CN102905698A - 包含ccr5拮抗剂、hiv-1蛋白酶抑制剂和药代动力学增强剂的组合疗法 - Google Patents
包含ccr5拮抗剂、hiv-1蛋白酶抑制剂和药代动力学增强剂的组合疗法 Download PDFInfo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了依靠至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种所述至少一种CCR5拮抗剂和/或至少一种HIV-1蛋白酶抑制剂的药代动力学增强剂的组合体用于HIV-1治疗的新的组合疗法。该组合体旨在用于在CCR5嗜性HIV-1病毒感染的未治疗过的患者中口服治疗选自HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS的疾病。
Description
发明领域
本发明涉及用于CCR5嗜性HIV-1(CCR5
tropic HIV-1)感染的未治疗过的患者(treatment-naïve patients)的新型组合疗法。
发明背景
用于HIV-1感染的未治疗过的患者的常规方案是基于多种药物的鸡尾酒疗法,该疗法通常包括两种NRTI和典型地是非核苷逆转录酶抑制剂(NNRTI)或蛋白酶抑制剂(PI)的第三种药物。这种方案的典型的例子是Atripla®,这是包含依非韦伦(efavirenz)
– 一种NNRTI – 600 mg、恩曲他滨(emtricitabine)
– 一种NRTI – 200 mg和富马酸替诺福韦酯(tenofovir
disoproxil fumarate) – 一种HIV-1核苷类似物逆转录酶抑制剂(nRTI) – 300
mg的固定剂量组合。另一个例子是在国际化、多中心、开放标签(open-label)、非劣效性(non-inferiority)的96周CASTLE研究中测试的组合,其中将440位未治疗过的患者随机化每天一次接受Reyataz®(硫酸阿扎那韦(atazanavir sulphate)) – 一种HIV-1蛋白酶抑制剂(PI) – 300 mg和利托那韦(ritonavir) – 另一种HIV-1 PI – 100
mg,443位患者随机化每天两次接受共同配制的洛匹那韦(lopinavir)
– 另一种HIV-1 PI – 400 mg和利托那韦100 mg。将阿扎那韦/r和洛匹那韦/r与每天一次剂量的Truvada®(即,恩曲他滨200 mg和富马酸替诺福韦酯300 mg的固定剂量组合)组合。在48周时阿扎那韦组(arm)遇到了实现检测不到的病毒载量(被定义为低于50拷贝/ mL的HIV-1 RNA)的非劣效性的主要终点。
由于领域中存在着关于核苷类似物的毒性的担忧,对于未治疗过的患者需要HIV-1 NRTI节约型方案(HIV-1 NRTI-sparing regimen)。此外,通过提供包含属于目前的方案的额外或不同的治疗性类别的药物的方案而拓宽对于未治疗过的患者的选择是有益的,因为可以降低病毒耐受的风险以及拓宽管理具有耐受核苷的病毒的患者的选择。
然而,今天,已知的鸡尾酒疗法中包括的每种药物的相对贡献仍然不确定,不可能预测,例如,从现有的组合去除NRTI是否会破坏协同活性或有利的互补耐受特征。通过在健康志愿者中的研究不能阐明这些方面,因为它不是简单的安全问题,但是关于HIV-1病毒对治疗的反应还存在不确定性。
趋化因子受体CCR5对炎症和感染性疾病的病理生理学的核心作用是已知的。发现CCR5共受体拮抗剂通过阻断宿主细胞上的gp-120病毒糖蛋白和CCR5趋化因子受体之间的相互作用而抑制HIV-1与宿主细胞的融合。以这种方式,CCR5拮抗剂能够防止细胞的感染,代表了HIV治疗的有效机制。本领域许多公开提供了不同化学类别的CCR5受体调节剂。代表性公开是Mills等.WO
98/25617,其涉及作为趋化因子受体活性的调节剂的取代的芳基哌嗪。进一步公开是WO 98/025605;WO 98/025604;WO
98/002151;WO 98/004554;和WO 97/024325,WO
00/38680和WO 01/90106。
EP-A-1284974中还公开了也称为马拉维罗(maraviroc)的N-{(1S)-3-[3-(3-异丙基-5-甲基-4H-1,2,4-三唑-4-基)-外-8-氮杂双环[3.2.1]辛-8-基]-1-苯丙基}-4,4-二氟环己烷甲酰胺;尤其见实施例4、6和7。马拉维罗是首个口服的批准药物,其属于CCR5拮抗剂类别。像所有CCR5拮抗剂,马拉维罗排他地通过CCR5共受体阻断HIV-1病毒的进入。因此,马拉维罗可以被定义为选择性CCR5拮抗剂,可用于治疗感染HIV-1病毒的CCR5嗜性版本的患者。
CCR5拮抗剂如马拉维罗通常与较少的副作用、CD4+细胞数的显著增加相关,似乎在减轻炎症中发挥作用,这可以对于病毒载量抑制提供益处。此外,已经注意到,未治疗过的患者倾向于更频繁地被CCR5嗜性病毒所感染,该病毒对于CCR5拮抗剂是敏感的。因此,在治疗早期使用MVC也是有益的,因为在后续阶段可以保留其它选择。最后,CCR5拮抗剂是仅有的在未暴露于药物的情况下HIV病毒可以失去敏感性的抗HIV类药物。因此,如果首先使用其它药物,临床医生可能失去使用CCR5拮抗剂的治疗选择。由于这些和其它原因,在未治疗过的患者的方案中包括CCR5拮抗剂是需要的。
在MERIT研究中研究马拉维罗在HIV-1未治疗患者中的疗效。该试验是随机的双盲临床研究,该试验被设计用来比较马拉维罗 300 mg每天两次(BID)与依非韦伦(efavirenz)(非核苷逆转录酶抑制剂(NNRTI))600 mg每天一次(QD)在CCR5嗜性HIV-1病毒感染的未治疗过的患者中的安全性和疗效,两者都与齐多夫定和拉米夫定(两种NRTI)口服施用。MERIT研究没有研究其它鸡尾酒疗法,尤其是NRTI节约型鸡尾酒疗法以及相关的给药方案。此外,初步结果强调,马拉维罗 300
mg QD组与依非韦伦组相比没有符合对于非劣效性的管理预先设定的标准。因此,终止了MVC
QD组。
在健康志愿者中实施的多项DDI(药物-药物相互作用)研究中进一步研究了其它包含马拉维罗的方案。例如,在健康受试者中实施的开放标签、随机的、安慰剂对照的研究评价了CYP3A4抑制剂(如HIV-1蛋白酶抑制剂)对马拉维罗的稳态药代动力学的单独且独特的组合(“Effects of CYP3A4 inhibitors on the pharmacokinetics of
maraviroc in healthy volunteers”, S. Abel等, Br J Clin Pharmacol.2008 Apr; 65 Suppl.1:27-37)。正如上面所强调的,DDI研究限于验证健康志愿者中的安全性。因此,它们对于阐明测试的鸡尾酒疗法对于治疗HIV-1感染的未治疗过的患者并定义对应的治疗有效剂量方案是否有效不是合适的基础。
最后,在未治疗患者中测试新的每天一次的包含CCR5的方案的疗效的愿望是在HIV治疗领域中已知的。然而,今天,没有关于这种新的疗法在HIV-1感染的患者中的疗效、耐受性、耐用性、便利性、所需给药、药代动力学模式、药物依从性、耐受性和总体安全性的数据。因此,除了在MERIT研究中测试的多药鸡尾酒疗法,为未治疗过的HIV-1感染的患者提供其它的包含CCR5的安全、有效并且负担得起的抗逆转录病毒药物的方案在今天仍然仅仅是一种愿望。
因此,本发明的一个目标是为CCR5嗜性HIV-1病毒感染的未治疗过的患者提供新的包含CCR5的方案(该方案尤其保证了安全性、有效性和最小的副作用)以及简化的给药方案和增强的依从性。
发明概述
