Indinavir Pharmacokinetics and Parmacodynamics in Children with Human Immunodeficiency Virus Infection

The indinavir dosage regimen currently used for human immunodeficiency virus (HIV)-infected children is not based on pharmacokinetic data obtained in the target patient population. The purpose of our study was to characterize indinavir pharmacokinetics and pharmacodynamics in HIV-infected children. Eleven children (age range, 9.0 to 13.6 years; weight range, 21.7 to 56.0 kg) receiving indinavir (500 mg/m(2) every 8 h) in combination with lamivudine and stavudine were studied. The correlation of indinavir pharmacokinetic parameters and demographic parameters was evaluated. Also, the pharmacodynamic relationship between parameters of indinavir exposure and parameters of renal toxicity and immunologic recovery was studied. The area under the indinavir concentration-time curve (AUC) and patient body surface area (BSA) showed a significant negative correlation (r = 0.73; P = 0.012). Patients with smaller BSA had excessive indinavir AUC compared to adults. On the other hand, the median minimum drug concentration in plasma (C(min)) was lower than that reported for adults. The maximum indinavir concentration in serum was higher in patients with renal toxicity (5 out of 11 children), but the difference was not statistically significant (15.3 ± 8.2 versus 9.8 ± 4.4 mg/liter; P = 0.19). There was a trend toward higher immunologic efficacy in patients with greater indinavir exposure: the time-averaged AUC of the percentage of CD4(+) lymphocytes over the baseline value for patients with indinavir C(min) > 95% inhibitory concentration (IC(95)) was higher than in patients with C(min) < IC(95) (P = 0.068). Our study suggests that a dose reduction may be appropriate for children with small BSA and that a 6-h dosage regimen may be indicated for a substantial percentage of patients. Due to the low number of patients enrolled in this study, our results should be confirmed by a larger study.

目前用于人类免疫缺陷病毒（HIV）感染儿童的茚地那韦（indinavir）给药方案，并未基于目标患者人群中获取的药代动力学（pharmacokinetic）数据。本研究旨在明确HIV感染儿童的茚地那韦药代动力学与药效动力学（pharmacodynamics）特征。本研究纳入11名年龄范围为9.0~13.6岁、体重范围为21.7~56.0kg的儿童，所有受试者均接受茚地那韦（500mg/m²，每8小时1次）联合拉米夫定（lamivudine）与司他夫定（stavudine）的治疗方案。研究评估了茚地那韦药代动力学参数与人口统计学参数的相关性，同时分析了茚地那韦暴露参数与肾毒性、免疫学恢复相关参数之间的药效动力学关系。

茚地那韦血药浓度-时间曲线下面积（AUC）与患者体表面积（BSA）呈显著负相关（r=0.73；P=0.012）。体表面积较小的患儿，其茚地那韦AUC高于成人受试者。另一方面，血浆茚地那韦的最低药物浓度（C_min）的中位数低于已报道的成人数据。本研究中11名患儿里有5名出现肾毒性，此类患儿的血清茚地那韦峰浓度更高，但该差异无统计学意义（15.3±8.2 vs 9.8±4.4 mg/L；P=0.19）。茚地那韦暴露量更高的患儿，其免疫学疗效呈现升高趋势：当茚地那韦C_min＞95%抑制浓度（IC₉₅）时，患儿CD4+淋巴细胞百分比较基线的时间平均AUC高于C_min＜IC₉₅的患儿（P=0.068）。

本研究提示，体表面积较小的患儿或许需要调整茚地那韦给药剂量，且相当比例的患者应考虑采用每6小时1次的给药方案。由于本研究纳入的患者数量有限，其研究结果需通过更大规模的研究予以验证。