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索拉非尼(多吉美)是什么

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甲苯磺酸索拉非尼片
  说明书
  请仔细阅读说明书并在医师指导下使用
  【药品名称】
  通用名称:甲苯磺酸索拉非尼片
  商品名称:多吉美
  英文商品名:Nexavar
  英文通用名:sorafenib
  英文名称:Sorafenib Tosylate Tablets
  汉语拼音:Jiabenhuangsuan Suolafeini Pian
  【成份】
  化学名称:4-(4-{3-[4-氯-3-(三氟甲基)苯基]脲基}苯氧基)-N2-甲基吡啶-2-羧酰胺-4-甲苯磺酸盐
  化学结构式:
  分子式:C21H16ClF3N4O3 • C7H8O3S
  索拉非尼化学式分子量:637.0
  【性状】
  本品为红色圆形片。
  【适应症】
  1、治疗不能手术的晚期肾细胞癌。
  2、治疗无法手术或远处转移的原发肝细胞癌。
  目前缺乏在晚期肝细胞癌患者中索拉非尼与介入治疗如肝动脉栓塞化疗(TACE)比较的随机对照临床研究数据,因此尚不能明确本品相对介入治疗的优劣,也不能明确对既往接受过介入治疗后患者使用索拉非尼是否有益(见【临床试验】项)。建议医生根据患者具体情况综合考虑,选择适宜治疗手段。
  【规格】
  0.2g
  【用法用量】
  推荐剂量
  推荐服用索拉非尼的剂量为每次0.4g(2×0.2g)、每日两次,空腹或伴低脂、中脂饮食服用。
  【服用方法】
  口服,以一杯温开水吞服。
  【治疗时间】
  应持续治疗直至患者不能临床受益或出现不可耐受的毒性反应。
  剂量调整及特殊使用说明
  对疑似不良反应的处理包括暂停或减少索拉非尼用量,如必需,索拉非尼的用量减为每日一次,每次0.4g(2×0.2g)。
  表1列出了根据皮肤毒性做相应的剂量调整的建议。
  皮肤不良反应分级 不良反应发生频率 建议剂量调整
  1级:麻痹,感觉迟钝,感觉异常,麻木感,无痛肿胀,手足红斑或不适但
  不影响日常活动 任何时间出现 继续使用本品,同时给予局部治疗以
  消除症状。
  2级:伴疼痛的手足红斑和肿胀,和/或影响日常生活的手足不适 首次出现 继续使用本品,同时给予局部治疗以消除症状。7天之内如果症状没有改善,见下
  7天之内症状没有改善或第二次、第三次出现 中断本品治疗直到毒性缓解至0-1级。当重新开始本品治疗时,减少至单剂量(每日0.4g) 第四次出现 终止本品治疗。
  3级:湿性脱皮,溃疡,手足起疱、疼痛或导致患者不能工作和正常生活的严重手足不适。 第一次出现或第二次出现 中断本品治疗直到毒性缓解至0-1级。当重新开始本品治疗时,减少至单剂量(每日0.4g)第三次出现 终止本品治疗。
  特殊人群
  儿童患者
  尚无儿童患者应用索拉非尼的安全性及有效性资料。
  老年人(65岁以上), 性别和体重不需根据患者的年龄(65岁以上)、性别或体重调整剂量。
  肝损害患者
  轻度和中度肝损害患者(Child-Pugh A和B)无需调整剂量。尚未进行重度肝损害患者(Child-Pugh C)应用索拉非尼的研究。
  肾损害患者
  轻度、中度或不需要透析的重度肾功能损害的患者无需调整剂量。尚未进行透析患者应用索拉非尼的研究。
  对于可能有肾损害危险的患者,建议对其体液平衡和电解质平衡进行监测。
  【不良反应】
  以下数据主要来自本品在晚期肝细胞癌和晚期肾细胞癌临床试验中获得的安全性数据,包括欧美和亚洲国家的数据(见【临床试验】项下)。
  因为临床试验是在广泛多样的条件下进行的,在某个临床试验中观察到的不良反应发生率不能与在其他临床试验中的发生率进行直接比较,也不能反映实际观察到的发生率。
  欧美关键的支持本品上市的临床研究的安全性数据:
  最常见的不良反应有腹泻,皮疹,脱发和手足皮肤反应(国际医学用语词典(MedDRA)对应为手足感觉不良综合征)。
  【禁忌】
  对索拉非尼或药物的非活性成分有严重过敏症状的患者禁用。
  【注意事项】
  本品必须在有使用经验的医生指导下服用。
  目前缺乏在晚期肝细胞癌患者中索拉非尼与介入治疗如TACE比较的随机对照临床研究数据,因此尚不能明确本品相对介入治疗的优势,也不能明确对既往接受过介入治疗后患者使用索拉非尼是否有益(见【临床试验】项)。建议医生根据患者具体情况综合考虑,选择适宜治疗手段。
  妊娠:育龄妇女在治疗期间应注意避孕。应告知育龄妇女患者,药物对胎儿可能产生的危害,包括严重畸形(致畸性),发育障碍和胎儿死亡(胚胎毒性)。孕期应避免应用索拉非尼。只有在治疗收益超过对胎儿产生的可能危害时,才能应用于妊娠妇女。
  在动物实验中已经发现索拉非尼有致畸性和胚胎-胎儿毒性(包括流产危险增加、发育障碍),并且这些危害作用在明显低于临床剂量时即出现。基于索拉非尼对多种激酶抑制的机理和动物实验结果,从而推测孕妇服用索拉非尼会危害胎儿。
  哺乳期妇女在索拉非尼的治疗期间应停止哺乳。
  皮肤毒性:手足皮肤反应和皮疹是服用索拉非尼最常见的不良反应。皮疹和手足皮肤反应通常多为NCI CTCAE 1到2级,且多于开始服用索拉非尼后的6周内出现。对皮肤毒性反应的处理包括局部用药以减轻症状,暂时性停药或/和对索拉非尼进行剂量调整。对于皮肤毒性严重或反应持久的患者需要永久停用索拉非尼。
  高血压:服用索拉非尼的患者高血压的发病率会增加。高血压多为轻到中度,多在开始服药后的早期阶段就出现,用常规的降压药物即可控制。应定期监控血压,如有需要则按照标准治疗方案进行治疗。对应用降压药物后仍严重或持续的高血压或出现高血压危象的患者需考虑永久停用索拉非尼。
  出血:服用索拉非尼治疗后可能增加出血机会。严重出血并不常见。一旦出血需治疗,建议考虑永久停用索拉非尼。
  华法林:部分同时服用索拉非尼和华法林治疗的患者偶发出血或INR升高。对合用华法林的患者应定期监测凝血酶原时间的改变、INR值并注意临床出血迹象。
  伤口愈合并发症:服用索拉非尼对伤口愈合的影响未进行正式的研究。需要做大手术的患者建议暂停索拉非尼,手术后患者何时再应用索拉非尼的临床经验有限,因此决定患者再次服用前应先从临床考虑,确保伤口愈合。
