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Use cases of registry-based randomized controlled trials-A review of the registries' contributions and constraints. 基于登记册的随机对照试验用例--对登记册的贡献和制约因素的审查。
IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 DOI: 10.1111/cts.70072
Nadine Kubesch, Sneha Gaitonde, Uarda Petriti, Elisabeth Bakker, Swati Basu, Laura Ellen Birks, Elodie Aubrun, Sieta T de Vries, Rahel Schneider

Registry-based randomized controlled trials (RRCTs) can combine the advantages of registries with those of randomization. This review aimed to expand the current knowledge on RRCT utilization and implementation by providing a comprehensive overview of RRCT use cases. A targeted literature search was conducted through July 2023 to identify articles on RRCTs. Information regarding the RRCT characteristics, their utilization, and the registries' contributions and the constraints faced was extracted. Descriptive statistics were used. We identified 102 RRCTs in 110 publications. RRCTs were mostly performed for the assessment of medical devices or surgical/clinical procedures (n = 45), followed by drugs (n = 30). More than half of the RRCTs were conducted in the Nordic countries (n = 58) and the most used registry types were health service registries/administrative health data (n = 63), followed by disease registries (n = 46). Approximately half of the RRCTs (n = 53) utilized additional data sources aside from registry data. The contribution of a registry to the RRCT was mostly for data collection and study follow-up (n = 90-92), followed by patient recruitment (n = 56-61), and randomization (n = 28-38), with varying levels of transparency in reporting. We collated author-reported constraints related to the used registries into four overarching themes, that is, data availability and completeness, data quality, representativeness, and registry infrastructure and accessibility. This review shows that RRCTs are already used in different domains and geographic regions. Guidelines on structured and transparent reporting of RRCT methods and the optimal use are, however, needed to inform decision-making by health authorities and to reach their full potential.

基于登记处的随机对照试验(RRCT)可以将登记处的优势与随机化的优势结合起来。本综述旨在通过全面概述RRCT的使用案例,扩展目前有关RRCT使用和实施的知识。我们在 2023 年 7 月之前进行了一次有针对性的文献检索,以确定有关 RRCT 的文章。提取了有关 RRCT 特征、其利用情况、登记处的贡献以及所面临的制约因素的信息。我们使用了描述性统计方法。我们在 110 篇出版物中发现了 102 项 RRCT。RRCT大多用于评估医疗器械或手术/临床程序(n = 45),其次是药物(n = 30)。一半以上的 RRCT 在北欧国家进行(n = 58),使用最多的登记类型是医疗服务登记/行政健康数据(n = 63),其次是疾病登记(n = 46)。大约一半的 RRCT(n = 53)利用了登记册数据以外的其他数据源。登记处对 RRCT 的贡献主要是数据收集和研究随访(90-92 例),其次是患者招募(56-61 例)和随机化(28-38 例),报告的透明度各不相同。我们将作者报告的与所使用登记处相关的限制因素整理为四大主题,即数据可用性和完整性、数据质量、代表性以及登记处基础设施和可访问性。此次审查表明,RRCT 已在不同领域和地理区域得到应用。然而,需要制定有关 RRCT 方法的结构化和透明报告以及最佳使用的准则,以便为卫生当局的决策提供信息,并充分发挥其潜力。
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引用次数: 0
Serum creatine kinase elevation following tyrosine kinase inhibitor treatment in cancer patients: Symptoms, mechanism, and clinical management 癌症患者接受酪氨酸激酶抑制剂治疗后血清肌酸激酶升高:症状、机制和临床处理。
IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-29 DOI: 10.1111/cts.70053
Hang Zhang, Kenneth K. W. To

