Clinical therapeutics最新文献_第5页

The Effect of Itraconazole on the Pharmacokinetics of Vepdegestrant, a PROteolysis TArgeting Chimera Estrogen Receptor Degrader, in Healthy Adult Participants 伊曲康唑对Vepdegestrant（一种蛋白水解靶向嵌合体雌激素受体降解剂）在健康成人体内药代动力学的影响

IF 3.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics

Pub Date : 2026-02-01 Epub Date: 2026-01-20 DOI: 10.1016/j.clinthera.2025.12.007

Lana Tran PharmD , Jennifer A. Winton MS , Kyle T. Matschke MAS , Alexandre Stouffs MD , Kimberly C. Lee MBA , Yuanyuan Zhang PhD , Weiwei Tan PhD

Purpose

Vepdegestrant (ARV-471) is an orally administered PROteolysis TArgeting Chimera estrogen receptor (ER) degrader that directly binds an E3 ligase and ER to trigger ubiquitination and subsequent proteasomal degradation of ER. Based on findings from a first-in-human phase 1/2 trial, vepdegestrant 200 mg once daily was selected as the recommended phase 3 dose and was evaluated in the phase 3 clinical study VERITAC-2 (NCT05654623) for the treatment of patients with ER-positive human epidermal growth factor receptor 2–negative breast cancer. Vepdegestrant is a substrate of cytochrome P450 (CYP)3A4 in vitro; therefore, its plasma exposure may increase when coadministered with CYP3A4 inhibitors, such as the strong index CYP3A4 inhibitor itraconazole. This study evaluated the effect of itraconazole on the pharmacokinetics (PK) and safety of vepdegestrant in healthy adults.

Methods

During this phase 1, open-label, 2-period, fixed-sequence study (NCT05538312), participants received 2 doses of vepdegestrant and multiple doses of itraconazole. In period 1, participants received a single dose of vepdegestrant 200 mg under fed conditions followed by a washout period of at least 10 days. In period 2, participants received itraconazole 200 mg once daily under fasted conditions on days 1–11 and a single dose of vepdegestrant 200 mg under fed conditions on day 5 with concomitant itraconazole administration. Plasma samples were collected predose and serially following each vepdegestrant dose. PK parameters calculated for vepdegestrant and its epimer metabolite, ARV-473, included area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC_inf) and maximum plasma concentration (C_max). Safety was monitored throughout the study.

Findings

A total of 12 healthy adult participants received vepdegestrant with (test) and without (reference) itraconazole. The vepdegestrant test/reference ratios of the adjusted geometric means (90% confidence intervals) for AUC_inf and C_max were 168.9% (157.7–180.9) and 152.2% (136.9–169.2), respectively. Similar increases in exposure were observed for ARV-473. All adverse events were mild or moderate, and no participants discontinued from the study due to adverse events.

Implications

Coadministration of multiple doses of itraconazole, a strong CYP3A4 inhibitor, increased vepdegestrant exposure by 69%, suggesting the involvement of CYP3A4-mediated metabolism, albeit not predominantly, in vepdegestrant elimination.

