临床研究报告
一期、随机、双盲、安慰剂对照多剂量治疗评估***在健康受试者中安全性、耐受性、药代动力学的研究
DCR学习代码：13172
赞助商研究代码：***-1H-01（SNO-2）
IND号：119145
***：临床1期研究
研究适应症：安全性，耐受性，药代动力学
研究期间：2014年2月16日（筛选出第一个主题）– 2014年11月11日（最新随访）
赞助商Nivalis Therapeutics，Inc.（以前为N30 Pharmaceuticals）
3122 Sterling Circle，Suite 200
美国科罗拉多州博尔德市80301
赞助商联系人Robert Hopkins，DVM，MS
电话：+1（720）945-7716
传真：+1（303）440-8399
研究者DaVita临床研究
11750 W. 2nd Place，Suite 300，Lakewood，CO 80228美国
研究人员克里斯·加洛韦（医学博士）
电话：+1（303）566-3100
传真：+1（303）542-7300
RN BSN的项目经理Marla Elhard
电话：+1（303）566-3005
传真：+1（855）544-8170
作者Christopher A. Graybill博士，医学作家（达维塔）
斯科特·布兰特利（Scott Brantley）博士，药代动力学科学家（Nuventra）
Eugene R. Heyman博士，高级生物统计学家（Cardiocore）
医学博士Daniel B. Goodman，副总裁兼医疗总监
（心脏）
格雷格·吉恩（Greg Ginn），硕士，生物统计学家（DaVita）
这份报告的日期：2015年9月18日
这项研究是遵循良好临床规范（GCP）的原则进行的，包括基本文件的存档。 本报告是按照国际协调会议（ICH）指南编写的。
概要
研究主题：一项1期，随机，双盲，安慰剂对照，多剂量评估***在健康受试者中的安全性，耐受性和药代动力学的剂量研究。
研究代码
DCR学习代码：13172
赞助商研究代码：***-1H-01（SNO-2）
IND号：119145
赞助商：Nivalis Therapeutics，Inc.（以前称为N30 Pharmaceuticals，Inc.）
3122 Sterling Circle，Suite 200，Boulder，CO 80301美国
赞助者联系人：Robert Hopkins，DVM，MS
研究中心：DaVita临床研究
11750 W. 2nd Place，Suite 300，Lakewood，CO 80228美国
项目经理：RN BSN的Marla Elhard
研究者：医学博士克里斯托弗·加洛韦（Christopher Galloway）
出版：撰写本报告时无
研究时间：初筛日期至最后随访时间：2014年2月16日– 2014年11月11日
临床阶段：I期
目标
主要目标：
•为了评估***在健康受试者剂量递增中的安全性和耐受性。
次要目标：
•多次服用后评估***及其主要代谢产物N91288的药代动力学（PK）。
方法
设计：
这计划作为一项双盲、随机、安慰剂对照、多剂量组研究，然而，后续增加了两个单剂量组，在这个研究的多剂量组中，至少计划4个递增组每组8个受试者（6个试验药，2个安慰剂），每一个受试者接受筛选（给药前28天到给药前3天），如果符合条件，在给药前一天返回医院并进行再次确认资格，合格受试者会收到***或安慰剂研究药物的口服剂量，在研究的第1天到第14天观察安全性问题，在临床研究单位的基地直到在第15天没有变化；药代动力学来自于研究第1天到第16天的早上。个别特殊的受试者可能持续49天从筛选期到研究结束，一个安全委员会收到每组完成后的安全性数据，来决定是否进入下一个增加剂量组的计划。改变计划剂量组，重复剂量组，或者根据协议中概述停止研究。
单剂量组每组也纳入8个受试者（6个试验药，2个安慰剂），分别评估单剂量组的PK和食物摄入的影响。
治疗方法：
•***（10、50、250和500 mg）胶囊，每天口服一次，连续14天（多次剂量组）或一次（单剂量组）
•匹配的安慰剂胶囊，每天口服一次
程序和评估：
资格筛选包括病史，人口统计学信息，既往和伴随用药，体格检查，体格测量（身高，体重，体重指数[BMI]），12导联心电图（ECG）评估，48小时动态ECG心律失常（Holter）监测）评估，生命体征测量，临床实验室检查（血清学，血液学，血液化学，尿液分析，妇女妊娠试验）以及药物和酒精检查
PK评估：***和N1979的血液和尿液PK评估
安全性：12导联心电图记录，不良事件（AE）监测，动态心电图（Holter），临床安全实验室测试，伴随用药，身体检查，脉搏血氧饱和度测定血红蛋白氧饱和度，妊娠试验，肺活量测定，遥测，生命体征，体重；
纳入的主要标准
年龄：18-55岁（含）
体重指数：≥19.5 kg / m2和≤32.0 kg / m2
对象：健康的白人男性和女性对象，无临床上重要的心脏发现史
研究药物
活性物质：***
剂型：胶囊
强度/批号：5 mg / N454451
强度/批号：25毫克/ N454891
强度/批号：50毫克/ N456044
制造商：Norwich Pharmaceuticals (Norwich, NY)
名称：安慰剂
剂型：胶囊
批号：N454450
制造商：Norwich Pharmaceuticals (Norwich, NY)
评估标准/主要结局
药效学：不适用
药动学：这是一项双盲、随机、安慰剂对照、多剂量组研究。4个递增剂量10, 50, 250 和500 mg，研究的每个组有8个受试者（6个试验药，2个安慰剂），在研究第1天到第14天，每个受试者收到研究药物的口服剂量，***或者安慰剂，然后追踪安全性和药动学评估；
血浆PK：第一天的PK参数取决于第一剂量组***的浓度-时间数据，包括最大浓度值（Cmax），最大浓度值的时间（Tmax），在浓度-时间曲线下计算从0时刻到最后可测量和无穷大下的面积（AUC0-t，AUCinf）；和最终消除半衰期(T½).，另外估计口服清除率(CL/F)和最大表观分布容积(Vz/F)，包含14天浓度-时间数据中***的稳态PK参数，Cmax, Tmax, t½, AUC0-12, AUC0-τ, CLss/F，以及累计比率(Racc)。
***主要经历了葡萄糖醛酸化，直至N1979，O-葡萄糖醛酸含量占所测葡萄糖醛酸代谢物总量的> 95％。N91288，酰基-葡糖醛酸苷是次要成分，占总含量的<3％.这代谢物的药动学参数由N1979和N91288离子体的总血浆浓度决定的，并被称为N1979,在PK报告和整个文章中的主要代谢物。N1979的在第一剂量组第一天浓度-时间数据包括：Cmax, Tmax, t½, AUC0-24,
AUCinf，原型代谢物与原型的比值（M/P），来自***的14天稳态PK参数浓度-时间数据包括：Cmax, Tmax, t½, AUCtau, Racc, and M/P 比值，通过至少使用3个时间点的对数值（终末期的）血浆浓度对数线性回归来估计最终消除半衰期
尿PK：队列2在D1计算***和代谢物N1979PK参数即肾脏清除率（Clt）和累积回收量（Ae0-t）原型
安全性：安全性评估是基于AE报告医学审查和12导联ECG测量，动态ECG（Holter），临床安全性实验室检测（包括血液学，CRP临床化学,尿液分析），伴随用药，体格检查，通过脉搏血氧仪测定的血红蛋白血样饱和度，孕检，肺活量，遥测，生命体征测量，和体重；
统计学方法
样本量大小测定，这是一个暴露动力学研究，因此对于统计学分析推断没有把握度，没有正式进行样本量测算；受试者数量的选择是基于可行性，被认为足以满足研究主题。
药动学参数：***和 N1979的PK参数被推导运用WinNonlin软件6.3版本，估计PK参数来自于使用非房室分析标准方法计算的血浆浓度，使用实际收集时间计算，使用方差分析比较PK参数；
安全性参数：将不良事件列表化；临床实验室检测，12导联ECG数据、生命体征数据被汇总描述，并描述了与基线相比的变化，ECG的分析数据（在第1-2天和第14-15天的3个时间点进行三次重复测量，以及在其他时间点进行单次测量），包括心率，QRS轴，PR间隔，QRS持续时间，RR间隔和 QT间隔；QTcF被计算。所有的ECG要通过合格的，能集中心脏安全性的心脏病专家进行。
