群体药代动力学研究：危重症患者中异康唑及其游离药物的药动学特征及其对适应性给药策略的影响。

Population Pharmacokinetics of Total and Unbound Isavuconazole in Critically Ill Patients: Implications for Adaptive Dosing Strategies.

机构信息

Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Medical Innovations, Postbox 9101, 6500 HB, Nijmegen, Geert Grooteplein Zuid 10, The Netherlands.

Radboud University Medical Center-Canisius Wilhelmina Ziekenhuis Center of Expertise for Mycology, Nijmegen, The Netherlands.

出版信息

Clin Pharmacokinet. 2023 Dec;62(12):1701-1711. doi: 10.1007/s40262-023-01305-8. Epub 2023 Oct 11.

BACKGROUND AND OBJECTIVES

Isavuconazole is a broad-spectrum antifungal agent for the management of invasive fungal disease. Optimised drug exposure is critical for patient outcomes, specifically in the critically ill population. Solid information on isavuconazole pharmacokinetics including protein binding in patients in the intensive care unit is scarce. We aimed to describe the total and unbound isavuconazole pharmacokinetics and subsequently propose a dosage optimisation strategy.

METHODS

A prospective multi-centre study in adult intensive care unit patients receiving isavuconazole was performed. Blood samples were collected on eight timepoints over one dosing interval between days 3-7 of treatment and optionally on one timepoint after discontinuation. Total and unbound isavuconazole pharmacokinetics were analysed by means of population pharmacokinetic modelling using NONMEM. The final model was used to perform simulations to assess exposure described by the area under the concentration-time curve and propose an adaptive dosing approach.

RESULTS

Population pharmacokinetics of total and unbound isavuconazole were best described by an allometrically scaled two-compartment model with a saturable protein-binding model and interindividual variability on clearance and the maximum binding capacity. The median (range) isavuconazole unbound fraction was 1.65% (0.83-3.25%). After standard dosing, only 35.8% of simulated patients reached a total isavuconazole area under the concentration-time curve > 60 mg·h/L at day 14. The proposed adaptive dosing strategy resulted in an increase to 62.3% of patients at adequate steady-state exposure.

CONCLUSIONS

In critically ill patients, total isavuconazole exposure is reduced and protein binding is highly variable. We proposed an adaptive dosing approach to enhance early treatment optimisation in this high-risk population.

CLINICAL TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT04777058.

背景与目的

伊曲康唑是一种广谱抗真菌药物，用于治疗侵袭性真菌感染。优化药物暴露对于患者的预后至关重要，尤其是在重症患者中。关于重症监护病房患者伊曲康唑药代动力学（包括蛋白结合）的信息很少。我们旨在描述总伊曲康唑和游离伊曲康唑的药代动力学，并随后提出优化剂量的策略。

方法

在接受伊曲康唑治疗的成年重症监护病房患者中进行了一项前瞻性多中心研究。在治疗第 3-7 天的一个给药间隔内采集 8 个时间点的血样，并在停药后可选采集一个时间点的血样。采用 NONMEM 进行群体药代动力学建模分析总伊曲康唑和游离伊曲康唑的药代动力学。最后，采用该模型进行模拟，以评估浓度-时间曲线下面积（AUC）所描述的暴露情况，并提出一种自适应给药方法。

结果

总伊曲康唑和游离伊曲康唑的群体药代动力学最好通过一种按比例缩放的两室模型来描述，该模型具有饱和蛋白结合模型和个体间清除率和最大结合能力的变异性。伊曲康唑游离分数的中位数（范围）为 1.65%（0.83-3.25%）。标准剂量后，只有 35.8%的模拟患者在第 14 天达到总伊曲康唑 AUC>60mg·h/L。提出的自适应给药策略使达到足够稳态暴露的患者比例增加到 62.3%。