患有结核病儿童的吡嗪酰胺血药浓度：两种剂量的对比研究
Pyrazinamide blood concentrations in children suffering from tuberculosis: a comparative study at two doses.
作者信息
Gupta Pooja, Roy Vandana, Sethi Gulshan Rai, Mishra Tarun Kumar
机构信息
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.
出版信息
Br J Clin Pharmacol. 2008 Mar;65(3):423-7. doi: 10.1111/j.1365-2125.2007.03069.x. Epub 2007 Dec 17.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
Pyrazinamide is recommended in doses varying from 15 to 40 mg kg(-1). The most commonly used average daily dose is 25 mg kg(-1). Its use is associated with dose dependent hepatotoxicity. Lower doses are not used because of lack of pharmacokinetic data especially in children. There is only one detailed study of pyrazinamide in children at a dose of 35 mg kg(-1).
WHAT THIS STUDY ADDS
This is the first study evaluating serum concentrations of pyrazinamide in children at a dose of 15 mg kg(-1) which is on the lower side of the recommended dose. The study also compared the serum concentrations and pharmacokinetics achieved with this dose with the widely used dose of 25 mg kg(-1) in children suffering from tuberculosis. The pharmacokinetics and pharmacodynamic indices of pyrazinamide were comparable with the 25 and 15 mg kg(-1) doses.
AIMS
To evaluate the pharmacokinetics and pharmacodynamic indices of pyrazinamide at doses of 15 and 25 mg kg(-1) in children suffering from tuberculosis.
METHODS
Twenty children with tuberculosis received pyrazinamide at a single dose of 25 mg kg(-1) (group I) and 15 mg kg(-1) (group II). Serial blood samples were collected and the drug concentrations were analyzed spectrophotometrically. The pharmacokinetic parameters were calculated and the duration of time for which pyrazinamide concentrations in serum remained above the pyrazinamide inhibitory concentrations of 20 microg ml(-1) and 25 microg ml(-1) was studied.
RESULTS
The mean peak serum concentration was 42.4 +/- 3.3 microg ml(-1) (95% CI +/- 6.5) and 38.6 +/- 3.9 microg ml(-1) (95% CI +/- 7.7) in groups I and II, respectively. The elimination half-life was 9.3 +/- 1.3 h and 10.5 +/- 2.3 h (P = 0.6) and clearance was 0.06 +/- 0.01 l h(-1) kg(-1) and 0.04 +/- 0.01 l h(-1) kg(-1) (P = 0.08) in groups I and II, respectively. Pharmacokinetic parameters and PKPD indices were comparable with both the doses.
CONCLUSIONS
The study indicates that comparable serum concentrations of pyrazinamide are attained with 25 mg kg(-1) and 15 mg kg(-1) doses in children. The elimination half-life was longer and volume of distribution greater in children than in the adult population.
关于该主题的已知信息
推荐的吡嗪酰胺剂量为15至40mg/kg（-1）。最常用的平均日剂量为25mg/kg（-1）。其使用与剂量依赖性肝毒性相关。由于缺乏药代动力学数据，尤其是儿童的数据，较低剂量未被采用。仅有一项对儿童使用35mg/kg（-1）剂量吡嗪酰胺的详细研究。
本研究的新增内容
这是第一项评估15mg/kg（-1）剂量（该剂量处于推荐剂量下限）儿童血清中吡嗪酰胺浓度的研究。该研究还比较了此剂量与广泛用于患结核病儿童的25mg/kg（-1）剂量所达到的血清浓度和药代动力学情况。吡嗪酰胺的药代动力学和药效学指标在25mg/kg（-1）和15mg/kg（-1）剂量时具有可比性。
目的
评估15mg/kg（-1）和25mg/kg（-1）剂量的吡嗪酰胺在患结核病儿童中的药代动力学和药效学指标。
方法
20名患结核病儿童接受了单次剂量为25mg/kg（-1）（第一组）和15mg/kg（-1）（第二组）的吡嗪酰胺治疗。采集系列血样，并用分光光度法分析药物浓度。计算药代动力学参数，并研究血清中吡嗪酰胺浓度保持高于20μg/ml（-1）和25μg/ml（-1）的吡嗪酰胺抑制浓度的持续时间。
结果
第一组和第二组的平均血清峰浓度分别为42.4±3.3μg/ml（-1）（95%CI±6.5）和38.6±3.9μg/ml（-1）（95%CI±7.7）。消除半衰期分别为9.3±1.3小时和10.5±2.3小时（P = 0.6），清除率分别为0.06±0.01l/h（-1）/kg（-1）和0.04±0.01l/h（-1）/kg（-1）（P = 0.08）。两组的药代动力学参数和PKPD指标具有可比性。
结论
该研究表明，儿童使用25mg/kg（-1）和15mg/kg（-1）剂量时可达到相当的吡嗪酰胺血清浓度。儿童的消除半衰期比成人更长，分布容积比成人大。
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