结果
受试者分布
总共有49例受试者被随机安排进入试验，47例受试者（96%）完成了试验，2例受试者由于个人原因（与实验无关）提前终止试验；总共49例受试者，其中37例男性12例女性，所有受试者均为白种人，受试者平均年龄（±标准差）是39.1 (11.4)岁。
***的暴露
参与试验受试者的分组与剂量安排如下：
多剂量组（剂量14天），每组6例受试者服用试验药，2例受试者服用安慰剂，总共有24例受试者服用N9115,9例服用安慰剂（包括一例替代受试者）。
•第1组: 10 mg
•第 2组: 50 mg
•第3组: 250 mg
•第4组: 500 mg
单剂量组，每组6例受试者服用***，2例受试者服用安慰剂；
•第2a组：50 mg
•第5组：250 mg（高脂餐）
药代动力学：药代动力学概述每天口服*** 10至500 mg，共14天，所有剂量组在给药后2小时内达到峰值浓度，从而迅速吸收。Cmax几何均值与剂量递增成比例增加。、AUC0-tau的增加略大于剂量增加比例。高脂餐组250 mg剂量的***Tmax为4小时，而在禁食状态下为1.5小时，但*** Cmax和AUC0-t相对于禁食状态的在90％以内，表明食物对*** PK的影响最小。低剂量下末期半衰期（t½）的几何平均估计值更长，低剂量下为10.5至14.9小时剂量，高剂量组约5个小时，分别为250和500 mg剂量。对于所有剂量组，稳态下的几何平均清除率范围在13.9至23.6 L / h之间，线性分析中注意到清除率的剂量依赖性降低。对于所有剂量组，暴露累积率Racc（AUC）和Racc（Cmax）的几何平均值最小，分别在> 1.2至> 1.33的范围内。这表明在低剂量每天重复一次后，***表现出最小的积累，而在测试的最高剂量下则没有积累。
每天口服10至500毫克后，***会通过葡萄糖醛酸化作用快速而广泛地代谢为两种非活性代谢物。 代谢物的浓度大约是100％到300％***血浆浓度。 血浆代谢物浓度的总和为N1979（O-葡萄糖醛酸）和N91288（酰基葡萄糖醛酸）。 N1979浓度> 95％，N91288浓度<5％。 因此，据报道代谢物PK值与N1979相同。
N1979出现相对较快，所有队列的峰值浓度均在不到4.0小时内达到.Cmax和AUCtau值以小于剂量比例的方式增加。 在较低剂量下，末期半衰期（t½）较大（10.4 – 11.6小时），在较高剂量下则较小（〜5小时）。 原型和代谢物之间半衰期值的相似性表明，N1979的消除受到形成速率的限制。 暴露累积比率Racc（AUC）和Racc（Cmax）介于0.9到1.3之间，表明多次给药时代谢产物暴露的累积量可忽略不计。 高脂食品的Tmax为5小时，而禁食状态的Tmax为3小时。 然而，与禁食状态相比，N1979 Cmax和AUC0-t值略高（106％-101％），表明食物对N1979 PK的影响最小。
在队列2的受试者中，在第1天评估了***和N1979（葡糖醛酸苷代谢产物）的尿排泄量。 ***和N1979的肾脏清除率较低，分别为1.31 L / h和3.67L / h。这代表了***和N1979普通健康成年人肌酐清除率的大约20％和50％，
分别。总体而言，***剂量的55％在24小时内排泄在尿液中，其中***占5％，代谢产物占50％（N1979和N91288）。由于***的肾脏清除率较低，且24小时内***的血浆浓度相对较低，因此代谢和/或其他非肾脏清除途径（可能是胆道清除）似乎是原型药物总体清除的主要原因。
***血浆药代动力学在第1天口服***后，血浆***浓度相对较快达到峰值，所有人群的中位Tmax值在1.50至5.00小时之间。在所有受试者中，给药后24小时血浆中***仍可定量。第2组的受试者在第1天不慎服用了25 mg，而不是计划的50 mg；因此，添加了同类群组2a以接受单次50 mg剂量。几何平均Cmax值随剂量的增加而增加，从10 mg的33.0 ng / mL增加到25 mg的111 ng / mL，245 ng / mL，1810 ng / mL，1600 ng / mL和3840 ng / mL ，50毫克，250毫克（禁食），250毫克（禁食）和500毫克剂量水平。对于10mg至500mg剂量水平，Cmax的几何平均％CV范围为14.0％至57.8％。与Cmax相似，AUC值随剂量增加而增加。几何平均AUClast值分别为327 h * ng / mL，893 h * ng / mL，1530 h * ng / mL，12000 h * ng / mL，10300 h * ng / mL和32400 h * ng / mL分别为10毫克，25毫克，50毫克，250毫克（禁食），250毫克（禁食）和500毫克剂量。对于10mg至500mg剂量水平，几何平均AUCinf值的范围为357h * ng / mL至32500h * ng / mL。
第1天的***暴露参数（Cmax，AUClast和AUCinf）呈线性且略有增加在最大剂量下大于剂量成比例的方式。对于10、25和50 mg剂量水平，***的表观清除率（CL / F）似乎与剂量无关，但对于250和500 mg剂量水平，其表观清除率（CL / F）相对较低。高脂餐后5分钟内给予***的平均Cmax和AUC值比空腹受试者给予***的平均Cmax和AUC值低约15％。
到第7天，除一名受试者外（在50毫克队列中），所有受试者的剂量前***浓度均可量化。由于与第1天和第14天相比，在第7天收集的血浆样品相对较少，因此第7天PK参数的估计值较不可靠。因此，第7天PK值应用于定性而非定量目的。
在10到500 mg剂量范围内，几何平均Cmax值以略大于剂量比例的方式从67.9 ng / mL增加到6200 ng / mL。对于10到500 mg剂量，最终相半衰期（t½）的几何平均估计值随着剂量从8.03小时增加到4.71小时而降低。与Cmax一致，AUC0-tau以大于剂量比例的方式增加，对于10 mg至500 mg组，其几何平均值为442 h * ng / mL至40800 h * ng / mL。
在第14天。所有受试者能获得***的浓度。与第一天相比，***的出现更加迅速，所有组的Tmax中位值均小于两个小时。与第一天相反， Cmax几何均值增加与剂量成正比，对10mg和500mg组，从84.3 ng/mL 增长到5800 ng/mL。与第一天一致，AUC0-tau以略大于剂量比例的方式增加。在低剂量最终消除半衰期的几何平均估计值更长，对10 mg和 50 mg 剂量组，值分别为在14.9到10.5；对250和50 0g剂量组的值分别为5.58和5.21。
在低剂量组中较长的半衰期更有可能取决于采样时间表，因为只有10 mg和 50 mg 剂量组水平采样时间达到48小时，在稳态状态下所有剂量组的清除率的几何均值范围在13.9-23.6 L/h之间，线性分析中记录了清除率的剂量依赖性在降低。在10、25、250 mg 组中暴露累计比的几何均值是大于1.2的，但是500mg组的是1.01。这表明每天重复一次后***展示了在低剂量组很低的累积值，在高剂量组没有累计值。对于所有剂量组检测峰浓度的几何均值累计比(Racc(Cmax)) >1.33，表明每天重复一次剂量，峰浓度增加中等程度。
代谢物N1979血浆药代动力学，在第1天口服***之后，N1979血浆浓度，无活性代谢物出现相对较快，显示Tmax值的中位数约为4.0小时。在所有受试者服药，N1979服药后24小时血浆中N1979仍然可测量，表明多剂量组中有累积效应。与空腹受试者相比，高脂餐后5分钟内服用***可使N1979 Cmax的均值和N1979的AUCinf几何均值值均高出约6％。 空腹状态下N1979的出现较快， Tmax值中位数比餐后状态早2.0小时。 总体而言，代谢物与原型的几何均值比值≥1.40，在较低剂量（10-50 mg）下可见最大比例。