  心肌缺血和/或心肌梗死:在试验11213中,治疗相关的心肌缺血/心肌梗死在索拉非尼组的发生率(2.9%)高于安慰剂组(0.4%)。在试验100554中,治疗相关的心肌缺血/心肌梗死在索拉非尼组的发生率为2.7%,在安慰剂组的发生率为1.7%。不稳定的冠心病患者和近期的心肌梗死患者没有入组这两项试验。对于发生心肌缺血和/或心肌梗死的患者应该考虑暂时或永久停用索拉非尼的治疗。
  胃肠道穿孔:胃肠道穿孔较为少见。在服用索拉非尼的患者中报告出现胃肠道穿孔的不足1%。在一些病例中,胃肠道穿孔和腹腔内肿瘤无关。应停止本品治疗(见【不良反应】)。
  肝损害:没有重度肝损害患者(Child-Pugh C级)服用索拉非尼的研究资料。由于索拉非尼主要是经肝脏消除,其在肝功能严重受损的患者中的暴露量会升高。
  药物-药物相互作用:
  UGT1A1 途径:建议索拉非尼和通过UGT1A1途径代谢/清除的药物(如伊立替康)联合应用时,需谨慎(见【药物相互作用】)。
  多烯紫杉醇:既往研究结果显示,多烯紫杉醇(75mg/m2或100mg/m2)与索拉非尼(0.2g或0.4g每日两次给药)联合应用时(索拉非尼在多烯紫杉醇用药时停用三天),可导致多烯紫杉醇的AUC增加36%-80%。建议本品与多烯紫杉醇联合应用时,需谨慎(见【药物相互作用】)。
  对驾驶和机器操作的影响:目前尚无索拉非尼对驾驶和机器操作的影响的研究。没有证据显示索拉非尼会影响驾驶和机器操作能力。
  【孕妇及哺乳期妇女用药】
  妊娠
  尚无妊娠期妇女服用索拉非尼的足够临床资料。动物实验表明药物存在生殖毒性包括致畸性。索拉非尼和其代谢产物可通过大鼠的胎盘屏障,推测索拉非尼可抑制胎儿的血管生成。
  育龄妇女在治疗期间应注意避孕。如在孕期应用索拉非尼,应告知患者药物对胎儿可能产生的危害,包括严重畸形(致畸性),发育障碍和胎儿死亡(胚胎毒性)。
  孕期避免应用索拉非尼。只有在治疗收益超过对胎儿产生的可能危害时,才应用于妊娠妇女(见【注意事项】)。
  育龄妇女
  动物实验表明索拉非尼具有致畸性和胚胎毒性。治疗期间和治疗结束至少2周内应采用足够的避孕措施。
  哺乳
  目前尚未知索拉非尼是否可进入人类乳汁。动物实验表明索拉非尼和/或其代谢产物可进入到乳汁中。由于很多药物从乳汁中分泌,并且索拉非尼对婴儿的作用尚未研究,因此妇女在该药治疗期间应停止哺乳。
  生殖能力
  动物实验结果表明索拉非尼可损害男性和女性的生殖能力。
  【儿童用药】
  尚无儿童患者应用索拉非尼的安全性和有效性资料。
  【老年用药】
  不需根据患者的年龄(65岁以上)调整剂量。
  【药物相互作用】
  CYP3A4诱导剂:利福平与索拉非尼持续联合应用可导致索拉非尼的AUC平均减少37%。其他CYP3A4诱导剂如贯叶连翘(或贯叶金丝桃,俗称圣约翰草)、苯妥英、卡马西平、苯巴比妥和地塞米松等可能加快索拉非尼的代谢,因而降低索拉非尼的药物浓度。
  CYP3A4抑制剂:酮康唑是CYP3A4的强抑制剂,健康男性志愿者使用酮康唑每日一次连续7天,同时口服索拉非尼单剂量每日50mg,索拉非尼的平均AUC并未改变。所以CYP3A4抑制剂影响索拉非尼代谢的可能性很小。
  CYP2C9底物:华法林是CYP2C9的底物,通过比较服用索拉非尼和安慰剂的患者来评估索拉非尼对华法林的影响。与安慰剂组相比索拉非尼合用华法林的患者的平均PT-INR值并未改变。但患者合用华法林时应定期监测INR值。
  CYP 同工酶选择性底物:咪达唑仑、右美沙芬和奥美拉唑分别为细胞色素CYP3A4、CYP2D6和CYP2C19的底物。索拉非尼与上述三种药物联合应用不会改变它们的暴露量。这表明对于这些细胞色素P450的同工酶,索拉非尼既不是抑制剂也不是诱导剂。
  和其他抗肿瘤药物的相互作用:临床试验中,索拉非尼和其他常规剂量的抗肿瘤药物进行了联合应用,包括吉西他滨,奥沙利铂,阿霉素和伊立替康。索拉非尼不影响吉西他滨和奥沙利铂的药物代谢。
  紫杉醇(225mg/m2)及卡铂(AUC=6)伴随本品(每日两次,每次0.1g,0.2g或0.4g)使用时(在使用紫杉醇/卡铂前后,停用本品3天),不会对紫杉醇的药代动力学造成显著影响。
  索拉非尼和阿霉素联合应用时可引起患者体内阿霉素的AUC值增加21%。索拉非尼和伊立替康合用时,由于伊立替康活性代谢产物SN-38通过UGT1A1酶途径进一步代谢,两者合用导致SN-38的AUC升高67%-120%,同时伊立替康的AUC值升高26%-42%。与此相关的临床意义尚未知。
  多烯紫杉醇(75mg/m2或100mg/m2,每21天一次)与索拉非尼(在21天的治疗周期中,从第2天到第19天,0.2g或0.4g每日两次给药)联合应用时(索拉非尼在多烯紫杉醇用药时停用三天),可导致多烯紫杉醇的AUC增加36%-80%,Cmax提高16%-32%。建议本品与多烯紫杉醇联合应用时,需谨慎。
  【药物过量】
  尚无索拉非尼服用过量的特殊治疗措施。
  索拉非尼的最高剂量为每次0.8g,每日两次,在此剂量下所观察到的主要不良反应为腹泻和皮肤毒副反应。
  如怀疑服用过量,则应停药并对患者进行相应的支持治疗。
  【临床试验】
  肾细胞癌:
  在以下4个临床试验中进行了索拉非尼治疗晚期肾细胞癌的安全性及有效性研究:
  试验11213是一项III期、国际多中心、随机、双盲、安慰剂对照研究,包括了903名至少接受过一次化疗或免疫治疗的不能手术或转移性肾癌患者。主要研究终点是总生存期(OS)和无进展生存期(PFS),次要研究终点是肿瘤反应率(RR)。患者被随机分为两组,试验组索拉非尼0.4g,每日两次(N=451),对照组给予安慰剂(N=452)。两组的基线人口统计学特征是均衡的。接近一半的患者ECOG*评分为0,另一半的患者为MSKCC**低预后组(* ECOG:东部肿瘤协作组;** MSKCC:纽约斯隆•凯特琳纪念癌症中心)。
  影像学可见的血管侵犯和/或肝外播散
  最终分析显示:索拉非尼相对于安慰剂在总生存期(OS)方面的优势具有统计学意义(HR=0.69,P=0.00058,见表18和图4)。在预设的分层因素(ECOG评分、影像学可见的血管侵犯和/或肝外肿瘤扩散出现与否,以及地区)中,风险比支持索拉非尼优于安慰剂。索拉非尼组的肿瘤进展时间(TTP)值高于安慰剂组(HR:0.58,p=0.000007,见表18和图5)。亚组分析结果中,乙型肝炎病毒阳性(实验室检查结果)患者的总生存期见表19和图6;丙型肝炎病毒阳性(实验室检查结果)患者的总生存期见表20;既往接受过TACE治疗的患者总生存期见表21。
