紮明(tirapazamine,Tirazone®)、注射用托泊替康鹽酸鹽(topotecan hydrochloride for injection,Hycamptin®)、長春鹼(vinblastine,Velban®)、長春新鹼(Oncovin®)及長春瑞濱(vinorelbine,Navelbine®)。
F.烷基化藥劑,包含VNP-40101M或克洛替嗪(cloretizine)、奧沙利鉑(oxaliplatin)(US 4,169,846、WO 03/24978及WO 03/04505)、葡磷醯胺(glufosfamide)、馬磷醯胺(mafosfamide)、凡畢複(etopophos)(US 5,041,424)、潑尼氮芥(prednimustine);曲奧舒凡(treosulfan);白消安;伊洛福芬(irofluven)(醯基富烯(acylfulvene));本可麥定(penclomedine);吡唑啉吖啶(pyrazoloacridine)(PD-115934);O6-苄基鳥嘌呤;地西他濱(decitabine)(5-氮雜-2-去氧胞苷);伯斯坦尼辛(brostallicin);絲裂黴素C(mitomycin C)(MitoExtra);TLK-286(Telcyta®);替莫唑胺(temozolomide);曲貝替定(trabectedin)(US
5,478,932);AP-5280(順鉑之鉑酸鹽調配物);泊非黴素(porfiromycin);及克萊拉德(clearazide)(二氯甲基二乙胺(meclorethamine))。
G.螯合劑,包含四硫鉬酸鹽(tetrathiomolybdate)(WO 01/60814);RP-697;嵌合T84.66(cT84.66);釓膦維司(gadofosveset)(Vasovist®);去鐵胺(deferoxamine);及博來黴素視情況與電穿孔(EPT)之組合。
H.生物反應改質劑,例如免疫調變劑,包含星型包菌素(staurosprine)及其大環類似物,包含UCN-01、CEP-701及米哚妥林(midostaurin)(參見WO 02/30941、WO 97/07081、WO 89/07105、US 5,621,100、WO 93/07153、WO 01/04125、WO 02/30941、WO 93/08809、WO 94/06799、WO 00/27422、WO 96/13506及WO 88/07045);角鯊胺(squalamine)(WO 01/79255);DA-9601(WO 98/04541及US 6,025,387);阿侖珠單抗(alemtuzumab);干擾素(例如IFN-a、IFN-b等);介白素,具體而言IL-2或阿地白介素(aldesleukin)以及IL-1、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12及其具有大於70%之原始人類序列之胺基酸序列之活性生物變體;六甲蜜胺(altretamine)(Hexalen®);SU 101或來氟米特(leflunomide)(WO 04/06834及US 6,331,555);咪唑并喹啉,例如瑞喹莫德(resiquimod)及咪喹莫特(imiquimod)(US 4,689,338、5,389,640、5,268,376、4,929,624、5,266,575、5,352,784、5,494,916、5,482,936、5,346,905、5,395,937、5,238,944及5,525,612);或SMIP,包含苯并吡咯、蒽醌、硫半卡腙及色胺酮(tryptanthrin)(WO 04/87153、WO 04/64759及WO 04/60308)。
I.癌症疫苗:抗癌症疫苗,包含Avicine®(Tetrahedron Lett.26:2269-70(1974));奧戈伏單抗(oregovomab)(OvaRex®);
Theratope®(STn-KLH);黑素瘤疫苗;GI-4000系列(GI-4014、GI-4015及GI-4016),其指向Ras蛋白中之5種突變;GlioVax-1;MelaVax;Advexin®或INGN-201(WO 95/12660);Sig/E7/LAMP-1,其編碼HPV-16 E7;MAGE-3疫苗或M3TK(WO 94/05304);HER-2VAX;ACTIVE,其刺激腫瘤之特異性T細胞;GM-CSF癌症疫苗;及基於單核球增多性李斯特菌(Listeria monocytogene)之疫苗。
