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An Innovative Approach to Optimize First‐In‐Human Minimal Anticipated Biological Effect Level Based Starting Dose in Oncology Trials for Bispecific T‐Cell Engagers: Experience from A Solid Tumor Bispecific T‐Cell Engager 在双特异性 T 细胞靶向药物的肿瘤学试验中,优化基于最小预期生物效应水平的首次人体试验起始剂量的创新方法:来自实体瘤双特异性 T 细胞参与疗法的经验
IF 6.7 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-17 DOI: 10.1002/cpt.3431
Di Zhou, Roman Kischel, Sabine Stienen, Danielle Townsley, Alexander Sternjak, Michael Lutteropp, Julie Bailis, Matthias Friedrich, Benno Rattel, Khamir Mehta, Vijay V. Upreti
Bispecific T‐cell engagers (Bi‐TCEs) have revolutionized the treatment and management of both hematological and solid tumor indications with opportunities to become best‐in‐class therapeutics for cancer. However, defining the dose and dosing regimen for the first‐in‐human (FIH) studies of Bi‐TCEs can be challenging, as a high starting dose can expose subjects to serious toxicity while a low starting dose based on traditional minimal anticipated biological effect level (MABEL) approach could lead to lengthy dose escalations that exposes seriously ill patients to sub‐therapeutic dosing. Leveraging our in‐depth and broad clinical development experience across three generations of Bi‐TCEs across both liquid and solid tumor indications, we developed an innovative modified MABEL approach for starting dose selection that integrates knowledge based on the target biology, indication, toxicology, in vitro, in vivo pharmacological evaluations, and translational pharmacokinetic/pharmacodynamic (PK/PD) modeling, together with anticipated safety profile. Compared to the traditional MABEL approach in which high effector to target (E:T) cell ratios are typically used, our innovative approach utilized an optimized E:T cell ratio that better reflects the tumor microenvironment. This modified MABEL approach was successfully applied to FIH dose selection for a half‐life extended (HLE) Bi‐TCE for gastric cancer. This modified MABEL approach enabled a 10‐fold higher starting dose that was deemed safe and well tolerated and saved at least two dose‐escalation cohorts before reaching the projected efficacious dose. This approach was successfully accepted by global regulatory agencies and can be applied for Bi‐TCEs across both hematological and solid tumor indications for accelerating the clinical development for Bi‐TCEs.
双特异性 T 细胞吸引剂(Bi-TCEs)彻底改变了血液病和实体瘤的治疗和管理,有机会成为一流的癌症治疗药物。然而,为双T细胞捕获剂的首次人体(FIH)研究确定剂量和给药方案具有挑战性,因为高起始剂量会使受试者面临严重毒性,而基于传统最小预期生物效应水平(MABEL)方法的低起始剂量则可能导致漫长的剂量升级,使重症患者面临亚治疗剂量。利用我们在液体和实体瘤适应症方面三代 Bi-TCE 深入而广泛的临床开发经验,我们开发了一种创新的修正 MABEL 方法,用于起始剂量的选择,该方法综合了基于靶点生物学、适应症、毒理学、体外和体内药理学评估、转化药代动力学/药效学 (PK/PD) 模型以及预期安全性的知识。传统的 MABEL 方法通常使用较高的效应细胞与靶细胞(E:T)比例,相比之下,我们的创新方法采用了优化的 E:T 细胞比例,能更好地反映肿瘤微环境。这种改良的 MABEL 方法被成功应用于胃癌半衰期延长 (HLE) BiTCE 的 FIH 剂量选择。这种改进的 MABEL 方法使起始剂量提高了 10 倍,被认为是安全且耐受性良好的,并且在达到预计有效剂量之前至少节省了两个剂量递增队列。这种方法已成功获得全球监管机构的认可,可用于血液病和实体瘤适应症的双 TCE,以加快双 TCE 的临床开发。
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引用次数: 0
Highlighted Articles 重点文章
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-17 DOI: 10.1002/cpt.3411
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引用次数: 0
Concomitant Use of Oral Anticoagulants with Oral Dipeptidyl Peptidase‐4 Inhibitors and Serious Bleeding Events 口服抗凝剂与口服二肽基肽酶-4 抑制剂同时使用与严重出血事件
IF 6.7 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-12 DOI: 10.1002/cpt.3442
Thanh Phuong Pham Nguyen, Charles E. Leonard, Colleen M. Brensinger, Warren B. Bilker, Sophie P. Chung, John R. Horn, Kacie Bogar, Todd A. Miano, Sean Hennessy
In a prior screening study, saxagliptin, a dipeptidyl peptidase‐4 inhibitor (DPP‐4i), was found to have an increased rate of serious bleeding when used concomitantly with several oral anticoagulants (OACs). We aimed to confirm or refute the associations between concomitant use of individual OACs and DPP‐4is and serious bleeding in a large US database, using self‐controlled case series (SCCS) and case‐crossover (CCO) designs. The study population was eligible Medicare beneficiaries co‐exposed to a DPP‐4i (precipitant) and either an OAC (object drug) or lisinopril (negative control object drug) in 2016–2020. For the SCCS, we used conditional Poisson regression to estimate adjusted rate ratios (RRs) between each co‐exposure (vs. not) and serious bleeding and divided the RR by the adjusted RR for the corresponding lisinopril + precipitant pair to obtain ratios of RRs (RRRs). For the CCO, we estimated the adjusted odds ratios (ORs) of exposure to the precipitant in the focal window vs. referent window using multivariable conditional logistic regression and divided the ORs in the object drug‐exposed cases over the ORs in negative object drug‐exposed cases to obtain the ratios of ORs (RORs). The adjusted RRRs for serious bleeding ranged from 0.32 (0.05–1.91) for apixaban/lisinopril + saxagliptin to 3.49 (1.29–9.48) for warfarin/lisinopril + linagliptin. The adjusted RORs ranged from 0.01 (0.00–0.20) for rivaroxaban/lisinopril + saxagliptin to 2.99 (0.74–12.11) for apixaban/lisinopril + linagliptin. While we could not confirm previously identified signals because of statistical imprecision, several numerically elevated estimates still warrant caution in concomitant use and further examination.
在之前的一项筛选研究中,发现二肽基肽酶-4 抑制剂 (DPP-4i) 沙格列汀与几种口服抗凝剂 (OAC) 同时使用时,严重出血的发生率会增加。我们的目的是利用自控病例系列(SCCS)和病例交叉(CCO)设计,在一个大型美国数据库中证实或反驳同时使用个别 OACs 和 DPP-4is 与严重出血之间的关联。研究对象是在 2016-2020 年期间共同接触过 DPP-4i(诱导剂)和 OAC(目标药物)或赖欣诺普利(阴性对照目标药物)的符合条件的医疗保险受益人。对于 SCCS,我们使用条件泊松回归来估算每种共同暴露(与未共同暴露)和严重出血之间的调整率比 (RR),并将 RR 除以相应的利辛普利 + 促效剂配对的调整率比,以获得 RR 比 (RRR)。对于 CCO,我们使用多变量条件逻辑回归估算了病灶窗与参照窗暴露于沉淀剂的调整后几率比(ORs),并将对象药物暴露病例的几率比除以对象药物阴性暴露病例的几率比,得出几率比(RORs)。阿哌沙班/利辛普利+沙格列汀的严重出血调整RRR为0.32(0.05-1.91),华法林/利辛普利+利拉利汀的严重出血调整RRR为3.49(1.29-9.48)。利伐沙班/利辛普利+沙格列汀的调整ROR为0.01(0.00-0.20),阿哌沙班/利辛普利+利拉利汀的调整ROR为2.99(0.74-12.11)。虽然由于统计不精确,我们无法确认之前确定的信号,但几个数值升高的估计值仍值得在同时使用时谨慎对待,并进行进一步检查。
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引用次数: 0
Characteristics of Drugs from Non‐Global Companies for Hematologic Malignancies and Impact on Global Regulatory Approval 非全球公司血液恶性肿瘤药物的特点及其对全球监管审批的影响
IF 6.7 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-10 DOI: 10.1002/cpt.3440
Kensuke Matsuda, Sumimasa Nagai, Koichi Sugimoto
The number of drugs developed by non‐global companies, including biotech start‐ups, has increased; however, their characteristics and impact on global regulatory approval are not well understood. Using a public database, we identified new molecular entities (NMEs) approved for hematologic malignancies in the US from January 2011 to December 2022. They were divided into those submitted by non‐global companies (non‐global group) and those by global companies (global group). We identified 48 NMEs, of which 19 (40%) were classified as non‐global. Of these, 13 (68%) were from US‐based companies. In the non‐global group, 63% (12/19) of the NMEs had received accelerated approval in the US, of which only 50% (6/12) had a post‐approval confirmatory trial by September 2023. Regarding the impact on the approval in the European Union (EU) and Japan, the unapproval rate of 2 years after US approval was higher in the non‐global group than in the global group in the EU (56% vs. 21%) and Japan (94% vs. 64%). In conclusion, many NMEs from non‐global companies had received accelerated approval in the US based on phase I/II trials. NMEs from non‐global companies had a higher unapproval rate at 2 years in both the EU and Japan.
非全球性公司(包括新成立的生物技术公司)开发的药物数量有所增加;然而,人们对这些药物的特点及其对全球监管审批的影响还不甚了解。利用公共数据库,我们确定了2011年1月至2022年12月期间美国批准的血液系统恶性肿瘤新分子实体(NME)。这些药物分为非全球公司(非全球组)提交的药物和全球公司(全球组)提交的药物。我们确定了 48 个 NME,其中 19 个(40%)被归类为非全球性公司。其中 13 家(68%)来自美国公司。在非全球组中,63%(12/19)的非处方药已在美国获得加速批准,其中只有 50%(6/12)的非处方药在 2023 年 9 月前进行了批准后的确证试验。关于对欧盟(EU)和日本批准的影响,在欧盟(56% 对 21%)和日本(94% 对 64%),非全球组在美国批准后 2 年的未批准率高于全球组。总之,许多来自非全球公司的非处方药在美国获得了基于I/II期试验的加速批准。在欧盟和日本,来自非全球公司的 NME 在 2 年后的未批准率较高。
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引用次数: 0
A User-Driven Framework for Dose Selection in Pregnancy: Proof of Concept for Sertraline. 用户驱动的妊娠期剂量选择框架:舍曲林的概念验证。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-09 DOI: 10.1002/cpt.3429
Charlotte Koldeweij, Caroline Dibbets, Bryony D Franklin, Hubertina C J Scheepers, Saskia N de Wildt