通过包含治疗有效量的至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种所述至少一种CCR5拮抗剂和/或至少一种HIV-1蛋白酶抑制剂的药代动力学增强剂的组合体(combination)而实现上述及其它目标,该组合体用于在CCR5嗜性HIV-1病毒感染的未治疗的患者中口服治疗疾病,所述疾病选自:HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS。
也通过包含治疗有效量的至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种所述至少一种CCR5拮抗剂和/或至少一种HIV-1蛋白酶抑制剂的药代动力学增强剂的组合体在制备用于CCR5嗜性HIV-1病毒感染的未治疗过的患者中口服治疗疾病的药物中的用途而实现上述及其它目标,所述疾病选自:HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS。
也通过用于口服施用于CCR5嗜性HIV-1病毒感染的未治疗过的患者的药物组合物而实现上述及其它目标,所述组合物包含治疗有效量的至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种所述至少一种CCR5拮抗剂和/或至少一种HIV-1蛋白酶抑制剂的药代动力学增强剂以及一种或多种药学上可接受的赋形剂、载体和/或稀释剂。
通过包含治疗有效量的至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种所述至少一种CCR5拮抗剂和/或至少一种HIV-1蛋白酶抑制剂的药代动力学增强剂的单位剂型而实现上述及其它目标,所述单位剂型用于在CCR5嗜性HIV-1病毒感染的未治疗过的患者中口服治疗疾病,所述疾病选自:HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS。
也通过包含治疗有效量的至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种所述至少一种CCR5拮抗剂和/或至少一种HIV-1蛋白酶抑制剂的药代动力学增强剂的试剂盒而实现上述及其它目标,所述试剂盒作为用于同时、单独或依次口服施用于CCR5嗜性HIV-1病毒感染的未治疗过的患者的组合制剂。
通过治疗选自HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS的疾病的方法而实现上述及其它目标,所述方法包含将治疗有效量的至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种所述至少一种CCR5拮抗剂和/或至少一种HIV-1蛋白酶抑制剂的药代动力学增强剂同时、单独或依次口服施用于CCR5嗜性HIV-1病毒感染的未治疗过的患者。
附图
图1是通过随访的中值(median)HIV-1 RNA(log10拷贝/ mL)的折线图。报告本发明的组合体(马拉维罗150 mg QD和阿扎那韦300 mg/利托那韦100 mg QD)和参照组合体(均为QD的阿扎那韦硫酸盐300 mg和利托那韦100 mg + 均为QD的恩曲他滨200
mg和富马酸替诺福韦酯300mg)的参数。N1和N2分别为在每个时间点时对于马拉维罗+阿扎那韦/利托那韦和阿扎那韦/利托那韦+恩曲他滨/替诺福韦的受试者的数量。基线计算为筛选、随机化和在开始治疗前第1天测量的平均值。在第7天和第14天,来自亚分析的一位受试者离开一天,这位受试者被包括在第7天、第14天的分析中;
图2是通过随访的离基线的中值HIV-1
RNA变化的折线图。上面对于图1做出的相同评价也适用于本图;
图3是通过随访的中值CD4细胞数的折线图。像图1,报告两条曲线:一条是本发明的组合体(马拉维罗150 mg QD和阿扎那韦300 mg/利托那韦100 mg QD),一条是参照组合体(均为QD的阿扎那韦硫酸盐300 mg和利托那韦100 mg+均为QD的恩曲他滨200 mg和富马酸替诺福韦酯300mg)。N1和N2分别为在每个时间点时对于马拉维罗+阿扎那韦/利托那韦和阿扎那韦/利托那韦+恩曲他滨/替诺福韦的受试者的数量。基线计算为筛选、随机化和在开始治疗前第1天测量的平均值;
图4是通过随访的离基线的中值CD4细胞数的折线图。上面对于图3做出的相同评价也适用于本图;
图5是通过随访的中值CD8细胞数的折线图。像图1,报告两条曲线:一条是本发明的组合体(马拉维罗150 mg QD和阿扎那韦300 mg/利托那韦100 mg QD),一条是参照组合体(均为QD的阿扎那韦硫酸盐300 mg和利托那韦100 mg + 均为QD的恩曲他滨200 mg和富马酸替诺福韦酯300mg)。N1和N2分别为在每个时间点时对于马拉维罗+阿扎那韦/利托那韦和阿扎那韦/利托那韦+恩曲他滨/替诺福韦的受试者的数量。基线计算为筛选、随机化和在开始治疗前第1天测量的平均值;
图6是通过随访的离基线的中值CD8细胞数的折线图。上面对于图5做出的相同评价也适用于本图。
发明的详细说明
下面讨论了本发明的特征和实施方案。当提到本发明的一个方面时,仅仅 – 例如组合(组合体,combination)) – 必须理解为,除非另外指明,相同的特征和实施方案,在可能的技术程度,也适用于本发明的所有其他方面 – 即这种组合体的用途、包含这种组合体的药物组合物、包含这种组合体的试剂盒、包含这种组合体的单位剂型和通过施用这种组合体的治疗方法。
在一个实施方案中,“所述至少一种CCR5拮抗剂和/或至少一种HIV-1蛋白酶抑制剂的药代动力学增强剂”(下文也称为“药代动力学增强剂”)优选是指通过抑制所述至少一种CCR5拮抗剂和/或至少一种HIV-1蛋白酶抑制剂,优选两者共同,的代谢途径而降低它们的代谢清除(在本申请中这也被称为“增强”或“增强活性”)的药物。
在一个实施方案中,所述至少一种药代动力学增强剂是至少一种CYP3A4抑制剂。以预测的方式评价指定的药物的体内CYP3A4抑制的体外测试是药物领域中已知的。例如,可以参考“Guidance for Industry – Drug interaction Studies –
Study Design, Data Analysis, and Implications for Dosing and labelling – Draft Guidance –
September 2006”,尤其是附录C1,C2和C3中所讨论的评论和测试。从美国FDA网站可获得该文件的电子拷贝。在一个实施方案中,CYP3A4抑制活性可以是所述至少一种药代动力学增强剂的唯一的药理作用或多种药理学上独特的作用之一。在一个实施方案中,所述至少一种CYP3A4抑制剂是在临床评价中引起血浆AUC值的≥5倍增加或CYP3A底物的清除超过80%减少的药物。典型的CYP3A底物可以选自咪达唑仑、丁螺环酮、非洛地平、洛伐他汀、曲普坦、西地那非、辛伐他汀和三唑仑。CYP3A4抑制剂和CYP3A底物的定义是根据美国FDA “Drug Development
and Drug Interactions:Table of Substrates, Inhibitors and Inducers” (i)表5 – CYP3A抑制剂的分类-强CYP3A抑制剂和(ii)表4 – 用于研究的特异性CYP酶的体内底物、抑制剂和诱导剂(口服施用)的各自的例子。
在一个实施方案中,所述至少一种药代动力学增强剂包括,优选由cobicistat或其药学上可接受的盐或溶剂化物组成。
在一个实施方案中,所述至少一种药代动力学增强剂包括,优选由与所述至少一种HIV-1蛋白酶抑制剂不同的第二种HIV-1蛋白酶抑制剂组成。因此,在这个实施方案中,本发明的组合体包括至少一种CCR5拮抗剂和至少两种HIV-1蛋白酶抑制剂。除非另外指明,下面的提到“至少两种HIV-1蛋白酶抑制剂”是指这个实施方案。