目的：Vepdegestrant （ARV-471）是一种口服蛋白水解靶向嵌合体雌激素受体（ER）降解剂，直接结合E3连接酶和ER，触发ER泛素化和随后的蛋白酶体降解。基于首次人体1/2期试验的结果，vepdegestrant 200mg每日一次被选为推荐的3期剂量，并在3期临床研究VERITAC-2 （NCT05654623）中进行评估，用于治疗er阳性人表皮生长因子受体2阴性乳腺癌患者。Vepdegestrant是体外细胞色素P450 (CYP)3A4的底物；因此，当与CYP3A4抑制剂（如强指数CYP3A4抑制剂伊曲康唑）合用时，其血浆暴露量可能增加。本研究评价了伊曲康唑对健康成人vevegestrant药代动力学（PK）和安全性的影响。方法：在这项开放标签、2期、固定顺序的1期研究（NCT05538312）中，参与者接受了2剂量的vepdegestrant和多剂量的伊曲康唑。在第一阶段，参与者在进食条件下接受单剂量200毫克的vevegestrant，然后进行至少10天的洗脱期。在第二阶段，参与者在第1-11天禁食条件下每天服用伊曲康唑200mg，在第5天进食条件下服用单剂量vepdegestrant 200mg，同时服用伊曲康唑。血浆样本在给药前和每次给药后依次采集。计算vepdegestrant及其外显体代谢物ARV-473的PK参数，包括从时间0外推到无限远的血浆浓度-时间曲线下面积（AUCinf）和最大血浆浓度（Cmax）。在整个研究过程中都对安全性进行了监测。结果：共有12名健康成人受试者接受了（试验）和（参考）伊曲康唑的vepdegestrant治疗。校正后的几何均值（90%置信区间）AUCinf和Cmax的vedegestrant检验/参考比分别为168.9%（157.7 ~ 180.9）和152.2%（136.9 ~ 169.2）。ARV-473暴露量也出现了类似的增加。所有不良事件均为轻度或中度，没有参与者因不良事件而中止研究。结论：多剂量伊曲康唑（一种强CYP3A4抑制剂）联合给药可使异位孕酮暴露增加69%，表明CYP3A4介导的代谢参与了异位孕酮的消除，尽管不是主要的。

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引用次数: 0

A Phase III Randomized Controlled Trial Evaluating the Efficacy and Safety of Azilsartan Medoxomil and Amlodipine Combination Therapy in Patients With Mild-to-Moderate Essential Hypertension Inadequately Controlled on Monotherapy 一项评估阿齐沙坦美多索米和氨氯地平联合治疗单药控制不充分的轻中度原发性高血压患者的疗效和安全性的III期随机对照试验

IF 3.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics

Pub Date : 2026-02-01 Epub Date: 2025-09-13 DOI: 10.1016/j.clinthera.2025.08.003

Dae-Hee Kim MD, PhD , Sang Hyun Lee MD, PhD , Kyung Ah Han MD, PhD , Moo Hyun Kim MD, PhD , Dong-Ju Choi MD, PhD , Marcin Grabowski MD, PhD , Pawel Miekus MD , Tzung-Dau Wang MD, PhD , Ching-Pei Chen MD , Sungha Park MD, PhD

Purpose

To assess the antihypertensive efficacy and safety of azilsartan medoxomil (AZM) and amlodipine (AML) combination therapy in patients with mild-to-moderate hypertension inadequately controlled by AZM or AML monotherapy.

Methods

In this multicenter, randomized, double-blind Phase III study (NCT05385770), patients with mild-to-moderate hypertension inadequately controlled with AZM 40/80 mg or AML 5/10 mg were randomized (1:1:1) to receive low-dose or high-dose AZM/AML combination therapy or continued monotherapy as control. Eligible patients completed a 4-week active run-in period before randomization. The primary endpoint was change from baseline in mean sitting systolic blood pressure (SBP) after 8 weeks of treatment.

Findings

A total of 890 patients were randomized. AZM/AML combination therapy resulted in significantly greater reductions in mean sitting SBP compared with AZM or AML monotherapy across all dose groups. Least-squares mean reductions in mean sitting SBP at week 8 ranged from 5.2 to 9.0 mm Hg across all monotherapy nonresponder groups, with all comparisons showing statistical significance (P < 0.05). Reductions in mean sitting diastolic blood pressure also favored combination therapy. Safety profiles were comparable across all treatment arms, with most adverse events mild or moderate in severity. No additional safety concerns were identified compared with monotherapy.

Implications

AZM/AML combination therapy was more effective than monotherapy in patients with mild-to-moderate hypertension inadequately controlled with either agent alone, even at maximum doses. Both low-dose and high-dose combinations were well tolerated. AZM/AML combination therapy may offer enhanced BP-lowering efficacy compared with other angiotensin II receptor blocker-based regimens.

