Bergshoeff Alina S, Fraaij Pieter L A, van Rossum Annemarie M C, Wolfs Tom F W, Geelen Sibyl P M, de Groot Ronald, Burger David M
University Medical Centre, Department of Clinical Pharmacy, Nijmegen, The Netherlands.
Antivir Ther. 2003 Jun;8(3):215-22.
The study describes the pharmacokinetics (PK) of the protease inhibitor nelfinavir and its active metabolite M8 in children and evaluates the influence of patient-related factors on nelfinavir plasma levels.
HIV-1-infected children treated with nelfinavir every 8 h (q8h) were eligible for inclusion in this retrospective study. 0-8 h intensive plasma pharmacokinetics (PK) sampling was performed at steady state. Nelfinavir maximum concentration (Cmax), area under the plasma concentration-time curve in 0-8 h (AUC0-8), trough level at the 8 h time point (C8) and relative apparent oral clearance (CI*F/kg) were calculated.
Twenty-four children (median age: 4.5 years, median nelfinavir dose: 28 mg/kg q8h) were included. Nelfinavir PK were highly variable: 10/24 children had an AUC0-8 below the value of 12.5 mg/l x h, which has previously been associated with an increased virological failure rate in children. With children aged < 2 years and a dose of 20 mg/kg q8h, a non-significant trend was observed to more AUC0-8 < 12.5 mg/l x h [odds ratio (OR) (95% CI): 2.44 (0.41-14.7) and 8.7 (0.79-95), respectively]. Nelfinavir C8 correlated strongly with AUC0-8 (r = 0.89, P < 0.001). C8 > 0.69 mg/l predicted an AUC0-8 > 12.5 mg/l x h with 71% sensitivity and 80% specificity. Dose of nelfinavir per body surface area was a better predictor of AUC0-8 than dose per body weight.
Nelfinavir PK show high interindividual variability in children. Children < 2 years old tend to be at increased risk for low nelfinavir levels. These data show that the nelfinavir dose of 20 mg/kg q8h is inadequate in most children. Also, these data suggest that paediatric dosing of nelfinavir based on body surface area should be considered. Therapeutic drug monitoring (TDM) can detect abnormal plasma levels and is therefore useful in optimizing nelfinavir therapy in HIV-infected children. However, further research is needed to more firmly establish a therapeutic range for nelfinavir in children.
本研究描述了蛋白酶抑制剂奈非那韦及其活性代谢产物M8在儿童体内的药代动力学（PK），并评估了患者相关因素对奈非那韦血浆水平的影响。
每8小时（q8h）接受奈非那韦治疗的HIV-1感染儿童符合纳入本回顾性研究的条件。在稳态下进行0 - 8小时的密集血浆药代动力学（PK）采样。计算奈非那韦的最大浓度（Cmax）、0 - 8小时血浆浓度-时间曲线下面积（AUC0-8）、8小时时间点的谷浓度（C8）以及相对表观口服清除率（CI*F/kg）。
纳入了24名儿童（中位年龄：4.5岁，中位奈非那韦剂量：28 mg/kg q8h）。奈非那韦的PK个体差异很大：24名儿童中有10名的AUC0-8低于12.5 mg/l×h，这一数值此前与儿童病毒学失败率增加相关。对于年龄<2岁且剂量为20 mg/kg q8h的儿童，观察到AUC0-8 < 12.5 mg/l×h有不显著的增加趋势[优势比（OR）（95%置信区间）：分别为2.44（0.41 - 14.7）和8.7（0.79 - 95）]。奈非那韦的C8与AUC0-8密切相关（r = 0.89，P < 0.001）。C8 > 0.69 mg/l预测AUC0-8 > 12.5 mg/l×h的敏感度为71%，特异度为80%。按体表面积计算的奈非那韦剂量比按体重计算的剂量能更好地预测AUC0-8。
奈非那韦在儿童中的PK个体间差异很大。2岁以下儿童出现低奈非那韦水平的风险往往增加。这些数据表明，大多数儿童每8小时20 mg/kg的奈非那韦剂量不足。此外，这些数据表明应考虑基于体表面积的奈非那韦儿科给药方案。治疗药物监测（TDM）可检测异常血浆水平，因此有助于优化HIV感染儿童的奈非那韦治疗。然而，需要进一步研究以更确切地确定儿童奈非那韦的治疗范围。