在一个实施方案中,“未治疗过的患者”是指被CCR5嗜性HIV-1病毒感染并且没有接受任何以前的HIV药物治疗的患者。在本实施方案中,未治疗过的患者的语言与已经接受一些HIV药物治疗并且将最终被称为经历过治疗的患者的患者并列使用。
在一个实施方案中,“未治疗过的患者”是指被CCR5嗜性HIV-1病毒感染并且没有接受任何以前的包含HIV-1蛋白酶抑制剂和/或CCR5拮抗剂药物的治疗的患者。在本实施方案中,然后,CCR5嗜性HIV-1感染的患者是未经HIV-1蛋白酶抑制剂和/或CCR5拮抗剂治疗的,但是可能已经施用了一种或多种其它HIV-1治疗药物。
在一个实施方案中,未治疗过的患者优选是成年的未治疗过的患者。
存在不同株的HIV-1病毒,其(主要)根据被病毒使用以获得进入宿主细胞的CD4 +和T-细胞共受体区分的。HIV-1的巨噬细胞(M-嗜性)株或非syncitia诱导株(non-syncitia-inducing
strains,NSI)使用β-趋化因子受体CCR5。HIV-1的T-嗜性株或syncitia诱导(SI)株使用α-趋化因子受体CXCR4用于进入。也存在HIV-1株,其能够无差别地(indifferently)使用CCR5和CXCR4共受体(双嗜性株)。基本上包含使用CCR5的病毒的HIV-1病毒群体通常被归类为CCR5嗜性HIV-1病毒。基本上包含使用CXCR4的病毒的HIV-1病毒群体通常被归类为CXCR4嗜性HIV-1病毒。同时包含使用CCR5和使用CXCR4的病毒的HIV-1病毒群体通常被归类为混合嗜性HIV-1病毒。可以通过CCR5或CXCR4共受体进入宿主CD4+细胞的HIV-1病毒群体通常被归类为双嗜性病毒HIV-1病毒。
在本发明的上下文中,“CCR5嗜性HIV-1病毒”优选是指包含可检测量的CCR5嗜性HIV-1病毒的病毒群体,CCR5嗜性HIV-1病毒占存在的HIV-1病毒总量的优选至少20%,更优选至少50%,更优选至少80%,甚至更优选至少95%。
本领域中已知鉴定患者中HIV-1病毒群体(即HIV-1嗜性)的方法。一种商业的方法是由Monogram Biosciences 开发的用于HIV治疗中使用的Trofile®分子测试。测试的结果显示患者是否被使用CCR5共受体、CXCR4共受体,或两者同时(双重的/混合的)进入细胞的病毒感染。
除非另外指明,“治疗”优选包括改善未治疗过的患者中的一个或多个下列参数: (i)HIV-1
RNA拷贝和(ii)CD4 +细胞数。优选地,同时改善了参数(i)和(ii)。除非另外指明,上面提到的改善一个或多个参数是指在相同患者中相对于指定的参数的基线值改善了相同参数的值。将基线值计算为在患者筛选随访、患者随机化和开始治疗前第1天患者中指定的参数的平均值。
在一个实施方案中,在治疗的至少两(2)周后、更优选至少七(8)周后,甚至更优选至少二十四(24)周后获得上面提到的一个或多个参数的改善。
在一个实施方案中,改善患者中的HIV-1 RNA拷贝是指获得HIV-1
RNA拷贝相对于基线的降低。在一个实施方案中,改善可以被计算为患者血浆的病毒载量,即绝对的HIV-1
RNA拷贝/mL。在本实施方案中,改善HIV-1
RNA拷贝优选是指获得小于400拷贝/mL,优选小于50拷贝/mL的病毒载量。在另一个实施方案中,改善可以被计算为患者血浆的相对于基线的HIV-1 RNA/mL的log10拷贝。在本实施方案中,降低优选为至少1.5
log10拷贝,更优选至少2.0 log10拷贝,甚至更优选至少2.0-3.0 log10拷贝。
在一个实施方案中,改善患者中的CD4+细胞数是指相对于基线增加中值CD4+细胞数。改善可以被计算为患者血浆的相对于基线的中值CD4+细胞/μL。优选地,增加为至少50 CD4+细胞/μL,更优选至少100 CD4+细胞/μL,甚至更优选至少150 CD4+细胞/μL,甚至更优选至少200 CD4+细胞/μL。
作为本发明的治疗的结果,获得未治疗过的患者的收缩HIV-1相关的机会性病症的风险的降低和/或获得患者对抗存在的HIV-1相关的机会性病症的能力的改善。HIV相关的机会性病症包括机会性感染和恶性肿瘤。HIV相关的机会性病症的例子,包括卡氏肺囊虫肺炎、弓形体病、isoporiasis、隐孢子虫病、念珠菌病、隐球菌病、组织胞浆菌病、球孢子菌病、结核分枝杆菌、非结核分枝杆菌感染、沙门氏杆菌、巨细胞病毒、单纯疱疹病毒、复发性或持续性上呼吸道感染、窦炎(sinuisitis)、中耳炎、细菌性脑膜炎、肺炎、败血症、oropharyngis candidaiasis、腹泻、肝炎、带状疱疹、平滑肌肉瘤、淋巴间隙肺炎(lymphoid interstiticial pneumonia)、诺卡氏菌病、散播性水痘,和脑的弓形体病、进行性多灶性白质脑病、卡波氏肉瘤、淋巴瘤、宫颈癌、HIV痴呆与HIV衰竭综合征。
除非另外指明,基因上与HIV-1相关的逆转录病毒感染是指由使用与HIV使用的相同的或相似的酶来完成它们的生活周期的HIV相关的病毒引起的感染。优选地,基因上与HIV-1相关的逆转录病毒感染选自HIV-1、HIV-2和其它相关的逆转录病毒的所有子类。
在一个实施方案中,本发明的组合体不包含HIV-1核苷酸逆转录酶抑制剂(NRTI)。在一个实施方案中,本发明的组合体不包含HIV-1核苷逆转录酶抑制剂(nRTI)。在一个实施方案中,本发明的组合体不包含在HIV-1整合酶抑制剂(例如雷特格韦)。在一个实施方案中,本发明的组合体不包含HIV-1
NRTI、nRTI和整合酶抑制剂。
在一个实施方案中,本发明的组合体不包含除了至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种药代动力学增强剂以外的HIV-1治疗药物。在一个实施方案中,本发明的组合体不包含除了至少一种CCR5拮抗剂和至少两种HIV-1蛋白酶抑制剂以外的HIV-1治疗药物。除非另外指明,HIV-1治疗药物是指至少在体内对HIV-1感染、基因上与HIV-1相关的逆转录病毒感染和AIDS有活性的药物。对HIV-1感染、基因上与HIV-1相关的逆转录病毒感染和AIDS的活性(下文被称为“抗HIV-1活性”)优选包括直接活性(即本身显示抗HIV-1活性的药物)和间接活性(即药物本身不显示抗HIV-1活性但增强了组合物中包含的一种或多种其它药物的直接的抗HIV-1活性的药物)。在一个实施方案中,抗HIV-1活性是直接活性。在一个不同的实施方案中,抗HIV-1活性是间接活性。在一个实施方案中,抗HIV-1活性可以是HIV-1治疗药物的唯一的药理作用或HIV-1治疗药物的多种药理上独特的作用之一。显示直接的抗HIV-1活性的HIV-1治疗药物经常根据它们的结构或对HIV病毒的作用机制被归类在治疗性类别中。例如,显示直接抗HIV-1活性的HIV-1治疗药物包括CCR5拮抗剂、HIV-1蛋白酶抑制剂、HIV-1 NNRTI、HIV-1 NRTI、HIV-1整合酶抑制剂、HIV-1融合抑制剂、HIV-1成熟抑制剂和病毒抑制剂。
在一个实施方案中,本发明的组合体不包含除了至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种药代动力学增强剂以外的药学活性物质(与赋形剂相反)。
在一个实施方案中,本发明的组合体由至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种所述至少一种CCR5拮抗剂和/或至少一种HIV-1蛋白酶抑制剂的药代动力学增强剂和,任选地,药学活性的赋形剂、载体和/或稀释剂组成。