Despite growing knowledge of pregnancy-induced changes in physiology that may alter maternal and fetal pharmacokinetics, evidence-based antenatal doses are lacking for most drugs. Pharmacokinetic modeling and expanding clinical data in pregnancy may support antenatal doses. We aimed to develop and pilot a comprehensive and user-driven Framework for Dose Selection in Pregnancy to support the clinical implementation of a best-evidence antenatal dose for sertraline. After initial development and evaluation by experts, the framework prototype was piloted to formulate an antenatal dosing strategy for sertraline in depression and anxiety disorders. Next, the framework was reviewed and assessed for usability by a multidisciplinary working committee of end-users comprising healthcare practitioners, experts from other disciplines including pharmacometrics, reproductive toxicology and medical ethics, alongside pregnant women and a partner. The resulting framework encompasses the following: rationale for drug selection, a comprehensive analysis of pharmacokinetic and dose-related efficacy and safety data, and implementation aspects including feasibility and desirability of the recommended antenatal dose based on a structured maternal and fetal benefit-risk assessment. An antenatal dose recommendation for sertraline, as a case study, was formulated using this approach and endorsed for clinical use by the working committee. Future applications of the framework for other drugs can further demonstrate its suitability for developing best evidence, acceptable and clinically feasible antenatal doses.