在第7天，除了1个受试者（50mg组）所有的受试者剂量前N1979浓度均可以被测量，由于在第7天血浆样本数量相对较少（与第1天和第14天相比），这个PK参数估计与其他天相比可能可靠性较低。基于这个原因，这些值常常用来定性，而不是定量的目的。10和500 mg 组,Cmax值的几何均值分别以小于剂量比例的方式从359 ng/mL 增加到 9580 ng/mL。末端半衰期的几何均值估计值在剂量组之前是一致的，值在5.61-6.09小时之间。对于 10 mg,、50 mg,、250 mg、500 mg组，与Cmax一致，AUC0-24比剂量比例增加，其几何均值分别是2020 h*ng/mL，8950 h*ng/mL, 47200 h*ng/mL, 83400 h*ng/mL。如第一天所见，根据***的低剂量（10 和50 mg），这个代谢物和原型的几何均值比是更高的。在500mg剂量水平,代谢物与原型Cmax几何均值比小于这个单位（0.0973），而其余组的比率均大于1。
在第14天，所有受试者均可以在药物服用前测出N1979浓度。N1979的出现是非常快的，所有组中Tmax值的中位数小于4小时。10 mg 到500 mg 组，Cmax值的几何均值的增加分别小于从389 ng/mL 到 8270 ng/mL的剂量比例。10 mg 到500 mg 剂量组水平，AUCtau的的增加是小于剂量比例的增加，其几何均值分别为2110 h*ng/mL 和 69600 h*ng/mL。末端半衰期在低剂量组更长，10 mg 和50mg剂量组值分别是11.6和10.4，250mg 和500mg剂量组值分别是5.77和5.74。对于低剂量组更长的半衰期可能取决于采样时间表，，因为只有10 mg和 50 mg 剂量组水平采样时间达到48小时。在原型和代谢物半衰期的值相似性表明N1979的消除受形成速率的影响。由于代谢物的末端消除半衰期不应该短于原型的末端消除半衰期，这N1979的末端消除半衰期很有可能在大部分受试者中被低估了。这暴露累计比值Racc(AUC) 的几何均值范围从0.88到1.09，表明多次给药的代谢物积累量可忽略不计。这峰浓度累计率(Racc(Cmax) 范围从0.907到1.33，进一步表明缺乏累计。在第14天代谢物和原型的Cmax几何均值比范围在0.898到2.91，AUCtau几何均值比范围在1.22到3.14。表明N1979的全身暴露是***的100% 至300%。
尿液药代动力学，*** 和 N1979的尿排泄，葡萄糖醛酸代谢物，在第2组受试者的第1天被评估。25 mg ***组的大约有5%（第2组第1天）被清楚，因为尿液中***没有变化，导致肾清除率低至1.31 L/h，大约是普通健康成人的肌酐清除率的20％。由于***较低的肾清除率和24小时内***的低血浆浓度，它表明代谢和/或其他非肾脏清除途径（可能是胆汁清除）的清楚是原型药物的全身清除的主要原因。
尿液中排出的N1979的几何平均质量为19.1 mg，它代表了25mg剂量组的50%。这N1979的肾脏清除率是3.67 L/h，大约是普通健康成人的肌酐清除率（7.2 L/h）的50％。
这个结果表明与原型药物相比，N1979主要经历了肾脏清除，正如表明的那样通过高剂量组清除和有更大的肾脏清除估计值。
综合，***剂量的55%在24小时内排除到尿液中，5%是原型，50%是代谢物（N1979 和 N91288）。
安全性：49例受试者中报道中有40名（81.6%）在研究期间至少有1次发生与治疗相关的不良事件。在第1组和第4组的所有受试者（这些接受***和 placebo14天的）报道了1个与药物相关的，而在第2a组（16.7%）和第5组（66.7%）只有很少的受试者报道与药物相关，可能是由于在这两组中***的给药时间更短。***有很好的耐药性，所有的与药物相关的严重程度为轻度，没有观察到与剂量相关的不良时间发生率增加，***没有比安慰剂更广泛的事件出现。一个最大耐受剂量是不确定，因为在高剂量试验中是没有剂量限制性毒性是确定的。
第1-4组，受试者合并安慰剂治疗（14天剂量）
药物相关报道频率最多的是接触性皮炎、头痛、头晕。在第1-4组中接受***或安慰剂的所有受试者中均发生接触性皮炎，在第1组和第2组中有3/6（50%）的受试者发生头痛，但是在第3组和第4组中，下降到0/6和1/6 (17%)， 1/9 (11%)发生在安慰剂受试者中。在第2组中有2/6(33%)的受试者发生头晕，且2/9（22%）发生在安慰剂组。在所有被报告的受试者中，对于心电图导联来说接触性皮炎被认为是次要的。由于接触性皮炎和头痛的发生频率，SOC皮肤和皮下组织疾病显示出TEAE的发生频率最高，并且SOC神经系统疾病显示了下一个TEAE最高频率，所有的TEAEs在严重程度上是轻度。
有19例受试者（38.8%）报告了与研究药物有相关性的TEAEs。在第1、2组（67%）这些事件百分比较第3、4组（33%）更高，在最后两个组中，发生率低于安慰剂组（56%）。由研究药物引起的报告最常见的不良事件是，发生头痛的总共有7个受试者（在第1、2、3、4组中分别是2例[33%],1例[17%],0例,1例[17%]，其中安慰剂1例[11%]）;发生头晕的总共有4名受试者（在第2组2例[33%]，安慰剂组2例[22%]）。发生口疮性口炎总共有3例受试者（第1组2例[33%]，安慰剂组1[11%]）;发生便秘的总共有3名受试者（第2组1例[17%],安慰剂1例[11%]）。所有的其他因素相关的不良时间被报告的仅仅只有1人。
这里没有严重不良事件，没有与药物相关的不良事件导致试验中断和停止，并且没有不良事件导致死亡。
在12导联ECT数据、临床实验室结果和其他的安全性数据显示没有重大临床意义事件。
第2a组和第5组（单次给药组）
接触性皮炎是报告最多的事件，第5组中有4例（67%）受试者发生，安慰剂有1例（25%）受试者发生。只有一个其他事件被报告：在2a组和安慰剂各有一例受试者发生头痛。
心血管安全，除了对心率的影响很小，ECG数据发现全部为阴性:所有治疗组，包括安慰剂，在第14天心率增加。***的500mg剂量组最高的心率和最大的增加是相关的，但是这个增加与其他剂量组和安慰剂没有明显差异。随着***剂量增加或*** or N1979的浓度的增加，更高的变化值没有一致的趋势。
没有AV传导干扰是和***的给药有关，在观察期内脑室内传导变化不一致。心肌复极不受***给药的影响，***, N91288, 或 N1979的QTcF和血浆浓度的改变是没有相关性的。
除了对心率影响很小以外，心电动态检测仪结果全部是阴性，24小时心率值的均值，最大值，最小值在治疗期间没有改变，虽然所有治疗组平均每小时心率值显示在第1天末与基线相比有微小增加。在第14天，*** 500 mg组的受试者HR每小时值显示最低高度，但是没有注意到一致的剂量趋势，对比安慰剂改变也没有明显差异。
新房异位的结果是正常的。这里有少数室上性心动过速发作，
所有22拍或更短的持续时间最大是147 bpm.，在研究中未发现明显的室性异常，除了在*** 50 mg组第二天单个受试者发生了短暂的心室发作。最大持续时间是6拍，最大总体心率是99bpm。动态心电图诊断结果不明显。
QTcF的均值是很窄的范围从398.5 到 426.8 msec，在观察的整个试验中，几乎没有发现变化。对所有治疗的QTcF的均值变化与基线相比是非常相似的，但是在第1天2-8小时和第14天的4小时确实显示出更大的减少趋势，变化的平均值是最小总体范围从18.6 msec（250 mg组,14天，4小时）到 9.9 msec（10 mg组，10天，服药前）。没有明显的剂量组的趋势。回归分析显示QTcF的改变和***的浓度，或N1979的浓度没有关系。回归的斜率近似为0.220 和0.235，非显著性P值为0.71和 0.65。从最低到最高的观察浓度QTcF预测变化值几乎相同，-0.7和 0.1 msec,***分别为-0.8和0.1msec，N1979分别为-0.8和0.1msec。
心电图和动态心电图检查结果是互相补充的，在这两种情况下，在*** 500 mg 治疗中显示心率最小的增加，与安慰剂相比没有显著差异。心脏加速的趋势仅仅与高剂量组有关，在增加时间或剂量趋势一致的情况下没有显示出药效学的效果。
结论
***-1H-01 (SNO-2)临床研究的主要目的是评估在健康受试者中每日一次口服胶囊14天评估***的安全性和耐受性。第二个目的是评估在健康受试者中***的药代动力学。36个受试者被随机分配服用***，所有受试者被纳入***及其代谢物N1979的药代动力学分析中。
***血浆PK结论
每日一次以10, 50, 250, 和500 mg剂量口服***胶囊14天，N9115的药代动力学结果如下：
