Watt Kevin M, Gonzalez Daniel, Benjamin Daniel K, Brouwer Kim L R, Wade Kelly C, Capparelli Edmund, Barrett Jeffrey, Cohen-Wolkowiez Michael
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
Antimicrob Agents Chemother. 2015 Jul;59(7):3935-43. doi: 10.1128/AAC.00102-15. Epub 2015 Apr 20.
Candida infections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. The PK data were analyzed using nonlinear mixed-effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution (V). The final model included the effect of serum creatinine (SCR) level on CL and the effect of ECMO on V as follows: CL (in liters per hour) = 0.019 × weight × (SCR/0.4)(-0.29) × exp(ηCL) and V (in liters) = 0.93 × weight × 1.4(ECMO) × exp(ηV). The fluconazole V was increased in children supported by ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12 mg/kg of body weight) and treatment (35 mg/kg) paired with standard maintenance doses to achieve exposures similar to those of children not on ECMO.
念珠菌感染是接受体外膜肺氧合（ECMO）支持的儿童感染性疾病相关死亡的主要原因。ECMO回路会改变药物的药代动力学（PK）；因此，标准的氟康唑给药剂量可能导致药物暴露不足。我们研究的目的是确定接受ECMO治疗的儿童中氟康唑的药代动力学。分析纳入了40名儿童的367份PK样本。使用非线性混合效应模型（NONMEM）对PK数据进行分析。单室模型最能描述这些数据。基础模型中纳入了体重对清除率（CL）和分布容积（V）的影响。最终模型纳入了血清肌酐（SCR）水平对CL的影响以及ECMO对V的影响，如下所示：CL（每小时升数）=0.019×体重×（SCR/0.4）（-0.29）×exp（ηCL），V（升）=0.93×体重×1.4（ECMO）×exp（ηV）。接受ECMO支持的儿童中氟康唑的V增加。因此，接受ECMO治疗的儿童预防（12mg/kg体重）和治疗（35mg/kg）时需要更高的氟康唑负荷剂量，并搭配标准维持剂量，以达到与未接受ECMO治疗的儿童相似的暴露水平。
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