CN106660937A - 用于治疗adhd的达斯曲林(dasotraline)剂量和方法 - Google Patents
用于治疗adhd的达斯曲林(dasotraline)剂量和方法 Download PDFInfo
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- CN106660937A CN106660937A CN201580027353.3A CN201580027353A CN106660937A CN 106660937 A CN106660937 A CN 106660937A CN 201580027353 A CN201580027353 A CN 201580027353A CN 106660937 A CN106660937 A CN 106660937A
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Abstract
本发明披露使用达斯曲林(dasotraline)治疗注意缺陷多动障碍(ADHD)的剂型和治疗方案。本文所述的组合物不呈现滥用可能。
Description
相关申请案的交叉参考
本申请案要求2014年5月13日申请的美国临时申请案61/992,619的优先权。US61/992,619的全部内容以引用的方式并入本文中。
技术领域
本发明涉及使用[(1R,4S)-4-(3,4-二氯苯基)-1,2,3,4-四氢-1-萘胺](达斯曲林)治疗注意缺陷多动障碍(ADHD)的剂型和治疗方案。
背景技术
注意缺陷多动障碍(ADHD)是影响儿童和青少年的常见病状并且一些人可以持续到成人期。尽管一些专家相信ADHD在8％到10％学龄儿童中发生，但国家心理卫生研究所(National Institute of Mental Health；NIMH)估计3％到5％儿童患有ADHD。大量证据表明约50％儿童可能不会发生ADHD。无论确切数字如何，ADHD都是儿童和成年人中的严重精神健康问题。
用于ADHD的治疗最通常呈刺激剂形式，如哌醋甲酯(例如 和)、安非他明(amphetamine)和右旋苯丙胺以及其前药尽管用刺激剂治疗多动症可能看起来违反常理，但认为刺激剂可活化负责注意力和精神集中状态的大脑回路，由此减轻多动症。对于许多儿童，ADHD药物减轻多动症和冲动性并且改良其精神集中、工作和学习能力。药物还可以改良身体协调。然而，当前指定的所有刺激剂皆呈现较高滥用可能。所有前述药物皆由DEA通过其II期疗程状况的分配来控制，其意指药物“具有较高滥用可能……并且可引起严重的心理和生理依赖性”。
因此，具有可以口服剂型形式、按可有效治疗ADHD但不存在滥用可能倾向的剂量提供的药物将是有利的。
反式4-(3,4-二氯苯基)-1,2,3,4-四氢-1-萘胺(其也称为反式枸橼酸舍曲林(transnorsertraline)或TNS)和其CNS药理学已描述于美国专利案7,105,699中。
发明内容
现发现反式4-(3,4-二氯苯基)-1,2,3,4-四氢-1-萘胺的(1R,4S)对映异构体，为方便起见，其本文中称为“达斯曲林”，在极特定剂量和剂量疗程下，提供ADHD的有效治疗而不具有可辨别的滥用倾向。
在一个方面中，本发明设计用于治疗ADHD同时最小化药物滥用风险的方法，其包含向经诊断患有ADHD的患者投与含有4mg达斯曲林的达斯曲林口服剂型。
在另一个方面中，本发明涉及治疗ADHD同时最小化药物滥用风险的方法，其包含向经诊断患有ADHD的患者每天一次投与达斯曲林的口服剂型，其中所述口服剂型含有4mg达斯曲林。
附图说明
图1是4mg达斯曲林对比安慰剂的从开始到第四周，作为时间函数的ADHD RS-IV总评分最小二乘平均值从基线的变化的图。
图2是基于CGI-S评分，4mg达斯曲林对比安慰剂的从开始到第四周，作为时间函数的最小二乘平均值从基线的变化的图。
图3是作为时间函数的达斯曲林的血清浓度(ng/mL)的图。
图4描绘在成瘾性对比时间的测量曲线上，两种剂量的安慰剂、哌醋甲酯和三种剂量达斯曲林的药物成瘾的6种并列比较。在这些曲线上，50％表示中性。
具体实施方式
达斯曲林[(1R,4S)-4-(3,4-二氯苯基)-1,2,3,4-四氢萘-1-胺是具有DNRI药理学的新型化合物。达斯曲林充当人类DA输送体(DAT；多巴胺吸收IC50 3nM)和NE输送体(NET；去甲肾上腺素吸收IC50 4nM)的强效抑制剂，和人类血清素输送体的较弱抑制剂(SERT；血清素吸收IC50 15nM)。