除非另外指明,用词CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂包括本文定义的任何CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂的任何游离的酸或碱或药学上可接受的盐、溶剂化物或前药(prodrug)。
CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂的药学上可接受的盐包括其酸加成盐和碱盐。
合适的酸加成盐是由形成非毒性盐的酸形成。例子包括乙酸盐、天冬氨酸盐(aspartat)、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、右旋樟脑磺酸盐(camsylate)、柠檬酸盐、乙二磺酸盐(edisylate)、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐(hibenzate)、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲硫酸盐、萘盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、rotate、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、蔗糖盐、硬脂酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐(tosylat)和三氟乙酸盐。CCR5拮抗剂盐的一个例子是PCT/IB2004/003153中公开的N-{(1S)-3-[3-内-(5-异丁酰-2-甲基-4,5,6,7-四氢-1-H-咪唑并[4,5-c]吡啶-1-基)-8-氮杂双环-[3.2.1]辛-8-基]-1-(3-氟苯基)丙基}乙酰胺富马酸盐。
合适的碱盐是由形成非毒性盐的碱形成。例子包括铝盐、精氨酸盐、苄星青霉素(benzathine)盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺(diolamine) 盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、油胺(olamine)盐、钾盐、钠盐、氨丁三醇盐和锌盐。
对于合适的盐的综述,见Stahl和Wermuth的"Handbook of Pharmaceutical Salts: Properties,
Selection, and Use"(Wiley-VCH, Weinheim, Germany, 2002)。
可以通过将指定的CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂和适当的期望的酸或碱的溶液一起混合而容易地制备CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂的药学上可接受的盐。可以从溶液中沉淀并通过过滤收集,或者可以通过溶剂的蒸发回收该盐。完全离子化的和几乎非离子化的盐的离子化的程度可能不同。
CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂可以以未溶剂化的和溶剂化物的形式同时存在。本文使用术语“溶剂化物”来描述包含CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂和一种或多种药学上可接受的溶剂分子,例如,乙醇,的分子复合物。当所述溶剂是水时,使用术语“水合物”。
除非另外指明,用词CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂包括其任何多晶型物和前药。还包括结晶的或无定形的产物。通过方法如沉淀、结晶、冷冻干燥、喷雾干燥或蒸发干燥可以获得这种产物,如,固体塞(solid
plugs)、粉末或薄膜。微波或射频干燥可以用于此目的。
CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂的所谓“前药”也在本发明的范围内。当施用于身体内或身体上时,可以将本身具有很少或没有药理活性的CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂的某些衍生物,例如,通过水解裂解,转换为具有希望活性的化合物。这种衍生物被称为“前药”。前药的使用的进一步信息可见'Pro-drugs
as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W
Stella)和'Bioreversible Carriers in Drug Design',
Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association)。
例如,可以通过用如,例如,H Bundgaard的"Design
of Prodrugs"(Elsevier, 1985)中所述的本领域技术人员已知为“前体部分(pro-moieties)”的特定部分替代CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂中存在的合适的官能团而产生本发明的前药。
例如,当指定的CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂包含醇官能团(-OH)时,本发明的前药的一些例子可以包括其酯或醚,例如,通过磷酸化替代氢。
CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂可以包含一个或多个不对称碳原子,因此可能以两种或更多种立体异构体存在。当例如指定的CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂包含烯基或亚烯基基团时,几何的顺式/反式(或Z/E)异构体是可能的。当化合物包含,例如,酮基或肟基或芳族部分时,互变异构的异构('互变异构')可以发生。结果就是,单一化合物可以表现出超过一种类型的异构现象。
CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂的所有立体异构体、几何异构体和互变异构体形式,包括表现出超过一种类型的异构现象的化合物和其中一种或多种的混合物被包括在本发明的范围内。当指定的CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂包含碱性或酸性部分时,还包括酸加成盐或碱盐,其中反离子(counterion)是有光学活性的,例如,D-乳酸盐或L-赖氨酸,或外消旋的,例如,DL-酒石酸盐或DL-精氨酸。
可以通过本领域技术人员公知的常规技术,例如,色谱法和分级结晶,分离顺式/反式异构体。
用于单个对映异构体的制备/分离的常规技术包括用,例如,手性高压液相色谱法(HPLC)从合适的光学纯的前体的手性合成或外消旋体(或盐或衍生物的外消旋体)的解析(resolution)。
或者,外消旋体(或外消旋前体)可以与合适的有光学活性的化合物,例如,醇,或者在指定的CCR5拮抗剂、HIV-1蛋白酶抑制剂和药代动力学增强剂包含酸性或碱性部分的情况下,酸或碱,如酒石酸或1-苯乙胺,相反应。通过色谱和/或分级结晶可以分离获得的非对映异构体混合物,通过本领域技术人员公知的方法将非对映异构体中的一种或两种转化为对应的纯对映异构体。
可以通过本领域技术人员已知的常规技术分离的立体异构体集合 - 见,例如E L
Eliel的"Stereochemistry of Organic
Compounds" (Wiley, New York, 1994)。
