OATP

点击上方的 行舟Drug ▲ 添加关注抗肿瘤抗体偶联药物临床药理学研究的若干问题与考虑来源《中国临床药理学与治疗学》  2023  Jan; 28(1)作者高丽丽，王玉珠，王燕，李健，王骏国家药品监督管理局药品审评中心摘要抗体偶联药物(antibody-drug conjugates，ADC)由靶向特异性抗原的抗体药物与有效载荷(如小分子细胞毒药物)通过连接子偶联而成，兼具传统小分子细胞毒药物的强大杀伤效应和抗体药物的肿瘤靶向性。截至2022年2月，美国食品药品监督管理局(FDA)已批准12个ADC抗肿瘤药物。本文通过分析已批准ADC药物的临床药理学审评报告结合相关指导原则，梳理ADC药物临床药理学的研究要点，发现在ADC药物研发中，除临床药理学方面的常规研究外，由于ADC特殊的抗肿瘤作用机制，其剂量选择以及特殊人群用药有着特殊的考虑。希望本文对国内研发人员在开发ADC药物时有所启示。关键词抗肿瘤; 抗体偶联药物; 临床药理学; FDA_正文_DC)是由一种小分子药物，也称为有效载荷(payload)，通过化学连接子和抗体或抗体片段偶联而成。ADC药物的抗体部分一般是通过针对与疾病相关(例如，肿瘤特异性抗原)的特异性抗原进行选择或工程化获得。当抗体与目标抗原结合时，ADC药物通过生理机制(例如，内吞作用) 内化，这时ADC药物暴露于低pH环境或溶酶体酶，降解抗体与连接子释放有效载荷，进而释放有效载荷在目标细胞发挥抗肿瘤的作用。截至2022年2月，美国食品药品监督管理局(FDA)共批准12款ADC，同时FDA在2022年2月发布《Clinical Pharmacology Considerations for Antibody-Drug Conjugates》(征求意见稿)以及国家监督管理局药品审评中心(CDE)于2022年9月发布《抗肿瘤抗体偶联药物临床研发技术指导原则》的征求意见稿。鉴于ADC药物由抗体、连接子和有效载荷组成，其临床药理学研究可能比单独小分子或大分子更为复杂。本文结合FDA和CDE关于ADC药物指导原则中临床药理学相关内容，并参考FDA已上市ADC药物的临床药理学审评报告进行具体进行分析，发现除一般临床药理学研究[1]之外，重点关注ADC药物在临床药理学研究方面的关键问题以及几点考虑，旨在为国内ADC药物临床药理学研究提供思路。1ADC药物临床药理学研究要点1.1 FDA指导原则FDA于2022年2月发布《Clinical Pharmacology Considerations for Antibody-Drug Conjugates》[2](征求意见稿)。该指导原则围绕ADC药物的生物分析方法、给药策略、剂量-暴露-效应关系、内在因素、QTc评估、免疫原性和药物-药物相互作用(DDI)等方面提出建议指导。1.1.1 给药策略方面ADC药物具有抗体对特异性靶点的选择性和小分子药物的细胞毒性。因此，制定ADC药物的最佳给药策略时需要仔细考察抗体和有效载荷的药代动力学(PK)和药效学(PD)之间的关系。由于有效载荷具有细胞毒性，有效载荷的全身暴露量即使增加较小，也可能会导致较大的安全性风险。从药物的安全性角度来看，有效载荷的毒性是剂量限制的主要因素。因此，深入了解ADC药物及其组成部分的PK和PD以及它们与安全性和有效性的关系，对优化ADC药物的给药策略至关重要。给药策略具体包括临床开发过程中的剂量选择以及结合内在因素和外在因素剂量调整两个方面。1.1.1.1 临床开发过程中的剂量选择推荐在ADC药物的首次人体研究中探索较宽的剂量范围，并在早期临床开发中选择多个剂量水平(例如，I期或II期研究中的队列扩展)，以获得ADC药物的安全性和有效性数据。在选择关键研究的给药策略时应考虑早期研究获得的总体耐受性数据。利用早期临床研究的数据评估ADC及其组成部分的暴露与安全性和/或有效性的关系可以支持关键研究给药策略的选择。此外，暴露-效应关系(E-R关系)也可为关键研究中特殊人群(例如，肝损害或肾损害的患者)给药策略的选择提供依据。应利用其他支持性数据，如药效学生物标志物数据和受体占用/靶点参与数据(target en-gagement data)，帮助临床研究和/或特殊人群进行给药策略的选择。1.1.1.2 结合内在因素和外在因素剂量调整由于ADC药物的不同组成部分可以独立地影响安全性和/或有效性，因此基于内在和外在因素(例如，肾或肝损害，DDI)的剂量调整具有挑战性。例如，将特殊人群的一个组成部分(通常是有效载荷)的暴露量与总体人群中的暴露量进行匹配，从而对特殊人群进行剂量调整。但这种匹配方式有可能改变ADC药物的暴露量，进而影响有效性。在ADC药物开发过程中应持续对内在和外在因素对PK、安全性和有效性的影响进行评估，进而为特殊人群等的剂量调整提供依据。对于特殊人群的PK和风险-获益比与总体人群相比预计不会发生显著改变的，不建议进行剂量调整。相反，特殊人群中不良事件的严重程度和频率与总体人群相比预计会增加，但剂量不能在不影响疗效的情况下进行调整，这时则可能建议避免用药。可从以下途径获得PK、有效性和安全性信息以支持剂量调整: (1)在剂量递增研究中纳入的特殊人群或伴随给药的患者信息。例如，与器官功能正常或无伴随用药的患者相比，设置一个较低剂量的交错队列(staggered cohort)。(2)安全性和有效性研究纳入了特殊人群或伴随给药的患者信息。(3)专门的特殊人群或DDI研究。应注意，在安全有效性研究中，应基于有效载荷的吸收、分布、代谢和排泄(ADME)以及早期研究中ADC药物的安全性/有效性结果纳入不同具有内在或外在因素的患者。此外，ADC药物可能不适合开展物质平衡研究，可以通过早期临床试验或动物研究获得数据评估或预测人体有效载荷的代谢和排泄途径。1.1.2 剂量-暴露-效应除评估ADC的剂量-效应关系外，还应对ADC及其组成部分进行E-R分析，以确定其暴露与安全性和有效性的关系。早期的E-R分析可为后期临床开发中不使用ADC组成部分或药理活性代谢物进行E-R分析提供依据。例如，早期的E-R分析显示有效载荷或药理活性代谢物的系统暴露较低，抗体没有药理活性，总抗体浓度与ADC药物的抗体浓度高度相关等。此外，如果已知抗体靶点在很大程度上进入体循环，E-R分析应只关注在循环中未结合靶点的ADC和/或总抗体。此类分析可包括以下考虑: (1)循环中与靶点结合的ADC相对于与靶点未结合(游离) ADC的相对浓度。(2)靶点结合的ADC与靶点未结合(游离) ADC浓度之间的相关性。(3)与靶点结合的ADC保留药理活性的潜力。1.1.3 内在因素内在因素(如肾或肝损害、药物基因组学、体重、年龄、性别、种族)可能影响ADC、其组成部分和药物活性代谢物(如有)的暴露，可通过以下途径进行评估: 根据临床研究数据采用群体药代动力学(PPK)进行分析; 或专门的研究。FDA指导原则关于特殊人群(肝功能损害、肾功能损害)和药物基因组学提出了一些特殊考虑要素，本文主要对特殊人群进行介绍。未偶联的有效载荷和药理活性代谢物(如有)可以通过肾脏或肝脏消除。肾功能或肝功能损害可能改变未偶联有效载荷的暴露量，进而可能会改变ADC药物的安全性和/或有效性。因此，所有ADC药物研发中应评价肾功能或肝功能损害对未偶联有效载荷PK的影响。器官损害可能影响ADC药物或总抗体的暴露。例如，如果使用抗体片段，且ADC的相对分子质量小于69000，ADC可能通过肾脏途径消除。此外，在肝损害患者中也观察到ADC暴露量的改变。应提供器官损害评估中包括或不包括ADC、其组成部分和药理活性代谢物的理由。建议通过考虑目标人群中的PK、安全性和有效性数据，在适当时对特殊人群进行剂量调整。如果关键研究中入组部分特殊人群，同时获得该人群的PK、安全性和有效性数据，可采用PPK评估器官损害对有效载荷、药理活性代谢物(如有)和/或其他ADC组成部分的影响。FDA建议: (1)评价非临床和早期临床研究中未偶联有效载荷、药物活性代谢物和/或其他ADC组成部分充分的ADME信息，支持在关键研究中纳入不同程度的器官损害人群。(2)在关键研究中进行充分的PK抽样，以评价器官损害对未偶联有效载荷、药理活性代谢物和/或其他ADC组成部分清除率的影响。(3)获得足够有关器官损害患者的安全性和有效性信息以了解暴露量改变(如有)对安全性和有效性的影响。需注意，为了提供足够的安全性和有效性信息，纳入的器官损伤患者的样本量应与FDA进行前瞻性讨论。还可对器官损害患者进行专门的研究(例如，剂量递增研究，药代动力学研究)，以指导特殊人群的给药建议。是否推荐和设计一个专门的研究取决于ADC的特征，例如: (1) ADC和/或未偶联有效载荷的ADME和系统暴露的潜在变化。