Aliaa Fouad, Emir Kobic, Nelson P Nicolasora, Melissa L Thompson Bastin, Paul M Adams, Yuwei Shen, Andrew J Fratoni, Xiaoyi Ye, Joseph L Kuti, David P Nicolau, Tomefa E Asempa
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Population pharmacokinetic analyses were conducted in Pmetrics using R software. The free time above the minimum inhibitory concentration (<i>f</i> T > MIC) and total daily area under the concentration time curve (AUC<sub>daily</sub>) were calculated.</p><p><strong>Results: </strong>Fourteen patients with effluent flow rates ranging from 2.1 to 5.1 L/h were enrolled. Cefiderocol concentrations best fitted a 2-compartment model. Mean ± standard deviation (SD) parameter estimates for clearance, central compartment volume, and intercompartment transfer constants (k<sub>12</sub> and k<sub>21</sub>) were 3.5 ± 1.5 L/hour, 10.7 ± 8.4 L, 3.9 ± 1.8 hours<sup>-1</sup>, and 2.2 ± 2.2 hours<sup>-1</sup>, respectively. With simulations based on product label dosing recommendations, all patients achieved 100% <i>f</i>T > MIC up to MIC 8 mg/L with an AUC<sub>daily</sub> (mean ± SD) of 1444 ± 423 mg × hour/L. Cefiderocol was well tolerated among the 14 patients.</p><p><strong>Conclusions: </strong>The current package insert dosing recommendations resulted in pharmacodynamically optimized cefiderocol exposures. Cefiderocol concentrations exceeded relevant MIC breakpoints in all patients at each effluent flow rate, and AUC<sub>daily</sub> was within the range observed in patients in the phase 3 clinical trials, suggestive of a safe and therapeutic drug profile.</p>","PeriodicalId":19517,"journal":{"name":"Open Forum Infectious Diseases","volume":"11 10","pages":"ofae451"},"PeriodicalIF":3.8000,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492798/pdf/","citationCount":"0","resultStr":"{\"title\":\"Validation of Cefiderocol Package Insert Dosing Recommendation for Patients Receiving Continuous Renal Replacement Therapy: A Prospective Multicenter Pharmacokinetic Study.\",\"authors\":\"Aliaa Fouad, Emir Kobic, Nelson P Nicolasora, Melissa L Thompson Bastin, Paul M Adams, Yuwei Shen, Andrew J Fratoni, Xiaoyi Ye, Joseph L Kuti, David P Nicolau, Tomefa E Asempa\",\"doi\":\"10.1093/ofid/ofae451\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Cefiderocol is the first antibiotic with effluent flow rate-based dosing recommendations outlined in the product label for patients receiving continuous renal replacement therapy (CRRT). We aimed to investigate the population pharmacokinetics of cefiderocol among patients receiving CRRT and validate these dosing recommendations.</p><p><strong>Methods: </strong>A multicenter, prospective cefiderocol pharmacokinetic study among intensive care unit patients receiving CRRT was conducted (2022-2023). Blood sampling was performed at steady-state and cefiderocol concentrations were assayed by validated liquid chromatography-tandem mass spectrometry. Population pharmacokinetic analyses were conducted in Pmetrics using R software. The free time above the minimum inhibitory concentration (<i>f</i> T > MIC) and total daily area under the concentration time curve (AUC<sub>daily</sub>) were calculated.</p><p><strong>Results: </strong>Fourteen patients with effluent flow rates ranging from 2.1 to 5.1 L/h were enrolled. Cefiderocol concentrations best fitted a 2-compartment model. Mean ± standard deviation (SD) parameter estimates for clearance, central compartment volume, and intercompartment transfer constants (k<sub>12</sub> and k<sub>21</sub>) were 3.5 ± 1.5 L/hour, 10.7 ± 8.4 L, 3.9 ± 1.8 hours<sup>-1</sup>, and 2.2 ± 2.2 hours<sup>-1</sup>, respectively. With simulations based on product label dosing recommendations, all patients achieved 100% <i>f</i>T > MIC up to MIC 8 mg/L with an AUC<sub>daily</sub> (mean ± SD) of 1444 ± 423 mg × hour/L. Cefiderocol was well tolerated among the 14 patients.</p><p><strong>Conclusions: </strong>The current package insert dosing recommendations resulted in pharmacodynamically optimized cefiderocol exposures. Cefiderocol concentrations exceeded relevant MIC breakpoints in all patients at each effluent flow rate, and AUC<sub>daily</sub> was within the range observed in patients in the phase 3 clinical trials, suggestive of a safe and therapeutic drug profile.