尽管人们对妊娠引起的生理变化有了越来越多的了解,这些变化可能会改变母体和胎儿的药代动力学,但大多数药物都缺乏以证据为基础的产前剂量。妊娠期药代动力学建模和不断扩大的临床数据可为产前剂量提供支持。我们旨在开发并试行一个全面的、用户驱动的妊娠期剂量选择框架,以支持舍曲林最佳循证产前剂量的临床实施。经过专家的初步开发和评估后,我们对该框架原型进行了试用,以制定抑郁症和焦虑症患者舍曲林的产前剂量策略。接下来,由医疗保健从业人员、药物计量学、生殖毒理学和医学伦理学等其他学科的专家以及孕妇和一名伴侣组成的最终用户多学科工作委员会对该框架进行了审查和可用性评估。最终形成的框架包括以下内容:药物选择的基本原理、药代动力学和剂量相关的疗效和安全性数据的综合分析,以及实施方面的内容,包括根据结构化的孕产妇和胎儿获益风险评估所推荐的产前剂量的可行性和可取性。以舍曲林为例,我们采用这种方法制定了产前剂量建议,并得到了工作委员会的认可,可用于临床。未来将该框架应用于其他药物,可进一步证明其适用于制定最佳证据、可接受且临床可行的产前剂量。
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引用次数: 0
Utility of Biomarker-Informed Drug Interaction Evaluation in Drug Development and Regulatory Decision Making. 以生物标志物为依据的药物相互作用评估在药物开发和监管决策中的实用性。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-09 DOI: 10.1002/cpt.3436
Akihiro Ishiguro, Hiroyuki Kusuhara, Emi Kimoto, So Miyoshi, Katsuhiko Mizuno, Motohiro Hoshino, Hiroshi Suzuki