J.反義療法:抗癌劑,包含反義組合物,例如AEG-35156(GEM-640);AP-12009及AP-11014(TGF-β2特異性反義寡核苷酸);AVI-4126;AVI-4557;AVI-4472;奧利默森(oblimersen)(Genasense®);JFS2;阿普卡生(aprinocarsen)(WO 97/29780);GTI-2040(R2核糖核苷酸還原酶mRNA反義寡聚物)(WO 98/05769);GTI-2501(WO 98/05769);脂質體囊封之c-Raf反義寡去氧核苷酸(LErafAON)(WO 98/43095);及Sirna-027(靶向VEGFR-1 mRNA之基於RNAi之治療劑)。
在一實施例中,其他治療劑係選自吉非替尼、埃羅替尼、貝伐單抗或Avastin®、帕妥珠單抗、曲司佐單抗、MEK162、他莫昔芬、氟維司群、卡培他濱、順鉑、卡鉑、西妥昔單抗、太平洋紫杉醇、替莫唑胺、來曲唑或依西美坦。
藉由代碼編號、通用名或商品名鑑別之藥物物質之結構可自網際網路現行版本之標準綱要「默克索引(The Merck Index)」獲得或自諸如國際專利(例如IMS世界公開案(IMS World Publication))或上下文所提及之出版物等資料庫獲得。其相應內容以引用方式併入本文中。
式(I)化合物及其他治療劑可以單一醫藥組合物、單獨以兩個或更多個單獨單位劑型或依序一起投與。包括其他治療劑之醫藥組合物或劑量單位形式可以本身已知之方式來製備且係彼等適於經腸(例如經口或經直腸)、局部及非經腸投與個體(包含哺乳動物(溫血動物),
例如人類)者。
特定而言,可同時或依序且以任一順序投與治療有效量之每一治療劑,且可單獨或以固定組合投與各組份。舉例而言,本發明之組合可包括:同時或以任一順序依序以聯合治療有效量、較佳以協同有效量(例如以對應於本文所闡述量之每日或間歇劑量)(i)投與呈游離形式或醫藥上可接受之鹽形式之第一治療劑(a)及(ii)投與呈游離形式或醫藥上可接受之鹽形式之治療劑(b)。組合之個別治療劑可在療法進程期間於不同時間單獨投與或以分次或單一組合形式同時投與。
「協同作用」或「協同」係指兩種治療劑(例如(a)式(I)化合物或其醫藥上可接受之鹽及(b)芳香酶抑制劑)產生(例如)減緩癌症疾病或病症、尤其癌症或其症狀之症狀性進展之效應之作用,其大於單獨投與每一治療劑之效應之簡單加和。可使用(例如)適宜方法計算協同效應,該等方法係(例如)S形-Emax方程式(Holford,N.H.G.及Scheiner,L.B.,Clin.Pharmacokinet.6:429-453(1981))、Loewe加性方程式(Loewe,S.及Muischnek,H.,Arch.Exp.Pathol Pharmacol.114:313-326(1926))及中值效應方程式(Chou,T.C.及Talalay,P.,Adv.Enzyme Regul.22:27-55(1984))。可將上文提及之每一方程式應用至實驗數據以生成相應圖形以有助於評定治療劑組合之效應。與上文提及之方程式有關之相應圖形分別係濃度-效應曲線、等效線圖曲線及組合指數曲線。可進一步藉由根據熟習此項技術者已知之方法計算組合之協同作用評分來展示協同作用。
端視所採用之特定化合物或醫藥組合物、投與模式、所治療病狀、所治療病狀之嚴重程度,組合中所採用之治療劑(a)或治療劑(b)中之每一者之有效劑量可有所變化。因此,根據包含以下之各種因素來選擇組合之劑量療法:患者之類型、物種、年齡、體重、性別及醫學病狀;擬治療病狀之嚴重程度;投與途徑;患者之腎及肝功能;及
所採用之特定化合物。熟習此項技術者之醫師、臨床醫師或獸醫可易於確定預防、對抗或阻止病狀進展所需治療劑之有效量並開具處方。在產生效能之範圍內達成治療劑濃度之最佳精度需要基於治療劑對靶位點之可用性之動力學之療法。此涉及對治療劑之分佈、平衡及消除之考慮。
可使用式(I)化合物或其醫藥上可接受之鹽及至少一種其他治療劑之組合治療之增殖性疾病的實例包含但不限於彼等陳述於上文中者。