</p>\",\"PeriodicalId\":19517,\"journal\":{\"name\":\"Open Forum Infectious Diseases\",\"volume\":\"11 10\",\"pages\":\"ofae451\"},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2024-10-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492798/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Open Forum Infectious Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/ofid/ofae451\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Open Forum Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/ofid/ofae451","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：头孢羟氨苄是第一种在产品标签中为接受连续性肾脏替代疗法（CRRT）的患者提供基于流出量的剂量建议的抗生素。我们旨在研究接受 CRRT 治疗的患者中头孢克洛的群体药代动力学，并验证这些用药建议：在接受 CRRT 的重症监护室患者中开展了一项多中心、前瞻性的头孢羟氨苄药代动力学研究（2022-2023 年）。在稳定状态下进行血液采样，并通过有效的液相色谱-串联质谱法检测头孢羟氨苄的浓度。使用 R 软件在 Pmetrics 中进行群体药代动力学分析。计算了高于最低抑制浓度的自由时间（f T > MIC）和每日总浓度时间曲线下面积（AUCdaily）：结果：14 名患者的污水流速为 2.1 至 5.1 升/小时。头孢羟氨苄的浓度最符合二室模型。清除率、中心隔室容积和隔室间转移常数（k12 和 k21）的平均值 ± 标准差 (SD) 参数估计值分别为 3.5 ± 1.5 升/小时、10.7 ± 8.4 升、3.9 ± 1.8 小时-1 和 2.2 ± 2.2 小时-1。根据产品标签上的剂量建议进行模拟，所有患者的 fT > MIC 高达 MIC 8 mg/L，AUCdaily（平均 ± SD）为 1444 ± 423 mg × 小时/L。14名患者对头孢羟氨苄的耐受性良好：结论：目前的包装说明书剂量建议可优化头孢羟氨苄的药效暴露。所有患者在每种流出流速下的头孢羟氨苄浓度都超过了相关的 MIC 断点，AUCdaily 在 3 期临床试验中观察到的患者范围内，这表明该药物具有安全和治疗作用。
Validation of Cefiderocol Package Insert Dosing Recommendation for Patients Receiving Continuous Renal Replacement Therapy: A Prospective Multicenter Pharmacokinetic Study.
Background: Cefiderocol is the first antibiotic with effluent flow rate-based dosing recommendations outlined in the product label for patients receiving continuous renal replacement therapy (CRRT). We aimed to investigate the population pharmacokinetics of cefiderocol among patients receiving CRRT and validate these dosing recommendations.
Methods: A multicenter, prospective cefiderocol pharmacokinetic study among intensive care unit patients receiving CRRT was conducted (2022-2023). Blood sampling was performed at steady-state and cefiderocol concentrations were assayed by validated liquid chromatography-tandem mass spectrometry. Population pharmacokinetic analyses were conducted in Pmetrics using R software. The free time above the minimum inhibitory concentration (f T > MIC) and total daily area under the concentration time curve (AUCdaily) were calculated.
Results: Fourteen patients with effluent flow rates ranging from 2.1 to 5.1 L/h were enrolled. Cefiderocol concentrations best fitted a 2-compartment model. Mean ± standard deviation (SD) parameter estimates for clearance, central compartment volume, and intercompartment transfer constants (k12 and k21) were 3.5 ± 1.5 L/hour, 10.7 ± 8.4 L, 3.9 ± 1.8 hours-1, and 2.2 ± 2.2 hours-1, respectively. With simulations based on product label dosing recommendations, all patients achieved 100% fT > MIC up to MIC 8 mg/L with an AUCdaily (mean ± SD) of 1444 ± 423 mg × hour/L. Cefiderocol was well tolerated among the 14 patients.
Conclusions: The current package insert dosing recommendations resulted in pharmacodynamically optimized cefiderocol exposures. Cefiderocol concentrations exceeded relevant MIC breakpoints in all patients at each effluent flow rate, and AUCdaily was within the range observed in patients in the phase 3 clinical trials, suggestive of a safe and therapeutic drug profile.
期刊介绍：
Open Forum Infectious Diseases provides a global forum for the publication of clinical, translational, and basic research findings in a fully open access, online journal environment. The journal reflects the broad diversity of the field of infectious diseases, and focuses on the intersection of biomedical science and clinical practice, with a particular emphasis on knowledge that holds the potential to improve patient care in populations around the world. Fully peer-reviewed, OFID supports the international community of infectious diseases experts by providing a venue for articles that further the understanding of all aspects of infectious diseases.
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