  表18:试验100554的有效性结果
  疗效参数 索拉非尼
  (N=299) 安慰剂
  (N=303) P值 HR
  (95% CI)
  总生存期(OS)[中位数,天
  (95% CI)]
  324
  (286, 405) 241
  (206, 276) 0.00058* 0.69
  (0.55, 0.87)
  肿瘤进展时间(TTP)**[中位数,天
  (95% CI)] 168
  (126, 210) 86
  (82, 120) 0.000007 0.58
  (0.45, 0.74)
  CI:置信区间,HR:风险比
  *在一项比较中,如果p值<0.0077,则可认为此项比较具有统计学意义(O’Brien Fleming停止边界)
  **根据RECIST标准判断的影像学进展
  图4:试验100554中总生存期(OS)的Kaplan-Meier曲线(意向治疗人群)
  图5:试验100554中肿瘤进展时间(TTP)的Kaplan-Meier曲线(意向治疗人群)
  表19:试验100554中乙型肝炎病毒阳性患者总生存期*
  索拉非尼组(N =40) 安慰剂组(N=31)
  中位总生存期(天) 359 186
  风险比(HR)
  (95% C.I.) 0.67
  (0.35, 1.31)
  *由于样本量有限,对亚组分析结果的解释应谨慎。
  图6:试验100554中乙型肝炎病毒阳性患者生存曲线
  表20:试验100554中丙型肝炎病毒阳性患者总生存期*
  索拉非尼组(N =93) 安慰剂组(N=84)
  中位总生存期(天) 426 241
  风险比(HR)
  (95% C.I.) 0.50
  (0.33, 0.78)
  *由于样本量有限,对亚组分析结果的解释应谨慎。
  表21:试验100554中既往接受过TACE治疗的患者总生存期
  索拉非尼组(N =86) 安慰剂组(N=90)
  中位总生存期(天) 362 302
  风险比(HR)
  (95% C.I.) 0.75
  (0.49, 1.14)
  *由于样本量有限,且存在基线不均衡因素,对亚组分析结果的解释应谨慎。
  【药理毒理】
  药理作用
  索拉非尼是多种激酶抑制剂,在体外可抑制肿瘤细胞增殖。
  索拉非尼抑制肿瘤细胞增殖,包括小鼠肾细胞癌、RENCA模型和无胸腺小鼠移植多种人肿瘤模型,并抑制肿瘤血管生成。
  毒理研究
  通过小鼠、大鼠、犬和兔评价了索拉非尼的临床前安全性。
  重复剂量毒性试验显示不同器官轻度至中度的改变(退化和再生)。
  幼年和发育期犬多次给药后可观察到对骨和牙齿的影响,包括索拉非尼剂量达600mg/m&sup2;体表面积时(相当于临床推荐剂量500mg/m&sup2;体表面积时的1.2倍)股骨骺板不规则增厚,此生长板附近骨髓细胞减少(200mg/m&sup2;/天)和牙质成分的改变(600mg/m&sup2;/天)。在成年犬未发现类似情况。
  致突变性:以哺乳动物细胞(中国仓鼠卵巢)进行了体外染色体畸变试验,索拉非尼在代谢激活时具遗传毒性。生产过程中某一中间体的体外细胞遗传学试验(Ames试验)结果为阳性,药品中其限度控制在0.15%以下。Ames试验和小鼠体内微核试验表明索拉非尼不具有遗传毒性(受试药物中此中间体含量为0.34%)。
  致癌性:未进行索拉非尼的致癌性试验。
  生殖毒性:未进行特异性动物生育力试验。重复用药毒性试验观察到动物的生殖器官改变,因此可预见药物对雄性和雌性生育力的损害。典型的改变包括大鼠睾丸、副睾、前列腺和精囊的退化和阻滞。当索拉非尼的日剂量达到150 mg/m&sup2;体表面积 (相当于临床推荐剂量500 mg/m&sup2;体表面积时的0.3倍) 时,这些效应比较明显。当剂量达到30 mg/m&sup2;/日时,在雌性大鼠的卵巢中可观察到黄体中心性坏死和卵泡发育停滞。对试验犬,当剂量达到600 mg/m&sup2;/日时,出现生精管退化;当剂量达到1200 mg/m&sup2;/日时,出现精液减少。
  大鼠、兔应用索拉非尼出现胚胎毒性、致畸性,包括母体和胎儿的体重减轻,流产机率增加,外表和内脏畸形增多。大鼠和兔口服剂量分别为6mg/m&sup2;/天、36mg/m&sup2;/天时观察到对胎儿的不良后果。
  【药代动力学】
  与口服溶液相比,服用索拉非尼片剂平均相对生物利用度为38%-49%。
  索拉非尼的清除半衰期约为25-48小时。与单剂量给药相比,重复给药7天可达到2.5-7倍的蓄积。
  给药7天后,索拉非尼血药浓度达到稳态,平均血药浓度峰谷比小于2。
  吸收分布
  索拉非尼口服后约3小时达到最高血药浓度。中度脂肪饮食与禁食状态下的生物利用度相似。高脂饮食时,索拉非尼的生物利用度较禁食状态时降低29%。
  当口服剂量超过0.4g每日两次时,平均Cmax和AUC的升高不成线性关系。
  在体外,索拉非尼与人血浆蛋白结合率为99.5%。
  代谢和清除
  索拉非尼主要在肝脏内通过CYP3A4介导的氧化作用代谢,除此之外,还有UGT1A9介导的糖苷酸代谢。
  血药浓度达到稳态时,索拉非尼在血浆中约占全部血液分析物70%-85%的比例。索拉非尼有8个已知代谢产物,其中5个在血浆中被检出。索拉非尼在血浆中的主要循环代谢产物为吡啶类-N-氧化物。体外试验表明,该物质的效能与索拉非尼相似,它包含了稳态血浆中约9%-16%的血液分析物。
  口服100 mg索拉非尼(溶液剂)后,96%的药物在14天内被消除,其中77%通过粪便排泄,19%以糖苷酸化代谢产物的形式通过尿液排泄。有51%的原形药物随粪便排泄,尿液中未发现原形药物。
  酶抑制性体外试验
  人肝微粒体试验表明索拉非尼竞争性地抑制CYP2C19,CYP2D6和CYP3A4。索拉非尼可升高某些药物(这些酶的底物)的血药浓度。
  索拉非尼通过UGT1A1和UGT1A9通路抑制糖苷酸代谢。当这些药物和索拉非尼合用时,可能会增加UGT1A1和UGT1A9的代谢底物的暴露浓度。
  体外试验显示索拉非尼抑制CYP2B6和CYP2C8,Ki值分别是6和1-2&micro;M。当和索拉非尼同时用药时,CYP2B6和CYP2C8的全身暴露量升高。