已在一系列临床试验中发现，当以4mg投与时，达斯曲林在治疗ADHD和具有不可检测的滥用倾向方面皆有效。此外，由于达斯曲林药物动力学的两种独特特征的组合(即不寻常的长血清半衰期，以及多巴胺转运体(DAT)抑制的缓慢起效)，可每天一次投与4mg达斯曲林，并且无需在每天的任何特定时间给药(即在每天任何时间给药)。达斯曲林的药物动力学和药效学特征表明DA和NE再吸收的持续、稳态抑制，其将解决病症中假设的机制潜在核心缺陷。
在下文所描述的研究中，在人类患者中的临床试验中证实达斯曲林治疗ADHD的功效和其不具有滥用可能。尽管不希望受当前理论约束，但可通过比较达斯曲林药理学与常规刺激剂并且具体来说，哌醋甲酯的药理学来断定这一临床结果的相干说明。
所提出的哌醋甲酯、安非他明和其它刺激剂的作用机制是释放和增加CNS多巴胺。这一释放在其对多巴胺传送机构的作用之后发生，其产生增加量的突触后多巴胺。哌醋甲酯的确切作用机制与安非他明和可卡因(cocaine)不同，但所有三种药物的净效果都是突触多巴胺增加。用经(11C)标记的哌醋甲酯和可卡因进行的放射研究发现两种药物的结合都位于相同的大脑区域(纹状体)中。当滥用哌醋甲酯时，认为伏隔核和眶额叶皮质纹状体中D1多巴胺受体的刺激与欣快症和重复使用有关。
霍夫曼(Hoffman)和莱夫科维茨(Lefkowitz)在其于古德曼(Goodman)和吉尔曼(Gilman)的治疗学的药理学基础(The Pharmacological Basis of Therapeutics),第9版中关于儿茶酚胺、拟交感神经药药物和肾上腺素能受体拮抗剂的章节中提出哌醋甲酯的药理学特性“与安非他明实质上相同于”并且滥用可能的注意事项与安非他明类似，尤其在具有“药物依赖性或酒精中毒病史”的患者中。
当经口投药时，哌醋甲酯由胃肠道快速和完全吸收。峰值浓度在给药之后1到2小时出现。哌醋甲酯的药物动力学半衰期是约2小时。当静脉内投与哌醋甲酯和可卡因时，其药物动力学非常类似，每种药物的大脑吸收百分比和其吸收率是并列的，但可卡因的大脑清除率比哌醋甲酯更快。在基底节和纹状体中，可卡因和哌醋甲酯在多巴胺输送体处的受体结合亲和力类似。值得注意的是，与静脉内哌醋甲酯的“高量”关联性是在基底节中出现峰值浓度之前产生。因此，滥用可能与纹状体中多巴胺含量的快速涌现有关。针对这一背景，达斯曲林不具有滥用可能将符合其药物动力学概况。达斯曲林呈现约10-12小时的时间最大浓度(tmax)(与哌醋甲酯的1-2小时相比)和47-77小时的血清半衰期(t1/2)。多巴胺缓慢增加的结果是不存在“高量”，并且长T1/2的结果是血清浓度逐渐增加到稳定状态。因此，如果经口投与的达斯曲林的剂量是4mg剂量，那么其将提供有效疗法而不诱导高量。
下文阐述的临床结果指示在约两到三周投药之后，含有4mg达斯曲林的口服剂型将提供ADHD的统计显著改良。4mg剂量的优势在于其在人类测试个体中产生最终有效血清浓度，同时最小化副作用的可能性并且不呈现药物成瘾反应。
在以下研究中，达斯曲林以其盐酸盐形式投与。除以游离碱形式投药以外，达斯曲林还可以配制成除盐酸盐以外的医药学上可接受的盐。术语“医药学上可接受的盐”指其中相对离子是来源于医药学上可接受的无毒性酸和碱的盐。用于本发明的化合物的盐的适合的医药学上可接受的酸包括例如乙酸、己二酸、褐藻酸、抗坏血酸、天冬氨酸、苯磺酸(苯磺酸)、苯甲酸、硼酸、丁酸、樟脑酸、樟脑磺酸、碳酸、柠檬酸、乙二磺酸、乙磺酸、乙二胺四乙酸、甲酸、反丁烯二酸、葡庚糖酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、氢碘酸、羟基萘甲酸、羟乙基磺酸、乳酸、乳糖酸、月桂基磺酸、马来酸、苹果酸、杏仁酸、甲烷磺酸、粘液酸、亚萘基磺酸、硝酸、油酸、双羟萘酸、泛酸、磷酸、特戊酸、聚半乳糖醛酸、水杨酸、硬脂酸、丁二酸、硫酸、鞣酸、酒石酸、特拉克酸(teoclatic)、对甲苯磺酸等。盐酸达斯曲林是优选盐，并且其制备方法和配制物描述于美国公开申请案2013/0116332中。本文中所描述的量是以游离碱形式计算的达斯曲林的量。可根据配制物中使用的达斯曲林的盐形式调节所述量，并且实际上，在下文所描述的临床研究中，使用使用等效于4mg游离达斯曲林的量的盐酸盐。
本发明的适用于经口投药的配制物可以离散单元形式呈递，如胶囊、扁胶剂或片剂，其各自含有4mg达斯曲林或含有4mg达斯曲林游离碱的等效物的盐。应理解，本发明的配制物可包括口服调配物领域中的其它常规试剂，例如着色剂、崩解剂和调味剂。
如本文中所使用，“治疗(treatment/treating)”或“减轻”或“改善”在本文中可互换地使用。这些术语指获得治疗效益并且根除或改善与ADHD相关联的一种或多种症状使得在患者中观察到改良(尽管患者可能仍患有ADHD)的方法。可由医生、医生的助理、护士或其它保健专业人员向经诊断患有ADHD的患者投与组合物。