目的：评价阿齐沙坦-美多索米（AZM）与氨氯地平（AML）联合治疗对AZM或AML单药控制不充分的轻中度高血压患者的降压疗效和安全性。方法：在这项多中心、随机、双盲III期研究（NCT05385770）中，AZM 40/ 80mg或AML 5/ 10mg控制不充分的轻中度高血压患者随机（1:1:1）接受低剂量或高剂量AZM/AML联合治疗或继续单药治疗作为对照。符合条件的患者在随机分组前完成了为期4周的积极磨合期。主要终点是治疗8周后平均坐位收缩压（SBP）较基线的变化。结果：共890例患者被随机分组。在所有剂量组中，与AZM或AML单药治疗相比，AZM/AML联合治疗导致平均坐位收缩压显著降低。在所有单药治疗无反应组中，第8周平均坐位收缩压的最小二乘平均值降低范围为5.2至9.0 mm Hg，所有比较均具有统计学意义（P < 0.05）。降低平均坐位舒张压也有利于联合治疗。所有治疗组的安全性具有可比性，大多数不良事件的严重程度为轻度或中度。与单药治疗相比，没有发现额外的安全性问题。结论：对于单用任何一种药物控制不充分的轻中度高血压患者，即使在最大剂量下，AZM/AML联合治疗也比单药治疗更有效。低剂量和高剂量联合用药均耐受良好。与其他基于血管紧张素II受体阻滞剂的方案相比，AZM/AML联合治疗可能提供更高的降压效果。

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引用次数: 0

Time Trends in Prescribing of Anxiolytic, Sedative, and Hypnotic Drugs in the United States 美国抗焦虑、镇静和催眠药物处方的时间趋势。

IF 3.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics

Pub Date : 2026-02-01 Epub Date: 2026-01-21 DOI: 10.1016/j.clinthera.2025.12.014

Zhengzhe Yang, Richard I. Shader MD, David J. Greenblatt MD

Purpose

Sedative, anxiolytic, and hypnotic (sleep-promoting) medications are extensively prescribed in clinical practice. Most are benzodiazepine (BZ) receptor agonists, but other drug classes are prescribed as well. Reliable quantitative data on the extent of prescribing, and changes in prescribing patterns over time, are needed to support risk-benefit decisions for individual patients and physicians, as well as public policy and regulatory decisions on product labeling, dosing recommendations, and use restrictions as applicable.

Methods

Retail and mail-order pharmacy dispensing data from 2006 to 2023 was evaluated using the Medical Expenditure Panel Survey component of the Agency for Healthcare Research and Quality, as appearing in the public domain (ClinCalc.com). Also evaluated was 2019 and 2023 data from the Centers for Medicare & Medicaid Services (CMS), providing federal health care coverage under Medicare Part D and Medicaid programs. Specific medications targeted were: BZ derivatives, zolpidem, and non-BZs taken for anxiety disorders and insomnia (buspirone, trazodone, and dual orexin receptor antagonists).

Findings

ClinCalc data indicated that prescribing of BZ-agonist agents (inclusive of zolpidem) was maximal in year 2014, then declined annually to about 50% of that maximum by year 2023. CMS Medicare Part D and Medicaid data reported a similar trend. The non-BZ sedating antidepressant trazodone was the most commonly prescribed hypnotic medication, with trazodone numbers more than double those for zolpidem by 2023. CMS Medicare Part D and Medicaid data reported similar trends. The dual orexin receptor antagonist hypnotics, available only as brand names at high cost, were not listed by ClinCalc, but CMS data indicated only modest use compared with trazodone.

Implications

The overall shift away from BZ agonist prescribing in the last decade has potential public health drawbacks as well as benefits, the balance of which is not established. The net clinical implications need close analysis using validated and objective biomedical and epidemiologic methodologies.