  CYP2C9底物
  人肝微粒体试验表明索拉非尼竞争性地抑制CYP2C9,其Ki值为7-8&micro;M。通过患者(索拉非尼组和安慰剂组)合用华法林来评价索拉非尼对CYP2C9底物的潜在作用,索拉非尼组患者的PT-INR相对于基线的平均变化并不高于安慰剂组。该结果表明索拉非尼并非CYP2C9的体内抑制剂。
  CYP3A4抑制剂
  酮康唑是CYP3A4的强抑制剂,健康男性志愿者使用酮康唑每日一次,每次400mg,连续7天,同时口服索拉非尼单剂量每日50mg,索拉非尼的平均血药浓度并未改变。
  CYP酶诱导性体外试验
  使用索拉非尼处理培养的人肝细胞后,CYP1A2和CYP3A4的活性没有改变。这表明索拉非尼不大可能是CYP1A2和CYP3A4的诱导剂。
  特殊人群的药代动力学
  老年人(65岁以上)、性别
  人口数据资料显示不需根据患者的年龄或性别调整剂量。
  儿童患者
  尚无儿童患者的药代动力学数据。
  肝损害患者
  索拉非尼主要由肝脏清除。
  轻度(Child-Pugh A,N=14)或中度(Child-Pugh B,N=8)肝损害患者的药物暴露与无肝功能损害患者的暴露范围一致。暴露量位于无肝损害患者的变化范围内。重度肝损害患者(Child-Pugh C)应用索拉非尼的药代动力学研究尚未进行。
  肾损害患者
  在一项临床药理学研究中,在正常肾功能患者、轻度肾功能损害(CrCL 50-80 ml/min)患者、中度肾功能损害(CrCL 30-50 ml/min)患者和不需要透析的重度肾功能损害(CrCL <30ml/min)患者(n=8/组)中,对索拉非尼(单剂量400 mg)的药代动力学进行了评价。索拉非尼的药代动力学未受到肾功能低减的影响。对于轻度、中度或不需要透析的重度肾功能损害患者不需要调整剂量。
  人种
  试验11559的药代动力学分析结果显示:索拉非尼血药浓度-时间曲线吸收相较慢、消除相时间长,药时曲线相对平缓。 索拉非尼及其代谢产物的药动学参数有显著的个体差异。本研究中,台湾和大陆人群索拉非尼的Cmax和AUC(0-12h)与日本人的数值相似,这些组别间测定到的数据范围有很大部分的重合。
  试验11849的药代动力学分析(24例)与之前的几个研究结果相似,稳态的血浆浓度在用药7日时达到,并在治疗期间相对稳定。药物代谢数据与日本的研究(试验10875)一致,索拉非尼Cmax,ss 及AUCss分别在3-4mg/L和30mg• h/L。每种代谢物的相对数量与日本、白种人的结果也是一致的。中国患者的索拉非尼药代动力学与其他研究人群的是相似的。
  试验12162是在健康志愿者中进行一项药代动力学研究,主要目的是比较索拉非尼在高加索人和亚洲人中的暴露情况。在对照的条件下,对健康的、年龄相当的受试者在禁食的状态下给药,且不伴随可能导致药动学干扰的联合用药。日本受试者和中国受试者代表亚洲人种入组该试验。研究共入组了40名日本人、38名中国人和40名高加索人。研究数据表明,索拉非尼在亚洲受试者中的暴露量(AUC)比高加索受试者低30%。与高加索受试者相比,日本受试者血浆中索拉非尼AUC的几何平均值低25%,中国受试者低35%。该研究中观察到的日本受试者与高加索受试者的差异(25%)低于此前报告的数值(45%)。日本受试者与高加索受试者的平均Cmax 间没有显著差异,中国受试者的平均Cmax 比高加索受试者低16%。
  在单剂量药动学人种间比较和稳态药动学人种间比较的过程中观察到的药代动力学差异与群体药代动力学评估情况一致。使用在癌症患者中进行的七项单药I期临床研究的数据和来源于健康受试者的支持性数据建立了索拉非尼的群体药代动力学模型。在主要分析数据集中,高加索受试者占大多数(64.7%,n=191),其次是亚洲人21.4%(日本人)。群体药动学分析(专门关注人种差异)的结果显示,日本患者的暴露量比高加索患者低28.9%。然而,根据最终建立的模型模拟出的亚洲人和高加索人的药-时曲线有重叠,提示两个人种的药代动力学差异可能不具有临床显著性。
  由于患者间存在高度的药代动力学个体差异,而且亚洲人和高加索人的AUC和Cmax数值存在高度重叠,考虑到亚洲肾细胞癌患者和高加索肾细胞癌患者相似的有效性和安全性数据,有关索拉非尼全身暴露量的微小的显在差异是不可能具有临床意义。
  【贮藏】
  低于25℃
  密封保存。请将药品放置在儿童触及不到的地方。
  【包装】
  60片/盒,铝铝包装。
  【有效期】
  30个月
  【执行标准】
  进口药品注册标准JX20070240
  【进口药品注册证号】
  H20060296
  【生产企业】
  生产企业:Bayer HealthCare AG
  拜耳医药保健股份公司 德国

==== 汉译英 ====
Sorafenib tosylate tablets
Manual
Please carefully read the instructions and under the guidance of the physician to use
【Drug name】
Common name: sorafenib tosylate tablets
Product Name: Nexavar
English Trade Name: Nexavar
English Common Name: sorafenib
English name: Sorafenib Tosylate Tablets
Pinyin: Jiabenhuangsuan Suolafeini Pian
【Ingredients】
Chemical name: 4 - (4 - (3 - [4 - chloro -3 - (trifluoromethyl) phenyl] ureido) phenoxy)-N2-methyl-pyridine -2 - carboxamide -4 - toluene sulfonamide salt
Chemical Structure:
Molecular formula: C21H16ClF3N4O3 ? C7H8O3S
Sorafenib Chemical formula Molecular weight: 637.0
【Properties】
This product is a red circular film.