Molecular targeted tyrosine kinase inhibitors (TKIs) have produced unprecedented treatment response in cancer therapy for patients harboring specific oncogenic mutations. While the TKIs are mostly well tolerated, they were reported to increase serum levels of creatine kinase (CK) and cause muscle metabolism-related toxicity. CK is an essential enzyme involved in cellular energy metabolism and muscle function. Elevated serum CK levels can arise from both physiological and pathological factors, as well as triggered by specific drug classes. The incidence of serum CK elevation induced by a few approved TKIs (brigatinib, binimetinib, cobimetinib-vemurafenib combination [Food and Drug Administration, United States]; aumolertinib, and sunvozertinib [only approved by National Medical Products Administration, China]) were over 35%. CK elevation-related symptoms include myopathy, myositis, inclusion body myositis (IBM), cardiotoxicity, rhabdomyolysis, rash, and acneiform dermatitis. High-level or severe symptomatic CK elevation may necessitate dose reduction and indirectly dampen TKI efficacy. This review presents an updated summary about the prevalence rate and recent research about mechanisms leading to TKI-induced serum CK elevation in cancer patients. The utility of monitoring serum CK levels for predicting TKI-induced adverse effects and their management will also be discussed.

分子靶向酪氨酸激酶抑制剂(TKIs)在癌症治疗中对携带特定致癌突变的患者产生了前所未有的治疗效果。虽然 TKIs 大多耐受性良好,但有报道称它们会增加血清中肌酸激酶(CK)的水平,并导致与肌肉代谢相关的毒性。肌酸激酶是一种参与细胞能量代谢和肌肉功能的重要酶。血清肌酸激酶水平升高可由生理和病理因素引起,也可由特定类别的药物引发。少数已获批准的 TKIs(brigatinib、binimetinib、cobimetinib-vemurafenib 组合[美国食品药品管理局];aumolertinib 和 sunvozertinib [仅获中国国家医药产品管理局批准])诱发血清 CK 升高的发生率超过 35%。CK升高相关症状包括肌病、肌炎、包涵体肌炎(IBM)、心脏毒性、横纹肌溶解、皮疹和痤疮样皮炎。高水平或严重的无症状 CK 升高可能需要减少剂量,并间接影响 TKI 的疗效。本综述总结了癌症患者中 TKI 诱导血清 CK 升高的患病率和最新研究机制。此外,还将讨论监测血清 CK 水平对于预测 TKI 引起的不良反应及其处理的实用性。
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引用次数: 0
Practical guide to SHAP analysis: Explaining supervised machine learning model predictions in drug development SHAP 分析实用指南:解释药物开发中的监督机器学习模型预测。
IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-28 DOI: 10.1111/cts.70056
Ana Victoria Ponce-Bobadilla, Vanessa Schmitt, Corinna S. Maier, Sven Mensing, Sven Stodtmann

Despite increasing interest in using Artificial Intelligence (AI) and Machine Learning (ML) models for drug development, effectively interpreting their predictions remains a challenge, which limits their impact on clinical decisions. We address this issue by providing a practical guide to SHapley Additive exPlanations (SHAP), a popular feature-based interpretability method, which can be seamlessly integrated into supervised ML models to gain a deeper understanding of their predictions, thereby enhancing their transparency and trustworthiness. This tutorial focuses on the application of SHAP analysis to standard ML black-box models for regression and classification problems. We provide an overview of various visualization plots and their interpretation, available software for implementing SHAP, and highlight best practices, as well as special considerations, when dealing with binary endpoints and time-series models. To enhance the reader's understanding for the method, we also apply it to inherently explainable regression models. Finally, we discuss the limitations and ongoing advancements aimed at tackling the current drawbacks of the method.