除非另外指明,本发明的所述至少一种CCR5拮抗剂,就它们能够通过排他地作用于CCR5趋化因子共受体而阻断HIV-1进入宿主细胞如CD4+细胞、T-细胞或巨噬细胞的意义而言,是选择性的CCR5拮抗剂(或抑制剂)。CCR5拮抗剂没有排他地使用感染宿主细胞的CXCR4共受体对HIV-1群体施加任何病毒进入阻断作用。
在一个实施方案中,本发明的所述一种或多种CCR5拮抗剂对于CCR5共受体具有小于1μM的IC50(通过Combadiere等, J. Leukoc. Biol., 60, 147-152 (1996)的MIP-1β测试确定)。在一个实施方案中,本发明的所述一种或多种CCR5拮抗剂对于CXCR4共受体具有大于10 μM的IC50(Dorr P.等.; “Maraviroc (UK-427,857), a Potent, Orally Bioavailable,
and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with
Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity”; Antimicrob Agents Chemother.2005 November; 49(11):4721 – 4732)。这些测试是结合和功能测试,即,它们可用于鉴定CCR5拮抗并基于CCR5拮抗剂的结合效率在CCR5拮抗剂中辨别。
在进一步的实施方案中,本发明的所述至少一种CCR5拮抗剂选自马拉维罗、NCB-9471、PRO-140、CCR5mAb004、TAK-779(WO 99/32468中公开的)、ZM-688523、4-氯-6-氟磺胺、TAK-220(WO
01/25200中公开的)、TAK-652(WO03014105中公开的,化学名为8-[4-(2-丁氧乙氧基)苯基]-1-异丁基-N-[4-[[(1-丙基-1H-咪唑并-5-基)甲基]亚硫酰基]苯基]-1,2,3,4-四氢-1-苦乌头碱-5-甲酰胺)、SC-351125、ancriviroc(以前被称为SCH-C)、vicriviroc (化学名为(4,6-二甲基嘧啶-5-基){4-[(3S)-4-{(1R)-2-甲氧基-1-[4-(三氟甲基)苯基]乙基}-3-甲基哌嗪-1-基]-4-甲基哌嗪-1-基}甲酮)、PRO-140、aplaviroc(以前被称为GW-873140、Ono-4128、AK-602)、AMD-887、INC-B9471、CMPD-167(化学名为N-甲基-N-((1R,3S,4S)-3-[4-(3-苄基-1-乙基-1H-吡唑-5-基)哌啶-1-基甲基]-4-[3-氟苯基]环戊二烯并-1-基]-D-缬氨酸))、1-内-{8-[(3S)-3-(乙酰氨基)-3-(3-氟苯基)丙基]-8-氮杂双环[3.2.1]辛-3-基}-2-甲基-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-5-甲酸甲酯、3-内-{8-[(3S)-3-(乙酰氨基)-3-(3-氟苯基)丙基]-8-氮杂双环[3.2.1]辛-3-基}-2-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-5-甲酸甲酯、1-内-{8-[(3S)-3-(乙酰氨基)-3-(3-氟苯基)丙基]-8-氮杂双环[3.2.1]辛-3-基}-2-甲基-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-5-甲酸乙酯和N-{(1S)-3-[3-内-(5-异丁酰-2-甲基-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-1-基)-8-氮杂双环[3.2.1]辛-8-基]-1-(3-氟苯基)丙基}乙酰胺) 以及上述的药学上可接受的盐、溶剂化物或衍生物。W0
03/084954和WO 05/033107中公开了最后四种化合物。
在仍进一步的实施方案中,所述一种或多种CCR5拮抗剂选自马拉维罗、vicriviroc、NCB-9471、PRO-140、CCR5mAb004、8-[4-(2-丁氧乙氧基)苯基]-1-异丁基-N-[4-[[(1-丙基-1H-咪唑并-5-基)甲基]亚硫酰基]苯基]-1,2,3,4-四氢-1-苦乌头碱-5-甲酰胺, 1-内-{8-[(3S)-3-(乙酰氨基)-3-(3-氟苯基)丙基]-8-氮杂双环[3.2.1]辛-3-基}-2-甲基-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-5-甲酸甲酯、3-内-{8-[(3S)-3-(乙酰氨基)-3-(3-氟苯基)丙基]-8-氮杂双环[3.2.1]辛-3-基}-2-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-5-甲酸甲酯、1-内-{8-[(3S)-3-(乙酰氨基)-3-(3-氟苯基)丙基]-8-氮杂双环[3.2.1]辛-3-基}-2-甲基-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-5-甲酸乙酯和N-{(1S)-3-[3-内-(5-异丁酰基-2-甲基-4,5,6,7-四氢-1H-咪唑并[4,5-c] 吡啶-1-基)-8-氮杂双环[3.2.1]辛-8-基]-1-(3-氟苯基)丙基}乙酰胺) 以及上述的药学上可接受的盐、溶剂化物或衍生物。
在一个仍进一步的实施方案中,本发明的组合体包含至少一种作为CCR5拮抗剂的马拉维罗。
在一个仍进一步的实施方案中,本发明的所述一种或多种CCR5拮抗剂仅仅是一种CCR5拮抗剂。
在一个仍进一步的实施方案中,本发明的所述一种或多种CCR5拮抗剂仅仅是一种CCR5拮抗剂,即马拉维罗。
蛋白酶抑制剂(PI)是用于治疗或预防,例如HIV和丙型肝炎,的感染的已知的治疗类的药物。HIV-1 PI通过抑制HIV-1蛋白酶(病毒用于切割新生蛋白用于新的病毒粒子(viron)的最后组装的酶)的活性而防止病毒复制。可以根据“J
Rose和C Craik, Structure-assisted design of
nonpeptide human immunodeficiency virus-1 protease inhibitors, Am J Respir Crit
Care Med 150 (1994), pp.S176 – S182”中讨论的方法和测试来进行蛋白酶抑制剂的筛选。
在一个实施方案中,本发明的组合体包括至少两种HIV-1蛋白酶抑制剂,其中,一种是利托那韦,另一种选自洛匹那韦、阿扎那韦、福沙那韦、地瑞那韦及其混合物,更优选选自洛匹那韦、阿扎那韦、地瑞那韦及其混合物。
在一个实施方案中,至少一种HIV-1蛋白酶抑制剂仅仅是一种HIV-1蛋白酶抑制剂。
在一个实施方案中,本发明的组合体包括至少两种HIV-1蛋白酶抑制剂,其中,一种是阿扎那韦,另一种是利托那韦(其组合体在下文也被称为“阿扎那韦/ r”或“利托那韦增强的阿扎那韦”)。
在一个实施方案中,组合体包括治疗有效量的马拉维罗、阿扎那韦和利托那韦。
在一个实施方案中,根据每天一次(QD)或每天两次(BID)的方案,优选每天一次(QD)的方案施用所述至少一种CCR5拮抗剂。
在一个实施方案中,根据每天一次(QD)或每天两次(BID)的方案,优选每天一次(QD)的方案,优选同时,施用所述至少一种HIV-1蛋白酶抑制剂和至少一种药代动力学增强剂。
在一个实施方案中,根据每天一次(QD)的方案,优选同时,施用所述至少一种CCR5拮抗剂、所述至少一种HIV-1蛋白酶抑制剂和至少一种药代动力学增强剂。
在一个另外的实施方案中,根据每天一次(QD)的方案施用所述至少一种CCR5拮抗剂,而根据每天两次(BID)的方案施用所述至少一种HIV-1蛋白酶抑制剂和至少一种药代动力学增强剂。