•***经历了快速吸收，所有组的Tmax均小于2小时。
•在10 mg至500 mg组中Cmax几何均值按剂量比例增加。
•同样，对于10 mg至500 mg组，稳态时AUCtau几何均值以略大于剂量比例的方式增加。
•较低剂量下末期半衰期的几何平均估计值（t½）更长，10和50 mg剂量组分别为14.9和10.5，而250和500 mg剂量分别为5.58和5.21。
•***在第14天之前（可能在第7天或之前）达到稳定状态。
•所有剂量组在稳态下的几何平均清除率范围在13.9至23.6 L / h之间，清除率与剂量有关，可能由于新陈代谢的饱和而降低。
•在低剂量每天重复一次之后，***显示出最小的累计（Racc（AUC）> 1.2），而在测试的最高剂量下则无累计。
•同样，所有试验剂量组的几何平均峰浓度累积比（Racc（Cmax））> 1.33，这表明，每天重复一次给药，峰浓度会略有增加。
•在高脂餐中服用250 mg ***不会影响平均Cmax和AUC值，这比空腹受试者的水平低约15％。
血浆代谢物N1979药代动力学结论
每天一次口服10、50、250和500 mg ***药物，共14天，导致其通过葡萄糖醛酸化作用快速和广泛地代谢为两种非活性代谢物，主要代谢为O-葡糖醛酸N1979（总代谢物的含量> 95％），并在较小程度上（总含量的<5％）转化为N91288的酰基葡糖醛酸苷。多次口服10 至500 mg剂量N9115后主要代谢物N1979的要药代动力学的总结如下：
•N1979的较快的出现，所有组的Tmax值中位数小于4小时。
•所有组中，Cmax几何均值以低于剂量比例方式增加，表明代谢可能达到饱和。
•类似的，AUCtau几何均值随着剂量的递增以低于剂量比例方式增加。
• N1979末端半衰期几何均值估计随着剂量递减而减小；
•原型与代谢物相似的半衰期值表明剂量的增加限制了N1979的形成速率。
•通过累计暴露比值的几何均值(Racc(AUC) 和 Racc(Cmax))显示N1979展示的多次暴露累积曝光量可忽略不计。
•Cmax 和 AUCtau代谢物和原型的几何均值比随着***剂量的增加而减少，范围是***.的300% 到 100%。
*** 和代谢物 N1979 尿液药代动力学
*** 和 N1979的尿液排泄，在第2组第1天受试者葡萄糖醛酸代谢物被评估。
•***的肾脏清除率低至1.17 L/h,，这大约是健康受试者肌酐清除率的20％，并且24小时内***低血浆浓度表明，对于原型药物总体清除率，代谢和/或其他非肾脏清除率是主要原因。
•••N1979肾脏清除率几何均值是3.67 L/h。
• ***的25 mg剂量（第2组第1天）约1.17 mg的***，大约5%未改变的原型药物通过尿液排出。
•被排除的N1979的几何平均质量是19.1 mg，大约是25mg剂量组的50%。
•25 mg剂量组55%（第2组，第1天）被排除在尿液中，50%是N1979，5%是没有变化的原型药物；
•这些结果表明***到N1979经历了广泛的新陈代谢，随后被排出在尿液中，约占剂量的50%。
安全性结论：
•多次递增剂量的***在普通健康志愿者中有很好的耐受性；
•频数最多的不良事件是接触性皮炎（38例受试者），头痛（8例受试者），和头晕（4例受试者）。SOC皮肤和皮下组织疾病的发生率最高，接触性皮炎事件是被认为与心电图和遥测评估相关的导线放置有关，SOC神经系统疾病显示出下一个最高的不良事件发生频率。
•这里没有严重不良事件，或与研究药物相关的不良事件导致停止和中断，所有的不良事件在研究完成之前被解决。
•心电图和动态心电图检查结果是互补的，在两种情况下，*** 500 mg试验中显示出轻微的心率增加，与安慰剂组没有明显差异。心脏加速的趋势仅仅与高剂量组有关，在增加时间或剂量趋势一致的情况下没有显示出药效学的效果。
•总体而言， ***-1H-01（SNO-2）心电图和动态心电图结果证明***具有强大的心脏安全性。
•在平均QTcF值变化中未发现剂量组趋势，回归分析显示QTcF改变与***浓度或代谢物N1979浓度无关。
•临床实验室结果，肺活量测定，生命体征或体格检查数据无临床上显著趋势。
后记：我此时此刻是翻译官，我此时此刻只能做翻译。没有什么是不可能的，保持专注度；我目前的翻译速度一篇文献的前几篇是8小时1页，主要耗时在专业名词上，在累计了专业名词后翻译速度是在8小时3页。
2021年5月13日星期四
专业名词积累
P3
1、 medical review错误的翻译为医药回顾，正确的是医学审查，
2、12-lead ECG measurements，12导联ECG测量。
3、ambulatory：move
4、Hematology：blood
5、urinalysis:bladder（toilet,body）, the waste liquid that collects in the bladder and that you pass from your body，analysis of urine, urinalysis;
6、concomitant：merge
7、hemoglobin oxygen saturation by pulse oximetry, 有没有认识的，oxygen，pulse
Hemoglobin：blood red egg white；
Saturation：饱和度
Oximetry：血氧仪
8、spirometry
9、telemetry：the process of using special equipment to send, receive and measure scientific data over long distances。
P3
10、inferential statistical analyses
11、Formal ；猜测正式的
12、performed，do
13、feasibility：likely to be achieved；this plan is feasibility.
14、sufficient,错译为有效性，正译为足够的；
15、derived: 推导
16、noncompartmental methods：非房室模型方法
17、plasma concentrations：血浆浓度
P3
18、Intensive：repeat
19、Triplicate：一式三份
20、Centralized：集中的
21、Cardiac：心脏病
22、cardiologists：心脏病专家
23、Prematurely：in advance
24、Caucasian ：White people
25、Cohort：group
26、each comprising:each group
P4
Pharmacokinetics resulted in rapid absorption
27、Oral:drink
28、Indicated:show
29、Peak：high
30、Rapid：quickly
31、post dose：
P5
32、the appearance of :……的出现
33、cohorts：group
34、In contrast to Day 1：compare
35、in geometric mean：trangal and square are geometric
36、roughly：
37、proportional：ration
38、terminal：end
P6
dependent upon the sampling chedule翻译错误，正确为取决于采样时间表
P7
likely owing to the shorter duration of *** administration in these 2 cohorts.
Duration:during
Owing：归咎于
and no events emerged that were more prevalent on *** than placebo
并且没有事件出现更加广泛在***超过安慰剂。
The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is
formation rate-limited with increase in dose.
