{"title":"头孢地罗在中国健康人体内的药动学、药动学/药效学及安全性研究。","authors":"Chuhan Zhang, Shuyan Yu, Size Li, Xiaojie Wu, Qiong Wei, Jinjie He, Guoying Cao, Haijing Yang, Jingjing Wang, Kohei Fujitani, Takayuki Katsube, Jing Zhang, Honghong Dou","doi":"10.1007/s12325-025-03147-1","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p>We aim to evaluate the safety and pharmacokinetic (PK) properties of cefiderocol in Chinese participants, following single and subsequent multiple administrations of 2 g q8h with 3-h intravenous infusion, and to predict its efficacy for the treatment of Gram-negative bacilli (GNB) infection based on PK/pharmacodynamic (PD) analysis.</p><h3>Methods</h3><p>This was an open-label, single-center, single- and multiple-dose phase I study, conducted from September 2022 to October 2022, with 12 eligible healthy Chinese adults (6 men and 6 women). The PK profiles were described by noncompartmental analysis and a two-compartment model using WinNonlin (v.8.1). Monte Carlo simulations (MCS) were performed by R (v.4.3.1) to obtain the probability of target attainment (PTA) as well as the cumulative fraction of response (CFR), based on the previously published data of susceptibility studies for cefiderocol in China.</p><h3>Results</h3><p>Both single and multiple doses of 2 g cefiderocol were well tolerated in healthy Chinese subjects, and no severe treatment-emergent adverse events occurred. The maximum plasma concentration of cefiderocol was observed approximately 3 h after administration and the half-life was about 2.6 h, with no accumulation after multiple dosing. It is worth noting that, the PK profiles, including CL, V1,<i> C</i><sub>max</sub>, <i>C</i><sub>trough</sub>, and AUC<sub>0–τ</sub>, were consistent with those of other populations, e.g., Caucasian. PK/PD analysis and MCS suggested that standard dosage regimen of cefiderocol would achieve satisfactory PTA and CFR (exceeding 90%) for Gram-negative pathogens with MICs up to 4 μg/mL, using the proposed <i>f</i><i>T</i><sub>>MIC</sub> target of 75.0%. Consistently, more than 90% of PTA was reached for <i>Enterobacterales</i>, <i>P. aeruginosa</i>, and <i>Acinetobacter</i> spp. with MICs up to 4 μg/mL at their respective 73.3%, 72.2%, and 88.1% <i>f</i><i>T</i><sub>>MIC</sub> targets, with CFR exceeding 95%. Especially for <i>S. maltophilia</i>, both the PTA and CFR reached nearly 100% for those with MICs as high as 8 μg/mL.</p><h3>Conclusions</h3><p>Cefiderocol is well tolerated by Chinese healthy participants at the dosage regimen of 2 g cefiderocol q8h via 3-h infusion, which is expected to achieve satisfactory efficacy in treating GNB infections in China, although further data for model optimization might still be required. To our knowledge, this is the first study to describe the PK properties of cefiderocol in Chinese subjects, and to predict its microbiological efficacy for treating GNB infection in China.</p><h3>Trial Registration</h3><p>ChiCTR2300076607.</p></div>","PeriodicalId":7482,"journal":{"name":"Advances in Therapy","volume":"42 5","pages":"2285 - 2297"},"PeriodicalIF":3.4000,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12325-025-03147-1.pdf","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetic, Pharmacokinetic/Pharmacodynamic, and Safety Investigations of Cefiderocol in Chinese Healthy Subjects\",\"authors\":\"Chuhan Zhang, Shuyan Yu, Size Li, Xiaojie Wu, Qiong Wei, Jinjie He, Guoying Cao, Haijing Yang, Jingjing Wang, Kohei Fujitani, Takayuki Katsube, Jing Zhang, Honghong Dou\",\"doi\":\"10.1007/s12325-025-03147-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Introduction</h3><p>We aim to evaluate the safety and pharmacokinetic (PK) properties of cefiderocol in Chinese participants, following single and subsequent multiple administrations of 2 g q8h with 3-h intravenous infusion, and to predict its efficacy for the treatment of Gram-negative bacilli (GNB) infection based on PK/pharmacodynamic (PD) analysis.</p><h3>Methods</h3><p>This was an open-label, single-center, single- and multiple-dose phase I study, conducted from September 2022 to October 2022, with 12 eligible healthy Chinese adults (6 men and 6 women). The PK profiles were described by noncompartmental analysis and a two-compartment model using WinNonlin (v.8.1). Monte Carlo simulations (MCS) were performed by R (v.4.3.1) to obtain the probability of target attainment (PTA) as well as the cumulative fraction of response (CFR), based on the previously published data of susceptibility studies for cefiderocol in China.</p><h3>Results</h3><p>Both single and multiple doses of 2 g cefiderocol were well tolerated in healthy Chinese subjects, and no severe treatment-emergent adverse events occurred. The maximum plasma concentration of cefiderocol was observed approximately 3 h after administration and the half-life was about 2.6 h, with no accumulation after multiple dosing. It is worth noting that, the PK profiles, including CL, V1,<i> C</i><sub>max</sub>, <i>C</i><sub>trough</sub>, and AUC<sub>0–τ</sub>, were consistent with those of other populations, e.g., Caucasian. 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引用次数: 0
