PDF(Pubmed)
Abstract：
OBJECTIVE: The pharmacokinetic (PK) profiles of voriconazole in intensive care unit (ICU) patients differ from that in other patients. We aimed to develop a population pharmacokinetic (PopPK) model to evaluate the effects of using extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and those of various biological covariates on the voriconazole PK profile.
METHODS: Modeling analyses of the PK parameters were conducted using the nonlinear mixed-effects modeling method (NONMEM) with a two-compartment model. Monte Carlo simulations (MCSs) were performed to observe the probability of target attainment (PTA) when receiving CRRT or not under different dosage regimens, different stratifications of quick C-reactive protein (qCRP), and different minimum inhibitory concentration (MIC) ranges.
RESULTS: A total of 408 critically ill patients with 746 voriconazole concentration-time data points were included in this study. A two-compartment population PK model with qCRP, CRRT, creatinine clearance rate (CLCR), platelets (PLT), and prothrombin time (PT) as fixed effects was developed using the NONMEM.
CONCLUSIONS: We found that qCRP, CRRT, CLCR, PLT, and PT affected the voriconazole clearance. The most commonly used clinical regimen of 200 mg q12h was sufficient for the most common sensitive pathogens (MIC ≤ 0.25 mg/L), regardless of whether CRRT was performed and the level of qCRP. When the MIC was 0.5 mg/L, 200 mg q12h was insufficient only when the qCRP was <40 mg/L and CRRT was performed. When the MIC was ≥2 mg/L, a dose of 300 mg q12h could not achieve ≥ 90% PTA, necessitating the evaluation of a higher dose.
METHODS: Modeling analyses of the PK parameters were conducted using the nonlinear mixed-effects modeling method (NONMEM) with a two-compartment model. Monte Carlo simulations (MCSs) were performed to observe the probability of target attainment (PTA) when receiving CRRT or not under different dosage regimens, different stratifications of quick C-reactive protein (qCRP), and different minimum inhibitory concentration (MIC) ranges.
RESULTS: A total of 408 critically ill patients with 746 voriconazole concentration-time data points were included in this study. A two-compartment population PK model with qCRP, CRRT, creatinine clearance rate (CLCR), platelets (PLT), and prothrombin time (PT) as fixed effects was developed using the NONMEM.
CONCLUSIONS: We found that qCRP, CRRT, CLCR, PLT, and PT affected the voriconazole clearance. The most commonly used clinical regimen of 200 mg q12h was sufficient for the most common sensitive pathogens (MIC ≤ 0.25 mg/L), regardless of whether CRRT was performed and the level of qCRP. When the MIC was 0.5 mg/L, 200 mg q12h was insufficient only when the qCRP was <40 mg/L and CRRT was performed. When the MIC was ≥2 mg/L, a dose of 300 mg q12h could not achieve ≥ 90% PTA, necessitating the evaluation of a higher dose.
摘要：
目的：伏立康唑在重症监护病房（ICU）患者中的药代动力学（PK）特征与其他患者不同。我们旨在开发一种群体药代动力学（PopPK）模型，以评估使用体外膜氧合（ECMO）和连续肾脏替代疗法（CRRT）以及各种生物协变量对伏立康唑PK谱的影响。
方法:使用具有两室模型的非线性混合效应建模方法(NONMEM)进行PK参数的建模分析。进行蒙特卡罗模拟（MCS）以观察在不同剂量方案下接受或不接受CRRT时达到目标（PTA）的概率，快速C反应蛋白（qCRP）的不同分层，和不同的最小抑制浓度（MIC）范围。
结果：本研究共纳入408例危重患者，其中746例伏立康唑浓度-时间数据点。具有qCRP的两室种群PK模型，CRRT,肌酐清除率（CLCR），血小板(PLT),和凝血酶原时间（PT）作为固定效应是使用NONMEM开发的。
结论：我们发现qCRP，CRRT,CLCR,PLT,PT影响伏立康唑清除率。最常用的200mgq12h的临床方案足以用于最常见的敏感病原体（MIC≤0.25mg/L），无论是否进行CRRT和qCRP水平。当MIC为0.5mg/L时,仅当qCRP<40mg/L并进行CRRT时，200mgq12h才不足。当MIC≥2mg/L时，300mgq12h的剂量不能达到≥90%PTA，需要评估更高的剂量。
方法:使用具有两室模型的非线性混合效应建模方法(NONMEM)进行PK参数的建模分析。进行蒙特卡罗模拟（MCS）以观察在不同剂量方案下接受或不接受CRRT时达到目标（PTA）的概率，快速C反应蛋白（qCRP）的不同分层，和不同的最小抑制浓度（MIC）范围。
结果：本研究共纳入408例危重患者，其中746例伏立康唑浓度-时间数据点。具有qCRP的两室种群PK模型，CRRT,肌酐清除率（CLCR），血小板(PLT),和凝血酶原时间（PT）作为固定效应是使用NONMEM开发的。
结论：我们发现qCRP，CRRT,CLCR,PLT,PT影响伏立康唑清除率。最常用的200mgq12h的临床方案足以用于最常见的敏感病原体（MIC≤0.25mg/L），无论是否进行CRRT和qCRP水平。当MIC为0.5mg/L时,仅当qCRP<40mg/L并进行CRRT时，200mgq12h才不足。当MIC≥2mg/L时，300mgq12h的剂量不能达到≥90%PTA，需要评估更高的剂量。