藉由已確立測試模型可展示,本發明之組合得到上文所闡述之有益效應。熟習此項技術者完全能夠選擇相關測試模型來證實該等有益效應。可(例如)在臨床研究或基本上如下文所闡述之測試程序中證實本發明組合之藥理學活性。
特定而言,適宜臨床研究係(例如)患有增殖性疾病(包含(例如)腫瘤疾病,例如乳癌)之患者中之開放標記、劑量遞增研究。特定而言,該等研究證實了本發明組合之治療劑之協同作用。可經由該等研究之結果(其由此為熟習此項技術者所習知)來直接測定對增殖性疾病之有益效應。特定而言,該等研究可適於比較使用治療劑之單一療法及本發明組合之效應。在一實施例中,遞增式(I)之α-同型異構體選擇性PI3K抑制劑化合物或其醫藥上可接受之鹽之劑量直至達成最大耐受劑量為止,且使用固定劑量投與組合配偶體。另一選擇為,以固定劑量投與式(I)化合物或其醫藥上可接受之鹽可且可遞增組合配偶體之劑量。每一患者可每天一次或每天一次以上(例如兩次)接收式(I)化合物或其醫藥上可接受之鹽之劑量。可在該等研究中(例如在12、18或24週之後)藉由每6週評估症狀評分來測定治療效能。
在本發明組合中,以約100mg至約450mg之日劑量投與式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5
天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向患者投與該式(I)化合物或其醫藥上可接受之鹽。
在一實施例中,本發明係關於藉由根據本發明之劑量療法進行投與來治療治療或預防增殖性疾病之方法,其中組合投與該式(I)化合物或其醫藥上可接受之鹽與至少一種其他治療劑。
在另一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用以製造用於根據本發明之劑量療法治療或預防增殖性疾病之醫藥之用途,其中組合投與該式(I)化合物或其醫藥上可接受之鹽與至少一種其他治療劑。
在另一實施例中,本發明係關於式(I)化合物或其醫藥上可接受之鹽用於根據本發明之劑量療法治療或預防增殖性疾病之用途,其中組合投與該式(I)化合物或其醫藥上可接受之鹽與至少一種其他治療劑。
本發明進一步係關於一種包裝,其包括醫藥組合物(包括日劑量為約100mg至約450mg之式(I)化合物或其醫藥上可接受之鹽以及一或多種醫藥上可接受之賦形劑)與說明之組合,該說明指示經口投與該醫藥組合物至少兩個連續5天週期且在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不投與該組合物。
可在活體外、在動物測試方法中以及在臨床研究中證實本發明之式(I)化合物之劑量療法之應用。舉例而言,本發明之式(I)化合物之應用可根據下文所闡述之方法來證實:
動物及維持條件:在雌性Hsd:無胸腺裸-nu CPB小鼠(Harlan Winkelmann,Germany)中實施實驗。動物在開始治療時為12至14週齡且在最佳衛生條件(Optimized Hygienic Condition,OHC)下圈養於
Makrolon III型籠(最多5只動物/籠)中並自由獲取食物及水。此外,亦在雌性裸Rowett大鼠Hsd:RH-Foxlrnu(Harlan(The Netherlands)中實施實驗。在施加化合物時,動物為6-9週齡。將動物在最佳衛生條件下圈養於Makrolon III型籠(最多2只動物/籠)中並自由獲取食物及水。在開始實驗之前,使其適應至少6天。
細胞系及細胞培養:使Rat1-Myr-p110α細胞在含有4.5g/l葡萄糖且補充有10%熱失活胎牛血清(FCS)、2mM L-麩醯胺酸、1mM丙酮酸鈉之達爾伯克氏改良伊格爾氏培養基(Dulbecco's Modified Eagle Medium,DMEM)中生長且在37℃下於5% CO2增濕氣氛中培育。使用胰島素-EDTA收穫細胞,再懸浮於培養基(具有添加劑)中且使用Casy®系統計數。最後,將細胞離心,以3×107個/ml之濃度懸浮於冰冷漢克氏平衡鹽溶液(Hanks' balanced salt solution,HBSS)中。自BioConcept(Allschwil,Switzerland)購買細胞培養試劑。