例如，未偶联有效载荷的系统暴露预期可能会存在有临床意义的显著变化，这时可能需要进行专门的器官损害研究。(2)剂量-暴露-效应关系: ADC与有效性的关系和未偶联有效载荷与安全性的关系。例如，暴露与有效性的关系较平坦，但暴露与安全性关系较为陡峭的，可能在不影响获益/风险的情况下，采用降低的起始剂量进行器官损害专门研究。(3)在临床试验，特别是有特殊人群入组的临床试验中观察到与暴露变化相关的安全信号。1.1.4 药物相互作用对未偶联的有效载荷和药理活性代谢物(如有)的DDI风险进行体外研究。尽管未偶联有效载荷的系统暴露可能相对较低，对于评价其作为潜在促变药的DDI具有重要意义。应基于体外DDI的结果和对目标患者群体伴随药物的了解，进行体内DDI研究。此外，可采用基于生理的药代动力学模型进行研究。值得注意的是，可通过考虑以下要素，进行前瞻性设计，从关键有效性研究中获得充分的体内DDI特征:(1)将伴随药物细化分为敏感底物(如果基于体外风险评估，未偶联的有效载荷和/或药理活性代谢物有可能成为促变药)，以及强或中度诱导剂或抑制剂。(2)伴随治疗药物的用药时间。(3)给药方案及伴随用药给药途径。(4)预先确定的分析方法。(5)对作为促变药的伴随药物进行适当的PK取样和检测。此外，在某些情况下，FDA建议对抗体部分的潜在DDI进行评估。如果ADC药物联合使用以下药物，建议进行DDI评估:(1)与ADC具有相同药效学靶点的药物。(2)阻断或干扰含有人IgG的Fc区域的ADC与FcRn之间的相互作用的药物。(3)如果ADC药物的PK受具有免疫原性的免疫抑制剂影响。1.1.5 其他除以上临床药理学研究外，对生物分析方法、QTc评估以及免疫原性方面建议如下。生物分析方法方面: 应对ADC、其组成部分以及药理活性的代谢物(如有)进行检测。如在后期开发中仅对ADC某一组成部分进行检测，应考虑: ADC、其组成部分以及药理活性的代谢物(如有)早期临床试验的PK特征。例如，总抗体和ADC浓度之间的相关性，未偶联的有效载荷和药理活性代谢物系统暴露的相关性; 相关的非临床药理学、PK或安全性数据。例如，关于ADC作用机制的非临床数据、未偶联抗体的药理活性数据、代谢物的药理活性数据; E-R数据，评估ADC的组成部分对安全性和/或有效性的影响程度。对于QTc研究，指导原则指出所有ADC药物研发应根据E14，提交QT延长风险评估和拟议的QT评估计划。一般来说，未偶联的有效载荷是ADC中唯一被认为可能存在QT延长潜在风险的组成部分。因此，ADC药物的QT评估计划应考虑小分子药物QT评估中可能涉及的所有因素。QT评估建议的任何分析都应使用有关有效载荷ADME特征的信息来确定。可通过早期临床试验中的心电图(ECG)监测结果以及未偶联有效载荷的定量分析结果进行评价。免疫原性方面: ADC药物的免疫反应可以由ADC药物的任何组成部分，包括抗体、有效载荷，或由偶联连接子产生。鉴于ADC药物通常具有相对狭窄的治疗窗，需评价ADC药物的免疫原性及其对PK、安全性和有效性的潜在影响。1.2 国内指导原则药品审评中心起草了《抗肿瘤抗体偶联药物临床研发技术指导原则》[3](征求意见稿)，有关临床药理学方面的内容如下: 1.2.1 最佳给药方案的探索合理的给药策略是影响ADC药物获益风险特征的关键因素。基于ADC药物的结构特征和作用特点，有效载荷毒性是主要的剂量限制因素，有效载荷系统暴露量相对较小程度的增加就有可能导致显著的不良反应。最佳给药策略的选择需综合考虑抗体和有效载荷之间的PK、PD差异，因此，在早期研究阶段全面了解ADC药物及其组成部分的PK和PD，以及尽可能探索其与安全性和有效性结果之间的关系非常重要，从而及时合理调整给药方案。例如，对由于血清峰浓度过高引起主要毒性的ADC，可以采用有效低剂量的分次给药策略，降低血清峰值浓度，从而提高安全性和耐受性。ADC药物与细胞毒性药物和单克隆抗体相比，在体内的分布、代谢、和清除过程具有其自身特点。ADC药物PK研究通常包括对偶联抗体、总抗体(偶联抗体和裸抗体)、非结合的小分子化合物及其活性代谢物(如果有)进行研究。为获得较充分的PK、安全性和有效性数据以支持最佳推荐剂量和给药方案的确定，建议早期扩展研究可在安全剂量范围内选择多个候选给药方案进行剂量扩展探索研究，同时可充分借助模型模拟等方法，并结合同类靶点药物相关临床试验数据综合评估。文章内容由凡默谷小编查阅文献选取，排版与编辑为原创。如转载，请尊重劳动成果，注明【来源：凡默谷公众号】。2FDA批准情况和其临床药理学研究内容截至2022年2月，FDA共批准了12个ADC药物，其上市基本信息以及其临床药理学研究内容汇总见表1。首先，由于有效载荷是发挥ADC抗肿瘤有效性的重要组成部分，因此对于ADC药物，关注有效载荷的相关信息十分必要。基于目前FDA已批准的12个ADC药物，有效载荷共7种，分别 monomethyl auristatin E (MMAE)、N-acetyl-gamma calicheamicin (NAc-calicheamicin)、emtansine (DM1)、pseudomonas exotoxin38 (PE38)、DNA拓扑异构酶I抑制剂、monomethyl auristatin F (MMAF) 以及DNA crosslinking pyrrolobenzodiazepine (PBD) dimer(图1)。Fig．1 Payload distribution of FDA approved ADC drugs ( Data as of Feb． 2022)MMAF: monomethyl auristatin F; PBD: pyrrolobenzodiazepine;MMAE: monomethyl auristatin E; DM1: emtansine;PE38: pseudomonas exotoxin 38．其次，结合以上已批准ADC药物的临床药理学研究情况汇总可知，一般ADC药物在上市前获得药物PK特征、E-R关系、特殊人群剂量调整、DDI以及QTc信息等。鉴于ADC药物的组成，ADC药物可能无法进行人体物质平衡研究，故已上市的ADC药物均未进行人体物质平衡研究。此外，鉴于ADC药物的给药途径为静脉给药，因此均未进行食物影响研究。对于ADC药物的PK特征，一般描述ADC药物进入人体后ADC本身、总抗体(未偶联的即未偶联到任何有效载荷分子的抗体和至少偶联一个有效载荷分子的抗体的总和)以及有效载荷的PK特征。由于ADC药物特殊的作用机制，其是将有效载荷直接递送到一个特定的部位，与使用这些有效载荷作为口服和静脉单药治疗的相比，有效载荷的系统暴露可能相对较低，因此有效载荷的PK可能无法准确的表征。例如GEMTU-ZUMAB OZOGAMICIN由于血浆中未偶联的calicheamicin的浓度较低，且只能在给药结束后短时间内测定，所以无法获得未偶联的cali-cheamicin可靠的PK特征。已上市ADC药物特殊人群的PK研究情形可分为以下几种: 一般是通过PPK的方法进行特殊人群的PK研究，经评价获得FDA的认可; 部分ADC药物进行了专门的特殊人群PK研究，经评价获得FDA的认可。例如ENFORTUMAB VEDOTIN-EJFV专门进行了一项肾损人群的PK研究; 部分ADC药物进行了肝损和/或肾损的研究，但FDA审评后建议上市后完成一项专门的肝损或肾损研究，如ADO-TRASTUZUMAB EMTANSINE由于T-DM1的暴露与三级以上的肝毒性有关，因此要求上市后进行一项肝损人群的PK研究; BELANTAMAB MAFODOTINBLMF要求上市后完成严重肾损人群和中度至重度肝损人群的PK和安全性; LONCASTUX-IMAB TESIRINE-LPYL建议上市后完成一项在中度至中度肝损人群开放、非随机、剂量递增研究，确定给药剂量并收集loncastuximab tesirine和SG3199的PK信息。已上市ADC药物的DDI研究情形如下: 75%的ADC药物进行了体外DDI研究; 部分ADC药物同时进行了体内DDI研究，如BRENTUXIMAB VEDOT-IN进行了CYP3A4药物: 咪达唑仑、利福平、酮康唑的DDI体内研究; FAM-TRASTUZUMAB DERUXTE-CAN-NXKI进行了与利托那韦(CYP3A强抑制剂和OATP抑制剂)和伊曲康唑(CYP3A的强抑制剂)的DDI体内研究; 由于与已上市产品偶联的有效载荷相同，直接借用已上市产品的DDI信息。如ENFOR-TUMAB VEDOTIN-EJFV的DDI信息来自brentux-imab vedotin; 结合PBPK和/或PPK的方法进行DDI研究，如POLATUZUMAB VEDOTIN-PIIQ，FAM-TRASTUZUMAB DERUXTECAN-NXKI等。