Background Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited. Materials and methods We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus. Results C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ± 1.68 mg/L (mean ± SD) and 106 ± 32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ± 0.03, 0.94 ± 0.46 and 27.1 ± 17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ± 32.1, 1.68 ± 0.72, 22.6 ± 11.0 and 650 ± 426 mg·h/L, respectively. Conclusion Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L.

中文翻译：

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健康志愿者单次和多次静脉输注后艾沙康唑在不同靶点的药代动力学

背景 侵袭性曲霉病是一种严重的真菌感染，影响包括中枢神经系统和肺部在内的多个器官系统。艾沙康唑是一种新型三唑类抗真菌剂，已显示出对抗曲霉菌的良好活性。然而，有关艾沙康唑渗透到 CNS 和 ELF 以及细胞内积累的数据仍然有限。材料和方法 我们对 12 名健康志愿者进行了一项前瞻性单中心药代动力学 (PK) 研究。受试者接受七剂 200 mg 艾沙康唑以达到假定的稳态。第一次和最后一次输注后，分别在 8 小时和 12 小时内进行血浆采样。所有受试者在最终剂量输注后 2、6 或 12 小时均接受一次腰椎穿刺和支气管肺泡灌洗。从六名受试者的血液中收集 PBMC，以确定 6、8 或 12 小时时的细胞内艾沙康唑浓度。 AUC/MIC 是针对 1 mg/L 的 MIC 值计算的，该值标志着烟曲霉和黄曲霉的 EUCAST 敏感性断点。结果 在假定的稳态条件下，血浆中艾沙康唑的 C max 和 AUC0-24h 分别为 6.57 ± 1.68 mg/L（平均值 ± SD）和 106 ± 32.1 h·mg/L。 CSF、ELF 和 PBMC 中测得的平均浓度分别为 0.07 ± 0.03、0.94 ± 0.46 和 27.1 ± 17.8 mg/L。稳态条件下血浆、CSF、ELF和PBMC中的AUC/MIC分别为106±32.1、1.68±0.72、22.6±11.0和650±426mg·h/L。结论 艾沙康唑对 ELF 的渗透性中等，对 CSF 的渗透性较低，而在 PBMC 中的积累较高。目前的给药方案导致所有受试者都有足够的血浆暴露来治疗 MIC ≤ 1 mg/L 的分离株。