【Indications】
1, treatment of inoperable advanced renal cell carcinoma.
2, treatment of inoperable or distant metastasis of primary hepatocellular carcinoma.
The current lack of advanced hepatocellular carcinoma in patients with sorafenib and interventional treatments such as transcatheter arterial chemoembolization (TACE) compared randomized controlled clinical study data, it is not yet clear of the product relative advantages and disadvantages of interventional therapy, nor a clear right past received after interventional therapy in patients with Sorafenib is useful (see clinical trials】 【above). Suggest that doctors according to the patients specific circumstances into account, select appropriate treatment.
【Specification】
0.2g
【Usage consumption】
Recommended dosage
Recommend taking Sorafenib for each dose of 0.4g (2 × 0.2g), twice a day, fasting or with low-fat, medium fat diet to take.
【Methods】 taking
Oral, in order to swallow a cup of warm water.
【Treatment time】
Treatment should continue until the patient can not be of clinical benefit or there can not be tolerated toxicity.
Dose adjustment and special instructions
The treatment of suspected adverse reactions, including suspension or reduction of Sorafenib dosage, if necessary, the use minus Sorafenib as once a day, every 0.4g (2 × 0.2g).
Table 1 lists accordingly under the skin, toxic dose of adjustment proposals.
Classification of skin adverse reactions adverse reactions to adjust the frequency of the recommended dosage
Level 1: numbness, dysesthesia, paresthesia, numbness, pain swelling, redness or discomfort, but hand-foot -
Does not affect the daily activities occur at any time to continue to the FDA, while giving the local treatment to
Elimination of symptoms.
2: with pain, redness and swelling of the hand, foot, and / or affect the daily lives of the hand, foot and is not the first time to continue to the FDA, while giving the local treatment to eliminate the symptoms. Within 7 days if symptoms do not improve, see below
Within 7 days of symptoms did not improve or second, third interruption treatment until the toxicity of this product to ease to 0-1 grade. When the re-start of the product treatment, reduced to a single dose (daily 0.4g) of the Fourth appears to terminate the product treatment.
Level 3: moist desquamation, ulceration, hand-foot-blistering, pain or lead to patients unable to work and normal life in a serious hand, foot discomfort. The first time or second break in treatment until the toxicity of this product to ease to 0-1 grade. When the re-start of the product treatment, reduced to a single dose (daily 0.4g) appears to terminate the third treatment of this product.
Special Populations
Children with
No children, Sorafenib patients with the safety and efficacy data.
The elderly (65 years), sex and weight, eliminates the need for patient's age (65 years), sex, or body weight adjusted dose.
In patients with liver damage
Liver damage in patients with mild and moderate (Child-Pugh A and B) without the need to adjust dosage. Yet to be conducted in patients with severe liver damage (Child-Pugh C) Application of Sorafenib study.
In patients with renal impairment
Mild, moderate or severe need of dialysis in patients with impaired renal function No dosage adjustment. Dialysis patients has not yet been applied Sorafenib study.
For the possible risk of renal damage in patients, it is recommended to their fluid balance and electrolyte balance monitoring.
Adverse reactions 【】
The following data come mainly from the product in advanced hepatocellular carcinoma and advanced renal cell carcinoma in clinical trials to obtain safety data, including Europe and the United States and Asian countries data (see under】 【clinical trials).
Because clinical trials are conducted under a wide variety of conditions, and, in particular observed in clinical trials, the incidence of adverse reactions in other clinical trials can not be in the direct comparison of the incidence, can not reflect the actual observed incidence.
Europe and the United States to support the product key listed on the safety of clinical research data:
The most common adverse events were diarrhea, rash, alopecia and hand-foot skin reaction (international medical terminology dictionary (MedDRA) corresponds to feel bad for the hand-foot syndrome).
【Taboo】
Sorafenib right of non-active ingredients or drugs with severe allergy symptoms is disabled.
【Note】
This product must have been used under the guidance of experienced doctors to take.
The current lack of advanced hepatocellular carcinoma in patients with sorafenib compared with the interventional treatment such as TACE randomized controlled clinical study data, it is not yet clear of the product relative advantages of interventional therapy, nor a clear right past received after interventional therapy in patients with Sorafenib is a useful (see clinical trials】 【above). Suggest that doctors according to the patients specific circumstances into account, select appropriate treatment.
Pregnancy: women of childbearing age should pay attention to contraception during treatment. Patients should inform women of childbearing age, drugs on the fetus that may arise from hazards, including severe malformation (teratogenicity), developmental disorders, and fetal death (embryo toxicity). Application should be avoided during pregnancy Sorafenib. Only in the treatment of income generated over the possible harm to the fetus only when applied to pregnant women.
In animal experiments, have been found Sorafenib has teratogenic and embryo - fetal toxicity (including increased risk of miscarriage, developmental disorders), and the role of these hazards was significantly lower than the clinical doses appears. Sorafenib based on a variety of kinase inhibitors on the mechanism and the results of animal experiments, which speculated that pregnant women taking sorafenib would endanger the fetus.
Breast-feeding women in the treatment of Sorafenib should stop breast-feeding during the period.
Skin Toxicity: hand-foot skin reaction and rash are taking Sorafenib the most common adverse reactions. Skin rash and hand-foot skin reaction are usually more for the NCI CTCAE 1 Dao 2 level, and rather than start taking Sorafenib occur within 6 weeks after. On the skin toxicity of the treatment, including medication to alleviate the symptoms of partial and temporary withdrawal and / or right Sorafenib dosage adjustment. For skin toxicity in patients with severe or long-lasting response to needs of permanently disabled Sorafenib.
Hypertension: Patients taking sorafenib incidence of hypertension will increase. Mostly mild to moderate hypertension, multiple medication at the beginning of the early stages of post-emergence use of conventional antihypertensive drugs can be controlled. Should regularly monitor the blood pressure, if necessary, then according to the standard treatment for treatment. On the application of antihypertensive drugs after severe or persistent high blood pressure or hypertensive crisis appears to be considered permanently disabled patients with Sorafenib.
Hemorrhage: taking Sorafenib may increase bleeding after treatment opportunities. Serious bleeding is uncommon. Once the number needed to treat bleeding, it is recommended to consider permanently disabled Sorafenib.
Warfarin: Some while taking sorafenib and warfarin therapy in patients with sporadic bleeding or INR increases. Right combination in patients with warfarin should be regular monitoring of changes in prothrombin time, INR value and pay attention to signs of clinical bleeding.
Wound healing complications: taking sorafenib on wound healing has not conducted a formal study. Big surgery patients need to propose to suspend the sorafenib, when the re-applied after surgery in patients with sorafenib clinical experience is limited, therefore decided to re-take should be preceded by patients from the clinical considerations, to ensure wound healing.