在一个实施方案中,以约150-约300mg量(die)(每天),更优选约150mg量(die)的量施用所述至少一种CCR5拮抗剂。
在一个实施方案中,以每天约400-约1,600 mg量,优选每天约400-约1000mg量,更优选每天约400mg量的量施用所述至少一种HIV-1蛋白酶抑制剂和至少一种药代动力学增强剂。
在一个实施方案中,所述至少一种药代动力学增强剂之一是利托那韦,它以每天约100-约200 mg量,优选每天100 mg量的量施用。
在一个实施方案中,所述至少一种HIV-1蛋白酶抑制剂是阿扎那韦,它以每天约300
mg量的量施用。
在一个实施方案中,本发明的组合体包括约150-约300mg的量的至少一种CCR5拮抗剂和约400-约1600mg的量的至少一种HIV-1蛋白酶抑制剂和至少一种药代动力学增强剂。
在一个实施方案中,本发明的组合体包括约150-约300mg的量的马拉维罗,约100-约200 mg的量的利托那韦和约300-800mg的量的至少另一种HIV-1蛋白酶抑制剂。
在一个实施方案中,本发明的组合体包括约150-约300mg的量的马拉维罗,约100-约200 mg的量的利托那韦和300mg的量的阿扎那韦。
在一个实施方案中,本发明的组合体包括马拉维罗150mg、阿扎那韦300mg和利托那韦100mg,其用于在CCR5嗜性HIV-1病毒感染的未治疗过的患者中口服治疗疾病,所述疾病选自HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS。在一个实施方案中,这种组合是用于每天一次(QD)的方案的口服治疗。
在本发明的组合体中,可以,在剂型方面,或单独地或彼此联同地;在它们的施用时间方面,或同时地、单独地或依次地,施用所述至少一种CCR5拮抗剂、所述至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学增强剂。例如,至少一种CCR5拮抗剂的施用可以在所述至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学增强剂中的任一种或两种的施用之前,同时,或之后。在一个实施方案中,同时或依次地,优选同时,施用所述至少一种CCR5拮抗剂、所述至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学增强剂。在一个实施方案中,分别地施用所述至少一种CCR5拮抗剂、所述至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学增强剂。优选地,所述至少一种CCR5拮抗剂的施用和所述至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学增强剂的最后施用之间的时间可以在3小时的给药间隔内变化。
在一个实施方案中,本发明的单位剂型是用于口服施用的单一剂型,其包含所有所述至少一种CCR5拮抗剂、所述至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学增强剂。
在一个实施方案中,本发明的单位剂型是用于口服施用的单一的或多重的剂型,其包含物理地分离的形式的所述至少一种CCR5拮抗剂、所述至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学增强剂。例如,这可以通过具有三种不同的剂型来实现这一点,第一种包含所述至少一种CCR5拮抗剂,第二种包含所述至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学性增强剂中的任一种,第三种剂型包含所述至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学增强剂中的至少另一种剂型。
在一个实施方案中,本发明的剂型是固体口服制剂,如片剂、包含颗粒的胶囊、液体、或粉末,锭剂(包括液体填充的)、咀嚼剂、多-和纳米颗粒、凝胶、固溶体、脂质体、薄膜(包括粘-粘合剂)、珠(ovules)、喷雾剂和液体制剂。优选地,本发明的单位剂型是片剂或胶囊。
在一个实施方案中,本发明的剂型是液体口服制剂,如悬浮液、溶液、糖浆和酏剂。这种制剂可以被用作软或硬胶囊中的填料,典型地包括载体,例如,水、乙醇、聚乙二醇、丙二醇、甲基纤维素或合适的油,和一种或多种乳化剂和/或悬浮剂。也可以通过,例如,从小袋,重构固体而制备液体制剂。
在另一方面,本发明包括用于口服施用于CCR5嗜性HIV-1病毒感染的未治疗过的患者的药物组合物,这种组合物包含治疗有效量的至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种药代动力学增强剂和一种或多种药学上可接受的赋形剂、载体和/或稀释剂。优选地,本文使用术语“赋形剂”来描述除了本发明的活性化合物以外的任何成。赋形剂的选择将在很大程度上取决于因素,如特定的施用方式、赋形剂对溶解度和稳定性的影响和剂型的性质。
适合用于本发明的化合物的递送的药物组合物和它们的制备方法对于本领域技术人员将是显而易见的。这种组合物和它们的制备方法可见,例如,Remington's
Pharmaceutical Sciences',第19版(Mack Publishing Company, 1995)。
通常口服施用本发明的化合物。口服给施用可能涉及吞咽,使得化合物进入胃肠道,或者可以采用颊或舌下施用,通过该方法化合物直接从嘴进入血流。
也可以以快速溶解、快速崩解的剂型使用本发明的化合物,如Liang和Chen
(2001)的Expert Opinion in Therapeutic Patents,
11 (6), 981-986中描述的那些。
对于片剂或胶囊剂型,根据剂量,药物可以组成剂型的1重量%-80重量%,更典型地剂型的5重量%-60重量%。除了药物以外,片剂通常包含崩解剂。崩解剂的例子包括羧基乙酸淀粉钠、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲基纤维素钠、交联聚维酮、聚乙烯吡咯烷酮、甲基纤维素、微晶纤维素、低级烷基取代的羟丙基纤维素、淀粉、预胶化淀粉和海藻酸钠。通常,崩解剂包括剂型的1重量%-25重量%,优选5重量%-20重量%。
通常使用粘合剂来为片剂制剂赋予粘合质量。合适的粘合剂包括微晶纤维素、明胶、糖类、聚乙二醇、天然的和合成的树胶、聚乙烯吡咯烷酮、预胶化淀粉、羟丙基纤维素和羟丙基甲基纤维素。片剂也可以包含稀释剂,如乳糖(一水合物、喷雾干燥的一水合物、无水的和类似物)、甘露醇、木糖醇、葡萄糖、蔗糖、山梨醇、微晶纤维素、淀粉和二水合磷酸氢钙。片剂也可以任选地包括表面活性剂,如月桂基硫酸钠、聚山梨酯80和助流剂,如二氧化硅和滑石粉。当存在时,表面活性剂可以包括片剂的0.2重量%-5重量%,助流剂可以包括片剂的0.2重量%-1重量%。片剂通常也包含润滑剂,如硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酰富马酸钠和硬脂酸镁与十二烷基硫酸钠的混合物。润滑剂通常包含片剂的0.25重量%-10重量%,优选0.5重量%-3重量%。其它可能的成分包括抗氧化剂、着色剂、调味剂、防腐剂和味道掩蔽剂。
示例性的片剂包含最高达约80%的药物,约10重量%-约90重量%的粘合剂,约0重量%-约85重量%的稀释剂,约2重量%-约10重量%的崩解剂,以及约0.25重量%-约10重量%的润滑剂。
可以直接或通过辊轴将片剂混合物压缩形成片剂。片剂混合物或混合物的部分或者在压片之前可以是湿式-、干式-或熔融-颗粒的、熔融凝结的,或者挤出的。最终制剂可以包含一层或多层,可以是包被的或未包被的;它甚至可以是被胶囊化的。在H.