藉由Maira等人,Molecular Cancer Therapeutics,11:317-328(2012)中所闡述之方法生成Rat1-myr-p110α細胞,其全部內容以引用方式併入本文中。簡言之,轉染Rat1細胞以藉由向N-末端添加肉豆蔻醯基化信號來穩定表現催化PI3K I類p110同型異構體α之組成型活性形式。
活體內腫瘤異腫移植物之確立:藉由將存於100μL HBSS(Sigma編號為H8264)中之5×106個細胞皮下注射至裸小鼠或裸大鼠之右翼中來確立Rat1-Myr-p110α腫瘤。對於效能實驗而言,在平均腫瘤體積大約為300mm3(在腫瘤細胞注射後14至15天)時,開始治療。對於單一劑量PK/PD實驗而言,在腫瘤達到大約400-500mm3之大小(在腫瘤細胞注射後21至23天)時,使用化合物A經口治療動物一次。
化合物調配及動物治療:以存於1%羧甲基纖維素:0.5% Tween® 80:98.5%去離子水中之均質懸浮液形式製備化合物A以用於投藥。每
4天一次製備新鮮懸浮液且儲存於4℃下。以10mL/kg之體積經口投與化合物A或媒劑。
抗腫瘤活性之評估:使用卡尺量測腫瘤體積且根據式:長度×直徑2×π/6進行測定。除腫瘤體積在治療過程中之呈現變化外,將抗腫瘤活性表示為T/C%(經治療動物之腫瘤體積平均變化/對照動物之腫瘤體積平均變化)×100。根據式((治療結束時之平均腫瘤體積-治療開始時之平均腫瘤體積)/治療開始時之平均腫瘤體積)×100計算消退(%)。每週記錄體重及腫瘤體積二至三次。
採樣:在最後治療後之不同時間點(1小時、2小時、4小時、8小時、12小時、16小時及24小時,n=2-3/時間點)將血樣收集至塗覆有K-EDTA之管中。將血樣離心且將所收集血漿立即在-80℃下冷凍直至最終處理為止。在屠宰時於7個時間點(1小時、2小時、4小時、8小時、12小時、16小時及24小時,n=2-3/時間點)收集腫瘤,快速冷凍且保持在-80℃下直至最終處理為止。
A. 動物組織粉碎:在解剖之後,將腫瘤在液氮中快速冷凍且儲存於-80℃下。使用具有在冷凍器中預冷卻至-80℃之金屬筒之Retsch球混合器磨機MM20(Arlesheim,Switzerland)粉碎經冷凍腫瘤。在乾冰上自金屬筒刮除粉末且轉移至預冷卻1.5mL埃彭道夫管(Eppendorf tube)中,同時避免熔化。
B. 用於量化化合物A之生物分析(LC/MS-MS):在單獨試驗中藉由使用超高壓液相層析/串聯質譜(UPLC/MS-MS)中測定血漿及腫瘤中化合物A之濃度。在將25μL內部標準(1μg/mL)添加至血漿或(20mg)腫瘤粉末之分析等分試樣(25μL)中後,藉由添加200μL乙腈使蛋白質沈澱。將上清液轉移至新鮮小瓶中。在蒸發至乾燥之後,將試樣再溶於60μL乙腈/水(1/1 v/v)中。在ACQUITY UPLC BEH C18管柱
(WatersTM 1.7μm粒徑,2.1×50mm,流動相由存於水中之0.1%甲酸(溶劑A)及存於乙腈中之0.1%甲酸(溶劑B)之混合物組成)上分離此溶液之等分試樣(5μL)。使用流速為600μL/min之程序變梯度。在使用95%溶劑A平衡之後,注射5μL試樣。在0.25min之潛伏期後,使用經0.65分鐘時段5-100%溶劑B之線性梯度、隨後保持0.35分鐘來洗脫試樣。藉由經0.25分鐘再平衡至開始條件來製備用於下一試樣之管柱。將管柱洗脫劑直接引入藉由MasslynxTM 4.1軟體控制之三相四極質譜儀TQDTM(Waters公司,Milford,MA,USA)之離子源中。使用電噴霧正離子化(ESI+)多反應監測來用於分析物之MS/MS檢測。化合物A及相應內部標準之前體至產物離子轉變匯總於下表中:
化合物A之量化限值(LOQ)設定於2.5ng/mL(小於30%之CV及總體偏差)。使用QuanLynxTM 4.1(Micromass)及ExcelTM 2007(Microsoft)實施回歸分析及其他計算。基於來自使用校準試樣(摻加至自使用媒劑治療之動物獲得之空白血漿或腫瘤中)構建之校準曲線之分析物/IS之峰面積比率,反計算未知試樣之濃度。
C. 經由反相蛋白質陣列(RPPA)方式量化Ser473 P-Akt及Akt。