附上原文：
CLINICAL STUDY REPORT
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of *** in Healthy Subjects
DCR study code: 13172
Sponsor study code: ***-1H-01 (SNO-2)
IND number: 119145
***: Clinical Phase 1 Study
Indication studied: Safety, tolerability, pharmacokinetics
Studied period: 16 February 2014 (first subject screened) – 11 November 2014 (last follow-up)
SPONSOR Nivalis Therapeutics, Inc. (formerly N30 Pharmaceuticals)
3122 Sterling Circle, Suite 200
Boulder, CO 80301, USA
Sponsor’s Contact Robert Hopkins, DVM, MS
Phone: +1 (720) 945-7716
Fax: +1 (303) 440-8399
INVESTIGATOR DaVita Clinical Research
11750 W. 2nd Place, Suite 300, Lakewood, CO 80228 USA
Investigators Chris Galloway, MD
Phone: +1 (303) 566-3100
Fax: +1 (303) 542-7300
Project Manager Marla Elhard, BSN, RN
Phone: +1 (303) 566-3005
Fax: +1 (855) 544-8170
AUTHORS Christopher A. Graybill, PhD, Medical Writer (DaVita)
Scott Brantley, PhD, Pharmacokinetic Scientist (Nuventra)
Eugene R. Heyman, PhD, Senior Biostatistician (Cardiocore)
Daniel B. Goodman, MD, Vice President and Medical Director
(Cardiocore)
Greg Ginn, MS, Biostatistician (DaVita)
Date of this report: 18 September 2015
This study was performed in compliance with the principles of Good Clinical Practice
(GCP), including the archiving of essential documents. This report was written in
compliance with the International Conference on Harmonization (ICH) guidelines.
CLINICAL STUDY REPORT
Nivalis Therapeutics, Inc.; ***-1H-01 (SNO-2)
18 September 2015
Confidential
2 SYNOPSIS
Study Title A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending
Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of *** in
Healthy Subjects
Study Code
DCR study code: 13172
Sponsor study code: ***-1H-01 (SNO-2)
IND number: 119145
Sponsor: Nivalis Therapeutics, Inc. (previously known as N30 Pharmaceuticals, Inc.)
3122 Sterling Circle, Suite 200, Boulder, CO 80301 USA
Sponsor’s Contact: Robert Hopkins, DVM, MS
Study Center: DaVita Clinical Research
11750 W. 2nd Place, Suite 300, Lakewood, CO 80228 USA
Project manager: Marla Elhard, BSN, RN
Investigator: Christopher Galloway, MD
Publication: None at time of writing this report
Study Period: Date of first screening to last follow-up: 16 February 2014 – 11 November 2014
Clinical Phase: Phase 1
Objectives
Primary Objective:
• To assess the safety and tolerability of escalating, multiple doses of *** in healthy subjects.
Secondary Objective:
• To assess the pharmacokinetics (PK) of *** and its primary metabolite, N91288, following multiple doses.
Methodology
Design:
This was planned as a double-blind, randomized, placebo-controlled, multiple ascending dose study; however, two single dose cohorts were also added. In the multiple ascending dose portion of the study, at least 4 ascending cohorts were planned with 8 subjects per cohort (6 active, 2 placebo). Each subject underwent screening (Day -28 to Day -3) and, if eligible, returned to the unit on Day -1 and eligibility was reconfirmed. Eligible subjects received an oral dose of investigational medicinal product (IMP), ***, or placebo once daily on Study Days 1 through 14 and were followed for safety while housed in the clinical research unit (CRU) until they were discharged on Day 15. Pharmacokinetics were followed from Study Day 1 through the morning of Study Day 16.Participation of an individual subject may have lasted approximately 49 days from the time of screening until the end-of-study follow-up call. A Safety Monitoring Committee (SMC) reviewed the safety data after completion of each cohort and decided whether to proceed to the next planned ascending dose cohort, modify the planned dose,repeat a dose, or stop the study according to the stopping rules outlined in the protocol.
The single dose cohorts also included 8 subjects per group (6 active, 2 placebo) and assessed single dose PK and effects of food intake, respectively.
Treatments:
• *** (10, 50, 250, and 500 mg) capsules, administered orally once daily for either 14 days (multiple dose cohorts) or one time (single dose cohorts)
• Matched placebo capsules, administered orally once daily
Procedures and Assessments:
Eligibility screening
Consisting of medical history, demographic information, prior and concomitant medications, physical examination, physical measurement (height, weight, body mass index [BMI]), 12-lead electrocardiogram (ECG) evaluation, 48-hour ambulatory ECG arrhythmia (Holter monitoring) assessment, vital signs
measurements, clinical laboratory tests (serology, hematology, blood chemistry,
urinalysis, pregnancy test for women), and drug and alcohol screen
PK assessments:
PK assessments of blood and urine for *** and N1979
Safety: 12-lead ECG recordings, adverse event (AE) monitoring, ambulatory ECG
(Holter), clinical safety laboratory tests, concomitant medications, physical
examinations, hemoglobin oxygen saturation by pulse oximetry, pregnancy testing,
spirometry, telemetry, vital signs, weight
Main Criteria for Inclusion
Age: 18-55 years, inclusive
BMI: ≥ 19.5 kg/m2 and ≤ 32.0 kg/m2
Subjects: Healthy Caucasian male and female subjects without a history of clinically
significant cardiac findings
Study Medication
Active substance: ***
Dosage form: Capsules
Strength/Lot number: 5 mg/N454451
Strength/Lot number: 25 mg/N454891
Strength/Lot number: 50 mg/N456044
Manufacturer: Norwich Pharmaceuticals (Norwich, NY)
Name: Placebo
Dosage form: Capsules
Lot number: N454450
Manufacturer: Norwich Pharmaceuticals (Norwich, NY)
Criteria for Evaluation/Endpoints
Pharmacodynamics: Not applicable.
Pharmacokinetics: This was a double-blind, randomized, placebo-controlled, multiple ascending dose study. Four ascending dose, 10, 50, 250 and 500 mg cohorts were studied with 8 subjects per cohort (6 active, 2 placebo).Each subject received an oral dose of investigational medicinal product (IMP), ***, or placebo once daily on
Study Days 1 through 14 and was followed for safety and pharmacokinetic (PK) assessments.
Plasma PK The Day 1 PK
parameters determined from the *** concentration-time data for the first dose included maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), area under the concentration-time curve calculated from time 0 to the last quantifiable concentration (AUC0-t) and to infinity (AUCinf), and terminal elimination half-life (T½). Additionally, oral clearance (CL/F) and apparent volume of distribution (Vz/F) were estimated. The steady-state PK parameters from the
*** on Day 14 concentrationtime data included: Cmax, Tmax, t½, AUC0-12, AUC0-τ, CLss/F, and accumulation ratio (Racc) were calculated.
*** undergoes glucuronidation, primarily to N1979, the O-glucuronide representing >95% of total glucuronide metabolites measured. N91288, the acyl-glucuronide was a minor component representing <3% of total. The metabolite pharmacokinetic parameters were determined from the total N1979 and N91288 plasma concentrations and are referred to as N1979, the primary metabolite in the SNO-2 PK report and throughout this document. The N1979 concentration-time data for the first dose on Day 1 included: Cmax, Tmax, t½, AUC0-24, AUCinf, and metabolite to parent (M/P) ratio. The steady-state PK parameters from the N1979 Day 14 concentration-time data included: Cmax, Tmax, t½, AUCtau, Racc, and M/P ratio. The terminal elimination half-life was estimated by log-linear regression of the plasma concentrations during the terminal phase on a logarithmic scale, using at least three time points.
Urine PK *** and metabolite (N1979) PK parameters derived from Cohort 2 on Day 1 were renal clearance (CLr) and cumulative amount of study drug recovered in urine (Ae0-t). In addition, combined parent and metabolite results are reported as total percent of dose excreted in urine.
Safety: Safety assessments were based on medical review of AE reports and the results of 12-lead ECG measurements, ambulatory ECG (Holter), clinical safety laboratory tests (including hematology, clinical chemistry with CRP, and urinalysis), concomitant medications, physical examinations, hemoglobin oxygen saturation by pulse oximetry, pregnancy testing, spirometry, telemetry, vital sign measurements, and weight.
Statistical Methods
Sample Size Determination: This was an exploratory PK study and, therefore, was not powered for inferential statistical analyses. Formal sample size calculations were not performed. The number of subjects was chosen based on feasibility and was considered sufficient to meet the study objectives.
Pharmacokinetic Parameters: PK parameters for *** and N1979 were derived using noncompartmental methods employing WinNonlin® Phoenix version 6.3 (Pharsight, St. Louis, MO). The PK parameters were estimated from the plasma concentrations using standard methods of noncompartmental analysis and were
calculated using actual collection times, and PK parameters were compared using analysis of variance.