The measurement of endogenous biomarkers in plasma and urine before and after administration of an investigational drug in a clinical study may provide an early indication of its drug-drug interaction (DDI) potential via a specific pathway. In the first international harmonized guideline on drug interaction studies, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M12, endogenous biomarkers have been recognized as an emerging approach in the transporter- and enzyme-based DDI risk assessment. Clinical Pharmacology Roundtable Conference 2024 held at Pharmaceuticals and Medical Devices Agency (PMDA) brought together experts from regulatory agencies, academia, and industries to discuss potential advantages and challenges of the biomarkers approach in drug development and regulatory decision making. This meeting report facilitates stakeholders involved in drug development in better understanding the utility of biomarker approaches and promotes early implementation of biomarker-informed DDI evaluation in regulatory use.

在临床研究中给药前后对血浆和尿液中的内源性生物标记物进行测量,可及早显示药物通过特定途径发生药物相互作用(DDI)的可能性。国际人用药品技术要求协调理事会 (ICH) M12 是国际上第一份关于药物相互作用研究的协调指南,其中内源性生物标志物被认为是基于转运体和酶的 DDI 风险评估的一种新兴方法。药品和医疗器械管理局(PMDA)举办的 2024 年临床药理学圆桌会议汇聚了来自监管机构、学术界和工业界的专家,共同讨论生物标记物方法在药物开发和监管决策中的潜在优势和挑战。这份会议报告有助于参与药物开发的利益相关者更好地了解生物标志物方法的效用,并促进在监管使用中尽早实施以生物标志物为依据的DDI评估。
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引用次数: 0
Partial Residual Plots as an Integrated Model Diagnostic Tool in Model-Based Meta-Analysis. 将部分残差图作为基于模型的 Meta 分析中的综合模型诊断工具》(Partial Residual Plots as an Integrated Model Diagnostic Tool in Model-Based Meta-Analysis)。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-08 DOI: 10.1002/cpt.3418
John Maringwa, Paul Matthias Diderichsen, Chandni Valiathan

The use of partial residual plots (PRPs) was explored as a model diagnostic tool in Model-based Meta-Analysis (MBMA). Mathematical derivations illustrating the concepts were followed by an MBMA example using publicly available literature data of anti-depressive treatments with fluoxetine and venlafaxine. An Emax dose-response model was identified for venlafaxine while a constant drug effect combining all dose levels vs. placebo was identified for fluoxetine. The larger the mean baseline Hamilton Depression Rating (HAMD) score, the larger the expected drug effect (P = 0.0122), based on the likelihood ratio test. Mean baseline HAMD score (range) was 25.4 (23.5, 29.4) and 20.8 (15, 26) while mean placebo change from baseline (range) was -9.02 (-12.2, -4.8) and - 6.22 (-10.9, -1.3) for venlafaxine and fluoxetine, respectively. Average baseline HAMD score appeared larger for venlafaxine compared to fluoxetine, albeit a wider range for fluoxetine. Placebo response seemed lower but also more variable in fluoxetine compared to venlafaxine studies. Observed data points tended to deviate from model predictions when the mean baseline HAMD and placebo response values associated with those data points differed substantially from the corresponding values used for the model prediction. Normalizing observed data addressed this, providing a "like-to-like" comparison with model predictions in PRP when assessing the effect of one covariate (dose) after normalizing for other covariates/effects (placebo response and mean baseline). PRPs provide a robust integrated diagnostic tool in MBMA that uses all data to show the correlation between response and any covariate while controlling for other covariates included in the model.

