他克莫司缓释剂治疗儿童原发性肾病综合征的药代动力学特点

doi:10.3969/j.issn.1671-167X.2017.05.011

摘要/Abstract

摘要： 目的他克莫司是一种新型钙调磷酸酶抑制剂,目前被广泛应用于成人肝或肾移植术后,也被逐渐广泛应用于肾病综合征患儿。他克莫司缓释胶囊是每日单次口服的缓释剂型,本研究目的是初步探讨他克莫司缓释剂治疗儿童原发性肾病综合征的药代动力学特征。方法 8例受试者系北京大学第一医院2011年6—8月原发性肾病综合征患儿。晨起单次口服不同剂量他克莫司缓释胶囊,给药剂量分别为0.02 mg/kg(n=2)、0.05 mg/kg(n=2)、0.10 mg/kg(n=4),在服药前及服药后1、2、4、6、8、10、12 h分别取静脉血1~2 mL,受试者不用影响他克莫司浓度的其他药物、食物及饮料。采用酶放大免疫分析法,测定他克莫司血药浓度,以Phoenix计算其药代动力学参数。结果药代动力学数据采用非房室模型分析。3个剂量组(0.02 mg/kg,0.05 mg/kg和0.10 mg/kg)药代动力学参数如下:血药峰浓度分别为(1.7±1.0) μg/L,(3.1±1.9) μg/L,(8.0±3.5) μg/L;药物浓度-时间曲线下面积分别为(47.2±47.1) h·μg/L,(84.0±13.1) h·μg/L,(175.6±107.1) h·μg/L;表观清除率分别为(0.8±0.9) L/(h·kg),(0.4±0.1) L/(h·kg),(1.9±1.3) L/(h·kg);经剂量归一化的表观分布容积分别为(7.0±3.4) L/kg,(12.4±8.4) L/kg,(73.6±68.6) L/kg。0.05 mg/kg剂量组经剂量归一化的血药峰浓度和经剂量归一化的药物浓度-时间曲线下面积的平均值均高于0.02 mg/kg及0.10 mg/kg剂量组。3个剂量组的药物浓度-时间曲线均呈现2次高峰,第一次高峰出现在服药后约2 h,服药后约12 h出现次级高峰;0.10 mg/kg剂量组药物浓度出现两次峰值的现象较0.02 mg/kg及0.05 mg/kg剂量组更显著。结论他克莫司缓释剂治疗原发性肾病综合征患儿的药代动力学存在个体间差异,本研究初步探讨了他克莫司缓释剂治疗儿童原发性肾病综合征的药代动力学特征,为后续大样本的研究提供了参考依据。

关键词: 他克莫司, 缓释剂, 单次口服, 儿科, 药代动力学

Abstract: Objective: Tacrolimus prolonged-release(PR) formulation is a new once-daily formulation of the calcineurin inhibitor tacrolimus, which is currently used in adult liver or kidney transplant patients,and is also gradually widely used in children with nephrotic syndrome.The present study was undertaken to preliminarily investigate the pharmacokinetic characteristics of tacrolimus PR in pediatric nephrotic syndrome recipients. Methods: This single-center open-label prospective study was performed in pediatric nephrotic syndrome recipients. Pharmacokinetic samples were collected from eight pediatric subjects with nephrotic syndrome from Department of Pediatric Nephrology in Peking University First Hospital between June and August 2011. They followed administration of single oral doses of tacrolimus PR formulation at 0.02 mg/kg (n=2), 0.05 mg/kg (n=2) and 0.10 mg/kg (n=4). Blood samples were taken before the dose and 1, 2, 4, 6, 8, 10, 12 and 24 h after drug intake. No other medicines or interacting food or drinks were taken during the study period. Blood concentrations were measured using an enzyme multiplied immunoassay technique. Pharmacokinetic analysis was performed using WinNolin Phoenix software Version 6.0(Pharsight, Cary, NC,USA). Results: The pharmacokinetic data were best described by a non-compartment model. Pharmacokinetic parameters of tacrolimus PR formulation in the 3 ascending doses groups (0.02 mg/kg,0.05 mg/kg and 0.10 mg/kg) were as follows: the maximum drug concentrations (C_max/D) were (1.7±1.0) μg/L, (3.1±1.9) μg/L, (8.0±3.5) μg/L, respectively;Areas under the drug concentration-time curve(AU_0-∞/D) were (47.2±47.1) h·μg/L, (84.0±13.1) h·μg/L, (175.6±107.1) h·μg/L, respectively; Oral clearance rates were (0.8±0.9) L/(h·kg), (0.4±0.1) L/(h·kg), (1.9±1.3) L/(h·kg), respectively; Body weight normalized distribution volumes were (7.0±3.4) L/kg, (12.4±8.4) L/kg and (73.6±68.6) L/kg, respectively. Both mean C_max normalized level for the administered dose(C_max/D) and mean AU_0-∞ normalized level for the administered dose (AU_0-∞/D) were higher in the 0.05 mg/kg dosage group than in the 0.02 and 0.10 mg/kg dosage group. There were two peaks in the drug concentrations in every dose group;a primary peak appeared at the end of about 2 h followed by a small secondary peak at h 12, which was more noticeable in the 0.10 mg/kg dose group than in the two lower dosages. Conclusion: The pharmacokinetic characteristics of tacrolimus PR formulation were initially explored in pediatric patients with nephritic syndrome. The data presented form a basis for subsequent larger scale studies on pharmacokinetics of tacrolimus PR formulation in nephritic syndrome children.

Key words: Tacrolimus, Prolonged-release formulation, Once daily, Pediatrics, Pediatric pharmacology

中图分类号:

R729

韩烨, 杜偲倩, 肖慧捷, 周颖, 丁洁, 丁娟娟, 崔一民. 他克莫司缓释剂治疗儿童原发性肾病综合征的药代动力学特点[J]. 北京大学学报(医学版), 2017, 49(5): 807-813.

HAN Ye, DU Si-qian, XIAO Hui-jie, ZHOU Yin, DING Jie, DING Juan-juan, CUI Yi-min. Pharmacokinetics of once daily prolonged-release formulation of tacrolimus in child-ren with primary nephrotic syndrome[J]. Journal of Peking University(Health Sciences), 2017, 49(5): 807-813.

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