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Population pharmacokinetic analysis of tacrolimus in Chinese cardiac transplant recipients
  1. Yan Gong1,
  2. Ming Yang2,
  3. Yongfeng Sun3,
  4. Jing Li4,
  5. Yongning Lu1,
  6. Xingang Li5,6
  1. 1Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  2. 2Department of Anesthesiology, Tianjin Eye Hospital, Tianjin, China
  3. 3Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  4. 4Department of Pharmacy, Children’s Hospital of Fudan University, Shanghai, China
  5. 5Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
  6. 6Precision Medicine Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
  1. Correspondence to Professor Yongning Lu, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 894367034{at}qq.com and Dr Xingang Li, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantanxili, Dongcheng District, Beijing 100050, China; lxg198320022003{at}163.com

Abstract

Objective Usage of tacrolimus is complicated by its narrow therapeutic index and wide between- and within-subject pharmacokinetic variability. We aimed to obtain more information regarding the influence of various covariates on the disposition of tacrolimus in the early phase after cardiac transplantation using a population pharmacokinetic method, and provide information for the individualisation of drug dosing in the clinical setting.

Methods Routine therapeutic drug monitoring concentrations (897 observations) were retrospectively collected from 146 hospitalised patients. One compartment model with first-order absorption (absorption rate constant Ka was fixed as 4.48/hour) was employed to establish the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Various demographic parameters, postoperative day and concomitant medications influencing drug clearance and distribution volume were investigated in this study. Bootstrap and prediction-corrected visual predictive check were employed to validate the final model. With the goal of tacrolimus trough concentrations within the therapeutic window, simulation was performed.

Results Pharmacokinetic parameter population typical estimates for clearance (CL/F) and apparent distribution volume (V/F) were 14.23 L/hour and 760.80 L, respectively. Postoperative day and co-administration of Wuzhi capsules were identified as important factors affecting CL/F. Total body weight was significantly associated with the V/F. Results of model evaluation indicated a good stable and precise performance of the final model. Based on the simulation results, a simple-touse dosage regimen table to guide clinicians with drug dosing was created.

Conclusion The final population model could provide information for the individualised dosing of tacrolimus for cardiac transplant recipients.

  • tacrolimus
  • cardiac transplantation
  • population pharmacokinetics
  • post-operative day
  • body weight
  • simulation
  • wuzhi capsules

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