氨苯砜在人类免疫缺陷病毒感染儿童中的群体药代动力学。

Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection.

作者信息

Mirochnick M, Cooper E, Capparelli E, McIntosh K, Lindsey J, Xu J, Jacobus D, Mofenson L, Bonagura V R, Nachman S, Yogev R, Sullivan J L, Spector S A

机构信息

Boston University School of Medicine, Boston, MA, USA.

出版信息

Clin Pharmacol Ther. 2001 Jul;70(1):24-32. doi: 10.1067/mcp.2001.115891.

DOI:10.1067/mcp.2001.115891

PMID:11452241

Abstract

BACKGROUND

Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity.

METHODS

We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration-time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity.

RESULTS

Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L/kg/h for CL/F, and 2.66 for the absorption rate constant. Of the clinical characteristics evaluated, dapsone CL/F was significantly increased by 50% in children taking rifabutin, by 39% in black children, and by 38% in children younger than 2 years old. Although no significant correlations were found between any dapsone exposure parameter and markers of toxicity, increased AUC was associated with a decreased risk of Pneumocystis carinii pneumonia (PCP).

CONCLUSION

Ethnicity, age, and concomitant rifabutin use were associated with dapsone CL/F, with more rapid clearance observed in black children, children younger than 2 years old, and children receiving rifabutin. Dapsone pharmacokinetic parameters were not associated with toxicity, but higher dapsone AUC was associated with decreased risk of PCP. Monitoring of serum dapsone levels may be needed for optimal management of dapsone for PCP prophylaxis in children.

摘要

背景

以往关于儿童氨苯砜药代动力学的研究规模过小，无法评估氨苯砜药代动力学参数与患者特征或疗效及毒性标志物之间的关系。

方法

我们采用群体分析法估算参与一项关于人类免疫缺陷病毒（HIV）感染儿童每日及每周服用氨苯砜的I/II期研究的儿童的氨苯砜药代动力学参数。使用NONMEM程序和单室开放模型，研究人口统计学和临床特征对口服清除率（CL/F）和口服分布容积（V/F）的影响。估算每位患者的药物暴露量（浓度-时间曲线下面积[AUC]以及给药前和给药后2小时的预测浓度），并将其与疗效及毒性标志物进行关联分析。

结果

60名儿童（中位年龄3岁；年龄范围2个月至12岁）在175次研究剂量后提供了412个氨苯砜浓度数据。最终参数估计值为V/F 1.40 L/kg，CL/F 0.0283 L/kg/h，吸收速率常数为2.66。在评估的临床特征中，服用利福布汀的儿童氨苯砜CL/F显著增加50%，黑人儿童增加39%，2岁以下儿童增加38%。虽然未发现任何氨苯砜暴露参数与毒性标志物之间存在显著相关性，但AUC增加与卡氏肺孢子虫肺炎（PCP）风险降低相关。