稱取大約20mg經冷凍組織粉末且在100μL NP40蛋白質裂解緩衝混合物(裂解緩衝原液(4℃):2.5mL 2M pH 7.8室溫Tris HCL、1mL室溫NP40(100%)、2.4mL 5M室溫NaCl、2.5mL 1M室溫NaF、4mL 1M-20℃ β甘油磷酸二鈉鹽五水合物及水(直至100mL);裂解緩衝液(4℃):10mL裂解緩衝原液;10uL 100mM 4℃ Na3VO3、10uL 1M-20℃ DTT、10uL 100mM 4℃ PMSF、10uL 1M-20℃苯甲脒及10uL-20℃微囊藻毒素)中裂解。
將每一試樣渦旋且在10,000rpm下離心10分鐘。在-80℃下實施冷凍解凍循環30分鐘。在以10 000rpm實施額外離心步驟10分鐘之後,將試樣儲存於-80℃下用於進一步分析。使用Coomassie Plus套組(23236號Thermo Scientific,Rockford,IL,USA)根據製造商之方案量化蛋白質濃度。將經稀釋試樣轉移至96孔板(269620號,NUNC)中且在595nm下使用來自Molecular Devices之SpectraMAX Plus板讀數儀量測吸光度。使用Softmax Pro 5.0軟體(Molecular Devices,USA)計算蛋白量且然後以1mg/mL使用相應裂解緩衝液正規化。使用補充有1mM原釩酸鈉(Sigma,目錄編號為S-6508)之CSBL1 CeLyA點片緩衝液(Zeptosens,目錄編號為9020)以1:10進一步稀釋經正規化試樣。將裂解液轉移至96孔V形底板(Fisher Scientific,目錄編號為6067Y),隨後實施離心步驟(5min,1500rpm,在19℃下,於埃彭道夫5810R離心器中)以去除未裂解細胞碎片。
使用MATRIX 2x2自動化移液工作站(Thermo Fisher Scientific,UK)將來自96孔V形底板之裂解液重格式化至384孔板(Greiner,目錄編號為781201)中。為獲得期望點片配置,藉由使用相應體積之裂解點片緩衝混合物(10%裂解緩衝液;補充有1mM原釩酸鈉之90% CSBL1點片緩衝液)稀釋細胞裂解液來將每一試樣稀釋至4種不同試樣濃度(d1=100%、d2=75%、d3=50%、d4=25%)。
使用基於壓電式微量分配之非接觸奈米點片機2.1(GeSiM,Grosserkmannsdorf,Germany)將試樣點片於ZeptoMARK® PWG蛋白質微陣列晶片(Zeptosens,Witterswil,Switzerland)上。以4種不同試樣濃度(d1=100%、d2=75%、d3=50%、d4=25%)藉由使用相應體積之點片裂解緩衝混合物稀釋細胞裂解液來將每一試樣點片。在點片ZeptoMARK®蛋白質微陣列之後,將晶片在37℃下培育1小時。為獲得均勻阻斷結果,經由超音波霧化器投與CeLyA阻斷緩衝液BB1
(Zeptosens,目錄編號為9040)。在阻斷20分鐘之後,使用去離子水(Milli-Q品質,18MΩ×cm)深度沖洗晶片且在氮氣流中乾燥。
然後,將ZeptoMARK®晶片轉移至ZeptoCARRIER(Zeptosens,目錄編號為1100)中,且使用200μL CAB1 CeLyA分析緩衝液(Zeptosens,目錄編號為9032)洗滌兩次。然後抽吸分析緩衝液且將每一室與100μL一級靶抗體(pAkt Ser473(批號為9)(Cell Signaling Technology,目錄編號為4060);Akt1 pan(批號為E0401)(Epitomics,目錄編號為1085-1);Zenon® Alexa Fluor 647兔(Invitrogen,目錄編號為Z25308))一起在室溫(RT)下培育過夜。在培育後,去除一級抗體,使用CAB1緩衝液將陣列洗滌兩次且進一步與100μL Alexa fluor 647標記抗兔IgG Fab片段(Invitrogen;Z25305號)一起在室溫下於黑暗中培育一小時。在培育之後,使用200μL CAB1緩衝液將陣列洗滌兩次。在ZeptoReader(Zeptosens,Witterswil,Switzerland)上使用雷射(激發波長為635nm)及CCD照相機讀取靶結合Fab片段之螢光。端視信號強度,使用1、3、5及10秒之暴露時間評價螢光信號。使用ZeptoVIEW Pro 2.0軟體(Zeptosens,Witterswil,Switzerland)分析每一陣列之螢光影像且計算每一信號之RFI(相對螢光強度)。