Lieberman和L. Lachman的"Pharmaceutical
Dosage Forms:Tablets, Vol. 1" Marcel Dekker, N. Y., N. Y., 1980 (ISBN
0-8247-6918-X)中讨论了片剂的配制。
通常将用于口服施用的固体制剂配制用于快速释放。修改的释放形式也是可能的。其它合适的释放技术如高能量分散体和渗透的和包被的颗粒可见Verma等, Pharmaceutical Technology On-line, 25 (2), 1-14 (2001)。WO 00/35298中描述了咀嚼性树胶用于实现控制释放口香糖的用途。
在另一方面,本发明涉及包含作为组合制剂的治疗有效量的至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种药代动力学增强剂的试剂盒,该组合制剂用于同时、分开或依次口服施用于CCR5嗜性HIV-1病毒感染的未治疗过的患者。在试剂盒中,可以方便地组合包含各种组分的组合物而用于共同施用。
在一个实施方案中,本发明的试剂盒包含
- 一种或多种离散的药物组合物,
◦ 其中至少一种包含所述至少一种CCR5拮抗剂和
◦ 至少另一种,其包含所述至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学增强剂,对于两种中的每一种优选离散的组合物,
任一种为组合的或物理上分离的形式,和
- 用于分别保留所述组合物的方式,如容器、分开的瓶或分开的箔包。
在本发明的一个实施方案中,试剂盒包括至少三种物理上独特的组合物,一种包含所述至少一种CCR5拮抗剂,一种包含至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学增强剂中的第一种,一种包含所述至少一种HIV-1蛋白酶抑制剂和所述至少一种药代动力学增强剂中的第二种和更多。优选地,在物理上独特的组合物中包含HIV-1蛋白酶抑制剂和药代动力学增强剂。
上面讨论的试剂盒的一个例子是用于片剂、胶囊和类似物的包装的熟悉的罩板包装。
本发明的试剂盒尤其适合用于在不同的剂量间隔施用单独的组合物。为了帮助依从性,试剂盒通常包括用于施用的说明书,并且可以用所谓的记忆帮助而提供。
在另一种方面,本发明涉及治疗选自HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS的疾病的方法,所述方法包括将治疗有效量的至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种药代动力学增强剂同时、单独或依次口服施用于CCR5嗜性HIV-1病毒感染的未治疗过的患者。
可以理解的是,上面公开的所有的实施方案和特征,尤其是关于剂量方案、作为可施用的量的成分的量、单一成分的施用的顺序和时机,适用于方法方面。
可以通过依靠上面公开的试剂盒和/或剂量单位形式进行本发明的治疗方法。
借助目前公开的本发明,现在实现了与传统的双NRTI的HIV治疗相似的病毒抑制,但是具有更低的副作用,具有发生病毒耐受的更低的可能,具有对于具有对逆转录酶抑制剂(包括非核苷抑制剂)耐受的病毒的人们中的使用的潜能。此外,在本发明的某些实施方案中,已经实施了每天一次(QD)的HIV-1的有效的方案,导致了在简化的给药方案和增强的依从性方面的进一步的优点。
鉴于下面提供的实施方案,本发明的进一步的实施方案和优点对于本领域技术人员将变得显而易见。
实施例1
每天一次与阿扎那韦/利托那韦共同施用的马拉维罗在未治疗过的HIV感染的患者中的药代动力学
马拉维罗(MVC)主要通过经由CYP3A4的代谢而清除。PK模型研究(内部进行的,没有公开)表明,ATV/R,强力的CYP3A4抑制剂,可以使每天一次的MVC给药成为可能。在关键的第3阶段MOTIVATE研究中,其中以优选的背景方案每天一次或两次将马拉维罗给予经历过治疗的患者,在MVC的平均浓度(Cavg)中的受试者间变异被认为主要受背景治疗的影响。
已经设计这种PK亚研究(substudy)来检查在没有其它背景治疗的混杂影响的情况下,与ATV/r组合体的每天150
mg MVC的PK。基于来自未治疗过的MERIT研究的暴露-反应分析(exposure-response
analysis),其中每天两次给药马拉维罗与齐多夫定/拉米夫定,在约75 ng/mL以上的Cavg实现了MVC的接近最大疗效。
将未治疗过的患者(N = 121)1:1随机化以接受与ATV/r
300/100 mg QD同时组合的MVC 150 mg QD或替诺福韦/恩曲他滨300/200
mg(TRUVADA®) QD,持续48周。在该PK 亚研究中,包括在参加的美国地点的MVC治疗组中的15位患者的亚组。在给药前和在第2周时给药后0.5、1、2、3、4、6、8、10和24小时时采集血浆样品。基于个体的血浆浓度-时间数据,使用实际的采样时间,通过非房室分析(non-compartmental
analyses)确定在第2周时的AUC24h、Cavg (AUC/τ)、Cmax和Cmin,确定概要统计。在PK亚研究中纳入15位受试者,都是男性;11位是白人,3位是黑人,1位受试者是混和种族。当与ATV/r 组合体每天一次给药时在第2周时MVC 的PK数据[中值(范围)]如下:AUC24
= 4330 ng·h/mL (1920-7310);Cavg = 180 ng/mL (80-305);Cmax = 650 ng/mL (178-1490);Cmin = 37.0 ng/mL (8.4-92.7)。基于来自MERIT研究的暴露-反应分析,所有15位受试者达到了接近最大病毒学疗效的目标的MVC Cavg
(≥75 ng/mL)。
该数据充分地验证了ATV/r使得以每天一次的150mg量给药MVC成为可能,从而达到了目标的MVC Cavg
(≥75 ng/mL),其提供了如MERIT研究中确定的MVC的接近最大疗效。
实施例2
为了确定是否可以将用CCR5拮抗剂的每天一次的核苷节约型方案安全有效地施用于CCR5-嗜性HIV感染的HIV阳性患者,进行了随机化的对照研究。在这项研究中,将HIV阳性患者随机化以接受阿扎那韦(300mg