Myocardial ischemia and / or myocardial infarction: the test 11213, the treatment-related myocardial ischemia / myocardial infarction in the sorafenib group incidence (2.9%) than in the placebo group (0.4%). 100,554 During the trial, the treatment-related myocardial ischemia / myocardial infarction in the sorafenib group incidence of 2.7% in the placebo group the incidence rate was 1.7%. In patients with unstable coronary artery disease and recent myocardial infarction is not into the group on these two experiments. For the occurrence of myocardial ischemia and / or myocardial infarction patients should consider temporarily or permanently disabled Sorafenib treatment.
Gastrointestinal perforation: gastrointestinal perforation very rare. In patients taking Sorafenib reported gastrointestinal perforation occurred less than 1%. In some cases, gastrointestinal perforation and intra-abdominal tumor has nothing to do. This product should be discontinued treatment (see adverse reactions 【】).
Liver damage: There is no liver damage in patients with severe (Child-Pugh C grade) taking Sorafenib research data. Sorafenib is mainly due to the liver through the elimination of severely damaged liver function in patients in the exposure will rise.
Drug - drug interactions:
UGT1A1 ways: Sorafenib and the adoption of the proposed means of UGT1A1 metabolism / clearance of the drug (eg, irinotecan) Joint application, need to be cautious (see】 【drug interactions).
Docetaxel: Past studies showed that docetaxel (75mg/m2 or 100mg/m2) and Sorafenib (0.2g or 0.4g twice daily administration) Joint application (Sorafenib in a multi-ene drug paclitaxel, when three days suspended), can lead to increase in docetaxel AUC of 36% -80%. Suggested that the product in combination with docetaxel, the need to be cautious (see】 【drug interactions).
Drivers and machine operators on the impact: There is no Sorafenib drivers and machine operators on the study of the impact. There is no evidence to suggest that sorafenib may affect the ability to drive and machine operators.
【Pregnant and lactating women drug】
Pregnancy
No pregnant women taking sorafenib sufficient clinical data. Animal experiments show that the existence of reproductive toxicity of drugs, including teratogenicity. Sorafenib and its metabolites through the placental barrier in rats, suggesting Sorafenib inhibit angiogenesis in the fetus.
Women of childbearing age should pay attention to contraception during treatment. Applications, such as Sorafenib during pregnancy, patients should be informed of drugs on the fetus that may arise from hazards, including severe malformation (teratogenicity), developmental disorders, and fetal death (embryo toxicity).
During pregnancy to avoid the application of Sorafenib. Only in the treatment of income generated over the possible harm to the fetus only when applied to pregnant women (see 【Note】).
Women of childbearing age
Animal experiments in Table Mingsuo La Fini has teratogenic and embryo toxicity. End of treatment, during treatment and at least 2 weeks should be adequate contraception.
Breastfeeding
Sorafenib is not yet known whether it can enter the human milk. Animal experiments in Table Mingsuo La Fini, and / or its metabolites may enter into the milk. Because many drugs from the milk secretion, and sorafenib have not studied the role of the baby, so women should stop breast-feeding during the drug treatment.
Fertility
Animal experimental results in Table Mingsuo La non-Nico damage the reproductive capacity of males and females.
Pediatric Use
No children, patients with Sorafenib the safety and efficacy data.
【Old medication】
Eliminates the need for patient's age (65 years) to adjust dosage.
【Drug interactions】
CYP3A4 inducers: rifampin combined with the continued application of Sorafenib Sorafenib can lead to an average of 37% of the AUC. Other CYP3A4 inducers, such as Hypericum perforatum (or Hypericum perforatum, commonly known as St. John's Wort), phenytoin, carbamazepine, phenobarbital and dexamethasone, which may accelerate the metabolism of sorafenib and thus decrease sorafenib Nigerian drug concentration.
CYP3A4 inhibitors: ketoconazole is a strong inhibitor of CYP3A4, healthy male volunteers once daily use of ketoconazole for 7 days, while a single dose of oral administration of sorafenib daily 50mg, sorafenib, the average AUC was not change. Therefore, impact of CYP3A4 inhibitor sorafenib metabolism is unlikely.
CYP2C9 substrates: Warfarin is a CYP2C9 substrate, by comparing the taking sorafenib and placebo in patients with Sorafenib in China to assess the effects of warfarin. Compared with the placebo group Sorafenib combined with warfarin in patients with an average of PT-INR value had not changed. But the combination in patients with warfarin should be regular monitoring of INR values.
CYP isozyme selective substrates: midazolam, dextromethorphan and omeprazole, respectively cytochrome CYP3A4, CYP2D6 and CYP2C19 substrates. Sorafenib in combination with the above-mentioned three kinds of drugs will not change their exposure. This shows that for these cytochrome P450 isozyme, sorafenib is neither an inhibitor nor inducer.
, And other anticancer drug interactions: clinical trials, sorafenib, and other conventional doses of antineoplastic agents carried out a joint application, including gemcitabine, oxaliplatin, doxorubicin, and irinotecan. Sorafenib does not affect gemcitabine and oxaliplatin in drug metabolism.
Paclitaxel (225mg/m2) and carboplatin (AUC = 6) with the product (twice a day, each 0.1g, 0.2g or 0.4g) used (in the use of paclitaxel / carboplatin before and after the stop the FDA 3 days), not the pharmacokinetics of paclitaxel have a significant impact.
Sorafenib and doxorubicin in patients with combined application can cause the body to doxorubicin AUC increased by 21%. Sorafenib and irinotecan combination, due to irinotecan active metabolite SN-38 by UGT1A1 pathway for further metabolism, the two combined result in SN-38 of the AUC increased 67% -120%, while irinotecan in AUC values increased 26% -42%. Related to this clinical significance is still unknown.
Docetaxel (75mg/m2 or 100mg/m2, once every 21 days) and Sorafenib (in the 21-day treatment cycle, from the first two days to the first 19 days, 0.2g or 0.4g twice daily for drugs) Joint application (Sorafenib drug docetaxel, when in the disabled for three days), can lead to increase in docetaxel AUC of 36% -80%, Cmax increased 16% -32%. Suggested that the product in combination with docetaxel, the need to be cautious.
Overdosage
Sorafenib overdose there is no specific treatment measures.
Sorafenib a maximum dosage of 0.8g, twice a day, at this dose observed major adverse reactions were diarrhea and skin toxicity.
Suspected overdose, patients should be discontinued and appropriate supportive care.
【Clinical trials】
Renal cell carcinoma:
In the following four clinical trials carried out Sorafenib treatment of advanced renal cell carcinoma of the safety and efficacy studies:
Is a Phase III trial 11213, the international multi-center, randomized, double-blind, placebo-controlled study, including 903 received at least one chemotherapy or immunotherapy in patients with unresectable or metastatic kidney cancer. Primary endpoint was overall survival (OS) and progression-free survival (PFS), secondary endpoint of the study was tumor response rate (RR). Patients were randomly divided into two groups, experimental group Sorafenib 0.4g, twice a day (N = 451), control group was given placebo (N = 452). The baseline demographic characteristics of the two groups balanced. Nearly half of the patients with ECOG * score of 0 and the other half of the patients MSKCC ** poor prognosis group (* ECOG: Eastern Cooperative Oncology Group; ** MSKCC: ? New York Sloan Kettering Memorial Cancer Center).