尽管人们对将人工智能(AI)和机器学习(ML)模型用于药物开发的兴趣与日俱增,但有效解释这些模型的预测仍然是一项挑战,这限制了它们对临床决策的影响。为了解决这个问题,我们提供了一份有关 SHapley Additive exPlanations(SHAP)的实用指南,这是一种流行的基于特征的可解释性方法,可以无缝集成到有监督的 ML 模型中,以深入了解其预测结果,从而提高其透明度和可信度。本教程侧重于将 SHAP 分析应用于回归和分类问题的标准 ML 黑盒模型。我们将概述各种可视化图及其解释、用于实施 SHAP 的可用软件,并重点介绍在处理二进制端点和时间序列模型时的最佳实践和特殊注意事项。为了加深读者对该方法的理解,我们还将其应用于内在可解释回归模型。最后,我们讨论了该方法的局限性和正在取得的进展,旨在解决该方法目前存在的缺点。
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引用次数: 0
Thai pharmacogenomics database −2 (TPGxD-2) sequel to TPGxD-1, analyzing genetic variants in 26 non-VIPGx genes within the Thai population 泰国药物基因组学数据库-2(TPGxD-2)是 TPGxD-1 的续集,分析泰国人口中 26 个非 VIPGx 基因的遗传变异。
IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-25 DOI: 10.1111/cts.70019
Shobana John, Sommon Klumsathian, Paravee Own-eium, Angkana Charoenyingwattana, Jakris Eu-ahsunthornwattana, Thanyachai Sura, Donniphat Dejsuphong, Piyamitr Sritara, Prin Vathesatogkit, Nartthawee Thongchompoo, Wiphaporn Thabthimthong, Nuttinee Teerakulkittipong, Wasun Chantratita, Chonlaphat Sukasem

Next-generation sequencing (NGS) has transformed pharmacogenomics (PGx), enabling thorough profiling of pharmacogenes using computational methods and advancing personalized medicine. The Thai Pharmacogenomic Database-2 (TPGxD-2) analyzed 948 whole genome sequences, primarily from the Electricity Generating Authority of Thailand (EGAT) cohort. This study is an extension of the previous Thai Pharmacogenomic Database (TPGxD-1) and specifically focused on 26 non-very important pharmacogenes (VIPGx) genes. Variant calling was conducted using Sentieon (version 201808.08) following GATK's best workflow practices. We then annotated variant call format (VCF) files using Golden Helix VarSeq 2.5.0. Star allele analysis was performed with Stargazer v2.0.2, which called star alleles for 22 of 26 non-VIPGx genes. The variant analysis revealed a total of 14,529 variants in 26 non-VIPGx genes, with TBXAS1 had the highest number of variants (27%). Among the 14,529 variants, 2328 were novel (without rsID), with 87 identified as clinically relevant. We also found 56 known PGx variants among the known variants (n = 12,201), with UGT2B7 (19.64%), CYP1B1 (8.9%), SLCO2B1 (8.9%), and POR (8.9%) being the most common. We reported a high frequency of intermediate metabolizers (IMs) in CYP2F1 (34.6%) and CYP4A11 (8.6%), and a high frequency of decreased functional alleles in POR (53.9%) and SLCO1B3 (34.9%) genes. This study enhances our understanding of pharmacogenomic profiling of 26 non-VIPGx genes of notable clinical importance in the Thai population. However, further validation with additional computational and reference genotyping methods is necessary, and novel alleles identified in this study should undergo further orthogonal validation.

