Department of Intensive Care Unit, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang West Road, Guangzhou 510120, Guangdong, China.
Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
J Glob Antimicrob Resist. 2021 Jun;25:238-263. doi: 10.1016/j.jgar.2021.03.011. Epub 2021 Apr 15.
Effective antifungal therapy is important to reduce mortality in patients with invasive fungal infections (IFIs). Numerous factors affect pharmacokinetic/pharmacodynamic (PK/PD) parameters in critically-ill patients. To guide individualised administration in critically-ill patients, it is of great significance to determine the population pharmacokinetics of caspofungin.
A prospective study in 42 ICU patients with IFIs was conducted in China. A population pharmacokinetic model of caspofungin was established using a non-linear mixed-effects model, which was utilised to investigate the effects of demographic indices, liver function and kidney function on pharmacokinetics. Additionally, appropriate dosages of caspofungin under various scenarios were determined based on MICs and probability of target attainment (PTA) at specific dosages.
In critically-ill Chinese patients, clearance (CL), volume of distribution (V) and area under the curve at steady-state (AUC) of caspofungin were 0.32 L/h, 6.77 L and 135.47 mg•h/L, respectively. Blood albumin and total bilirubin levels were factors affecting CL, while body weight was the only factor affecting V among Chinese people with relatively low weight compared with other populations. A maintenance dose of 50 mg caspofungin achieved a high PTA for treating IFIs caused by Candida albicans (MIC ≤ 0.06 mg/L) and Candida glabrata (MIC ≤ 0.125 mg/L). The maintenance dose of caspofungin should be adjusted to 70-200 mg for IFIs caused by C. albicans (MIC, 0.06-0.125 mg/L). For IFIs caused by Candida parapsilosis, an MIC > 0.03 mg/L is associated with a very low PTA, but higher doses of caspofungin or alternative antifungals need to be further studied.
The population pharmacokinetic model established here described well the PK/PD characteristics of caspofungin in critically-ill Chinese patients. These results could guide the formulation of individualised caspofungin dosing regimens for critically-ill patients.
有效的抗真菌治疗对于降低侵袭性真菌感染（IFI）患者的死亡率非常重要。许多因素会影响重症患者的药代动力学/药效学（PK/PD）参数。为了指导重症患者的个体化给药，确定卡泊芬净的群体药代动力学具有重要意义。
在中国进行了一项针对 42 例IFI 重症患者的前瞻性研究。使用非线性混合效应模型建立卡泊芬净的群体药代动力学模型，以研究人口统计学指标、肝功能和肾功能对药代动力学的影响。此外，根据 MIC 和特定剂量下的目标达标概率（PTA），确定了在不同情况下卡泊芬净的合适剂量。
在重症中国患者中，卡泊芬净的清除率（CL）、分布容积（V）和稳态时的曲线下面积（AUC）分别为 0.32 L/h、6.77 L 和 135.47 mg•h/L。血白蛋白和总胆红素水平是影响 CL 的因素，而体重是与其他人群相比体重较轻的中国人中唯一影响 V 的因素。50mg 卡泊芬净的维持剂量可实现高 PTA，用于治疗白念珠菌（MIC≤0.06mg/L）和光滑念珠菌（MIC≤0.125mg/L）引起的 IFI。对于白念珠菌（MIC，0.06-0.125mg/L）引起的 IFI，卡泊芬净的维持剂量应调整至 70-200mg。对于近平滑念珠菌引起的 IFI，MIC>0.03mg/L 与极低的 PTA 相关，但需要进一步研究更高剂量的卡泊芬净或其他抗真菌药物。
本研究建立的群体药代动力学模型很好地描述了卡泊芬净在重症中国患者中的 PK/PD 特征。这些结果可以指导重症患者个体化卡泊芬净给药方案的制定。