目的：镇静、抗焦虑和催眠（促进睡眠）药物在临床实践中被广泛使用。大多数是苯二氮卓（BZ）受体激动剂，但其他药物类别也被规定。需要关于处方范围和处方模式随时间变化的可靠定量数据，以支持个体患者和医生的风险-收益决策，以及关于产品标签、剂量建议和使用限制的公共政策和监管决策。方法：2006年至2023年零售和邮购药房配药数据评估使用医疗保健研究和质量机构的医疗支出小组调查组成部分，出现在公共领域（ClinCalc.com）。还评估了医疗保险和医疗补助服务中心（CMS） 2019年和2023年的数据，该中心在医疗保险D部分和医疗补助计划下提供联邦医疗保险。针对的特定药物有：BZ衍生物、唑吡坦和用于焦虑症和失眠的非BZ（丁旋环酮、曲唑酮和双食欲素受体拮抗剂）。结果：临床数据显示，bz激动剂（包括唑吡坦）的处方量在2014年达到最大值，然后逐年下降，到2023年约为最大值的50%。CMS医疗保险D部分和医疗补助数据也报告了类似的趋势。非bz镇静抗抑郁药曲唑酮是最常用的催眠药物，到2023年，曲唑酮的用量是唑吡坦的两倍多。CMS医疗保险D部分和医疗补助数据报告了类似的趋势。双重食欲素受体拮抗剂催眠药，只有高成本的品牌，没有被ClinCalc列出，但CMS数据显示，与曲唑酮相比，只有适度的使用。启示：在过去十年中，BZ激动剂处方的总体转变既有潜在的公共卫生弊端，也有益处，其平衡尚未确定。净临床影响需要使用经过验证和客观的生物医学和流行病学方法进行密切分析。

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引用次数: 0

Safeguarding Cannabis for Medical Use: Clinical Risks, Regulatory Gaps, and the Path Toward Equitable Standards. 保护大麻的医疗用途：临床风险，监管差距，以及通往公平标准的道路。

IF 3.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics

Pub Date : 2026-01-29 DOI: 10.1016/j.clinthera.2025.12.011

Shawn P Collins

Cannabis has moved into mainstream clinical use, yet the systems that should guarantee patient safety still lag. Oversight in the United States remains fragmented across states, with inconsistent thresholds, variable testing panels, and enforcement that often follows rather than prevents harm. Microbial contamination persists in regulated markets. Pathogenic Aspergillus has been detected in products that passed culture-based screens. Case reports in immunocompromised patients underscore real clinical consequences. Chemical contaminants, pesticides, heavy metals, and solvents, add cumulative risk and plausibly affect drug metabolism. State reforms have tried to tighten controls. Massachusetts required single-laboratory testing and digital certificate uploads. Those changes limited obvious lab shopping but left a fundamental flaw in place: cultivators and manufacturers still choose the samples. When sampling is compromised, even excellent laboratory work cannot protect patients. The 2025 suspension of Assured Testing Laboratories, along with recalls and lab actions in other states, shows the system's weakest points. International models demonstrate better paths. Canada uses pathogen-specific assays and broad pesticide panels, with high compliance. The European Medicines Agency has drafted pharmacopoeial standards for cannabis flos. Germany and Israel regulate cannabis as a medical product and link quality to reimbursement and distribution. My position is that U.S. policy should move to pathogen-specific molecular testing, harmonized chemical limits, and independent, regulator-controlled sampling. Equity protections are essential so safe products are accessible, not exclusive. Patients deserve cannabis regulated with the seriousness we expect for any therapeutic agent.

大麻已经进入主流临床使用，但应该保证患者安全的系统仍然滞后。美国的监管在各州之间仍然是支离破碎的，门槛不一致，测试小组多变，执法往往是紧随其后，而不是防止伤害。微生物污染在受监管的市场中持续存在。在通过培养筛选的产品中检测到致病性曲霉。免疫功能低下患者的病例报告强调了真实的临床后果。化学污染物、杀虫剂、重金属和溶剂会增加累积风险，并可能影响药物代谢。国家改革试图加强控制。马萨诸塞州要求单实验室测试和数字证书上传。这些变化限制了明显的实验室购物，但留下了一个根本性的缺陷：种植者和制造商仍然选择样品。当采样受到损害时，即使是优秀的实验室工作也无法保护患者。2025年“保证测试实验室”的暂停，以及其他州的召回和实验室行动，显示了该系统的弱点。国际模式展示了更好的道路。加拿大采用病原体特异性分析和广泛的农药小组，具有很高的合规性。欧洲药品管理局已经起草了大麻花的药典标准。德国和以色列将大麻作为医疗产品加以管制，并将质量与报销和分销联系起来。我的立场是，美国的政策应该转向病原体特异性的分子检测，统一的化学限量，以及独立的、监管机构控制的抽样。公平保护是必不可少的，这样安全产品就可以获得，而不是排他性的。病人应该像对待任何治疗药物那样认真对待大麻。

