Hong Ying, Shaw Peter J, Nath Christa E, Yadav Satya P, Stephen Katherine R, Earl John W, McLachlan Andrew J
Faculty of Pharmacy, Pharmacy Building (A15), Camperdown Campus, University of Sydney, Sydney, NSW 2006, Australia.
Antimicrob Agents Chemother. 2006 Mar;50(3):935-42. doi: 10.1128/AAC.50.3.935-942.2006.
A population pharmacokinetic model of liposomal amphotericin B (L-AmB) in pediatric patients with malignant diseases was developed and evaluated. Blood samples were collected from 39 pediatric oncology patients who received multiple doses of L-AmB with a dose range from 0.8 to 5.9 mg/kg of body weight/day. The patient cohort had an average age of 7 years (range, 0.2 to 17 years) and weighed an average of 28.8 +/- 19.8 kg. Population pharmacokinetic analyses were performed with NONMEM software. Pharmacokinetic parameters, interindividual variability (IIV), between-occasion variability (BOV), and intraindividual variability were estimated. The influence of patient characteristics on the pharmacokinetics of L-AmB was explored. The final population pharmacokinetic model was evaluated by using a bootstrap sampling technique. The L-AmB plasma concentration-time data was described by a two-compartment pharmacokinetic model with zero-order input and first-order elimination. The population mean estimates of clearance (CL) and volume of distribution in the central compartment (V1) were 0.44 liters/h and 3.12 liters, respectively, and exhibited IIV (CL, 10%) and significant BOV (CL, 46% and V1, 56%). The covariate models were CL (liters/h) = 0.44 . e(0.0152.(WT-21)) and V1 (liters) = 3.12.e(0.0241.(WT-21)), where WT is the patient's body weight (kg) centered on the study population cohort median of 21 kg. Model evaluation by the bootstrap procedure indicated that the full pharmacokinetic model was robust and parameter estimates were accurate. In conclusion, the pharmacokinetics of L-AmB in pediatric oncology patients were adequately described by the developed population model. The model has been evaluated and can be used in the design of rational dosing strategies for L-AmB antifungal therapy in this special population.
建立并评估了恶性疾病儿科患者的脂质体两性霉素B（L-AmB）群体药代动力学模型。从39名接受多剂量L-AmB的儿科肿瘤患者中采集血样，剂量范围为0.8至5.9mg/（kg体重/天）。患者队列的平均年龄为7岁（范围为0.2至17岁），平均体重为28.8±19.8kg。使用NONMEM软件进行群体药代动力学分析。估计药代动力学参数、个体间变异性（IIV）、给药间隔间变异性（BOV）和个体内变异性。探讨了患者特征对L-AmB药代动力学的影响。通过自抽样技术评估最终的群体药代动力学模型。L-AmB血浆浓度-时间数据由具有零级输入和一级消除的二室药代动力学模型描述。清除率（CL）和中央室分布容积（V1）的群体均值估计分别为0.44升/小时和3.12升，并表现出IIV（CL，10%）和显著的BOV（CL，46%和V1，56%）。协变量模型为CL（升/小时）=0.44.e(0.0152.(WT - 21))和V1（升）=3.12.e(0.0241.(WT - 21))，其中WT是患者体重（kg），以研究群体队列中位数21kg为中心。通过自抽样程序进行的模型评估表明，完整的药代动力学模型稳健且参数估计准确。总之，所建立的群体模型充分描述了儿科肿瘤患者中L-AmB的药代动力学。该模型已经过评估，可用于设计针对该特殊人群的L-AmB抗真菌治疗的合理给药策略。
