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已发表论文
他克莫司在肾移植受者中的群体药代动力学/药效学模型：CYP3A5 基因型及五酯胶囊联合用药的影响
Authors Xiang Q, Yang Y, Li G , Chen S, Yang Y, Liu L, Yu X
Received 11 June 2025
Accepted for publication 20 August 2025
Published 16 September 2025 Volume 2025:19 Pages 8375—8389
DOI https://doi.org/10.2147/DDDT.S542786
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Prof. Dr. Tin Wui Wong
Qiulin Xiang,1 Yi Yang,1 Guoxing Li,1 Song Chen,1,2 Yingying Yang,1,3 Ling Liu,4 Xian Yu1
1Department of Phase I Clinical Trial Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Pharmacy Department, The People’s Hospital of Liangjiang New Area, Chongqing, People’s Republic of China; 3College of Pharmacy, Chongqing Medical University, Chongqing, People’s Republic of China; 4Urinary Nephrophathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
Correspondence: Ling Liu, Email 302112@hospital.cqmu.edu.cn Xian Yu, Email 303671@cqmu.edu.cn
Object: Tacrolimus is a crucial immunosuppressant used to prevent renal transplant rejection. While, long-term application of tacrolimus can lead to several adverse reactions that worsen patient prognosis, such as posttransplantation diabetes mellitus and renal injury. This study developed population pharmacokinetic/pharmacodynamic (PK/PD) models from clinical data to investigate the relationships between tacrolimus dose, exposure, and adverse effects in renal transplant recipients.
Methods: Demographics, the CYP3A5 genotype, laboratory results, and co-medications were tested as covariates, and dose simulations were performed based on the final models. The population PK model was described by a one-compartment model with first-order elimination and a fixed absorption rate. The CYP3A5 genotype, Wuzhi (WZ) capsule, and postoperative days were significant covariates of tacrolimus clearance. Fasting plasma glucose (FPG) and estimated glomerular filtration rate (eGFR) were characterized by the trough concentration (C0) of tacrolimus in a PK/linear model and maximal inhibitory effect, respectively. Age significantly influenced the baseline FPG and eGFR. The initial eGFR was strongly affected by hemoglobin.
Results: The simulations revealed that patients with CYP3A5*1 treated without WZ capsule, for whom no less than 3 mg q12 h as the initial dose was needed, whereas patients with CYP3A5*3/*3 combined with WZ capsule might experience kidney damage even if the dose is 2 mg q12 h; thus, patients with the CYP3A5*3/*3 genotype combined with WZ capsule are not recommended.
Conclusion: The population PK/PD models quantified the relationships between tacrolimus dose, exposure, and adverse effects in renal transplant patients, which could serve as a reference for optimizing the individualized dosage of tacrolimus.
Keywords: tacrolimus, PK/PD model, exposure‒response analysis, renal transplant, individualized treatment
1Department of Phase I Clinical Trial Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Pharmacy Department, The People’s Hospital of Liangjiang New Area, Chongqing, People’s Republic of China; 3College of Pharmacy, Chongqing Medical University, Chongqing, People’s Republic of China; 4Urinary Nephrophathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
Correspondence: Ling Liu, Email 302112@hospital.cqmu.edu.cn Xian Yu, Email 303671@cqmu.edu.cn
Object: Tacrolimus is a crucial immunosuppressant used to prevent renal transplant rejection. While, long-term application of tacrolimus can lead to several adverse reactions that worsen patient prognosis, such as posttransplantation diabetes mellitus and renal injury. This study developed population pharmacokinetic/pharmacodynamic (PK/PD) models from clinical data to investigate the relationships between tacrolimus dose, exposure, and adverse effects in renal transplant recipients.
Methods: Demographics, the CYP3A5 genotype, laboratory results, and co-medications were tested as covariates, and dose simulations were performed based on the final models. The population PK model was described by a one-compartment model with first-order elimination and a fixed absorption rate. The CYP3A5 genotype, Wuzhi (WZ) capsule, and postoperative days were significant covariates of tacrolimus clearance. Fasting plasma glucose (FPG) and estimated glomerular filtration rate (eGFR) were characterized by the trough concentration (C0) of tacrolimus in a PK/linear model and maximal inhibitory effect, respectively. Age significantly influenced the baseline FPG and eGFR. The initial eGFR was strongly affected by hemoglobin.
Results: The simulations revealed that patients with CYP3A5*1 treated without WZ capsule, for whom no less than 3 mg q12 h as the initial dose was needed, whereas patients with CYP3A5*3/*3 combined with WZ capsule might experience kidney damage even if the dose is 2 mg q12 h; thus, patients with the CYP3A5*3/*3 genotype combined with WZ capsule are not recommended.
Conclusion: The population PK/PD models quantified the relationships between tacrolimus dose, exposure, and adverse effects in renal transplant patients, which could serve as a reference for optimizing the individualized dosage of tacrolimus.
Keywords: tacrolimus, PK/PD model, exposure‒response analysis, renal transplant, individualized treatment