下一代测序(NGS)改变了药物基因组学(PGx),利用计算方法实现了对药物基因的全面分析,推动了个性化医疗的发展。泰国药物基因组数据库-2(TPGxD-2)分析了 948 个全基因组序列,主要来自泰国发电局(EGAT)的队列。该研究是之前泰国药物基因组数据库(TPGxD-1)的延伸,特别关注 26 个非非常重要的药物基因(VIPGx)。我们按照 GATK 的最佳工作流程实践,使用 Sentieon(201808.08 版)进行了变异调用。然后,我们使用 Golden Helix VarSeq 2.5.0 对变异调用格式 (VCF) 文件进行了注释。我们使用 Stargazer v2.0.2 对 26 个非 VIPGx 基因中的 22 个基因进行了明星等位基因分析。变异分析显示,26 个非 VIPGx 基因中共有 14,529 个变异,其中 TBXAS1 的变异数最多(27%)。在这 14529 个变异中,有 2328 个是新变异(无 rsID),其中 87 个被确定为临床相关变异。在已知变异(n = 12,201)中,我们还发现了 56 个已知的 PGx 变异,其中 UGT2B7(19.64%)、CYP1B1(8.9%)、SLCO2B1(8.9%)和 POR(8.9%)最为常见。我们发现,CYP2F1(34.6%)和 CYP4A11(8.6%)基因的中间代谢者(IMs)频率较高,而 POR(53.9%)和 SLCO1B3(34.9%)基因的功能减弱等位基因频率较高。这项研究加深了我们对泰国人群中 26 个具有显著临床重要性的非 VIPGx 基因的药物基因组分析的了解。然而,有必要使用更多的计算和参考基因分型方法进行进一步验证,本研究中发现的新等位基因也应进行进一步的正交验证。
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引用次数: 0
Absolute oral bioavailability of milvexian spray-dried dispersion formulation under fasted and fed conditions in healthy adult participants: An intravenous microtracer approach 健康成年参与者在空腹和进食条件下口服米维仙喷雾干燥分散制剂的绝对生物利用度:静脉微示踪法
IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-25 DOI: 10.1111/cts.70058
Praneeth Jarugula, Sharif Soleman, Hyunmoon Back, Lisa J. Christopher, Dara Hawthorne, Ronald Aronson, Anh Bui, Angela Mirzac, Antoinette Ajavon-Hartmann, Vidya Perera, Bindu Murthy, Samira Merali

Milvexian is an oral, small-molecule factor XIa inhibitor being developed to prevent thromboembolic events. This study assessed the absolute bioavailability (F) of milvexian following single doses of milvexian spray-dried dispersion (SDD) formulation under fed and fasted conditions, and milvexian solution, in healthy adult participants using an intravenous microtracer approach. This was a phase I, open-label, partially randomized, 4-sequence, 5-period crossover study. After fasting for ≥10 h, participants received milvexian 200-mg oral solution with a 100-μg 14C milvexian intravenous microtracer at the time of maximum observed plasma concentration. Following a 3-day washout, participants were randomized to 1 of 4 milvexian SDD treatment sequences in a crossover fashion: 25 mg fasted, 25 mg fed, 200 mg fasted, or 200 mg fed. Pharmacokinetic data were collected up to 72 h postdose. Seventeen participants were dosed, and 14 completed treatment. Under fasted conditions, milvexian F was ~100%, 58.2%, and 54.2% following administration of the oral solution, 25 mg SDD, and 200 mg SDD, respectively. Under fed conditions, milvexian F following 25 mg and 200 mg SDD was 44.3% and 75.6%, respectively. The milvexian SDD formulation at 25 mg and 200 mg resulted in similar F in a fasted state; under fed conditions, milvexian F decreased at 25 mg and increased at 200 mg. These findings clarify pharmacokinetic-related gaps observed in previous studies.