D. PK-PD建模:使用Phoenix WinNonlin 6.3(Pharsight)且使用自小鼠或大鼠效能研究生成之數據之非房室非參數性疊加方式模擬在多次投藥之後的平均血漿濃度時間特徵。預測係基於自端點斜率(λZ)計算之累積比率,從而容許自簡單或複雜之投藥時間表進行預測。
統計學分析:使用一級腫瘤生長及體重之絕對值製作組間統計學對比(單因素ANOVA(one way ANOVA)且隨後鄧奈特測試(Dunnett’s test)(對於正常分佈之數據);秩方差分析(ANOVA on Ranks)(對於非正常分佈之數據);隨後,鄧奈特測試(對於相等組大小)或杜恩測試
(Dunn’s test)(對於非相等組大小))。將顯著程度設定為p<0.05。藉由使用梯形法則方法測定在最後治療後24h記錄之曲線下面積(AUC)。使用SigmaStat實施所有統計學計算。
遵循上述方法確立化合物A之臨床前PK-PD-效能-耐受性模型。
對於用於化合物A之此臨床前PK-PD-效能-耐受性模型:
用於化合物A之藥物動力學研究及PK建模:化合物A之藥物動力學在所測試劑量之範圍內為線性(圖1 A:12.5、25及50mg/kg(每天一次),在裸小鼠中;圖1 B:12.5、25、40及80mg/kg(每天一次),在裸大鼠中),且與裸小鼠中12.5mg/kg與50mg/kg之間AUC之類似變化有關。在裸大鼠中對於至多80mg/kg之劑量而言觀察到類似關係。圖2A及2B提供非參數性疊加模型來展示在以50mg/kg(每天一次,在裸小鼠中)及40mg/kg(每天一次,在裸大鼠中)經口投與化合物A之後觀察血漿濃度與預測血漿濃度之關係。(圖2A及B)。圖3A及B提供觀察血漿濃度及模型預測之對比且指示。此所用PK模型在裸小鼠(R2=0.99,n=25,p<0.001)中於低於150mg/kg(每天一次)之劑量下且在裸大鼠(R2=0.89,n=31,p<0.01)中於低於100mg/kg(每天一次)之劑量下極具預測性。另外,圖4A指示,此所用PK模型亦預測模擬在裸小鼠中每天兩次(2qd)給予之化合物A之PK特徵。
重複此PK建模研究以證實先前發現,亦即此PK模型預測模擬在裸小鼠中每天兩次(2qd)給予之化合物A之PK特徵。此重複研究之結果提供於圖4B中且再證實,此PK模型預測模擬在裸小鼠中每天兩次(2qd)給予之化合物A之PK特徵。此圖4B數據提供於本文中以僅顯示裸小鼠中PK建模研究之進一步證實。
A. Akt磷酸化之調變:藉由使用RPPA及來自多種動物(裸小
鼠及大鼠)及在使用化合物A治療後之多個時間點下之匹配試樣中之具體腫瘤藥物濃度量測Akt磷酸化程度來測定得到50%(活體內IC50)及80%(活體內IC80)S473P-Akt抑制(分別為0.6μmol/L及4μmol/L)的腫瘤含量與對照(圖5)。在校正小鼠中化合物A之血漿蛋白質結合時(PPB=91.2%),活體內IC50(53nmol/L)及IC80(352nmol/L)值大致分別近似於74nmol/L及301nmol/L之活體外細胞IC50及IC80。
B. Rat1-myr-p110α腫瘤模型中化合物A之抗腫瘤活性:以各種劑量將化合物A經口投與具有Rat1-myr-p110α腫瘤之小鼠及大鼠。腫瘤生長抑制結果匯總於下文中:
抑制似乎為劑量依賴性。在高於25mg/kg之日劑量下於裸小鼠及大鼠中及在高於12.5mg/kg之每天兩次劑量下於裸小鼠中觀察到腫瘤消退。
C. PK/PD/效能關係:圖6提供暴露(如藉由超過活體內IC80之時間所量測)與抗腫瘤效能之間之關係。另外,在抗腫瘤效能等級與超過IC80之藥物暴露持續時間(如藉由超過活體內IC80之時間所量測)
之間鑑別到近線性關係(R2=0.89;圖7)。自此關係測得,對於至少25%之投藥間隔而言,化合物A需要80%之Akt磷酸化抑制以誘導腫瘤停滯,且此路徑抑制程度必須持續至少45%之投藥間隔以產生30%腫瘤消退。
圖8提供在以6.25mg/kg至70mg/kg(每天一次及每天兩次)投藥經口投與化合物A之後觀察腫瘤生長抑制與模型預測腫瘤生長抑制之對比。因此,此PK/PD關係模型可預測使用各種劑量化合物A經口治療之小鼠及大鼠中替代投藥療法之抗腫瘤效能(R2=0.93,n=12,p<0.001)。