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引用次数: 0

Letters From the Field: Challenges and Opportunities in the Development of Botanical Drugs From Cannabis 来自现场的信件：大麻植物药物开发的挑战和机遇。

IF 3.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics

Pub Date : 2026-01-01 Epub Date: 2025-12-19 DOI: 10.1016/j.clinthera.2025.11.010

Justyna Kulpa PhD, Schuyler A. Pruyn MS, George Hodgin MBA

Cannabis and cannabis-derived products (CCDPs) have gained recognition for their therapeutic potential, driving legal and social shifts worldwide. In the United States, state-level medical cannabis programs exist alongside the federal drug development framework, which remains the gold standard for ensuring safety and efficacy. The Food and Drug Administration (FDA) botanical drug development guidance provides a structured approval pathway for plant-derived products, including CCDPs, accounting for their unique chemical complexity. Despite this guidance, significant gaps persist in preclinical and clinical data, particularly for minor cannabinoids. Development of botanical drugs from cannabis is further complicated by regulatory oversight from the Drug Enforcement Administration, which constrains the cultivation, handling, and distribution of cannabis and imposes logistical and security requirements during drug development. This article discusses the unique experience of drug developers navigating the scientific and regulatory challenges inherent in advancing CCDPs toward FDA drug approval. Collaborative efforts among federally compliant drug developers, regulatory bodies, healthcare providers, academic institutions, investors, and patients/patient advocacy groups are critical to generate rigorous, reproducible evidence to support the safe and effective use of CCDPs in medical conditions where they hold the greatest therapeutic potential. Such partnerships can advance studies that elucidate cannabinoid pharmacology, optimize dosing with rigorously characterized materials via clinically relevant routes, and identify clinical outcomes that are meaningful to patients. Advancing CCDPs through federally compliant drug development pathways will enable the translation of promising botanical therapies into safe, effective, and evidence-based treatments, ultimately informing clinical practice and benefiting patients.

大麻和大麻衍生产品（ccdp）因其治疗潜力而获得认可，推动了全球法律和社会变革。在美国，州级医用大麻项目与联邦药物开发框架同时存在，这仍然是确保安全性和有效性的黄金标准。美国食品和药物管理局（FDA）植物药物开发指南为植物衍生产品（包括ccdp）提供了结构化的审批途径，考虑到其独特的化学复杂性。尽管有这样的指导，临床前和临床数据仍然存在重大差距，特别是对于少量大麻素。从大麻中提取植物药物的开发由于缉毒局的监管监督而变得更加复杂，缉毒局限制大麻的种植、处理和分销，并在药物开发过程中提出后勤和安全要求。本文讨论了药物开发人员在推进ccdp获得FDA药物批准的过程中应对科学和监管挑战的独特经验。符合联邦法规的药物开发人员、监管机构、医疗保健提供者、学术机构、投资者和患者/患者倡导团体之间的合作努力对于生成严格的、可重复的证据来支持在医疗条件下安全有效地使用ccdp至关重要，因为ccdp具有最大的治疗潜力。这种伙伴关系可以推进研究，阐明大麻素药理学，通过临床相关途径优化具有严格特征的材料的剂量，并确定对患者有意义的临床结果。通过符合联邦法规的药物开发途径推进ccdp，将使有希望的植物疗法转化为安全、有效和基于证据的治疗方法，最终为临床实践提供信息并使患者受益。

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引用次数: 0

Centering Individuals With Mental Illness as an At-Risk Group in the Era of Cannabis Legalization and Commercialization 以大麻合法化与商业化时代的精神疾病高危人群为中心。