在基于模型的元分析(MBMA)中,部分残差图(PRP)作为一种模型诊断工具得到了探讨。在对概念进行数学推导之后,使用公开文献数据对氟西汀和文拉法辛的抗抑郁治疗进行了 MBMA 示例。为文拉法辛确定了一个最大剂量反应模型,而为氟西汀确定了一个结合所有剂量水平与安慰剂的恒定药物效应模型。根据似然比检验,平均基线汉密尔顿抑郁评分(HAMD)越高,预期药物效应越大(P = 0.0122)。文拉法辛和氟西汀的平均基线 HAMD 评分(范围)分别为 25.4(23.5,29.4)和 20.8(15,26),而安慰剂与基线相比的平均变化(范围)分别为-9.02(-12.2,-4.8)和-6.22(-10.9,-1.3)。与氟西汀相比,文拉法辛的平均基线HAMD评分似乎更高,尽管氟西汀的评分范围更广。与文拉法辛研究相比,氟西汀的安慰剂反应似乎更低,但变化也更大。当与数据点相关的 HAMD 和安慰剂反应平均基线值与模型预测所用的相应值相差很大时,观察数据点往往会偏离模型预测值。对观察到的数据进行归一化处理可解决这一问题,在对其他协变量/效应(安慰剂反应和平均基线)进行归一化处理后,在 PRP 中评估一个协变量(剂量)的效应时,可与模型预测进行 "相似 "比较。PRP 在 MBMA 中提供了一个强大的综合诊断工具,它使用所有数据显示响应与任何协变量之间的相关性,同时控制模型中包含的其他协变量。
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引用次数: 0
Rare Diseases Linked to Mutations in Vitamin Transporters Expressed in the Human Blood–Brain Barrier 与人类血脑屏障中表达的维生素转运体突变有关的罕见疾病
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-05 DOI: 10.1002/cpt.3433
Sook Wah Yee, Joanne Wang, Kathleen M. Giacomini

Recent advances have significantly enhanced our understanding of the role of membrane transporters in drug disposition, particularly focusing on their influence on pharmacokinetics, and consequently, pharmacodynamics. The relevance of these transporters in clinical pharmacology is well acknowledged. Recent research has also underscored the critical role of membrane transporters as targets in human diseases, including their involvement in rare genetic disorders. This review focuses on transporters for water-soluble B vitamins, such as thiamine, riboflavin, and biotin, essential cofactors for metabolic enzymes. Mutations in transporters, such as SLC19A3 (thiamine), SLC52A2, and SLC52A3 (riboflavin), and SLC5A6 (multiple B vitamins including pantothenic acid and biotin) are linked to severe neurological disorders due to their role in the blood–brain barrier, which is crucial for brain vitamin supply. Current treatments, mainly involving vitamin supplementation, often result in variable response. This review also provides a short perspective on the role of the transporters in the blood-cerebrospinal fluid barrier and highlights the potential development of pharmacologic treatments for rare disorders associated with mutations in these transporters.

最近的研究进展大大提高了我们对膜转运体在药物处置中的作用的认识,尤其是它们对药物动力学的影响,进而对药效学的影响。这些转运体与临床药理学的相关性已得到公认。最近的研究还强调了膜转运体作为人类疾病靶点的关键作用,包括它们在罕见遗传疾病中的参与。本综述重点关注水溶性 B 族维生素(如硫胺素、核黄素和生物素)的转运体,它们是代谢酶的重要辅助因子。SLC19A3(硫胺素)、SLC52A2 和 SLC52A3(核黄素)以及 SLC5A6(多种 B 族维生素,包括泛酸和生物素)等转运体的突变与严重的神经系统疾病有关,因为它们在血脑屏障中起着重要作用,而血脑屏障对脑部维生素的供应至关重要。目前的治疗方法主要是补充维生素,但往往效果不一。这篇综述还从一个简短的角度阐述了转运体在血-脑脊液屏障中的作用,并强调了针对与这些转运体突变有关的罕见疾病的药物治疗的潜在发展。
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引用次数: 0
Diagnosis and Management of Parathyroid Carcinoma 甲状旁腺癌的诊断和治疗。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-05 DOI: 10.1002/cpt.3432
Alexander Lazzaro, Grace (Qing) Zhao, Matthew Kulke

Parathyroid carcinoma (PC) is a rare malignancy, often characterized by the unregulated secretion of parathyroid hormone. The sequelae of severe hypercalcemia together with direct complications from tumor dissemination in patients with advanced disease are usually fatal. Due to its rarity, formal studies to guide the diagnosis and management of parathyroid carcinoma are lacking. However, recent data from case reports, case series, and registry studies suggest the emergence of new and effective treatment approaches for this understudied disease. We reviewed existing literature on the diagnosis and management of parathyroid carcinoma. Our findings suggest that traditional approaches such as surgical resection for both localized and metastatic diseases continue to play an important role in patient management. For patients with unresectable disease, newer systemic treatment approaches, including the use of temozolomide and tyrosine kinase inhibitors, may offer clinical benefit.

