Laboratory of Clinical Pharmacokinetics, School of Pharmacy, Nihon University, Chiba, Japan.
J Clin Pharm Ther. 2012 Jun;37(3):356-63. doi: 10.1111/j.1365-2710.2011.01297.x. Epub 2011 Aug 24.
Fluconazole is an antifungal agent that is commonly used to treat patients with serious systemic fungal infections in intensive care units. Fosfluconazole is a phosphate prodrug of fluconazole, which was developed to reduce the volume of fluid required to administer fluconazole by intravenous injection. The objective of this study was to characterize the pharmacokinetics of the antifungal fluconazole after the intravenous administration of the prodrug fosfluconazole or fluconazole in critically ill patients with serious systemic fungal infections, by population pharmacokinetic analysis using the nonmem software package.
Clinical biochemical data including serum fluconazole levels were obtained from 57 patients treated in the intensive care unit along with two naïve pooled patients gleaned from previous reports. The pharmacokinetic model of fluconazole was estimated using a one-compartment model. The probability that the area under the concentration-time curve is higher than 800 μg h/mL was determined by simulation.
It was assumed that all the administered fosfluconazole was converted to fluconazole with an estimated fosfluconazole-fluconazole conversion rate constant of 2·05/h. The significant covariates for clearance for fluconazole (CL) and volume of distribution for fluconazole (Vd) were resulted in creatinine clearance (CLcr) and body weight (BW), respectively, in the final pharmacokinetic model equations: CL (L/h) = 0·799 × CLcr (mL/min)/92·7 and Vd (L) = 48·1 × BW (kg)/65 , where the interpatient variabilities in CL and Vd and the intrapatient variability were 44·8%, 79·7% and 19·8%, respectively. On the basis of the results of the Monte Carlo simulation, the probabilities of target attainment were 60%, 26% and 11% for 400 mg/day administration as fluconazole equivalent at CLcr values of 40, 70 and 100 mL/min, respectively.
The present population pharmacokinetic analysis strongly indicates that fosfluconazole (and fluconazole) dosage should be optimized in terms of CLcr in critically ill patients.
氟康唑是一种抗真菌药物，常用于治疗重症监护病房中患有严重系统性真菌感染的患者。伏立康唑是氟康唑的磷酸盐前药，旨在通过静脉注射减少氟康唑所需的液体量。本研究的目的是通过非参数软件包的群体药代动力学分析，描述严重系统性真菌感染的重症患者静脉给予前体药物伏立康唑或氟康唑后抗真菌氟康唑的药代动力学特征。
从重症监护病房治疗的 57 例患者以及从以前的报告中收集的 2 例未使用的合并患者中获得包括血清氟康唑水平在内的临床生化数据。使用单室模型估计氟康唑的药代动力学模型。通过模拟确定浓度-时间曲线下面积高于 800μg h/mL 的概率。
假设所有给予的伏立康唑均转化为氟康唑，估计伏立康唑-氟康唑转化率常数为 2.05/h。氟康唑清除率（CL）和氟康唑分布容积（Vd）的显著协变量分别为肌酐清除率（CLcr）和体重（BW），最终药代动力学模型方程为：CL（L/h）= 0.799×CLcr（mL/min）/92.7和 Vd（L）= 48.1×BW（kg）/65，其中 CL 和 Vd 的个体间变异性和个体内变异性分别为 44.8%、79.7%和 19.8%。基于 Monte Carlo 模拟的结果，在 CLcr 值分别为 40、70 和 100 mL/min 时，400mg/天作为氟康唑等效剂量给药的目标达标概率分别为 60%、26%和 11%。
本群体药代动力学分析强烈表明，应根据 CLcr 优化重症患者伏立康唑（和氟康唑）的剂量。