A. 葡萄糖及胰島素濃度之調變:為評價化合物A是否擾亂葡萄糖體內穩態,量測血漿胰島素及血糖濃度且與來自多種動物及多個時間點之匹配試樣中之血漿藥物濃度進行比較。在此分析中,胰島素血漿濃度與化合物A血漿濃度成正比例增加,而血糖濃度維持接近正常至最大20μmol/L化合物A(在裸小鼠中,圖9A及B)及最大15μmol/L化合物A(在裸大鼠中,圖10A及10B)。然而,在裸小鼠中高於20μmol/L且在裸大鼠中高於15μmol/L下,化合物濃度依賴性葡萄糖有所增加,此將導致觀察到高血糖症,但胰島素血漿濃度會升高。因此,將小鼠及大鼠中之化合物A相關高血糖症臨限值分別定義為20μmol/L及15μmol/L。
B. PK/PD/耐受性關係:另外,在體重損失等級與高於化合物A高血糖症臨限值(20μmol/L(對於裸小鼠)及15μmol/L(對於裸大鼠);R2=0.98,圖11)之暴露持續時間之間觀察到近線性關係。自此關係應理解,化合物暴露程度應持續不超過高於血糖症截止值之35%之投藥間隔以維持小鼠及大鼠中低於5%之體重損失。
使用增加劑量之化合物A每天一次經口治療之小鼠模擬效能曲線(如藉由高於S473P-Akt之IC80臨限值之時間分數所測定)及耐受性曲線(如藉由高於化合物A高血糖症臨限值(20μmol/L)之暴露持續時間所測定)以圖形形式展示於圖12中。該建模表明,在70mg/kg(每天一次)之劑量下(小於5% BW損失),在兩個連續治療之間65%之時間內達成80%pAkt抑制,從而得到55%腫瘤消退(圖12,圖7)。若以每天兩次(2qd)35mg/kg之形式給出70mg/kg(每天一次)之劑量,該模型指示,在兩個連續治療之間100%之時間內達成80% pAkt抑制,從而得到腫瘤消退。在裸大鼠中,將高血糖症臨限值設定為15μmol/L,在兩個連續治療之間83%之時間內,30mg/kg(每天一次)之劑量(無BW損失)將得到80% pAkt抑制,從而得到80%腫瘤消退(圖13,圖7)。
基於前述分析,用於上述化合物A之臨床前PK-PD-效能-耐受性建模係預測化合物A之下列投藥時間表之效能及耐受性的有價值工具:每天一次(q.d.)或每天兩次(b.i.d.)經口投與化合物A連續5天,隨後在兩天內並不投與化合物A(循環1),且然後在一或多個後續循環中重複相同投藥療法[亦即,每天一次(q.d.)或每天兩次(b.i.d.)經口投與化合物A連續5天,隨後在兩天內並不投與化合物A]。此替代投藥時間表稱為「替代時間表1」。如本文中所闡述,此模型在本文中用於探究及指導臨床研究中之劑量排程。
圖14提供展示具有Rat1-myr P110α腫瘤之裸大鼠中化合物A之模擬效能之圖形,其中以20mg/kg及替代時間表1(A)以及以14mg/kg(每天一次)及連續日時間表(亦即無休藥期)(B)經口投與化合物A。圖15提供具有Rat1-myr P110α腫瘤之裸大鼠中之模擬血漿PK特徵,其中以20mg/kg及替代時間表1以及以14mg/kg(每天一次)及連續日時間
表(亦即無休藥期)經口投與化合物A。
基於模型模擬(圖7),化合物A之替代時間表1可(a)達成每天一次(q.d.)根據連續每日時間表經口投與化合物A之裸大鼠中所觀察之類似或改良抗腫瘤效能,及(b)若在兩個治療時段之間45%之時間內化合物A血漿濃度高於pAkt IC80,則在整個治療時段內達成至少部分消退(30%腫瘤消退)。基於等效AUC,300-350mg/天(口服)化合物A之人類劑量(Cmax:3500ng/ml=8μmol/L;AUC:35000h.ng/ml=80h.μmol/L)對應於裸大鼠中之20mg/kg替代時間表1口服劑量。連續日時間表口服劑量中每天一次之相應總劑量為14mg/kg。
根據裸大鼠中之此模型(圖13),20mg/kg化合物A將得到大約60%腫瘤消退。因此,替代時間表1及裸大鼠中20mg/kg之預測效能呈現於圖14A中。最大效能為60%消退且在2天休藥期結束時恢復至30%消退。14mg/kg日投藥之預測效能為連續30%腫瘤消退(圖14 B)。
小鼠及大鼠中使用14mg每天一次以連續日時間表或使用20mg以替代時間表1經口治療後之預測化合物A血漿濃度不超過15μmol(高血糖症臨限值)。(圖15)