摘要
摘要：本研究旨在评价头孢地罗在中国受试者中单次及随后多次给药2 g / 8h并静脉滴注3 h的安全性和药代动力学（PK）特性，并基于PK/药效学（PD）分析预测其治疗革兰氏阴性杆菌（GNB）感染的疗效。方法：这是一项开放标签、单中心、单剂量和多剂量的I期研究，于2022年9月至2022年10月进行，共有12名符合条件的健康中国成年人（6男6女）。采用WinNonlin （v8.1）软件进行非区室分析和双区室模型描述PK谱。利用R （v.4.3.1）软件进行蒙特卡罗模拟（MCS），以获得目标达成概率（PTA）和累积反应分数（CFR），该模拟基于先前发表的中国头孢地罗药物敏感性研究数据。结果：中国健康受试者单次和多次给药2g头孢地罗耐受性良好，未发生严重的治疗不良事件。头孢地罗在给药后约3 h出现血药浓度最大值，半衰期约2.6 h，多次给药后无蓄积。值得注意的是，包括CL、V1、Cmax、Ctrough和AUC0-τ在内的PK谱与其他种群（如高加索人）一致。PK/PD分析和MCS结果表明，头孢地罗标准给药方案对MIC为4 μg/mL的革兰氏阴性病原菌的PTA和CFR均可达到满意的90%以上（以建议的ft> MIC目标为75.0%）。同样，对于MIC值高达4 μg/mL的肠杆菌、铜绿假单胞菌和不动杆菌，在其分别为73.3%、72.2%和88.1% fT>的MIC靶点上，PTA达到90%以上，CFR超过95%。特别是嗜麦芽葡萄球菌，当mic为8 μg/mL时，PTA和CFR均接近100%。结论：头孢地罗2 g q8h滴注3 h给药方案在中国健康受试者中耐受性良好，有望在中国治疗GNB感染取得满意的疗效，但仍需进一步的数据来优化模型。据我们所知，这是第一次描述头孢地罗在中国受试者中的PK特性，并预测其在中国治疗GNB感染的微生物学功效。试验注册：ChiCTR2300076607。
Pharmacokinetic, Pharmacokinetic/Pharmacodynamic, and Safety Investigations of Cefiderocol in Chinese Healthy Subjects
Introduction
We aim to evaluate the safety and pharmacokinetic (PK) properties of cefiderocol in Chinese participants, following single and subsequent multiple administrations of 2 g q8h with 3-h intravenous infusion, and to predict its efficacy for the treatment of Gram-negative bacilli (GNB) infection based on PK/pharmacodynamic (PD) analysis.
Methods
This was an open-label, single-center, single- and multiple-dose phase I study, conducted from September 2022 to October 2022, with 12 eligible healthy Chinese adults (6 men and 6 women). The PK profiles were described by noncompartmental analysis and a two-compartment model using WinNonlin (v.8.1). Monte Carlo simulations (MCS) were performed by R (v.4.3.1) to obtain the probability of target attainment (PTA) as well as the cumulative fraction of response (CFR), based on the previously published data of susceptibility studies for cefiderocol in China.
Results
Both single and multiple doses of 2 g cefiderocol were well tolerated in healthy Chinese subjects, and no severe treatment-emergent adverse events occurred. The maximum plasma concentration of cefiderocol was observed approximately 3 h after administration and the half-life was about 2.6 h, with no accumulation after multiple dosing. It is worth noting that, the PK profiles, including CL, V1, Cmax, Ctrough, and AUC0–τ, were consistent with those of other populations, e.g., Caucasian. PK/PD analysis and MCS suggested that standard dosage regimen of cefiderocol would achieve satisfactory PTA and CFR (exceeding 90%) for Gram-negative pathogens with MICs up to 4 μg/mL, using the proposed fT>MIC target of 75.0%. Consistently, more than 90% of PTA was reached for Enterobacterales, P. aeruginosa, and Acinetobacter spp. with MICs up to 4 μg/mL at their respective 73.3%, 72.2%, and 88.1% fT>MIC targets, with CFR exceeding 95%. Especially for S. maltophilia, both the PTA and CFR reached nearly 100% for those with MICs as high as 8 μg/mL.
Conclusions
Cefiderocol is well tolerated by Chinese healthy participants at the dosage regimen of 2 g cefiderocol q8h via 3-h infusion, which is expected to achieve satisfactory efficacy in treating GNB infections in China, although further data for model optimization might still be required. To our knowledge, this is the first study to describe the PK properties of cefiderocol in Chinese subjects, and to predict its microbiological efficacy for treating GNB infection in China.
期刊介绍：
Advances in Therapy is an international, peer reviewed, rapid-publication (peer review in 2 weeks, published 3–4 weeks from acceptance) journal dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of therapeutics and interventions (including devices) across all therapeutic areas. Studies relating to diagnostics and diagnosis, pharmacoeconomics, public health, epidemiology, quality of life, and patient care, management, and education are also encouraged.
The journal is of interest to a broad audience of healthcare professionals and publishes original research, reviews, communications and letters. The journal is read by a global audience and receives submissions from all over the world. Advances in Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an international and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of all scientifically and ethically sound research.
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