在4周治疗周期内，每天一次使用4mg对比安慰剂，评估患有ADHD的成年人中达斯曲林的功效和安全性的2期、随机、双盲、平行群、多中心、门诊研究。研究由三个周期组成，包括筛选、治疗和清除/随访，如下文所述。在成年人提示下使用ADHD分级量表版本IV(ADHDRS-IV)评估功效。使用临床数据储存库系统评估对认知的作用。在整个研究期间，通过收集生理检查、12导联心电图(ECG)、生命体征、不良事件(AE)、血液学、血液化学、尿分析、失眠严重度指数(ISI)和哥伦比亚自杀严重度分级量表(Columbia-Suicide Severity RatingScale；C-SSRS)来监测安全性和耐受性。使用所测量的血浆达斯曲林浓度进行群体药物动力学方法。
所有个体在基线处(第1天)的ADHD RS-IV评分≥26并且CGI-S评分≥4。在第1天，经由相互作用反应系统将个体随机分入治疗组(4mg达斯曲林)或安慰剂组，并且在当晚睡觉之前开始服用研究药物。在第1天到第28天，个体在家在每晚大致相同时间自行投与研究药物。在第1天之后，个体在第8、15、22和29天返回诊所。在第1天开始并且在治疗周期期间的每次访问时，完成ADHD RS-IV、温德-蕾赫尔成年人注意缺陷障碍量表(Wender-ReimherrAdult Attention Deficit Disorder Scale；WRAADDS)和临床总体印象严重度(CGI-S)。在基线以及第15天和第29天管理临床数据储存库系统。在第1、8、15、22和29天收集用于达斯曲林血浆浓度的抽血。
在4周治疗周期结束(第29天)时，突然停用药物，并且个体进入2周清除期以监测在清除期间的达斯曲林血浆浓度，使用医生戒断检查表(Physician WithdrawalChecklist)评估戒断症状的出现，并且测定在停用研究药物之后治疗作用的持续时间。在第36和43天，个体返回诊所并且完成ADHD RS-IV、WRAADDS和CGI-S。在第43天完成临床数据储存库系统。
结果以图形方式呈现于图1和2中。图1是基于ADHD RS-IV总评分，4mg达斯曲林对比安慰剂的从开始到第四周，作为时间函数的最小二乘平均值从基线的变化的图。图2是基于CGI-S评分，4mg达斯曲林对比安慰剂的从开始到第四周，作为时间函数的LS平均值从基线的变化的图。在第三周和第四周，差异是统计差异(p<0.05)。达斯曲林组对比安慰剂组，在第4周，温德-蕾赫尔ADD总评分并未改良到足以实现统计显著性，但注意力困难分量的分项评分展示统计显著改良。
在计算机化认知评估量表中，未观察到达斯曲林对注意力、工作记忆或间歇性记忆的测量值的显著主要作用。治疗突发性不良事件(TEAE)高于安慰剂组中的TEAE的百分比。大部分不良事件评定为轻微或中度；评定为严重的事件的发生率在达斯曲林组中是6％并且在安慰剂组中是2.7％。在达斯曲林组中，引起停用(并且在≥2名患者中发生)的最常见不良事件是失眠(2.6％)和焦虑(2.6％)。
当以时间函数形式检验达斯曲林的血清浓度(ng/mL)时，发现血清浓度在第四周开始进入稳定区。在更早的研究过程中，观察到4mg达斯曲林的单次剂量产生约1.5ng/mL的最大血清浓度(Cmax)，其是极缓慢地获得(tmax>6小时)并且无任何“迅速增加”。图3是在单次投药后，作为时间函数的达斯曲林浓度(ng/mL)的图。
由其它研究(未展示)，发现在约5-6ng/mL下实现50％DAT位点占有率，即达斯曲林在单次投药后并未实现足以占据50-75％DAT位点的浓度。因此，由临床试验可发现4mg剂型可在两周的每天一次投药之后实现疗效，并且由血清浓度研究可发现其在不存在DAT占有率迅速增加的情况下实现。在本研究中，达斯曲林4mg/d在稳定状态下产生6ng/mL的平均浓度。达斯曲林4mg/d也降低循环DHPG含量，表明去甲肾上腺素输送体的重要抑制。DNRI机制区分达斯曲林与阿托西汀(atomoxetine)，阿托西汀是仅抑制去甲肾上腺素输送体的非刺激剂。达斯曲林的缓慢吸收和长消除半衰期与安非他明、哌醋甲酯和阿托西汀的药物动力学相反。也可以使用4mg剂型作为一系列剂量的成员，使得可向上或向下进行剂量滴定，从4mg剂量到5、6、7或8mg剂量，或从6、7或8mg的初始起始剂量到4mg的保持剂量。举例来说，可在数天时段内以4毫克/天给药，接着在数天时段内以6毫克/天给药并且最终以8毫克/天给药，或反之亦然。也可以从2mg向上或向下滴定。
因为相信哌醋甲酯和类似DAT抑制剂的滥用可能与DAT位点的快速占据相关联，进行达斯曲林的研究以观察其是否将不存在与其它刺激剂相关联的滥用倾向。
