Mao Juehui, Cheng Yunshan, Liu Dong, Zhang Bo, Li Xiping
Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
Drug Des Devel Ther. 2024 Dec 28;18:6379-6388. doi: 10.2147/DDDT.S503463. eCollection 2024.
Sirolimus is a commonly used immunosuppressant administered after solid organ transplantation. It is characterized by a narrow therapeutic window and highly variable exposure, necessitating the identification of the sources of variability and design of individualized drug therapies.
This study aimed to perform a population pharmacokinetic (PK) analysis of sirolimus in adult liver transplant recipients and develop dosing regimen recommendations according to patient characteristics.
A total of 216 measurements of whole blood sirolimus concentrations in 103 adult patients were obtained for analysis. Covariates influencing the PKs of sirolimus were investigated using a stepwise procedure. Monte Carlo simulations were conducted to recommend dosing regimens for patients with different levels of covariates.
A one-compartment model with first-order elimination provided the best fit of the data. Hematocrit (HCT) significantly influenced the apparent clearance of sirolimus. Monte Carlo simulations showed that for patients with a low HCT level of 28%, dosing regimens of 1.5 mg qd or 1 mg qd alternating with 1.5 mg qd should be recommended. For patients with a normal HCT level, the recommended dosing regimens were 1 mg qd, 2 mg qod, or 0.5 mg qd alternating with 1 mg qd.
Based on our population PK model of sirolimus in adult liver transplant recipients, which has the largest sample size to date, we recommend to tailor dosing regimens to various HCT levels in such patients.
西罗莫司是实体器官移植后常用的免疫抑制剂。其特点是治疗窗窄且暴露量高度可变，因此需要确定变异性来源并设计个体化药物治疗方案。
本研究旨在对成年肝移植受者的西罗莫司进行群体药代动力学（PK）分析，并根据患者特征制定给药方案建议。
共获取了103例成年患者的216次全血西罗莫司浓度测量值用于分析。采用逐步法研究影响西罗莫司药代动力学的协变量。进行蒙特卡洛模拟，为不同协变量水平的患者推荐给药方案。
具有一级消除的单室模型最能拟合数据。血细胞比容（HCT）显著影响西罗莫司的表观清除率。蒙特卡洛模拟表明，对于HCT水平低至28%的患者，应推荐每日1.5mg或每日1mg与每日1.5mg交替使用的给药方案。对于HCT水平正常的患者，推荐的给药方案为每日1mg、隔日2mg或每日0.5mg与每日1mg交替使用。
基于我们在成年肝移植受者中建立的西罗莫司群体PK模型（该模型是迄今为止样本量最大的），我们建议针对此类患者的不同HCT水平调整给药方案。