已上市的ADC药物均进行了E-R分析和免疫原性的分析，同时已上市的ADC药物仅除MOXE-TUMOMAB PASUDOTOX-TDFK之外，均进行正式的QT评估且均采用了c-QT的方法。3讨论经汇总并评价已上市ADC药物的临床药理学研究以及上市后临床药理学的要求等，笔者发现ADC药物的研发中临床药理学需注意以下几点。3.1 最优剂量的选择12个已批准的ADC药物，除1个产品无法获得临床药理学详细资料外，其中要求上市后继续进行剂量优化的占36% (4/11)，包括ADO-TRASTUZUMAB EMTANSINE (Kadcyla)，INOTUZUMAB OZOGAMICIN (Bespon-sa)，GEMTUZUMAB OZOGAMICIN (Mylotarg)以及BELANTAMAB MAFODOTIN-BLMF (Blenrep)。进一步分析其原因，有以下几种情况: ①E-R分析显示批准的剂量不良反应发生率较高，提示较低剂量可能更优。例如Besponsa结果显示批准剂量下静脉闭塞性疾病不良反应发生率较高，但暴露与有效性的关系较为平坦，提示较低剂量可能更优。Blenrep的E-R分析显示更高的暴露或更高的剂量导致角膜检查结果和血小板减少的可能性增加，而这与疗效的相应改善无关，提示较低剂量可能更优。②确证性研究尚未完成，如Kadcy-la。③批准剂量为联合治疗，上市后进行单药剂量的研究。例如，Mylotarg首次于2000年加速批准9mg/m2单药治疗CD33阳性的急性髓系白血病患者，上市后发现致死性肝毒性和静脉闭塞性疾病(VOD)的发生率高于临床试验，因此说明书中增加黑框警告。一项确证性研究结果显示6mg/m2单药治疗时患者并未获益但导致较高的毒性，因此2022年撤市。新增一项适应症联合DNR/AraC治疗急性髓系白血病患者，给药剂量3mg/m2。同时FDA建议上市后进行单药治疗时的剂量优化研究。3.2 特殊人群的剂量调整由于ADC药物特殊的结构组成，一般相对分子质量高于肾脏排泄的60000Da临界值，因此理论上不通过肾脏清除。对于肾损害人群的PK研究一般通过临床研究中纳入部分肾损害患者采用PPK的方法进行研究。但ENFORTUMAB VEDOTIN-EJFV专门进行了一项肾损研究，可能是由于本品目标人群为尿路上皮癌，包括肾盂癌、输尿管癌、膀胱癌以及尿道癌等患者，其肾脏清除可能与一般人群不同，需开展专门的研究进行验证。由于ADC药物中有效载荷为小分子药物，一般需进行肝损害人群的PK研究。一般可通过临床研究中纳入肝损害人群进行PPK研究，但需要考虑以下方面。①纳入人群的样本量，有时由于样本量不够，可能要求上市后继续收集安全性数据或要求上市后完成一项独立的肝损害人群PK研究。例如，belantamab mafodotin临床药理学审评报告显示，PPK数据集根据NCI-ODWG标准，192例(66%)为肝功能正常患者(66%)，24例(8%)为轻度肝损害患者，2例(<1%)为中度肝损害患者，无严重肝损害患者。中度肝损害或重度肝损害的患者中进行PK稀疏采样但由于样本量有限，模拟得到的PK结果具有较大的不确定性，不能可靠地用于确定相应人群的剂量调整。因此需要在中度至重度肝损伤患者进行独立的研究以支持剂量调整; LONCASTUXIMAB TESIRINE-LPYL的PPK结果显示肝损害可能会增加未偶联的SG3199的暴露量并增加安全性风险但中度肝损害人群仅1例，重度肝损害人群0例，建议上市后完成一项在中度至中度肝损人群开放、非随机、剂量递增研究，确定给药剂量，同时收集loncastuximab tesirine和SG3199的PK; FAM-TRASTUZUMAB DERUX-TECAN-NXKI的PPK研究中仅1例中度肝损人群，FDA建议剂量可用于中度肝损伤患者，并进行密切的安全监测，要求上市后继续收集至少10例中度肝损人群的安全性数据。②结合E-R关系，基于肝损害人群暴露量的变化，说明书对部分人群进行情况区分，如限制部分人群避免使用等。例如POLATUZUMAB VE-DOTIN-PIIQ的临床试验包括肝功能正常或轻度损害的患者，PPK研究显示轻度肝损害人群中MMAE暴露AUC升高40%，Cmax升高37%，暴露量与安全性的关系显示轻度肝损害患者发生不良反应的发生率略高，但轻度损伤患者的耐受性没有显著差异。降低POLATUZUMAB VEDOTIN-PIIQ的剂量以匹配MMAE的暴露可能会导致ADC水平的降低，MMAE的暴露是有效性的主要影响因素，因此对于轻度肝损人群不建议进行剂量调整。但由于没有中度或重度肝损害患者的数据，且根据同类药物的临床经验，肝损害水平增加的患者不良事件发生率有增加的趋势。因此，建议对中度或重度肝损害的患者避免使用。③结合E-R关系，如显示肝损害可能会增加增加安全性风险，考虑在上市后要求进行一项独立的肝损害人群的PK研究。例如LONCASTUX-IMAB TESIRINE-LPYL的PPK研究显示肝损伤可能会增加未偶联的SG3199的暴露量并增加安全性风险且中度1例，重度0例。上市后完成一项在中度至中度肝损人群开放、非随机、剂量递增研究，确定给药剂量同时收集loncastuximab tesirine和SG3199的PK。3.3 充分利用已知信息ADC药物一般由3个部分组成，且有效载荷是发挥ADC药物抗肿瘤有效性的重要组成部分。多个ADC药物偶联了相同的有效载荷，因此对于偶联相同的有效载荷的ADC药物可以借用既往产品的DDI信息，特殊人群信息等，同时结合自身的E-R关系等评价是否需要进行剂量调整或用药人群的限制等。例如，在评价Fam-trastuzumab deruxtecan中度肝损害患者是否需要剂量调整时，基于以下几点进行考虑: 目前还没有人体质量平衡研究来确定MAAA-118a的主要消除途径。根据大鼠的研究，超过70%的MAAA-1181a在肝脏中代谢，提示肝脏是主要的消除途径。但是，在DDI研究 (Study A104)中，联合使用伊曲康唑(强CYP3A抑制剂)或利托那韦(CYP3A和OATP1B抑制剂)并没有增加MAAA-1181a的暴露量。这些数据间接表明，在中度肝损害的患者中，MAAA-1181a暴露增加的风险较低。目前缺乏有效性数据支持对中度肝损害患者的剂量调整。低于5.4mg/kg剂量的数据有限，无法评估低剂量下有效性是否维持不变。Fam-trastuzumab deruxtecan在推荐剂量下可耐受，标签上包含足够的安全监测计划。在剂量为5.4mg/kg (12%)和≥为6.4mg/kg (23%)时，观察到肝脏AST/ALT/ALT水平升高，但低于其他批准的类似抗体药物偶联物T-DM1，即79%。同时在当前的说明书中有足够的剂量调整计划进而监测药物安全性。基于上述理由，FDA建议对中度肝损害的患者不调整剂量。然而，FDA建议申请人在正在进行的试验中收集至少10名中度肝损害患者的安全数据，并在最终的分析报告中提交这些数据。此外，在说明书撰写时也需同时考虑既往与之相同的有效载荷产品的信息。例如ENFOR-TUMAB VEDOTIN-EJFV与BRENTUXIMAB VE-DOTIN含有相同的有效载荷，后者在中度和重度肝损人群中3级以上不良反应发生率和死亡率较高，因此前者说明书中提示中度或重度肝损人群避免使用; 同时考虑说明书的一致性，前者说明书中同样提示“本品与CYP3A4抑制剂合用时需进行紧密监测”。3.4 其他对于采用PPK进行DDI研究，如指导原则要求，需详细记录合并用药等情况。例如，LON-CASTUXIMAB TESIRINE-LPYL在评价DDI时由于未记录给药情况，给DDI评价带来不确定性。由于ADC药物的免疫反应可以由ADC的任何组成部分，包括抗体、有效载荷，或由偶联连接子产生。因此在ADC研发过程中需特别关注免疫反应的发生。由于ADC药物组成较为复杂，具有独特的PK特征，因此PPK模型的建立需进行充分的验证以更好的支持暴露量模拟; 同时，由于抗肿瘤药物剂量选择由传统的寻找最大耐受剂量转向最优剂量的选择，建议充分考虑确定最优剂量的全部信息，尽早结合E-R关系进行科学评价，并对特殊人群剂量调整给出科学建议。ADC药物是目前发展最快的抗癌药物之一。国内已有多个ADC药物获批上市，如荣昌生物的维迪西妥单抗、云顶新耀的戈沙妥珠单抗等，并有多个ADC药物处在临床开发阶段。由于ADC药物的组成和作用机制，其具有复杂的PK特征、肿瘤靶向以及不可避免的副作用等特点，临床药理学研究结合药物PK以及E-R分析对ADC的剂量选择以及特殊人群的剂量调整等方面发挥着重要的作用。望本文可以给相关ADC药物临床药理学研究人员提供启示和研究思路。参考文献详见 《中国临床药理学与治疗学》  2023  Jan; 28(1)文章信息源于公众号凡默谷，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。学如逆水行舟，不进则退；心似平原走马，易放难收。行舟Drug每日更新 欢迎订阅+医药大数据|行业动态|政策解读