IF 3.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics

Pub Date : 2026-01-01 Epub Date: 2025-12-06 DOI: 10.1016/j.clinthera.2025.11.009

Andrew S. Hyatt MD

引用次数: 0

Bioequivalence and Safety Study of Ranolazine Extended-Release Tablets in Chinese Healthy Subjects Under Fasting and Fed Conditions: A Randomized, Open-Label, Single-Dose, Cross-Over, Comparative Pharmacokinetic Study 雷诺嗪缓释片在空腹和空腹条件下的生物等效性和安全性研究：随机、开放标签、单剂量、交叉、比较药代动力学研究。

IF 3.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics

Pub Date : 2026-01-01 Epub Date: 2025-11-25 DOI: 10.1016/j.clinthera.2025.11.002

Xing Chen MM , Yaming Li MM , Genshan Ma PhD

Purpose

The bioequivalence of the generic (Test formulation, T) and the originator (Reference formulation, R) ranolazine extended-release tablets was assessed in Chinese healthy subjects under fasting and fed conditions.

Methods

The study was conducted in accordance with a randomized, open, single-dose, 2-period, self-crossover design, with 36 subjects enrolled in each of the fasting and fed trials. Each subject received a 500 mg T or R tablet under fasting or fed conditions. Blood samples collected up to 48 h post-dose were determined for plasma concentrations of ranolazine by LC-MS/MS. The primary pharmacokinetic parameters were analyzed using a non-compartmental model, and geometric mean ratio (GMRs) for T/R and their 90% confidence interval (CI) were calculated for bioequivalence assessment. Adverse events (AEs) were monitored throughout, with safety assessments performed.

Results

The 90% CIs for the GMRs of the primary pharmacokinetic parameters (C_max, AUC_0-t, and AUC_0-∞) between the T and R administered under fasting conditions were 95.17% (85.48%–105.96%), 97.55% (87.52%–108.73%), and 94.75% (85.26%–105.30%), respectively. Similarly, under fed conditions, the 90% CIs for the GMRs of C_max, AUC_0-t, and AUC_0-∞ were 92.88% (84.25%–102.40%), 98.41% (92.66%–104.52%) and 97.60% (92.13%–103.41%), respectively. All values fell within the 80.00% to 125.00% range, thus meeting bioequivalence criteria. No serious AEs were reported during the study, indicating favorable safety and tolerability.

Implications

The test formulation, ranolazine extended-release tablets, demonstrated a similar safety profile to the reference formulation, Ranexa, and was shown to be bioequivalent in healthy Chinese subjects in both fasting and fed conditions.

Clinical trial registration

ClinicalTrials.gov, identifier: NCT07054255.

目的：评价仿制药（试验配方，T）和原研药（参比配方，R）雷诺嗪缓释片在空腹和喂养条件下的生物等效性。方法：采用随机、开放、单剂量、2期、自交叉设计，禁食组和喂养组各36例。每位受试者在禁食或进食条件下服用500mg T或R片。采用LC-MS/MS法测定给药后48 h血液样本的雷诺嗪血药浓度。采用非室室模型分析主要药代动力学参数，计算T/R的几何平均比（GMRs）及其90%置信区间（CI），进行生物等效性评价。全程监测不良事件（ae），并进行安全性评估。结果：空腹给药T与R的主要药代动力学参数（Cmax、AUC0- T和AUC0-∞）gmr的90% ci分别为95.17%（85.48% ~ 105.96%）、97.55%（87.52% ~ 108.73%）和94.75%（85.26% ~ 105.30%）。同样，在投料条件下，Cmax、AUC0-t和AUC0-∞的gmr的90% ci分别为92.88%（84.25% ~ 102.40%）、98.41%（92.66% ~ 104.52%）和97.60%（92.13% ~ 103.41%）。所有数值均在80.00% ~ 125.00%范围内，符合生物等效性标准。研究期间没有严重的不良反应报告，表明良好的安全性和耐受性。结论：试验制剂雷诺嗪缓释片与参比制剂雷尼沙具有相似的安全性，并且在空腹和喂养条件下对健康的中国受试者具有生物等效性。临床试验注册：ClinicalTrials.gov，标识符：NCT07054255。