Milvexian 是一种口服小分子 XIa 因子抑制剂,正在开发用于预防血栓栓塞事件。本研究采用静脉微量示踪法评估了健康成年参与者在进食和禁食条件下单次服用米维仙喷雾干燥分散体(SDD)制剂和米维仙溶液后的米维仙绝对生物利用度(F)。这是一项 I 期、开放标签、部分随机、4 序 5 期交叉研究。参与者禁食≥10小时后,在观察到血浆浓度最大值时接受米维仙200毫克口服溶液和100微克14C米维仙静脉微示踪剂。经过 3 天的冲洗后,参与者以交叉方式被随机分配到 4 种米维仙 SDD 治疗序列中的一种:25 毫克空腹、25 毫克进食、200 毫克空腹或 200 毫克进食。药代动力学数据收集至服药后 72 小时。17 名参与者接受了给药,其中 14 人完成了治疗。在空腹条件下,服用口服溶液、25 毫克 SDD 和 200 毫克 SDD 后,米维仙 F 分别为 ~100%、58.2% 和 54.2%。在进食条件下,服用 25 毫克和 200 毫克 SDD 后的 Milvexian F 分别为 44.3% 和 75.6%。在空腹状态下,25 毫克和 200 毫克的米维仙 SDD 制剂产生的 F 值相似;在进食状态下,25 毫克的米维仙 F 值降低,200 毫克的米维仙 F 值升高。这些发现澄清了以往研究中观察到的药代动力学相关差距。
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引用次数: 0
Asia-inclusive drug development leveraging principles of ICH E5 and E17 guidelines: Case studies illustrating quantitative clinical pharmacology as a foundational enabler 利用 ICH E5 和 E17 指南的原则进行亚洲包容性药物开发:案例研究说明定量临床药理学是基础性的推动因素。
IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-24 DOI: 10.1111/cts.70050
Hong Lu, Lena Klopp-Schulze, Jatinder Kaur Mukker, Dandan Li, Yoshihiro Kuroki, Jayaprakasam Bolleddula, Nadia Terranova, Kosalaram Goteti, Wei Gao, Rainer Strotmann, Jennifer Dong, Karthik Venkatakrishnan

With the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guidelines in effect from 2018, the design of Asia-inclusive multiregional clinical trials (MRCTs) has been streamlined, thereby enabling efficient simultaneous global development. Furthermore, with the recent regulatory reforms in China and its drug administration joining the ICH as a full regulatory member, early participation of China in the global clinical development of novel investigational drugs is now feasible. This would also allow for inclusion of the region in the geographic footprint of pivotal MRCTs leveraging principles of the ICH E5 and E17. Herein, we describe recent case examples of model-informed Asia-inclusive global clinical development in the EMD Serono portfolio, as applied to the ataxia telangiectasia and Rad3-related inhibitors, tuvusertib and berzosertib (oncology), the toll-like receptor 7/8 antagonist, enpatoran (autoimmune diseases), the mesenchymal–epithelial transition factor inhibitor tepotinib (oncology), and the antimetabolite cladribine (neuroimmunological disease). Through these case studies, we illustrate pragmatic approaches to ethnic sensitivity assessments and the application of a model-informed drug development toolkit including population pharmacokinetic/pharmacodynamic modeling and pharmacometric disease progression modeling and simulation to enable early conduct of Asia-inclusive MRCTs. These examples demonstrate the value of a Totality of Evidence approach where every patient's data matter for de-risking ethnic sensitivity to inter-population variations in drug- and disease-related intrinsic and extrinsic factors, enabling inclusive global development strategies and timely evidence generation for characterizing benefit/risk of the proposed dosage in Asian populations.

随着国际人用药品技术要求协调会议(ICH)E17 指南从 2018 年起生效,亚洲包容性多区域临床试验(MRCT)的设计得到简化,从而实现了高效的全球同步开发。此外,随着中国近期的监管改革以及中国药监局作为正式监管成员加入 ICH,中国尽早参与全球新型研究药物的临床开发已成为可能。这也使得该地区可以利用 ICH E5 和 E17 的原则,纳入关键 MRCT 的地域范围。在此,我们将介绍EMD雪兰诺公司最近在共济失调性毛细血管扩张症和Rad3相关抑制剂tuvusertib和berzosertib(肿瘤)的全球临床开发中采用亚洲包容性模式的案例、tuvusertib和berzosertib(肿瘤学)、收费样受体7/8拮抗剂恩帕坦(自身免疫性疾病)、间充质-上皮转化因子抑制剂特罗替尼(肿瘤学)以及抗代谢药物克拉德里滨(神经免疫性疾病)。通过这些案例研究,我们说明了种族敏感性评估的实用方法,以及模型信息药物开发工具包的应用,包括群体药代动力学/药效学建模和药物计量学疾病进展建模和模拟,以便尽早开展亚洲包容性 MRCT。这些例子证明了 "证据整体性 "方法的价值,在这种方法中,每个患者的数据都很重要,可用于降低种族对药物和疾病相关的内在和外在因素的人群间差异的敏感性,从而实现包容性的全球开发战略,并及时生成证据,以确定拟议剂量在亚洲人群中的获益/风险特征。
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引用次数: 0
Mevalonate in blood and muscle: Response to atorvastatin treatment and the relationship to statin intolerance in patients with coronary heart disease 血液和肌肉中的甲羟戊酸:冠心病患者对阿托伐他汀治疗的反应以及与他汀类药物不耐受的关系。
IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-23 DOI: 10.1111/cts.70025
Trine Lauritzen, John Munkhaugen, Stein Bergan, Elise Sverre, Kari Peersen, Sofia Lindahl, Einar Husebye, Nils Tore Vethe