QD)和利托那韦100 mg QD以及马拉维罗(150mgQD)或Truvada,所述患者以前从未被治疗过,其具有使用CCR5共受体的病毒并且没有任何耐受突变。
将121位患者纳入研究中;马拉维罗组60位,Truvada组61位。在两个治疗组中患者的基线特征相似。获得观察24周后的结果并表示在图1-6中。在第24周时达到小于400和小于50拷贝/ mL(这是HIV治疗的接受的治疗目标)的患者分别为93%和90% (Truvada和马拉维罗)以及89%和80%(Truvada和马拉维罗)。接受马拉维罗的患者经历了195个细胞的CD4+的增加,而接受Truvada的患者经历了173个细胞的增加。在马拉维罗组有4次停药,在Truvada 组有3次。方案的安全性是可比较的。
这项初步研究表明,在24周观察时,实验性的每天一次的核苷节约型方案作为阿扎那韦和利托那韦以及Truvada的护理标准,是安全有效的。图1-6的曲线的右侧上的分歧是由于在试验后期受试者的数量仍然较低。
Claims (16)
1.组合体,用于在CCR5嗜性HIV-1病毒感染的未治疗过的患者中口服治疗疾病,其包含治疗有效量的至少一种CCR5拮抗剂、至少一种HIV-1蛋白酶抑制剂和至少一种所述至少一种CCR5拮抗剂和/或至少一种HIV-1蛋白酶抑制剂的药代动力学增强剂,所述疾病选自HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS。
2.权利要求1的组合体,包含用于在CCR5嗜性HIV-1病毒感染的未治疗过的患者中口服治疗疾病的治疗有效量的至少一种CCR5拮抗剂和至少两种HIV-1蛋白酶抑制剂,所述疾病选自HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS。
3.权利要求1或2的组合体,其中不包含HIV-1核苷酸逆转录酶抑制剂(NRTI)。
4.前述权利要求中任何一项或多项的组合体,其中所述至少一种CCR5拮抗剂选自马拉维罗、NCB-9471、PRO-140、CCR5mAb004、TAK-779、ZM-688523、4-氯-6-氟磺胺、TAK-220、TAK-652、SC-351125、ancriviroc、vicriviroc、PRO-140、aplaviroc、AMD-887、INC-B9471、CMPD-167、1-内-{8-[(3S)-3-(乙酰氨基)-3-(3-氟苯基)丙基]-8-氮杂双环[3.2.1]辛-3-基}-2-甲基-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-5-甲酸甲酯、3-内-{8-[(3S)-3-(乙酰氨基)-3-(3-氟苯基)丙基]-8-氮杂双环[3.2.1]辛-3-基}-2-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-5-甲酸甲酯、1-内-{8-[(3S)-3-(乙酰氨基)-3-(3-氟苯基)丙基]-8-氮杂双环[3.2.1]辛-3-基}-2-甲基-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-5-甲酸乙酯和N-{(1S)-3-[3-内-(5-异丁酰-2-甲基-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-1-基)-8-氮杂双环[3.2.1]辛-8-基]-1-(3-氟苯基)丙基}乙酰胺) 及其药学上可接受的盐或溶剂化物。
5.前述权利要求中任何一项或多项的组合体,其中所述至少一种CCR5拮抗剂包括马拉维罗。
6.前述权利要求中任何一项或多项的组合体,其中所述至少一种HIV-1蛋白酶抑制剂选自沙奎那韦、茚地那韦、奈非那韦、安普那韦、洛匹那韦、阿扎那韦、福沙那韦、替拉那韦和地瑞那韦,其中所述至少一种药代动力学增强剂是利托那韦。
7.前述权利要求中任何一项或多项的组合体,包含约150-约300mg的量的马拉维罗,约100-约200 mg的量的利托那韦和约300mg的量的阿扎那韦。
8.前述权利要求中任何一项或多项的组合体,包含用于每天一次(QD)方案的口服治疗的马拉维罗 150 mg,阿扎那韦 300mg和利托那韦 100 mg。
9.权利要求1-8中任何一项或多项所定义的组合体在制备用于在CCR5嗜性HIV-1病毒感染的未治疗过的患者中口服治疗疾病的药物的用途,所述疾病选自HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS。
10.权利要求9的用途,其中在未治疗过的患者中改善了至少HIV-1 RNA拷贝和CD4+细胞数。
11.用于口服施用于CCR5嗜性HIV-1病毒感染的未治疗过的患者的药物组合物,所述组合物包含权利要求1-8中任何一项或多项所定义的组合以及一种或多种药学上可接受的赋形剂、载体和/或稀释剂。
12.单位剂型,包含权利要求1-8中任何一项或多项所定义的组合体,用于在CCR5嗜性HIV-1病毒感染的未治疗过的患者中口服治疗疾病,所述疾病选自HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS。
13.权利要求12的单位剂型,其作为用于口服施用的单一的或多重的剂型,包含以物理分离形式的所述至少一种CCR5拮抗剂和所述至少两种HIV-1蛋白酶抑制剂。
14.试剂盒,包含权利要求1-8中任何一项或多项所定义的组合体,其作为用于同时、单独或依次口服施用于CCR5嗜性HIV-1病毒感染的未治疗过的患者的组合制剂。
15.权利要求14的试剂盒,包含至少三种物理上独特的组合物,一种包含所述至少一种CCR5拮抗剂,一种包含所述至少一种HIV-1蛋白酶抑制剂以及一种包含所述至少一种药代动力学增强剂。
16.治疗选自HIV-1感染、基因上与HIV相关的逆转录病毒感染和AIDS的疾病的方法,所述方法包括将权利要求1-8中任何一项或多项所定义的组合体同时、单独或依次口服施用于CCR5嗜性HIV-1病毒感染的未治疗过的患者。
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