LAVAL, QC / ACCESSWIRE / October 24, 2022 / Bausch Health Companies Inc. (NYSE:BHC)(TSX:BHC) ("Bausch Health") and its gastroenterology business, Salix Pharmaceuticals, Ltd. ("Salix"), today announced four posters and one abstract featuring data for XIFAXAN® (rifaximin), TRULANCE® (plecanatide) and RELISTOR® (methylnaltrexone bromide) that are being presented at the American College of Gastroenterology® (ACG) 2022 Annual Scientific Meeting, which is taking place October 21-26 in Charlotte, North Carolina. The complete list of Salix research being featured at ACG 2022 includes: XIFAXAN Staller, Kyle et al. "The Strong Association Between Bloating, Abdominal Pain, and Global Irritable Bowel Syndrome Symptom Scores in IBS With Diarrhea: A Phase 3 Trial Pooled Correlation Analysis of Individual Symptoms." Cash, Brooks D. et al. "Rifaximin Improves Both Fecal Urgency and Stool Consistency in Adults With Irritable Bowel Syndrome With Diarrhea: A Composite Endpoint Analysis of Two Randomized, Phase 3 Trials." TRULANCE Sayuk, Gregory S. et al. "Plecanatide Improves Severe Abdominal Pain and Severe Bloating in Individuals With Irritable Bowel Syndrome With Constipation: A Pooled Analysis of Two Phase 3 Trials." Staller, Kyle et al. "Plecanatide Improves Symptoms of Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation Across Age Subgroups: an Analysis of Four Phase 3 Trials." RELISTOR Shah, Mehta N, et al. "Impact of Patient Subgroups on the Efficacy and Safety of Methylnaltrexone for Opioid-induced Constipation in Patients With Advanced Illness." About XIFAXAN® Indications XIFAXAN® (rifaximin) 550 mg tablets are indicated for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults and for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. IMPORTANT SAFETY INFORMATION XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. There is an increased systemic exposure in patients with severe (Child-Pugh Class C) hepatic impairment. Caution should be exercised when administering XIFAXAN to these patients. Caution should be exercised when concomitant use of XIFAXAN and P-glycoprotein (P-gp) and/or OATPs inhibitors is needed. Concomitant administration of cyclosporine, an inhibitor of P-gp and OATPs, significantly increased the systemic exposure of rifaximin. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-gp inhibitors may further increase the systemic exposure to rifaximin. In clinical studies, the most common adverse reactions for XIFAXAN were: HE (≥10%): Peripheral edema (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%) IBS-D (≥2%): Nausea (3%), ALT increased (2%) INR changes have been reported in patients receiving rifaximin and warfarin concomitantly. Monitor INR and prothrombin time. Dose adjustment of warfarin may be required. XIFAXAN may cause fetal harm. Advise pregnant women of the potential risk to a fetus. To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or . Please click here for full Prescribing Information. About TRULANCE Indication Trulance (plecanatide) 3 mg tablets is indicated in adults for the treatment of Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C). IMPORTANT SAFETY INFORMATION WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS Trulance® is contraindicated in patients less than 6 years of age; in nonclinical studies in young juvenile mice administration of a single oral dose of plecanatide caused deaths due to dehydration. Use of Trulance should be avoided in patients 6 years to less than 18 years of age. The