Statin-associated muscle symptoms are frequently reported and often lead to discontinuation of statin therapy with an increased risk of cardiovascular events. In vitro studies suggest that statin-mediated inhibition of the mevalonate pathway leads to muscle cell toxicity. We aimed to determine the relationship between mevalonate, LDL-cholesterol, and atorvastatin metabolites in patients with coronary heart disease and self-perceived muscle side effects. Furthermore, we assessed the correlation between mevalonate in blood and muscle and the relationship to statin intolerance due to muscle symptoms. We used blood plasma from a randomized crossover trial (n = 70) and muscle biopsies and plasma from a subgroup in a subsequent open intervention study (n = 26). Both studies tested atorvastatin 40 mg/day. Seven patients did not tolerate ≥3 statins throughout the follow-up and were classified as statin-intolerant. Mevalonate in blood plasma decreased during atorvastatin treatment (median difference −38%, range −77% to 43%, p < 0.001), whereas mevalonate in muscle tissue was not lowered (0.05%, range −47% to 145%). Mevalonate correlated poorly with LDL-cholesterol and atorvastatin metabolites (Spearman's rho −0.28 to 0.10). The statin-intolerant patients had a smaller reduction in circulating mevalonate compared with the tolerant patients; median difference −8.1 (−22 to 3.5) nmol/L versus −25 (−93 to 12) nmol/L, p = 0.028. A similar observation was made for LDL-cholesterol. Cutoffs based on these biomarkers classified >50% correctly as tolerant. Inhibition of the mevalonate pathway does not appear to be the mechanism underlying statin intolerance in the present study. Further studies of mevalonate as a biomarker for statin tolerance are needed to clarify the potential.

与他汀类药物相关的肌肉症状经常见诸报端,这些症状往往会导致患者停止他汀类药物治疗,从而增加心血管事件的风险。体外研究表明,他汀类药物介导的甲羟戊酸途径抑制会导致肌肉细胞毒性。我们旨在确定冠心病患者体内甲羟戊酸、低密度脂蛋白胆固醇和阿托伐他汀代谢物与自我感觉的肌肉副作用之间的关系。此外,我们还评估了血液和肌肉中的甲羟戊酸与他汀类药物因肌肉症状导致的不耐受之间的相关性。我们使用的血浆来自一项随机交叉试验(n = 70),肌肉活检和血浆来自随后一项开放干预研究的一个亚组(n = 26)。两项研究都测试了阿托伐他汀 40 毫克/天。七名患者在整个随访期间不能耐受≥3种他汀类药物,被归类为他汀类药物不耐受者。在阿托伐他汀治疗期间,血浆中的甲羟戊酸减少(中位数差异为-38%,范围为-77%至43%,P为50%),被正确归类为耐受。在本研究中,抑制甲羟戊酸途径似乎不是他汀类药物不耐受的机制。需要进一步研究甲羟戊酸作为他汀耐受性生物标志物的可能性。
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引用次数: 0
Elucidation of DPP-4 involvement in systemic distribution and renal reabsorption of linagliptin by PBPK modeling with a cluster Gauss–Newton method 利用聚类高斯-牛顿法建立 PBPK 模型,阐明 DPP-4 参与利拉利汀的全身分布和肾脏重吸收。
IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1111/cts.70047
Ryo Nakamura, Takashi Yoshikado, Yasunori Aoki, Yuichi Sugiyama, Koji Chiba