进行单次剂量、随机、双盲、双假设、安慰剂和活性控制交叉研究(每位个体进行6次治疗访问)。在健康娱乐性刺激剂使用者中比较三种剂量的达斯曲林(8mg、16mg和36mg)与安慰剂以及40mg和80mg哌醋甲酯(阳性对照)的滥用可能。个体参与医学筛选访问(访问1)，一个4天住院病人鉴定阶段(访问2)、由六个5天治疗访问组成的治疗阶段(访问3到8)和安全性随访(访问9)。在21天筛选访问内，个体参与和参加检核阶段，其中其以随机双盲交叉方式接收60mg哌醋甲酯或符合条件的安慰剂。给药时间间隔约24小时以确保个体可区分和展示阳性对照的正性作用。
年龄是18到55周岁(包含性)的健康雌性和雄性个体(其为具有可卡因经历并且通过哌醋甲酯鉴定阶段的娱乐性中枢神经系统(CNS)刺激剂使用者)随机接受治疗。
在每此治疗访问的第1天进行药物投药，接着进行药效学(PD)、药物动力学(PK)和安全性评估直到给药后72小时。个体以随机、双盲、双假设方式接受以下6种治疗中的每一种(每次治疗访问一种)：8mg达斯曲林、16mg达斯曲林、36mg达斯曲林、40mg哌醋甲酯、80mg哌醋甲酯或安慰剂。个体根据6×6威廉广场设计(William square design)随机接受6种治疗序列中的一种。在每此治疗访问(访问3到8)时接收的胶囊是相同的。在每此治疗访问时进行连续药效学和药物动力学评估。进行达斯曲林的药物动力学分析。安全性监测包括生命体征、临床实验室测试和不良事件(AE)的常规评估，以及给药后至少12小时的连续遥测监测。治疗访问间隔至少21天(从给药当天开始)的清除间隔。个体在最后一次治疗访问结束后，在约14天内返回安全性随访。
三十五名个体完成研究，基于事后能力计算，其仍引起大于90％能力以侦测安慰剂与哌醋甲酯之间的均数差。阳性对照物哌醋甲酯的作用符合具有滥用可能的刺激剂药物，因为在大部分药效学终点观察到与安慰剂相比的显著不同，包括药物成瘾视觉模拟评分(Drug Liking Visual Analog Scale)的主要测量值。与这些结果一致，哌醋甲酯与强刺激剂作用相关联，如通过次要刺激剂测量值测量，并且坚定认为哌醋甲酯是刺激剂(例如d-安非他明、甲基苯丙胺或可卡因)并且在药物类似性视觉模拟评分(Drug SimilarityVisual Analog Scale)中坚定认为不是安慰剂。这些结果表明研究有效并且个体和测量值对评估刺激剂药物的滥用相关作用敏感。哌醋甲酯受到全部个体“喜爱”，个体愿意再次服用哌醋甲酯，并且与安慰剂相比，愿意为哌醋甲酯付出更多。另一方面，在大部分药效学终点，达斯曲林的作用并不与安慰剂的作用显著不同，并且在所有药效学终点，8mg剂量展示与安慰剂类似的概况。因此，服用治疗性剂量的达斯曲林的患者或最初参与用单一片剂或胶囊进行的实验的滥用者不应经历滥用相关主观作用。甚至在16mg情况下，存在极少的与安慰剂的统计显著差异。结果以图形方式展示于图4中，其比较两种剂量的安慰剂、哌醋甲酯和三种剂量的达斯曲林的药物成瘾性。
前述研究说明达斯曲林的单次4mg经口给药(每天一次)提供治疗ADHD的功效，同时避免滥用可能。
制备具有以下组成的四毫克胶囊和安慰剂：
量(毫克/胶囊)
以下是本发明的其它方面：
一种用于治疗ADHD同时最小化药物滥用风险的方法，其包含向经诊断患有ADHD的患者投与达斯曲林的口服剂型，其中所述口服剂型含有4mg达斯曲林。
一种用于治疗ADHD的方法，其包含通过在一天内向需要这类治疗的个体经口投与呈片剂或胶囊形式的第一剂量来开始治疗，其中所述片剂或胶囊包含4mg达斯曲林，并且通过每天一次经口投与包含4mg达斯曲林的片剂或胶囊来继续所述治疗。
一种片剂或胶囊，其包含4.5mg盐酸达斯曲林和一种或多种药物赋形剂。
Claims (3)
1.一种用于治疗ADHD同时最小化药物滥用风险的方法，其包含向经诊断患有ADHD的患者投与达斯曲林(dasotraline)的口服剂型，其中所述口服剂型含有4mg达斯曲林。
2.根据权利要求1所述的方法，其中所述口服剂型含有4mg呈盐酸盐形式的达斯曲林。
3.根据权利要求3所述的方法，其中所述剂型由4.5mg盐酸达斯曲林和多种药学上可接受的赋形剂组成。
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| PCT/US2015/030357 WO2015175523A1 (en) | 2014-05-13 | 2015-05-12 | Dosage of dasotraline and method for treatment of adhd |
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| US4556676A (en) * | 1979-11-01 | 1985-12-03 | Pfizer Inc. | Antidepressant derivatives of trans-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine |
| US4981870A (en) * | 1989-03-07 | 1991-01-01 | Pfizer Inc. | Use of 4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine derivatives in the treatment of psychosis, inflammation and as immunosuppressants |
| WO2004024669A1 (en) * | 2002-09-16 | 2004-03-25 | Sepracor, Inc. | Treatment of cns disorders with trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine and its formamide |
| CN102740842A (zh) * | 2009-12-04 | 2012-10-17 | 桑诺维恩药品公司 | 反式降舍曲林的制剂、盐和多晶型物及其应用 |
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- 2015-05-12 WO PCT/US2015/030357 patent/WO2015175523A1/en active Application Filing
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- 2015-05-12 US US15/310,351 patent/US10076503B2/en active Active
- 2015-05-12 CA CA2948839A patent/CA2948839A1/en not_active Abandoned
- 2015-05-12 CN CN201580027353.3A patent/CN106660937A/zh active Pending
- 2015-05-12 JP JP2016567529A patent/JP2017515849A/ja active Pending
- 2015-05-12 EP EP15792455.6A patent/EP3143000A4/en not_active Withdrawn
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4556676A (en) * | 1979-11-01 | 1985-12-03 | Pfizer Inc. | Antidepressant derivatives of trans-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine |
| US4981870A (en) * | 1989-03-07 | 1991-01-01 | Pfizer Inc. | Use of 4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine derivatives in the treatment of psychosis, inflammation and as immunosuppressants |
| WO2004024669A1 (en) * | 2002-09-16 | 2004-03-25 | Sepracor, Inc. | Treatment of cns disorders with trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine and its formamide |
| CN102740842A (zh) * | 2009-12-04 | 2012-10-17 | 桑诺维恩药品公司 | 反式降舍曲林的制剂、盐和多晶型物及其应用 |
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| EP3143000A1 (en) | 2017-03-22 |
| AU2015259346A1 (en) | 2016-12-08 |
| KR20170005088A (ko) | 2017-01-11 |
| WO2015175523A1 (en) | 2015-11-19 |
| US20170266134A1 (en) | 2017-09-21 |
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