Imaging visible vascular invasion and / or extrahepatic spread
The final analysis showed that: sorafenib versus placebo in the overall survival (OS) the strengths of statistically significant (HR = 0.69, P = 0.00058, Table 18 and Figure 4). In the pre-stratification factors (ECOG score, radiological visible vascular invasion and / or extrahepatic tumor spread occurs or not, and regional), the hazard ratio is superior to placebo in support of Sorafenib. Sorafenib group time to tumor progression (TTP) is higher than the placebo group (HR: 0.58, p = 0.000007, Table 18 and Figure 5). Subgroup analysis, the hepatitis B virus-positive (laboratory test results) overall survival in patients with Table 19 and Figure 6; hepatitis C virus-positive (laboratory test results) in patients with overall survival in Table 20; past patients received TACE overall survival in Table 21.
Table 18: Test the validity of the results of 100,554
Efficacy parameters Sorafenib
(N = 299) placebo
(N = 303) P value HR
(95% CI)
Overall survival (OS) [median, days
(95% CI)]
324
(286, 405) 241
(206, 276) 0.00058 * 0.69
(0.55, 0.87)
Time to tumor progression (TTP) ** [median, days
(95% CI)] 168
(126, 210) 86
(82, 120) 0.000007 0.58
(0.45, 0.74)
CI: Confidence interval, HR: hazard ratio
* In a comparison, if p = "0.0077, may be considered that such comparison is statistically significant (O'Brien Fleming stop border)
** According to RECIST criteria to judge the progress of imaging
Figure 4: Test 100,554 in overall survival (OS) of the Kaplan-Meier curve (intention to treat population)
Figure 5: Test 100,554 in time to tumor progression (TTP) of the Kaplan-Meier curve (intention to treat population)
Table 19: Test 100,554 in overall survival in patients with hepatitis B virus-positive period *
Sorafenib group (N = 40) placebo group (N = 31)
The median overall survival period (days) 359,186
Hazard ratio (HR)
(95% C.I.) 0.67
(0.35, 1.31)
* Due to the limited sample size for subgroup analysis results should be interpreted with caution.
Figure 6: Test 100,554 in the survival curves in patients with hepatitis B virus-positive
Table 20: Test 100,554 in hepatitis C virus-positive patients, overall survival *
Sorafenib group (N = 93) placebo group (N = 84)
The median overall survival period (days) 426,241
Hazard ratio (HR)
(95% C.I.) 0.50
(0.33, 0.78)
* Due to the limited sample size for subgroup analysis results should be interpreted with caution.
Table 21: Test 100,554 in the past received TACE overall survival in patients treated with
Sorafenib group (N = 86) placebo group (N = 90)
The median overall survival period (days) 362,302
Hazard ratio (HR)
(95% C.I.) 0.75
(0.49, 1.14)
* Due to the limited sample size, and there is not a balanced baseline factors, subgroup analysis results should be interpreted with caution.
【Pharmacology and toxicology】
Pharmacological
Sorafenib is a multi-kinase inhibitor, inhibit tumor cell proliferation in vitro.
Sorafenib inhibit tumor cell proliferation, including the murine renal cell carcinoma, RENCA model and non-thymus transplantation in mice a variety of human tumor model and inhibition of tumor angiogenesis.
Toxicology
By mice, rats, dogs and rabbits evaluated sorafenib pre-clinical safety.
Repeated dose toxicity test in different organs showed mild to moderate changes (degeneration and regeneration).
Childhood and development period of dogs was observed after multiple doses of bone and teeth, including sorafenib dose of 600mg / m2 body surface area (for the equivalent of the clinical recommended dose of 500mg / m2 body surface area 1.2 times the time ) Unit epiphyseal plate irregular thickening of the growth plate in the vicinity of bone marrow cells decreased (200mg / m2 / day) and dental changes in qualitative composition (600mg / m2 / day). In adult dogs did not find a similar situation.
Mutagenicity: The mammalian cell (Chinese hamster ovary) were in vitro chromosome aberration test, Sorafenib in the metabolic activation, a genetic toxicity. An intermediate in the production process in vitro cytogenetics test (Ames test) results are positive, drug control, their limits from 0.15% or less. Ames test and micronucleus test in mice Table Mingsuo La Fini does not have a genetic toxicity (tested drugs in this intermediate concentration 0.34%).
Carcinogenicity: Not for the carcinogenicity of Sorafenib trial.
Reproductive toxicity: the absence of specific animals, fertility test. Repeat drug toxicity observed in animal reproductive organs change, so for the foreseeable drugs on male and female fertility damage. Typical changes include rat testis, the Deputy testis, prostate and seminal vesicle degradation and block. When the daily dose of sorafenib to 150 mg / m2 body surface area (equivalent to the clinical recommended dose of 500 mg / m2 body surface area 0.3 times the time), the more obvious these effects. When the dose reached 30 mg / m2 / day when the ovaries in female rats can be observed in central necrosis of luteal and follicular development stagnation. The experimental dogs, when the dose reached 600 mg / m2 / day when there seminiferous tube degradation; When the dose reached 1200 mg / m2 / day when the semen appears to reduce.
Rats, rabbits application Sorafenib appears embryo toxicity, teratogenicity, including maternal and fetal weight loss, increased risk of miscarriage, appearance and an increase in visceral malformations. Rat and rabbit oral dose of 6mg / m2 / day, 36mg / m2 / day observed adverse effects on the fetus.
Pharmacokinetics】
Compared with the oral solution, taking Sorafenib tablets mean relative bioavailability of 38% -49%.
Sorafenib clearance half-life of approximately 25-48 hours. Compared with the single dose administration, repeated administration of 7 days, up to 2.5-7 times the accumulation.
Administered 7 days after sorafenib plasma concentrations reached steady state, with an average peak-trough plasma concentration ratio of less than 2.
Absorption Distribution
Sorafenib is about 3 hours after oral administration peak plasma concentrations. Moderate-fat diet and fasting state, the bioavailability of similarity. High-fat diet, sorafenib bioavailability compared with fasting state, reduced by 29%.
When the oral doses greater than 0.4g twice daily, the mean Cmax and AUC of the increase in not a linear relationship.
In vitro, sorafenib with human plasma protein binding rate was 99.5%.
Metabolism and clearance
Sorafenib, mainly in the liver through CYP3A4-mediated oxidation metabolism, in addition to UGT1A9-mediated metabolism of glucuronide.
Steady state plasma concentration, Sorafenib in plasma accounts for about 70% of whole blood analytes -85% ratio. Sorafenib has eight known metabolites, of which 5 were detected in plasma. Sorafenib in the plasma of the main circulating metabolite of pyridine-N-oxide. In vitro tests showed that the substance of the performance and Sorafenib is similar to the steady-state plasma contains about 9% -16% of their blood analyte.
