伏立康唑对接受造血干细胞移植的慢性肉芽肿病患儿他克莫司群体药代动力学及初始剂量优化的影响
Effects of voriconazole on population pharmacokinetics and optimization of the initial dose of tacrolimus in children with chronic granulomatous disease undergoing hematopoietic stem cell transplantation.
作者信息
Chen Xiao, Wang Dongdong, Lan Jianger, Wang Guangfei, Zhu Lin, Xu Xiaoyong, Zhai Xiaowen, Xu Hong, Li Zhiping
机构信息
Department of Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Department of Hematology and Oncology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
出版信息
Ann Transl Med. 2021 Sep;9(18):1477. doi: 10.21037/atm-21-4124.
BACKGROUND
This study aimed to explore the effects of voriconazole on population pharmacokinetics and optimization of the initial dose of tacrolimus in children with chronic granulomatous disease (CGD) undergoing hematopoietic stem cell transplantation (HSCT).
METHODS
Thirty-four children with CGD undergoing HSCT were assessed to establish a population pharmacokinetic model (PPM) using the non-linear mixed effect. Tacrolimus concentrations were simulated by the Monte Carlo method in children weighing <25 kg at different doses.
RESULTS
In the final model, weight and concomitant use of voriconazole were included as covariates. With the same weight, the relative value of tacrolimus clearance was 1:0.388 in children not taking voriconazole: children taking voriconazole. Compared with children not taking voriconazole, the measured tacrolimus concentrations were all higher in children taking voriconazole (P<0.01); however, these were not corrected by dose or body weight for concentration differences. Thus, we simulated the tacrolimus concentrations using different body weights (5-25 kg) and different dose regimens (0.1-0.8 mg/kg/day) for the same body weight and dose. Tacrolimus concentrations in children taking voriconazole were higher than those in children not taking voriconazole (P<0.01). Also, in children with CGD undergoing HSCT who were not taking voriconazole, the initial dose regimen of 0.5 mg/kg/day was recommended for body weights of 5-10 kg, and 0.4 mg/kg/day was recommended for body weights of 10-25 kg. In children with CGD undergoing HSCT who were taking voriconazole, an initial dose regimen of 0.3 mg/kg/day was recommended for body weights of 5-25 kg.
CONCLUSIONS
We established, for the first time, a PPM of tacrolimus in children with CGD undergoing HSCT in which voriconazole significantly increased tacrolimus concentrations. In addition, the initial dose of tacrolimus in children with CGD undergoing HSCT was recommended.
背景
本研究旨在探讨伏立康唑对接受造血干细胞移植（HSCT）的慢性肉芽肿病（CGD）患儿他克莫司群体药代动力学的影响及初始剂量的优化。
方法
对34例接受HSCT的CGD患儿进行评估，采用非线性混合效应建立群体药代动力学模型（PPM）。通过蒙特卡罗方法模拟不同剂量下体重<25 kg儿童的他克莫司浓度。
结果
在最终模型中，体重和伏立康唑的联合使用作为协变量。相同体重下，未服用伏立康唑儿童与服用伏立康唑儿童他克莫司清除率相对值为1:0.388。与未服用伏立康唑的儿童相比，服用伏立康唑的儿童他克莫司实测浓度均较高（P<0.01）；然而，这些浓度差异未通过剂量或体重进行校正。因此，我们针对相同体重和剂量，模拟了不同体重（5-25 kg）和不同剂量方案（0.1-0.8 mg/kg/天）下的他克莫司浓度。服用伏立康唑儿童的他克莫司浓度高于未服用伏立康唑的儿童（P<0.01）。此外，对于未服用伏立康唑的接受HSCT的CGD患儿，体重5-10 kg时推荐初始剂量方案为0.5 mg/kg/天，体重10-25 kg时推荐0.4 mg/kg/天。对于服用伏立康唑的接受HSCT的CGD患儿，体重5-25 kg时推荐初始剂量方案为0.3 mg/kg/天。
结论
我们首次建立了接受HSCT的CGD患儿他克莫司的PPM，其中伏立康唑显著增加了他克莫司浓度。此外，还推荐了接受HSCT的CGD患儿他克莫司的初始剂量。
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