The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (LNG) exhibits target-mediated drug disposition (TMDD) in clinical settings, characterized by saturable binding to plasma soluble DPP-4 (sDPP-4) and tissue transmembrane DPP-4 (tDPP-4). Previous studies have indicated that saturable renal reabsorption of LNG contributes to its nonlinear urinary excretion observed in humans and wild-type mice, but not in Dpp-4 knockout mice. To elucidate the mechanisms underlying these complex phenomena, including DPP-4-related renal reabsorption of LNG, we employed physiologically-based pharmacokinetic (PBPK) modeling combined with a cluster Gauss–Newton method (CGNM). The CGNM facilitated the exploration of parameters in rat and human PBPK models for LNG and the determination of parameter identifiability. Through PBPK–CGNM analysis using reported autoradiography data ([14C]-LNG) in wild-type and Dpp-4-deficient rats, DPP-4-specific distributions of LNG in various tissues were clearly differentiated from nonspecific parts. By fitting to human plasma concentrations and urinary and fecal excretions of LNG after intravenous and oral administrations, multiple unknown PBPK parameters were simultaneously estimated by the CGNM. Notably, the amount of tDPP-4 and the reabsorption clearance for LNG–DPP-4 complexes were identifiable, indicating their critical role in explaining the complex nonlinear pharmacokinetics of LNG. Compared with previous PBPK analyses, the CGNM allowed us to incorporate greater model complexity (e.g., consideration of tDPP-4 expressions and in vitro binding kinetics), ultimately resulting in a more accurate reproduction of LNG's TMDD. In conclusion, by considering LNG as a high-affinity probe for DPP-4, comprehensive PBPK–CGNM analyses suggested a dynamic whole-body distribution of DPP-4, including its involvement in the renal reabsorption of LNG.

二肽基肽酶-4(DPP-4)抑制剂利拉利汀(LNG)在临床上表现出靶向介导的药物处置(TMDD),其特点是与血浆可溶性 DPP-4(sDPP-4)和组织跨膜 DPP-4(tDPP-4)的可饱和结合。先前的研究表明,LNG 的肾脏重吸收饱和作用导致了其在人类和野生型小鼠中的非线性尿排泄,但在 Dpp-4 基因敲除小鼠中却没有发现这种作用。为了阐明这些复杂现象背后的机制,包括与 DPP-4 相关的 LNG 肾重吸收,我们采用了基于生理学的药代动力学(PBPK)模型,并结合聚类高斯-牛顿法(CGNM)。CGNM 有助于探索大鼠和人类 LNG PBPK 模型中的参数,并确定参数的可识别性。通过使用报告的野生型大鼠和 Dpp-4 基因缺陷大鼠的自显影数据([14C]-LNG)进行 PBPK-CGNM 分析,LNG 在不同组织中的 DPP-4 特异性分布与非特异性分布被清楚地区分开来。通过拟合 LNG 在静脉注射和口服后的人体血浆浓度以及尿液和粪便排泄量,CGNM 同时估算出了多个未知的 PBPK 参数。值得注意的是,tDPP-4 的数量和 LNG-DPP-4 复合物的重吸收清除率是可识别的,这表明它们在解释 LNG 复杂的非线性药代动力学方面起着至关重要的作用。与以前的 PBPK 分析相比,CGNM 使我们能够纳入更复杂的模型(如考虑 tDPP-4 表达和体外结合动力学),最终更准确地再现 LNG 的 TMDD。总之,通过将 LNG 视为 DPP-4 的高亲和力探针,全面的 PBPK-CGNM 分析表明了 DPP-4 在全身的动态分布,包括参与 LNG 的肾重吸收。
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引用次数: 0
On placental and lactational transfer of IgG-based therapeutic proteins – Current understanding and knowledge gaps from a clinical pharmacology perspective 基于 IgG 的治疗蛋白在胎盘和哺乳期的转移--从临床药理学角度看当前的认识和知识差距。
IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1111/cts.70049
Daphne Guinn, Katherine Kratz, Kristie Baisden, Sarah Ridge, Sonaly McClymont, Elimika Pfuma Fletcher, Tamara Johnson, Yow-Ming Wang