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引用次数: 0

KOMZIFTI (Ziftomenib)

IF 3.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics

Pub Date : 2026-01-01 Epub Date: 2025-12-25 DOI: 10.1016/j.clinthera.2025.12.010

Paul Beninger MD, MBA

引用次数: 0

Phase 1 Study Evaluating the Effect of Food and Omeprazole-Induced Gastric pH Change on the Pharmacokinetics and Safety of Imlunestrant in Healthy Females 评价食物和奥美拉唑诱导的胃pH值变化对健康女性注射剂药代动力学和安全性影响的一期研究。

IF 3.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics

Pub Date : 2026-01-01 Epub Date: 2025-11-21 DOI: 10.1016/j.clinthera.2025.10.007

Amita Datta-Mannan PhD , Elaine Shanks PhD , Eunice Yuen PhD , Yingying Guo PhD , Xuejing Aimee Wang PhD

Purpose

To assess the effect of low-fat food intake and the effect of a gastric acid reducing agent (omeprazole) on imlunestrant pharmacokinetics (PK), safety, and tolerability.

Methods

A phase 1, open-label cohort study (NCT04840888) in healthy adult females of non-childbearing potential Food effect was evaluated in cohort 1 in which, participants were randomized (1:1) to fasted/fed or fed/fasted crossover treatment sequences and received one dose of 400 mg imlunestrant once-daily in each fed (a low-fat meal; 500 calories, 13% fat) or fasted state with 4 days washout period between doses. Omeprazole’s effect was evaluated in cohort 2, in which participants received imlunestrant in fixed treatment sequence with a washout period between doses: (1) a single dose of 400 mg imlunestrant alone on Day 1, (2) no treatment between Day 2–Day 5, (3) 40 mg omeprazole alone once-daily between Day 5–8, and (4) 400 mg imlunestrant + 40 mg omeprazole on Day 9. Blood samples for PK assessments were collected for the evaluation of the areas under the concentration curve AUC_(0-96h), AUC_(0-∞), maximum observed drug concentration (C_max), time of maximum observed drug concentration (Τ_max); their geometric least squares (GLS) mean ratios were calculated. Safety assessments involved monitoring of adverse events (AEs), clinical chemistry, hematology, vital signs, 12-lead electrocardiogram, and physical examination.

Findings

Eight females were enrolled in cohort 1 and 10 in cohort 2. In cohort 1, PK parameters were statistically significantly increased with GLS mean ratios (90% CI): 1.99 (1.67, 2.36) in AUC_(0-96h), 2.04 (1.41, 2.94) in AUC_(0-∞), and 3.55 (2.83, 4.45) in C_max, following dosing with imlunestrant in the fed state compared to the fasted state. The change in Τ_max was not statistically significant. In cohort 2, the change in PK parameters of imlunestrant when dosed alone and in the presence of the PPI omeprazole were not statistically significant and were comparable. Imlunestrant was well tolerated, and no clinically meaningful findings were recorded in either cohort.

Implications

Low-fat food intake resulted in increases of ∼2-fold in AUC and ∼3.6-fold in C_max. Therefore, patients will be instructed to abstain from food consumption two hours before and one hour after taking imlunestrant. Concomitant use of imlunestrant and omeprazole displayed a low risk of drug-drug interaction, therefore imlunestrant may be taken with a proton pump inhibitor such as omeprazole. A single oral dose of 400 mg imlunestrant was generally well tolerated in healthy females regardless of food or omeprazole intake.

