Crommentuyn Kristel M L, Scherpbier Henriëtte J, Kuijpers Taco W, Mathôt Ron A A, Huitema Alwin D R, Beijnen Jos H
Department of Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
Pediatr Infect Dis J. 2006 Jun;25(6):538-43. doi: 10.1097/01.inf.0000215242.70300.95.
The objectives of this study are to develop and validate a population pharmacokinetic model that adequately describes the pharmacokinetics of nelfinavir and its active metabolite M8 in HIV-1-infected children; to define factors involved in the pharmacokinetic variability, which could aid in defining dosing strategies; and to correlate the pharmacokinetics to the treatment response.
Protease inhibitor-naive, HIV-1-infected children were included. A population pharmacokinetic model of nelfinavir and M8 was developed using NONMEM. Bayesian analysis was used to estimate pharmacokinetic values. A pharmacokinetic-pharmacodynamic analysis was performed to study relationships between these values and the virologic response to therapy.
From 38 children, 724 nelfinavir and 636 M8 plasma concentrations were available. The pharmacokinetics of both compounds were described simultaneously with a one-compartment model with first-order elimination. Clearance (CL/F) and volume of distribution (V/F) were 32.6 L/h (interindividual variability [IIV]: 31.6%) and 281 L/h (IIV: 29.7%) for nelfinavir and 86.2 L/h (IIV: 43.1%) and 42.3 L/h for M8. No factors could be defined that affected the pharmacokinetics of nelfinavir or M8. The overall virologic response was 78% (HIV-1 RNA <500 copies/mL, on-treatment analysis). No differences in exposure to nelfinavir and M8 were observed between responders and nonresponders. The only factor distinguishing the two groups was a higher baseline HIV-1 RNA concentration in nonresponders.
A model was developed and validated that adequately described the population pharmacokinetics of nelfinavir and M8 in a childhood population. No factors affecting dosing strategies were identified, and no correlation could be demonstrated between the exposure to nelfinavir and M8 and the virologic treatment response.
本研究的目的是建立并验证一个能充分描述奈非那韦及其活性代谢产物M8在HIV-1感染儿童体内药代动力学的群体药代动力学模型；确定参与药代动力学变异性的因素，这有助于确定给药策略；并将药代动力学与治疗反应相关联。
纳入未接受过蛋白酶抑制剂治疗的HIV-1感染儿童。使用NONMEM建立奈非那韦和M8的群体药代动力学模型。采用贝叶斯分析来估计药代动力学值。进行药代动力学-药效学分析以研究这些值与治疗病毒学反应之间的关系。
从38名儿童中获得了724个奈非那韦和636个M8血浆浓度数据。两种化合物的药代动力学用具有一级消除的单室模型同时描述。奈非那韦的清除率（CL/F）和分布容积（V/F）分别为32.6 L/h（个体间变异性[IIV]：31.6%）和281 L/h（IIV：29.7%），M8的清除率和分布容积分别为86.2 L/h（IIV：43.1%）和42.3 L/h。未发现影响奈非那韦或M8药代动力学的因素。总体病毒学反应为78%（治疗期分析，HIV-1 RNA<500拷贝/mL）。在反应者和无反应者之间未观察到奈非那韦和M8暴露的差异。区分两组的唯一因素是无反应者中较高的基线HIV-1 RNA浓度。
建立并验证了一个能充分描述儿童群体中奈非那韦和M8群体药代动力学的模型。未发现影响给药策略的因素，且未证明奈非那韦和M8暴露与病毒学治疗反应之间存在相关性。