Safety Parameters: AEs were tabulated; clinical laboratory tests, 12-lead ECG data, vital signs data, and physical examinations data were summarized descriptively and changes from Baseline were described. Analysis of ECG data (with intensive, triplicate measurements at 3 timepoints on Days 1-2 and Days 14-15 in addition to single measurements at other timepoints) included heart rate rhythm, QRS axis, PR interval, QRS duration, RR interval, and QT interval; QTcF was calculated. All ECGs were evaluated by qualified, centralized cardiac safety cardiologists.
Results
Subject Disposition
A total of 49 subjects were randomized into the study, and 47 subjects (96%) completed the study. Two subjects discontinued the study prematurely for personal reasons (unrelated to the study). Of the 49 total subjects, 37 were male and 12 were female. All subjects were Caucasian. The mean age (±SD) of subjects was 39.1 (11.4) years.
*** Exposure
The following describes the assignment of study subjects to cohort and dose:
Multiple-dose (14 days of dosing) cohorts, each comprising 6 subjects on active *** and 2 subjects on placebo, with a total of 24 subjects dosed with ***, and 9 with placebo (including 1 replacement subject).
• Cohort 1: 10 mg
• Cohort 2: 50 mg
• Cohort 3: 250 mg
• Cohort 4: 500 mg
Single dose cohorts, each comprising 6 subjects on active *** and 2 subjects on placebo:
• Cohort 2a: 50 mg
• Cohort 5: 250 mg (dosed with high-fat meal)
Pharmacokinetics
Pharmacokinetics Summary Oral administration of *** from 10 to 500 mg once daily for 14 days resulted in rapid absorption as indicated by the peak concentrations achieved within 2 hours post dose for all dose groups.
The geometric mean Cmax values increased in a roughly dose proportional manner. Similarly, the AUC0-tau increased in a slightly greater than dose proportional manner. Administration of 250 mg dose of *** with high-fat food resulted in a Tmax of 4 hours relative to 1.5 hours in fasted state. However, *** Cmax and AUC0-t values relative to those at fasted state were within 90%, indicating minimal effects of food on *** PK.Geometric mean estimates of the terminal phase half-life (t½) were longer at lower doses with values of 10.5 to 14.9 hours for the low doses, and approximately 5 hours of the high dose groups, 250 and 500 mg doses. The geometric mean clearance at steady-state ranged between 13.9 and 23.6 L/h for all dose groups, with a dose dependent decrease in clearance noted in the linearity analysis. The geometric mean of the exposure accumulation ratios, Racc(AUC) and Racc(Cmax), was minimal, ranging >1.2 to >1.33, respectively for all dose groups. This indicates
that *** displays minimal accumulation following repeat once-daily dosing at low doses and no accumulation at the highest dose tested.
*** underwent rapid and extensive metabolism via glucuronidation to two inactive metabolites, following oral administration of 10 to 500 mg once daily. The metabolite concentrations were approximately 100% to 300% of *** plasma concentrations. Plasma metabolite concentrations were measured as a sum of N1979, the O-glucuronide, and N91288, the acyl glucuronide. N1979 concentrations were >95% and N91288 concentrations were <5% of the total sum. Therefore, the metabolite PK values are reported as that of N1979.
N1979 appearance was relatively rapid, with peak concentrations reached in less than 4.0 hours for all cohorts.
The Cmax and AUCtau values increased in a less than dose proportional manner. The terminal phase half-life (t½) was larger (10.4 – 11.6 hours) at lower doses, and smaller (~5 hours) for the high doses. The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is formation rate-limited. The
exposure accumulation ratios, Racc(AUC) and Racc(Cmax), ranged from 0.9 to 1.3, indicating negligible accumulation of metabolite exposure with multiple dosing. High-fat food resulted a Tmax of 5 hours relative to 3 hours in fasted state. However, N1979 Cmax and AUC0-t values were slightly greater (106% - 101%) relative to those at fasted state, indicating minimal effects of food on N1979 PK.
The urinary excretion of *** and N1979, the glucuronide metabolite, were evaluated on Day 1 in Cohort 2 subjects. *** and N1979 exhibited a low renal clearance of 1.31 L/h and 3.67L/h, respectively. This represents roughly 20% and 50% of the creatinine clearance of an average healthy adult for *** and N1979,
respectively. Overall, 55% of the *** dose was excreted in the urine over 24 hours, 5% as *** and 50% as metabolites (N1979 and N91288). Due to the low renal clearance of *** and the relatively low plasma concentrations of *** at 24 hours, it appears that metabolism and/or other non-renal clearance routes of elimination (possibly biliary) are primarily responsible for the overall clearance of the parent drug. *** Plasma Pharmacokinetics Following oral administration of *** on Day 1, plasma *** concentrations peaked relatively rapidly with median Tmax values ranging between 1.50 and 5.00 hours across all cohorts. *** remained quantifiable in plasma 24 hours post-dose in all subjects. Subjects in Cohort 2 were inadvertently dosed 25 mg on Day 1 instead of planned 50 mg; therefore, Cohort 2a was added to receive a single 50 mg dose. The geometric mean Cmax values increased with an increase in dose from 33.0 ng/mL at 10 mg, to 111 ng/mL, 245 ng/mL, 1810 ng/mL, 1600 ng/mL, and 3840 ng/mL at the 25 mg, 50 mg, 250 mg (fasted), 250 mg (fed), and 500 mg dose levels, respectively. The geometric mean %CV for Cmax ranged from 14.0% to 57.8%, for the 10 mg to 500 mg dose levels. Similarly to Cmax, AUC values increased with an increase in dose. The geometric mean AUClast values were 327 h*ng/mL, 893 h*ng/mL, 1530 h*ng/mL, 12000 h*ng/mL, 10300 h*ng/mL, and 32400 h*ng/mL for the 10 mg 25 mg, 50 mg, 250 mg (fasted), 250 mg (fed), and 500 mg dose levels, respectively. The geometric mean AUCinf values ranged from 357 h*ng/mL, to 32500 h*ng/mL for the 10 mg to 500 mg dose levels.*** exposure parameters on Day 1 (Cmax, AUClast, and AUCinf) increased in a linear and slightly greater than dose proportional manner at the highest dose. The apparent clearance (CL/F) of *** appeared to be relatively
independent of dose for the 10, 25, and 50 mg dose levels but was slightly lower for the 250 and 500 mg dose levels. Administration of *** within 5 minutes of a high-fat meal resulted in mean Cmax and AUC values roughly 15% lower than those when *** was administered to fasting subjects.
By Day 7, all but one subject (in the 50 mg Cohort) had quantifiable pre-dose *** concentrations. Day 7 PK parameter estimates are less reliable since relatively fewer plasma samples were collected on Day 7 compared to Days 1 and 14. Therefore, the Day 7 PK values should be used for qualitative, rather than quantitative, purposes.
The geometric mean Cmax values increased in a slightly greater than dose proportional manner from 67.9 ng/mL to 6200 ng/mL over the 10 to 500 mg dose range. Geometric mean estimates of the terminal phase half-life (t½) decreased with increasing dose from 8.03 to 4.71 hours for the 10 to 500 mg doses. Consistent with Cmax, AUC0-tau increased in a greater than dose-proportional manner, with geometric means of 442 h*ng/mL to 40800 h*ng/mL for the 10 mg to 500 mg cohorts.
