Fluconazole is frequently used for the treatment of invasive Candida infections in critically ill patients. However, alterations in renal functions might influence fluconazole clearance. Therefore, our objective was to study the impact of renal function on the population pharmacokinetics of fluconazole in critically ill patients with various degrees of renal function or undergoing continuous renal replacement therapy (CRRT). This was an open-label, multicenter observational study. Critically ill patients receiving fluconazole were included. Baseline and clinical data were collected. At days 3 and 7 of enrollment, blood samples were drawn for pharmacokinetic curves. Additionally, daily trough samples were taken. A nonlinear mixed-effects model was built, followed by Monte Carlo simulations for assessment of exposure to various dosages of fluconazole. Nineteen patients were included with a median age of 64.4 (range, 23 to 81) years and median weight of 82.0 (range, 44.0 to 119.5) kg. A linear two-compartment model best described fluconazole pharmacokinetics and demonstrated higher clearance than expected in critically ill patients. Simulations showed that daily dosages of 600 mg and 800 mg are needed for intensive care unit (ICU) patients with normal renal function and patients on CRRT, respectively, to achieve the EUCAST-recommended target fAUC (area under the concentration-time curve for the free, unbound fraction of the drug)/MIC ratio of 100. In conclusion, fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and CRRT. Trough concentrations correlated well with the AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend doses of 400 mg for patients with poor to moderate renal function, 600 mg for patients with adequate renal function, and 800 mg for patients treated with CRRT. (This study has been registered at ClinicalTrials.gov under identifier NCT02666716.)

中文翻译：

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重症患者氟康唑的次最佳剂量：是时候重新考虑剂量。

氟康唑常用于治疗侵袭性念珠菌重症患者的感染。但是，肾脏功能的改变可能会影响氟康唑的清除率。因此，我们的目的是研究肾功能对氟康唑对各种程度肾功能或正在接受连续肾脏替代疗法（CRRT）的危重患者的总体药代动力学的影响。这是一个开放式，多中心的观察性研究。包括接受氟康唑治疗的重症患者。收集基线和临床数据。在入组的第3天和第7天，抽取血样用于药代动力学曲线。另外，每天采集槽样品。建立了非线性混合效应模型，然后进行了蒙特卡洛模拟，以评估不同剂量氟康唑的暴露量。纳入19例患者，中位年龄为64.4岁（范围 23至81）岁，体重中位数为82.0（范围：44.0至119.5）kg。线性两室模型最好地描述了氟康唑的药代动力学，并显示出比重症患者预期更高的清除率。模拟显示，肾功能正常的重症监护病房（ICU）患者和接受CRRT的患者分别需要每日600 mg和800 mg的剂量，才能达到EUCAST推荐的目标f AUC（药物自由，未结合部分的浓度-时间曲线下的面积）/ MIC的比率为100。总之，氟康唑的清除率在ICU患者中变化很大，并且强烈依赖于肾功能和CRRT。谷浓度与AUC密切相关，从而为使用治疗药物监测的定制剂量提供了机会。对于肾功能较差至中度的患者，我们建议剂量为400 mg，对于肾功能适当的患者，建议剂量为600 mg，CRRT治疗的患者为800 mg。（该研究已在ClinicalTrials.gov上注册，编号为NCT02666716。）