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Introduction <p>We aim to evaluate the safety and pharmacokinetic (PK) properties of cefiderocol in Chinese participants, following single and subsequent multiple administrations of 2&#xa0;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> Methods <p>This was an open-label, single-center, single- and multiple-dose phase&#xa0;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> Results <p>Both single and multiple doses of 2&#xa0;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&#xa0;h after administration and the half-life was about 2.6&#xa0;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&#xa0;μg/mL, using the proposed <i>f</i><i>T</i><sub>&gt;MIC</sub> target of 75.0%. Consistently, more than 90% of PTA was reached for <i>Enterobacterales</i>, <i>P.&#xa0;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>&gt;MIC</sub> targets, with CFR exceeding 95%. Especially for <i>S.&#xa0;maltophilia</i>, both the PTA and CFR reached nearly 100% for those with MICs as high as 8 μg/mL.</p> Conclusions <p>Cefiderocol is well tolerated by Chinese healthy participants at the dosage regimen of 2&#xa0;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> Trial Registration <p>ChiCTR2300076607.</p>

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Pharmacokinetic, Pharmacokinetic/Pharmacodynamic, and Safety Investigations of Cefiderocol in Chinese Healthy Subjects

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月13日

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  • 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

摘要

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.

Trial Registration

ChiCTR2300076607.