By Day 14, all subjects had quantifiable pre-dose *** concentrations. Compared to Day 1, the appearance of *** was more rapid, with median Tmax values less than 2.0 hours for all cohorts. In contrast to Day 1, the increase in geometric mean Cmax values was roughly dose proportional from 84.3 ng/mL to 5800 ng/mL for the 10 mg to 500 mg cohorts. Consistent with Day 1, the AUC0-tau increased in a slightly greater than dose proportional manner. Geometric mean estimates of the terminal phase half-life (t½) were longer at lower doses with values of 14.9 and 10.5 for the 10 and 50 mg doses, respectively, and 5.58 and 5.21 for the 250 and 500 mg doses, respectively. The longer half-lives at the lower dose groups are likely dependent upon the sampling schedule as the 10 and 50 mg dose levels were the only ones sampled out to 48 hours. The geometric mean clearance at steady-state ranged between 13.9 and 23.6 L/h for all dose groups, with a dose dependent decrease in clearance noted in the linearity analysis. The geometric mean of the exposure accumulation ratios (Racc(AUC)) was >1.2 for the 10, 25, and 250 mg cohorts, but was 1.01 for the 500 mg cohort. This indicates that *** displays minimal accumulation following repeat once-daily dosing at low doses and no accumulation at the highest dose
tested. The geometric mean peak concentration accumulation ratios (Racc(Cmax)) were >1.33 for all doses tested,indicating that peak concentrations increased to modest extent with repeat once-daily dosing.N1979 Metabolite Plasma Pharmacokinetics Following oral administration of *** on Day 1, plasma
concentrations of N1979, the inactive metabolite, appeared relatively rapidly with median Tmax values around 4.0 hours. N1979 remained quantifiable in plasma 24 hours post-dose in all subjects, indicating the potential for accumulation with multiple dosing. Administration of *** within 5 minutes of a high-fat meal resulted in roughly 6% higher mean N1979 Cmax and approximately equal mean N1979 AUCinf values compared to the values for fasting subjects. Appearance of N1979 was quicker in the fasted state, with a median Tmax value 2.0 hours earlier than the fed state. Overall, the geometric mean metabolite to parent ratios were ≥ 1.40, with the largest ratios seen at the lower (10-50 mg) doses.
By Day 7, all but one subject (in the 50 mg Cohort) had quantifiable pre-dose N1979 concentrations. Due to the relatively small (compared to Days 1 and 14) number of plasma samples on Day 7, the PK parameter estimates are likely less reliable than those on other days. For this reason, these values should be used for qualitative, rather than quantitative, purposes. The geometric mean Cmax values increased in a less than dose proportional manner from 359 ng/mL to 9580 ng/mL for the 10 and 500 mg cohorts, respectively. Geometric mean estimates of the terminal phase half-life (t½) were consistent between doses, with values between 5.61 and 6.09 hours. Consistent with Cmax, AUC0-24 increased than dose-proportional manner, with geometric means of 2020 h*ng/mL,8950 h*ng/mL, 47200 h*ng/mL, and 83400 h*ng/mL for the 10 mg, 50 mg, 250 mg, and 500 mg Cohorts,respectively. As seen on Day 1, the geometric mean metabolite to parent ratios were higher following the lower (10 and 50 mg) doses of ***. The geometric mean metabolite to parent ratio for Cmax at the 500 mg dose level was less than unity (0.973), whereas the remainder of the ratios were greater than 1.
By Day 14, all subjects had quantifiable pre-dose N1979 concentrations. The appearance of N1979 was relatively rapid, with median Tmax values less than 4.0 hours for all cohorts. The increase in geometric mean Cmax values was less than dose proportional from 389 ng/mL to 8270 ng/mL for the 10 mg to 500 mg cohorts, respectively. AUCtau increased in a less than dose proportional manner with geometric mean values of 2110 h*ng/mL to 69600 h*ng/mL for the 10 to 500 mg dose levels, respectively. Geometric mean estimates of the terminal phase half-life (t½) were larger at lower doses with values of 11.6 and 10.4 at 10 and 50 mg doses, respectively, and 5.77 and 5.74 at the 250 and 500 mg doses, respectively. The longer half-lives for the lower dose groups are likely dependent upon the sampling schedule as the 10 and 50 mg dose levels were the only ones sampled out to 48 hours. The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is formation rate-limited.
Since the terminal elimination half-life of a metabolite should not be shorter than the terminal elimination half-life of the parent, the terminal elimination half-life of N1979 is likely underestimated in many subjects. The geometric means of the exposure accumulation ratios (Racc(AUC)) ranged from 0.880 to 1.09, indicating negligible
accumulation of metabolite exposure with multiple dosing. The peak concentration accumulation ratios (Racc(Cmax)) ranged from 0.907 to 1.33, further indicating the lack of accumulation. The geometric mean metabolite to parent ratios on Day 14 ranged between 0.898 and 2.91 for Cmax and between 1.22 and 3.14 for AUCtau, indicating systemic exposure to N1979 is between 100% and 300% of that of ***.
Urine Pharmacokinetics The urinary excretion of *** and N1979, the glucuronide metabolite, was evaluated on Day 1 in Cohort 2 subjects. Approximately 5% of the 25 mg *** dose (Cohort 2, Day 1) was eliminated as unchanged *** in the urine, resulting in a low renal clearance of 1.31 L/h, which is roughly 20% of the creatinine clearance of an average healthy adult. Due to the low renal clearance of *** and the relatively low plasma concentrations of *** at 24 hours, it appears that metabolism and/or other non-renal clearance routes of elimination (possibly biliary) are primarily responsible for the overall clearance of the parent drug.
A geometric mean mass of N1979 excreted in the urine was 19.1 mg, which represents approximately 50% of the 25 mg dose. The geometric mean renal clearance of N1979 was 3.67 L/h that is roughly 50% of the creatinine clearance of an average healthy adult (7.2 L/h).These results suggest that N1979 primarily undergoes renal clearance, as indicated by the high percent of dose eliminated and the greater renal clearance estimates as compared to those of the parent drug.
Overall, 55% of the *** dose was excreted in the urine over 24 hours, 5% as parent and 50% as metabolites (N1979 and N91288).
Safety
Adverse Events Forty (40) of 49 total subjects (81.6%) reported at least 1 TEAE during study participation. All subjects (those receiving *** and placebo for 14 days) in Cohorts 1 through 4 reported a TEAE, whereas fewer subjects in Cohort 2a (16.7%) and Cohort 5 (66.7%) reported TEAEs, likely owing to the shorter duration of *** administration in these 2 cohorts. *** was well tolerated, all TEAEs were mild in severity, no dose related increases in the incidence of adverse events were noted, and no events emerged that were more prevalent on *** than placebo. A maximum tolerated dose was not identified because no dose limiting toxicities were identified at the highest dose tested.Cohorts 1 – 4 and combined placebo treated subjects (14-day dosing) The most frequently reported TEAEs were contact dermatitis, headache, and dizziness. Contact dermatitis occurred in all subjects who received *** or placebo in Cohorts 1 through 4; headache occurred in 3/6 (50%) subjects in Cohorts 1 and 2 but decreased to 0/6 and 1/6 (17%) in Cohorts 3 and 4 compared with 1/9 (11%) subjects on placebo; dizziness occurred in 2/6 (33%) subjects in Cohort 2 and 2/9 subjects on placebo (22%). Of note, the contact dermatitis was considered to be secondary to the ECG leads in all subjects in which it was reported. Due to the frequency of contact dermatitis and headache, the SOC Skin and Subcutaneous Tissue Disorders displayed the highest frequency of TEAEs, and the SOC Nervous System Disorders displayed the next highest frequency of TEAEs. All TEAEs were mild in severity.Nineteen subjects (38.8%) reported TEAEs that were causally related to the study drug. A higher percentage of these events were observed in Cohorts 1 and 2 (67%) than in Cohorts 3 and 4 (33%). In the latter two cohorts, the incidence was less than on placebo (56%). The most frequently reported adverse events that were attributed to study drug were: headache occurring in a total of 7 subjects (2 [33%], 1 [17%], 0, 1 [17%], in Cohorts 1, 2, 3, and 4, respectively, and 1 [11%] on placebo); dizziness occurring in a total of 4 subjects (2 [33%] in Cohort 2 and 2 [22%] on placebo); aphthous stomatitis occurring in 3 subjects (2 [33%] in Cohort 1 and 1 [11%] on placebo); and constipation occurring in 2 subjects (1 [17%] in Cohort 2 and 1 [11%] on placebo). All other causally related TEAEs were reported by only 1 subject. There were no SAEs, no TEAEs resulting in study drug discontinuation or interruption, and no AEs resulting in death.
There were no clinically significant trends in 12-lead ECG data, clinical laboratory results, or other safety data. Cohorts 2a and 5 (single dose administration) Contact dermatitis was the most frequently reported event, occurring in 4 (67%) subjects in Cohort 5 and 1 (25%) subject on placebo. The only other event reported was headache occurring in 1 subject each in Cohort 2a and on placebo.
