The Population Pharmacokinetic Models of Tacrolimus in Chinese Adult Liver Transplantation Patients

Abstract

Aim. The aim of this study was to establish population pharmacokinetic models of tacrolimus in Chinese adult liver transplantation patients. Methods. Tacrolimus dose and concentration data (n = 435) were obtained from 47 Chinese adult liver transplant recipients, and the data were analyzed using a nonlinear mixed-effect modeling (NONMEM) method. Results. The structural model was a two-compartment model with first-order absorption. The typical population values of tacrolimus for the pharmacokinetic parameters of apparent clearance (CL/F), apparent distribution volume of the central compartment (V 2/F), intercompartmental clearance (Q/F), apparent distribution volume of the peripheral compartment (V 3/F), and absorption rate (k a) were 11.2 L/h, 406 L, 57.3 L/h, 503 L, and 0.723 h−1, respectively. The interindividual variabilities of these parameters were 16.2%, 163%, 19.7%, 199%, and 74.3%, respectively, and the intraindividual variability of observed concentration was 26.54%. The covariates retained in the final models were postoperative days (POD) and dosage per day (DOSE) on CL/F. Conclusion. Population pharmacokinetic models of tacrolimus were developed in Chinese adult liver transplant patients. These results could provide the interpretation of the outcome of pharmacokinetics modeling and the impact of covariate tested on individualized tacrolimus therapy.

Population pharmacokinetic model and Bayesian estimator for 2 tacrolimus formulations in adult liver transplant patients

“…The TAC PK parameters exhibited a high interpatient variability, which was well described using either POPPK modelling approach. The high variability we observed is in accordance with previous reports in paediatric or adult liver transplant recipients . Moreover, we observed that PK parameter estimates were significantly different between TAC TD and TAC OD and between day 7 and week 6 for both formulations.…”

“…Indeed, TAC PK is affected by several factors including time after transplantation, patient demographics and graft type. Additionally, in the first days after liver transplantation, the recovery of liver function influences TAC clearance in de novo liver transplant patients, which may explain the (relatively) lower accuracy of our Bayesien estimators at D7 in the present study. Moreover, corticosteroids used during the immediate post transplantation period are well known to affect the PK of TAC .…”

Impact of Donor and Recipient CYP3A5*3 Genotype on Tacrolimus Population Pharmacokinetics in Chinese Adult Liver Transplant Recipients

“…However, this model K a was fixed at 4.48 h -1 , which may lead to inaccurate estimation of CL/F. In our study, we estimated that the K a of liver transplantation was 0.163 h -1 , and the result was close to that of Lu et al 17 (K a = 0.419 h -1 ) and Zhu et al 30 (K a = 0.732 h -1 ). In our model, we tested these covariates on the PK parameters of TAC, but they were not significant.…”

A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients

“…Therefore, a twocompartment model (as demonstrated in this study) was more reasonable to describe tacrolimus pharmacokinetic behavior. The volume of distribution in the peripheral compartment for tacrolimus between the healthy volunteers and the liver transplant patients can be reasonably assumed to be similar based on previous publications [38][39][40] . A two-compartment model of tacrolimus was developed by combining the dense data from the healthy volunteers and the sparse data from the liver transplant patients, which allowed us to capture more information on pharmacokinetic behaviors, especially in the patients.…”