Oral administration of 100 mg sorafenib (SOLUTION), the 96% of the drug is eliminated within 14 days, of which 77% of the excreted through the feces, 19% of the glycosides in the form of acid metabolites excreted through the urine. 51% of the prototype drug excretion with feces, urine is not found in the prototype drug.
Enzyme inhibition in vitro
Human liver microsome test table Mingsuo La Fini competitive inhibit CYP2C19, CYP2D6 and CYP3A4. Zorra, higher non-Nicole certain drugs (substrates of these enzymes) and plasma concentrations.
Sorafenib inhibited by UGT1A1 and UGT1A9 pathways glucuronide metabolism. When these drugs and sorafenib in combination, may increase the metabolism of UGT1A1, and UGT1A9 substrates are exposed to.
In vitro tests have shown Sorafenib inhibit CYP2B6 and CYP2C8, Ki values were 6 and 1-2μM. When and Sorafenib drug at the same time, when, CYP2B6 and CYP2C8 increased systemic exposure.
CYP2C9 substrate
Human liver microsome test table Mingsuo La Fini competitive inhibit CYP2C9, its Ki value of 7-8μM. By patients (sorafenib group and the placebo group) to evaluate the combination of warfarin Sorafenib on the potential role of CYP2C9 substrate, sorafenib group of patients with PT-INR compared with baseline, the average change is not high in the placebo group. The results in Table Mingsuo La Fini is not a CYP2C9 inhibitor in vivo.
CYP3A4 inhibitors
Ketoconazole is a strong CYP3A4 inhibitor ketoconazole healthy male volunteers once daily use, each 400mg, for 7 days, while a single dose of oral administration of sorafenib daily 50mg, sorafenib, the average plasma concentration has not changed.
CYP enzymes induced in vitro
Sorafenib treatment using cultured human liver cells, CYP1A2 and CYP3A4 activity has not changed. This shows that the non-Nigerian Mingsuo La CYP1A2 and CYP3A4 is unlikely to be the induction agent.
Pharmacokinetics of special populations
The elderly (65 years), sex
Population statistics indicate that eliminates the need for patient's age or gender to adjust dosage.
Children with
Patients with no children, the pharmacokinetics data.
In patients with liver damage
Sorafenib mainly by the liver removed.
With mild (Child-Pugh A, N = 14) or moderate (Child-Pugh B, N = 8) liver damage in patients with drug exposure and no exposure of patients with impaired liver function in the same range. Exposure in patients with liver damage without the changes in range. In patients with severe liver damage (Child-Pugh C) Application of Sorafenib pharmacokinetic studies have not been carried out.
In patients with renal impairment
In a clinical pharmacology study, in patients with normal renal function, mild renal impairment (CrCL 50-80 ml / min) in patients with moderate renal impairment (CrCL 30-50 ml / min) in patients with and without dialysis of severe renal impairment (CrCL <30ml/min) in patients (n = 8 / group) for sorafenib (single dose of 400 mg) pharmacokinetics were evaluated. Sorafenib pharmacokinetics has not been reduced renal function with low impact. For the mild, moderate or severe need of dialysis patients with impaired renal function do not need to adjust the dose.
Race
Test 11559 pharmacokinetic analysis showed that: Sorafenib plasma concentration - time curves of absorption phase slower elimination phase a long time and concentration-time curve is relatively flat. Sorafenib and its metabolites in pharmacokinetic parameters of significant individual differences. In this study, Taiwan and the mainland populations Sorafenib the Cmax and AUC (0-12h) and the Japanese values are similar between these groups measured in the range of data that the great majority of the overlap.
Test 11849 pharmacokinetic analysis (24 cases) and previous research results of several similar, steady-state plasma concentrations of the drug reached on the 7th, and during the treatment is relatively stable. Drug metabolism data and the Japanese study (experiment 10875) Unanimously, Sorafenib Cmax, ss and AUCss at 3-4mg / L and 30mg ? h / L. The relative amount of each metabolite and Japan, white the result is the same. China Sorafenib in patients with other Pharmacokinetics study population is similar.
Test 12162 is carried out in healthy volunteers, a pharmacokinetic study, the main aim is to compare sorafenib in the Caucasus and Asians in the exposure. In control conditions, the pairs of healthy, age-matched subjects in the fasting state administration, and not accompanied could lead to interference with pharmacokinetics of combination therapy. Japanese subjects and Chinese subjects were recruited on behalf of the Asian ethnic origin, the pilot. Study is into the group of 40 Japanese, 38 Chinese and 40 Caucasian. The data show that sorafenib in Asian subjects in the exposure (AUC) than in Caucasian subjects by 30%. Compared with the Caucasian subjects, the Japanese subjects Sorafenib in plasma AUC of the geometric mean lower 25% of Chinese subjects with low 35%. Observed in the study of Japanese subjects and the differences between Caucasian subjects (25%) was lower than previously reported values (45%). Japanese and Caucasian subjects, the average Cmax subjects were no significant differences between the Chinese subjects, the average Cmax subjects were 16% lower than that in the Caucasus.
In the single dose pharmacokinetic comparison between race and steady-state pharmacokinetic comparison between race in the process observed pharmacokinetic differences and population pharmacokinetics consistent assessment of the situation. Used in cancer patients has been conducted of the seven single-agent Phase I clinical study data and from healthy volunteers supporting data to establish a group of Sorafenib pharmacokinetic model. Concentrated in the main analysis of data, the Caucasus, the majority of subjects (64.7%, n = 191), followed by Asians, 21.4% (Japanese). Population pharmacokinetics analysis (focusing exclusively on ethnic differences) showed that the exposure of Japanese patients, 28.9% lower than Caucasian patients. However, according to the eventual establishment of a model to simulate the Asians and Caucasians medicine - time curves overlap, suggesting that two ethnic differences in pharmacokinetics may not be clinically significant.
Because exist between patients with a high degree of individual differences in pharmacokinetics, but also Asians and Caucasians AUC and Cmax values there is a high degree of overlap, taking into account the Asian and Caucasian patients with renal cell carcinoma in patients with renal cell carcinoma similar to the efficacy and safety data, Sorafenib about systemic exposure of the tiny difference is not significant in the clinical significance.
【Storage】
Less than 25 ℃
Kept under seal. Please medicines kept out of children's reach places.
【Packing】
60 / box, aluminum and aluminum packaging.
【Valid Period】
30 months
【Executive Standard】
Imported drug registration standards JX20070240
【Imported drug registration证号】
H20060296
【Manufacturer】
Manufacturer: Bayer HealthCare AG
Bayer HealthCare AG, Germany

Tags: 索拉非尼(多吉美)

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更新日期: 2012-01-13 16:10
作者: : mcyclub
修订: 1.5

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