safety and efficacy of Trulance have not been established in pediatric patients less than 18 years of age. Contraindications Trulance is contraindicated in patients less than 6 years of age due to the risk of serious dehydration. Trulance is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. Warnings and Precautions Risk of Serious Dehydration in Pediatric Patients Trulance is contraindicated in patients less than 6 years of age. The safety and effectiveness of Trulance in patients less than 18 years of age have not been established. In young juvenile mice (human age equivalent of approximately 1 month to less than 2 years), plecanatide increased fluid secretion as a consequence of stimulation of guanylate cyclase-C (GC-C), resulting in mortality in some mice within the first 24 hours, apparently due to dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than older patients to develop severe diarrhea and its potentially serious consequences. Use of Trulance should be avoided in patients 6 years to less than 18 years of age. Although there were no deaths in older juvenile mice, given the deaths in young mice and the lack of clinical safety and efficacy data in pediatric patients, use of Trulance should be avoided in patients 6 years to less than 18 years of age. Diarrhea Diarrhea was the most common adverse reaction in the four placebo-controlled clinical trials for CIC and IBS-C. Severe diarrhea was reported in 0.6% of Trulance-treated CIC patients, and in 1% of Trulance-treated IBS-C patients. If severe diarrhea occurs, the health care provider should suspend dosing and rehydrate the patient. Adverse Reactions In the two combined CIC clinical trials, the most common adverse reaction in Trulance-treated patients (incidence ≥2% and greater than in the placebo group) was diarrhea (5% vs 1% placebo). In the two combined IBS-C clinical trials, the most common adverse reaction in Trulance-treated patients (incidence ≥2% and greater than in the placebo group) was diarrhea (4.3% vs 1% placebo). Please also see the full Prescribing Information, including BOXED Warning, for additional risk information. About RELISTOR INDICATIONS RELISTOR® (methylnaltrexone bromide) is an opioid antagonist. RELISTOR tablets and RELISTOR injection are indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. RELISTOR injection is also indicated for the treatment of OIC in adults with advanced illness or pain caused by active cancer who require opioid dosage escalation for palliative care. IMPORTANT SAFETY INFORMATION RELISTOR tablets and injection are contraindicated in patients with known or suspected mechanical gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation. Cases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie's syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit pro using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn's disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their healthcare provider. Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia and should be monitored for adequacy of analgesia and symptoms of opioid withdrawal. Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal. The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with RELISTOR. In nursing mothers, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. A dosage reduction of RELISTOR tablets and RELISTOR injection is recommended in patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault). No dosage adjustment of RELISTOR tablets or RELISTOR injection is needed in patients with mild renal impairment. A dosage reduction of RELISTOR tablets is recommended in patients with moderate (Child-Pugh Class B) or severe (Child- Pugh Class C) hepatic impairment. No dosage adjustment of RELISTOR tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A). No dosage adjustment of RELISTOR injection is needed for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, monitor for methylnaltrexone-related adverse reactions and dose adjust per Prescribing Information as may be indicated. In the clinical studies, the most common adverse reactions were: OIC in adult patients with chronic non-cancer pain RELISTOR tablets (≥ 2% of RELISTOR patients and at a greater incidence than placebo): abdominal pain (14%), diarrhea (5%), headache (4%), abdominal distention (4%), vomiting (3%),hyperhidrosis (3%),anxiety (2%), muscle spasms (2%), rhinorrhea (2%), and chills (2%). RELISTOR injection (≥ 1% of RELISTOR patients and at a greater incidence than placebo): abdominal pain (21%), nausea (9%),diarrhea (6%), hyperhidrosis (6%), hot flush (3%),tremor (1%), and chills (1%). OIC in adult patients with advanced illness RELISTOR injection (≥ 5% of RELISTOR patients and at a greater incidence than placebo): abdominal pain (29%) flatulence (13%), nausea (12%),dizziness (7%), and diarrhea (6%). To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800- FDA-1088 or [Please click here for full Prescribing Information for RELISTOR tablets and RELISTOR injection.] OR [Please see accompanying full Prescribing Information for RELISTOR tablets and RELISTOR injection.] About Salix Salix Pharmaceuticals is one of the largest specialty pharmaceutical companies in the world committed to the prevention and treatment of gastrointestinal diseases. For more than 30 years, Salix has licensed, developed and marketed innovative products to improve patients' lives and arm health care providers with life-changing solutions for many chronic and debilitating conditions. Salix currently markets its product line to U.S. health care providers through an expanded sales force that focuses on gastroenterology, hepatology, pain specialists and primary care. Salix is headquartered in Bridgewater, New Jersey. For more information about Salix, visit and connect with us on Twitter and LinkedIn. About Bausch Health Bausch Health Companies Inc. (NYSE/TSX:BHC) is a global diversified pharmaceutical company whose mission is to improve people's lives with our health care products. We develop, manufacture and market a range of products primarily in gastroenterology, hepatology, neurology, dermatology, international pharmaceuticals and eye health, through our controlling ownership interest in Bausch + Lomb. With our leading durable brands, we are delivering on our commitments as we build an innovative company dedicated to advancing global health. Forward-looking Statements This news release may contain forward-looking statements about the future performance of the Company, which may generally be identified by the use of the words "anticipates," "hopes," "expects," "intends," "plans," "should," "could," "would," "may," "believes," "subject to" and variations or similar expressions. These statements are based upon the current expectations and beliefs of management and are subject to certain risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Actual results are subject to other risks and uncertainties that relate more broadly to the Company's overall business, including those more fully described in the Company's most recent annual report on Form 10-K and detailed from time to time in the Company's other filings with the U.S. Securities and Exchange Commission and the Canadian securities administrators, which factors are incorporated herein by reference. Investor Contact: Christina Cheng ir@bauschhealth.com (514) 856-3855 (877) 281-6642 (toll free) Media Contact: Kevin Wiggins corporate.communications@bauschhealth.com (908) 541-3785 Gianna Scalera salixcommunications@bauschhealth.com (908) 541-2110 ©2022 Salix Pharmaceuticals or its affiliates. TRULANCE and RELISTOR are trademarks of Salix Pharmaceuticals or its affiliates. The XIFAXAN 550 mg product and the XIFAXAN trademark are licensed by Alfasigma S.p.A. to Salix Pharmaceuticals or its affiliates. SAL.0113.USA.22 SOURCE: Bausch Health Companies Inc. View source version on accesswire.com:

Bausch Health logo (PRNewsfoto/Bausch Health Companies Inc.) LAVAL, QC, June 20, 2022 /PRNewswire/ -- Bausch Health Companies Inc. (NYSE/TSX: BHC) ("Bausch Health") and its gastroenterology business, Salix Pharmaceuticals, ("Salix"), one of the largest specialty pharmaceutical companies in the world committed to the prevention and treatment of gastrointestinal (GI) and liver diseases and disorders, today announced its presence at the European Association for the Study of the Liver's (EASL) International Liver Congress™ (ILC) 2022 through the presentation of new XIFAXAN® (rifaximin) data that was selected for inclusion in the program. ILC 2022 is being held virtually and in-person in London, United Kingdom, from June 22-26, 2022. The data will be presented in the Cirrhosis and its complications session on Saturday, June 25, 2022. "As a leading pharmaceutical company specializing in hepatology, Salix continues to invest in research and development to address the scientific and clinical unmet needs in liver disease. We continue our close collaboration with the medical community to advance treatment of life-threatening conditions such as overt hepatic encephalopathy (OHE), improve standard of care and quality of life of liver patients. To this end, the work to be presented at EASL highlights the fact that early identification and management of OHE precipitating factors is an important component of an overall disease management strategy to reduce the risk of OHE recurrence and HE-related hospitalizations," said Tage Ramakrishna, M.D., chief medical officer and president of Research & Development, Bausch Health. The research to be featured at ILC 2022 and available via the meeting's online platform is as follows: XIFAXAN Bajaj, Jasmohan S. et al. "Identification of overt hepatic encephalopathy precipitating factors: a pooled analysis of 3 clinical trials of rifaximin plus lactulose" Poster #SAT517 About XIFAXAN XIFAXAN® (rifaximin) 550 mg tablets are indicated for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults and for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. IMPORTANT SAFETY INFORMATION XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. There is an increased systemic exposure in patients with severe (Child-Pugh Class C) hepatic impairment. Caution should be exercised when administering XIFAXAN to these patients. Caution should be exercised when concomitant use of XIFAXAN and P-glycoprotein (P-gp) and/or OATPs inhibitors is needed. Concomitant administration of cyclosporine, an inhibitor of P-gp and OATPs, significantly increased the systemic exposure of rifaximin. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-gp inhibitors may further increase the systemic exposure to rifaximin. In clinical studies, the most common adverse reactions for XIFAXAN were: HE (≥10%): Peripheral edema (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%) IBS-D (≥2%): Nausea (3%), ALT increased (2%) INR changes have been reported in patients receiving rifaximin and warfarin concomitantly. Monitor INR and prothrombin time. Dose adjustment of warfarin may be required. XIFAXAN may cause fetal harm. Advise pregnant women of the potential risk to a fetus. To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or . Please click here for full Prescribing Information. About Salix Salix Pharmaceuticals is one of the largest specialty pharmaceutical companies in the world committed to the prevention and treatment of gastrointestinal diseases. For more than 30 years, Salix has licensed, developed and marketed innovative products to improve patients' lives and arm health care providers with life-changing solutions for many chronic and debilitating conditions. Salix currently markets its product line to U.S. health care providers through an expanded sales force that focuses on gastroenterology, hepatology, pain specialists and primary care. Salix is headquartered in Bridgewater, New Jersey. For more information about Salix, visit and connect with us on Twitter and LinkedIn. About Bausch Health Bausch Health Companies Inc. (NYSE/TSX: BHC) is a global diversified pharmaceutical company whose mission is to improve people's lives with our health care products. We develop, manufacture and market a range of products primarily in gastroenterology, hepatology, neurology, dermatology, international pharmaceuticals and eye health, through our 90% ownership of Bausch + Lomb Corporation. With our leading durable brands, we are delivering on our commitments as we build an innovative company dedicated to advancing global health. For more information, visit and connect with us on Twitter and LinkedIn. Forward-looking Statements This news release may contain forward-looking statements, which may generally be identified by the use of the words "anticipates," "hopes," "expects," "intends," "plans," "should," "could," "would," "may," "believes," "estimates," "potential," "target," or "continue" and variations or similar expressions. These statements are based upon the current expectations and beliefs of management and are subject to certain risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. These risks and uncertainties include, but are not limited to, the risks and uncertainties discussed in the Bausch Health Companies Inc.'s (Bausch Health) most recent annual report on Form 10-K and detailed from time to time in Bausch Health's other filings with the U.S. Securities and Exchange Commission and the Canadian Securities Administrators, which factors are incorporated herein by reference. They also include, but are not limited to, risks and uncertainties caused by or relating to the evolving COVID-19 pandemic, and the fear of that pandemic and its potential effects, the severity, duration, and future impact of which are highly uncertain and cannot be predicted, and which may have a material adverse impact on Bausch Health, including but not limited to its project development timelines, and costs (which may increase). Readers are cautioned not to place undue reliance on any of these forward-looking statements. These forward-looking statements speak only as of the date hereof. Bausch Health undertakes no obligation to update any of these forward-looking statements to reflect events or circumstances after the date of this news release or to reflect actual outcomes, unless required by law. The XIFAXAN 550 mg product and the XIFAXAN trademark are licensed by Alfasigma S.p.A. to Salix Pharmaceuticals and its affiliates. ©2022 Salix Pharmaceuticals or its affiliates. SAL.0083.USA.22 Investor Contact: Christina Cheng [email protected] (514) 856-3855 (877) 281-6642 (toll free) Media Contact: Lainie Keller [email protected] (908) 927-1198 Gianna Scalera [email protected] 908-541-2110 SOURCE Bausch Health Companies Inc.