Population pharmacokinetics and dosing regimen optimization of tacrolimus in Chinese pediatric hematopoietic stem cell transplantation patients

1. Several tacrolimus population pharmacokinetic (PPK) models in hematopoietic stem cell transplantation (HSCT) patients have been set up to recommend an optimal dosage schedule. However, the PPK model of Chinese pediatric HSCT patients has not been reported. The study is to investigate whether published PPK models of HSCT patients can be used to simulate Chinese pediatric HSCT patients and establish the tacrolimus PPK model of Chinese pediatric HSCT patients. 2. Published PPK models were collected from the literature and assessed using Chinese pediatric HSCT patients via the individual prediction error method. The establishment of tacrolimus PPK model in Chinese pediatric HSCT patients was characterized with nonlinear mixed-effects modeling (NONMEM). 3. Three published HSCT PPK models were identified, two of which could be applied to our external dataset. However, these models were dissatisfactory in terms of individual prediction error and, hence, inadequate for extrapolation. Finally, a new tacrolimus PPK model in Chinese pediatric HSCT patients was established. Based on the simulation results of our model, new initial dosage suggestions were recommended. In conclusion, the tacrolimus PPK model in Chinese pediatric HSCT patients was presented and the model could be used to predict individualized dosing regimens in children with HSCT.

1. 已针对造血干细胞移植（hematopoietic stem cell transplantation，HSCT）患者构建多款他克莫司群体药代动力学（population pharmacokinetic，PPK）模型，以推荐最优给药方案。但目前尚无针对中国儿科HSCT患者的PPK模型相关报道。本研究旨在探究已发表的HSCT患者PPK模型是否可用于模拟中国儿科HSCT患者，并建立中国儿科HSCT患者的他克莫司PPK模型。
2. 研究人员从文献中搜集已发表的PPK模型，并采用个体预测误差法，以中国儿科HSCT患者数据对其进行评估。中国儿科HSCT患者他克莫司PPK模型的构建采用非线性混合效应模型（nonlinear mixed-effects modeling，NONMEM）完成。
3. 本研究共筛选出3篇已发表的HSCT患者PPK模型，其中2款可适用于本研究的外部数据集。但上述模型在个体预测误差方面表现不佳，因此不适用于外推应用。最终，本研究建立了一款全新的中国儿科HSCT患者他克莫司PPK模型。基于本模型的模拟结果，我们提出了新的初始给药方案建议。综上，本研究构建了中国儿科HSCT患者的他克莫司PPK模型，该模型可用于预测HSCT患儿的个体化给药方案。