Cardiovascular Safety Findings for ECG data were uniformly negative, with the exception of a minimal effect on heart rate (HR): all treatment groups, including Placebo, had increases of HR on Day 14. The 500 mg dose of *** was associated with the highest HRs and greatest increases, but the increases were not markedly different from the other dose groups or Placebo. There were no consistent trends for higher values of change with increasing dose of *** or increasing concentrations of *** or N1979.No disturbance of AV conduction was associated with administration of ***. There were no consistent trends of intra-ventricular conduction to vary over the observation period. Cardiac repolarization was not affected by administration of ***. There was no relationship between change of QTcF and plasma concentrations of ***, N91288, or N1979.
Holter monitoring findings were consistently negative, again with the exception of a minimal effect on heart rate. Mean, maximum, and minimum 24-hour HR values were unchanged during treatment, although mean hourly HR values showed minor increases from Baseline late on Day 1 for all treatment groups. On Day 14, hourly values of HR showed minimal elevation for subjects in the *** 500 mg group, but no consistent dose trends were noted and changes were not clearly different from Placebo.
Findings for atrial ectopy were normal. There were a small number of supraventricular tachycardia episodes, all 22 beats or fewer in duration with a maximum rate of 147 bpm. Significant ventricular ectopy was not noted during the study, with the exception of 2 brief episodes of ventricular runs in a single subject on *** 50 mg on Day 2. The maximum duration was 6 beats and maximum overall heart rate was 99 bpm. Holter diagnostic findings were unremarkable.
Mean QTcF values were in a narrow range of 398.5 to 426.8 msec. Little variation was noted across the time course of observations. Mean changes of QTcF from Baseline were quite similar for all treatments, but did show a tendency to greater decreases on Day 1 Hour 2 to Hour 8 and on Day 14 Hour 4. The mean values of change were minimal overall ranging from -18.6 msec (250 mg group, Day 14, Hour 4) to 9.9 msec (10 mg group, Day 10, predose). No dose group trends were seen. Regression analysis showed no relationship of change of QTcF with concentration of *** or, separately, with the concentration of N1979. The slopes of the regressions were nearly flat, 0.220 and 0.235, and had non-significant p-values of 0.71 and 0.65. Value of predicted change of QTcF for the lowest to highest observed concentration were nearly identical, -0.7 and 0.1 msec, respectively for *** and from -0.8 and 0.1 msec, respectively for N1979.
The ECG and Holter heart rate findings were complementary and, in both cases, showed minor increases of heart rate during *** 500 mg treatment, not clearly different from placebo. The trend for the cardiac acceleration was associated solely with the highest dose without indication of a pharmacodynamic effect either for timing of the increases or for a consistent dose trend.
Conclusions
The primary objective of Clinical Study ***-1H-01 (SNO-2) was to evaluate the safety and tolerability of *** administered as a once daily oral capsule for 14 days in healthy subjects. A secondary objective was to evaluate the PK of *** in this subject population. Of the 36 subjects who were randomized to receive ***,
all were included in the PK analysis of *** and its metabolite, N1979.
*** Plasma PK Conclusions
The oral administration of *** at 10, 50, 250, and 500 mg once daily for 14 days results in the following *** PK:
• *** undergoes rapid absorption as indicated by a Tmax of less than 2 hours for all cohorts.
• The geometric mean Cmax values increased roughly dose proportional for the 10 mg to 500 mg cohorts.
• Similarly, the geometric mean AUCtau at steady state increased in a slightly greater than dose proportional manner for the 10 mg to 500 mg cohorts.
• Geometric mean estimates of the terminal phase half-life (t½) were longer at lower doses with values of 14.9 and 10.5 for the 10 and 50 mg doses, respectively, and 5.58 and 5.21 for the 250 and 500 mg doses, respectively.
• *** reached steady state before Day 14, possibly before or by Day 7.
• The geometric mean clearance at steady-state ranged between 13.9 and 23.6 L/h for all dose groups, with a dose dependent decrease in clearance, possibly due to saturation of metabolism.
• *** displays minimal accumulation (Racc(AUC) >1.2) following repeat once-daily dosing at low doses and no accumulation at the highest dose tested.
• Similarly, the geometric mean peak concentration accumulation ratios (Racc(Cmax)) were >1.33 for all doses tested, indicating that peak concentrations increased slightly with repeat once-daily dosing.
• Administration of 250 mg of *** with a high-fat meal did not affect the mean Cmax and AUC values, which were roughly 15% lower than the levels in fasting subjects.
N1979 Metabolite Plasma PK Conclusions
The oral administration of *** at 10, 50, 250 and 500 mg once daily for 14 days resulted in the rapid and extensive metabolism of *** via glucuronidation to two inactive metabolites, mainly to O-glucuronide N1979 (>95% of total metabolite) and, to a lesser extent (<5% of total), to N91288, the acyl glucuronide. The PK values for
the primary metabolite N1979 following repeat oral dosing of *** at 10 to 500 mg are summarized below.
• The appearance of N1979 was relatively rapid, with median Tmax values less than 4.0 hours for all cohorts.
• The geometric mean Cmax values increased in a less than dose proportional manner for all cohorts, suggesting possible saturation of metabolism.
• Similarly, the geometric mean AUCtau increased in a less than dose proportional manner with increase in dose.
• N1979 geometric mean estimates of the terminal phase half-life (t½) decreased with increase in dose.
• The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is formation rate-limited with increase in dose.
• N1979 shows negligible accumulation of exposure with multiple dosing as shown by the geometric means of the exposure accumulation ratios (Racc(AUC) and Racc(Cmax)).
• The geometric mean metabolite to parent ratios for Cmax and AUCtau decreased with an increase in N911115 dose, ranged from 300% to 100% of that of ***.
*** and N1979 Metabolite Urine PK The urinary excretion of *** and N1979, the glucuronide metabolite, was evaluated on Day 1 in Cohort 2 subjects.
• Renal clearance of *** was low 1.17 L/h, which is roughly 20% of the creatinine clearance in healthy subjects and the relatively low plasma concentrations of *** at 24 hours suggest that metabolism and/or other non-renal clearance routes of elimination (possibly biliary) are primarily responsible for the overall clearance of the parent drug.
• The geometric mean renal clearance of N1979 was 3.67 L/h.
• Approximately 1.17 mg of ***, approximately 5% of the 25 mg of *** dose (Cohort 2, Day 1) was eliminated unchanged parent drug in the urine
• The geometric mean mass of N1979 excreted was 19.1 mg, which represents approximately 50% of the 25 mg dose.
• A total of 55% of the 25 mg dose (Cohort 2, Day 1) was eliminated in the urine, with 50% as N1979 and 5% as unchanged parent drug.
• These results suggest that *** undergoes extensive metabolism to N1979 which was subsequently eliminated in the urine, representing approximately 50% of the dose.
Safety Conclusions
• Multiple, ascending doses of *** were well tolerated in normal healthy volunteers.
• The most frequently reported TEAEs were dermatitis contact (38 subjects), headache (8 subjects), and dizziness (4 subjects). The SOC Skin and Subcutaneous Tissue Disorders displayed the highest frequency of TEAEs, where contact dermatitis events were thought to be related to the lead placement associated with ECG and telemetry assessments, and the SOC Nervous System Disorders displayed the next highest frequency of TEAEs.
• There were no SAEs or TEAEs resulting in study drug discontinuation or interruption. All TEAEs were resolved prior to study completion.
• The ECG and Holter heart rate findings were complementary and, in both cases, showed minor increases of heart rate during *** 500 mg treatment, not clearly different from placebo. The trend for the cardiac acceleration was associated solely with the highest dose without indication of a pharmacodynamic effect either for timing of the increases or for a consistent dose trend.
• Overall, Protocol ***-1H-01 (SNO-2) ECG and Holter results demonstrated robust cardiac safety for ***.
• No dose group trends were seen in change in mean QTcF values. Regression analysis showed no relationship of change of QTcF with concentration of *** or, separately, with the concentration of N1979.
• There were no clinically significant trends in clinical laboratory results, spirometry, vital sign, or physical examination data.
Date of report: 18 September 2015