甲状旁腺癌(PC)是一种罕见的恶性肿瘤,通常以甲状旁腺激素分泌失调为特征。晚期患者通常会因严重的高钙血症以及肿瘤扩散引起的直接并发症而死亡。由于甲状旁腺癌非常罕见,目前还缺乏正式的研究来指导甲状旁腺癌的诊断和治疗。不过,最近来自病例报告、系列病例和登记研究的数据表明,这种研究不足的疾病正在出现新的有效治疗方法。我们回顾了有关甲状旁腺癌诊断和治疗的现有文献。我们的研究结果表明,对局部和转移性疾病进行手术切除等传统方法仍在患者治疗中发挥着重要作用。对于无法切除的患者,包括替莫唑胺和酪氨酸激酶抑制剂在内的新型全身治疗方法可能会带来临床益处。
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引用次数: 0
First-in-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor 评估 BMS-986308:肾外髓质钾通道抑制剂的安全性、药代动力学和药效学的首次人体研究。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-02 DOI: 10.1002/cpt.3430
Sharif I. Soleman, Juan Maya, Paul Levesque, Atif Mohammad, Lisa Christopher, Justin Schumacher, Aparna Nanduri, Pitchumani Sivakumar, Marc Kozinn, Philippe Costet, Chang Wang, Jeremy Richter, Dara Hawthorne, Anh Bui, Veena S. Rao, Daniel Dickerson, Jeffrey Testani, Francisco Ramírez-Valle, Frédéric Baribaud, Bindu Murthy, Samira Merali

In patients with heart failure (HF) who respond inadequately to loop diuretic therapy, BMS-986308, an oral, selective, reversible renal outer medullary potassium channel (ROMK) inhibitor may represent an effective diuretic with a novel mechanism of action. We present data from the first-in-human study aimed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) following single ascending doses of BMS-986308 in healthy adult participants. Forty healthy participants, aged from 20 to 55 years, and body mass index (BMI) from 19.8 to 31.6 kg/m2 were assigned to 1 of 5 dose cohorts (1, 3, 10, 30, and 100 mg) and randomized (6:2) to receive BMS-986308 oral solution or matching placebo. Following administration, BMS-986308 was rapidly absorbed with a median time to maximum concentration (Tmax) of 1.00 to 1.75 h and exhibiting a mean terminal half-life (t1/2) of approximately 13 h. Dose proportionality was evident in BMS-986308 area under the concentration-time curve (AUC), while maximum concentration (Cmax) was slightly greater than dose-proportional. We observed that urine output (or diuresis; mL) and urinary sodium excretion (or natriuresis; mmol) increased in a dose-dependent manner, starting at a minimum pharmacologically active dose of 30 mg. The largest mean changes from baseline in diuresis and natriuresis occurred in both the 6- and −24 h post-dose period following administration of 100 mg (1683.0 mL and 2055.3 mL, and 231.7 mmol and 213.7 mmol, respectively; ***P < 0.001). Overall, single-dose BMS-986308 was found to be safe, well-tolerated, with an excellent PK profile, and substantial diuretic and natriuretic activity.

对于襻利尿剂治疗效果不佳的心力衰竭(HF)患者,BMS-986308--一种口服、选择性、可逆的肾外髓钾通道(ROMK)抑制剂--可能是一种具有新型作用机制的有效利尿剂。我们展示了首次人体研究的数据,该研究旨在评估健康成人服用单次升剂量 BMS-986308 后的安全性、耐受性、药代动力学 (PK) 和药效学 (PD)。研究人员将 40 名年龄介于 20 至 55 岁之间、体重指数(BMI)介于 19.8 至 31.6 kg/m2 之间的健康参与者分配到 5 个剂量组(1、3、10、30 和 100 毫克)中的一个,并随机(6:2)接受 BMS-986308 口服液或匹配的安慰剂。给药后,BMS-986308吸收迅速,达到最大浓度(Tmax)的中位时间为1.00至1.75小时,平均终末半衰期(t1/2)约为13小时。BMS-986308的浓度-时间曲线下面积(AUC)明显呈剂量比例关系,而最大浓度(Cmax)略高于剂量比例关系。我们观察到,从最低药理活性剂量 30 毫克开始,尿量(或利尿;毫升)和尿钠排泄量(或利尿;毫摩尔)的增加呈剂量依赖性。在服用 100 毫克后的 6 小时和 24 小时内,尿量和钠排泄量与基线相比的平均变化最大(分别为 1683.0 毫升和 2055.3 毫升,以及 231.7 毫摩尔和 213.7 毫摩尔;***P
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引用次数: 0
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Clinical Pharmacology & Therapeutics
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