假設PD與效能之間之關係在人類及異種移植物中類似,此模型及分析可用於預測人類對替代時間表1之腫瘤反應。
Claims (15)
- 一種式(I)化合物或其醫藥上可接受之鹽之用途,
- 如請求項1之用途,其中該式(I)化合物或其醫藥上可接受之鹽之該日劑量為約200mg至約400mg。
- 如請求項1之用途,其中每天一次(q.d.)以約100mg至約450mg之日劑量經口投與該式(I)化合物或醫藥上可接受之鹽至少兩個連續5天週期。
- 如請求項1之用途,其中每天兩次(b.i.d)以約100mg至約450mg之日劑量經口投與該式(I)化合物或醫藥上可接受之鹽至少兩個連續5天週期。
- 如請求項1至4中任一項之用途,其中在一個連續5天週期與其隨後連續5天週期之間約2天之時段內並不向該患者投與該化合物或其醫藥上可接受之鹽。
- 如請求項3之用途,其中在一個連續5天週期中該化合物或其醫藥上可接受之鹽之最後一次投與與其隨後連續5天週期中該化合物或其醫藥上可接受之鹽之第一次投與間約3天之時段內並不向 該患者投與該化合物或其醫藥上可接受之鹽。
- 如請求項4之用途,其中在一個連續5天週期中該化合物或其醫藥上可接受之鹽之最後一次投與與其隨後連續5天週期中該化合物或其醫藥上可接受之鹽之第一次投與間約2.5天之時段內並不向該患者投與該化合物或其醫藥上可接受之鹽。
- 如請求項1之用途,其中在兩個或更多個該連續5天週期中投與該式(I)化合物或其醫藥上可接受之鹽直至減輕、減小或緩解該患者中至少一種副效應之嚴重程度、發生率或頻率為止。
- 如請求項8之用途,其中該副效應係選自以下之病狀:嗜中性白血球減少症、膽紅素升高、心臟毒性、不穩定型心絞痛、心肌梗塞、持續性高血壓、周邊感覺或運動神經病變/疼痛、肝臟功能障礙、紅血球及/或白血球計數減小、高血糖症、噁心、食欲降低、腹瀉、疹(例如斑丘疹、痤瘡樣等)及超敏性(例如擦傷敏感性增加)、光敏性、虛弱/疲勞、嘔吐、口腔炎、口腔黏膜炎、胰臟炎、味覺障礙及消化不良。
- 如請求項1之用途,其中該增殖性疾病係癌症。
- 如請求項1之用途,其中該增殖性疾病係選自以下之癌症:肺癌、支氣管癌、前列腺癌、乳癌(包含散發性乳癌及考登病(Cowden disease)受害者)、結腸癌、直腸癌、結腸癌瘤、結腸直腸腺瘤、胰臟癌、胃腸癌、肝細胞癌、胃癌(stomach cancer、gastric cancer)、卵巢癌、鱗狀細胞癌瘤及頭頸癌。
- 如請求項1之用途,其中組合投與該式(I)化合物或其醫藥上可接受之鹽與至少一種其他治療劑。
- 一種治療療法,其包括以約100mg至約450mg之日劑量向患者經口投與治療有效量之如請求項1之式(I)化合物或其醫藥上可接受之鹽至少兩個連續5天週期,其中在一個連續5天週期與其隨 後連續5天週期之間約2天至約3天之時段內並不向該患者投與該式(I)化合物或其醫藥上可接受之鹽。
- 一種包裝,其包括醫藥組合物與說明之組合,該醫藥組合物包括日劑量為約100mg至約450mg之如請求項1之式(I)化合物或其醫藥上可接受之鹽以及一或多種醫藥上可接受之賦形劑,該說明指示經口投與該醫藥組合物至少兩個連續5天週期且在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不投與該組合物。
- 一種治療或預防增殖性疾病之方法,其包括第一,根據連續每日時間表經由經口投與向有需要之患者以每天約100mg至約450mg之量投與如請求項1之式(I)化合物或其醫藥上可接受之鹽;第二,在向該患者投與該式(I)化合物或其醫藥上可接受之鹽之後測得該患者具有選自以下之副效應:嗜中性白血球減少症、膽紅素升高、心臟毒性、不穩定型心絞痛、心肌梗塞、持續性高血壓、周邊感覺或運動神經病變/疼痛、肝臟功能障礙、紅血球及/或白血球計數減小、高血糖症、噁心、食欲降低、腹瀉、疹及超敏性、光敏性、虛弱/疲勞、嘔吐、口腔炎、口腔黏膜炎、胰臟炎、味覺障礙及消化不良;及第三,將該式(I)化合物或其醫藥上可接受之鹽之該投與減小至約100mg至約450mg的日劑量經由經口投與至少兩個連續5天週期,其中在一個連續5天週期與其隨後連續5天週期之間約2天至約3天之時段內並不向該患者投與該化合物或其醫藥上可接受之鹽。
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