Maternal medication use may expose the developing fetus through placental transfer or the infant through lactational transfer. Because pregnant and lactating individuals have been historically excluded from early drug development trials, there is often limited to no human data available to inform pharmacokinetics (PK) and safety in these populations at the time of drug approval. We describe the known mechanisms of placental or lactational transfer of IgG-based therapeutic proteins and use clinical examples to highlight the potential for fetal or infant exposure during pregnancy and lactation. Placental transfer of IgG-based therapeutic proteins may result in systemic exposure to the developing fetus. A lactational transfer may be associated with local gastrointestinal (GI) exposure in the infant and may also result in systemic exposure, although data are very limited as proteins have shown instability in the GI tract. Understanding of PK and pharmacodynamic (PD) effects of IgG-based therapeutic proteins in infants exposed in utero as well as the potential exposure through human milk and its clinical implications is critical for developing treatment strategies for pregnant or lactating individuals. We share the current knowledge gaps and considerations for future evaluations to inform PK, PD, and the safety of IgG-based therapeutic proteins for safe use during pregnancy and lactation. With the increasing use of IgG-based therapeutic proteins in treating chronic diseases during pregnancy and lactation, there is a need to improve the quantity and quality of data to inform the safe use in pregnant and lactating individuals.

孕产妇用药可能会通过胎盘转移接触到发育中的胎儿,或通过哺乳转移接触到婴儿。由于孕妇和哺乳期妇女历来被排除在早期药物开发试验之外,因此在药物批准时,这些人群的药代动力学(PK)和安全性方面的人体数据往往非常有限,甚至根本没有。我们描述了已知的基于 IgG 的治疗蛋白的胎盘或哺乳期转移机制,并通过临床实例强调了妊娠期和哺乳期胎儿或婴儿暴露的可能性。基于 IgG 的治疗蛋白的胎盘转移可能会导致发育中的胎儿全身暴露。哺乳期转移可能与婴儿的局部胃肠道(GI)暴露有关,也可能导致全身暴露,但数据非常有限,因为蛋白质在胃肠道中显示出不稳定性。了解基于 IgG 的治疗用蛋白质在婴儿子宫内的 PK 和药效学 (PD) 影响以及通过母乳的潜在暴露及其临床意义,对于制定孕妇或哺乳期患者的治疗策略至关重要。我们分享了当前的知识差距和未来评估的注意事项,以便为孕期和哺乳期安全使用 IgG 治疗蛋白提供 PK、PD 和安全性方面的信息。随着妊娠期和哺乳期使用 IgG 治疗蛋白治疗慢性疾病的情况越来越多,有必要提高数据的数量和质量,以便为妊娠期和哺乳期患者的安全使用提供信息。
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引用次数: 0
Correction to “Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary endpoints: A systematic review” 更正 "成人和儿童复发性多发性硬化症 II 期和 III 期试验设计及其主要终点:系统综述"。
IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-21 DOI: 10.1111/cts.70052

Katsutoshi Hiramatsu, Hideki Maeda. Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary end points: A systematic review. Clin Transl Sci. 2024;17:e13794.

We apologize for this error.

Katsutoshi Hiramatsu, Hideki Maeda.成人和儿童复发性多发性硬化症II期和III期试验设计及其主要终点:系统综述。Clin Transl Sci. 2024;17:e13794.We apologize for this error.
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引用次数: 0
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