目的：评价低脂食物摄入和胃酸还原剂（奥美拉唑）对肠道药代动力学（PK）、安全性和耐受性的影响。方法：一项1期开放标签队列研究（NCT04840888），在无生育潜力的健康成年女性中评估食物效应，在队列1中，参与者被随机（1:1）分配到禁食/喂食或喂食/禁食交叉治疗序列，在每次喂食（低脂餐；500卡路里，13%脂肪）或禁食状态下每天接受一次400毫克的免疫耐受剂，两次剂量之间有4天的洗脱期。在队列2中评估了奥美拉唑的效果，其中参与者按照固定的治疗顺序接受imlunestrant，并在剂量之间有一个洗脱期：(1)第1天单独服用单剂量400mg imlunestrant，(2)第2- 5天不治疗，(3)第5-8天每天服用40mg奥美拉唑，(4)第9天400mg imlunestrant + 40mg奥美拉唑。取血进行PK评估，评价浓度曲线下面积AUC（0-96h）、AUC（0-∞）、最大观察药物浓度（Cmax）、最大观察药物浓度时间（Τmax）；计算其几何最小二乘（GLS）平均比值。安全性评估包括监测不良事件（ae）、临床化学、血液学、生命体征、12导联心电图和体格检查。研究结果：8名女性被纳入队列1,10名女性被纳入队列2。在队列1中，与禁食相比，在喂食状态下给药后，PK参数的GLS平均比值（90% CI）显著增加，AUC（0-96h）为1.99 (1.67,2.36)，AUC（0-∞）为2.04 (1.41,2.94)，Cmax为3.55（2.83,4.45）。Τmax的变化无统计学意义。在队列2中，单独给药和与PPI奥美拉唑联合给药时，imlunestrant的PK参数变化无统计学意义，具有可比性。Imlunestrant耐受性良好，在两个队列中均未记录有临床意义的发现。结论：低脂食物摄入导致AUC增加~ 2倍，Cmax增加~ 3.6倍。因此，患者将被指示在服用大便前两小时和服药后一小时不要进食。同时使用imlunestrant和奥美拉唑显示药物相互作用的风险较低，因此imlunestrant可以与质子泵抑制剂如奥美拉唑一起服用。健康女性不论摄入何种食物或奥美拉唑，单次口服400mg imlunestrant通常耐受良好。

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引用次数: 0

Leukocytoclastic Vasculitis and Profound Cytopenias Following Teicoplanin Therapy: A Case Report on Glycopeptide Cross-Reactivity 替柯planin治疗后的白细胞分裂性血管炎和深度细胞减少：糖肽交叉反应一例报告。

IF 3.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics

Pub Date : 2026-01-01 Epub Date: 2025-12-08 DOI: 10.1016/j.clinthera.2025.11.008

Qimei Wei PhD, Wen Jiang MSc, Xinshuang Chen MSc, Hao Cai MSc, Rui Feng MSc, Shanshan Dong PhD

Purpose

To report a case of teicoplanin-induced leukocytoclastic vasculitis with concurrent bicytopenia.

Methods

A 61-year-old male with penicillin allergy and postaortic valve replacement was switched from vancomycin to teicoplanin for Enterococcus faecalis endocarditis due to renal impairment concerns.

Findings

On day 9 of teicoplanin therapy, pruritic maculopapular eruptions developed alongside neutropenia (absolute neutrophil count 1.5 × 10⁹/L) and thrombocytopenia (platelets 152 × 10⁹/L). After drug discontinuation, platelet count further declined to a nadir of 5 × 10⁹/L, requiring transfusions. Clinical recovery paralleled rash resolution.

Implications

This case highlights the risks of glycopeptide cross-reactivity and the importance of close hematologic monitoring.

目的：报告一例替柯planin诱导的白细胞破裂性血管炎并发双氧体减少症。方法：1例61岁男性，青霉素过敏，术后行瓣膜置换术，因粪肠球菌心内膜炎引起肾功能损害，由万古霉素改为替柯普兰。结果：在teicoplanin治疗的第9天，瘙痒性黄斑丘疹伴中性粒细胞减少（绝对中性粒细胞计数1.5 × 10⁹/L）和血小板减少（血小板152 × 10⁹/L）。停药后，血小板计数进一步下降至5 × 10⁹/L的最低点，需要输血。临床恢复与皮疹消退平行。意义：本病例强调了糖肽交叉反应的风险和密切血液学监测的重要性。

引用次数: 0