Population pharmacokinetics of tacrolimus in Chinese adult liver transplant patients

Abstract

Tacrolimus is widely used in organ transplantation to prevent rejection. However, the narrow therapeutic window and the large inter-and intra-individual variability in the pharmacokinetics (PK) of tacrolimus make it difficult for individualization of dosing. This study aimed at developing a population pharmacokinetic model for estimating the oral clearance of tacrolimus in Chinese liver transplant patients, and identifying factors that contribute to the PK variability of tacrolimus. Data of 151 liver transplant patients who received tacrolimus were analyzed in this study. The population PK model was analyzed and the covariates including population demographic and biochemical characteristics, drug combination, and genetic polymorphism were explored using non-linear mixed-effects modeling approach. A single-compartment population PK model was developed, and the final model was CL/F = (14.6-2.38 � cytochrome P450 (CYP) 3A5−3.72 � WZC+1.04 � (POD/9) +2.48 � COR) � Exp(η i ), where CYP3A5 was 1 for CYP3A5*3/*3, Wuzhi Capsule (WZC) was 1 when patients took tacrolimus combined with WZC, otherwise it was 0, corticosteroids (COR) was 1 when patients take tacrolimus combined with COR, otherwise, it was 0, POD was the post-operative day. Visual inspection and bootstrap indicated that the final model was stable and robust. In this study, we developed the first tacrolimus population PK model in Chinese adult liver transplant patients. We first determined the influence of WZC on tacrolimus in these people, which could provide useful PK information for the drug combination of tacrolimus and WZC. We also revealed the influence of genetic polymorphism of CYP3A5, POD, and a combination of COR on tacrolimus PK. Therefore, these significant factors should be taken into consideration in optimizing dosage regimens.

Prospective population pharmacokinetic study of tacrolimus in adult recipients early after liver transplantation: A comparison of Michaelis-Menten and theory-based pharmacokinetic models

“…Both final models indicated that only the CYP3A5*3 genotype recipients significantly affected tacrolimus PK in liver transplant patients, consistent with published data ( Zhu et al, 2015 ; Teng et al, 2022 ). Liver transplant recipients with CYP3A5*1*3 or CYP3A5*1*1 had 16.8% higher CL pl /F and 36.5% lower K m values than those of CYP3A5*3*3 carriers.…”

“…POD, considered a major surrogate for many time-dependent variables ( Pou et al, 1998 ; Teng et al, 2022 ), was also identified as an alternative indicator of time-dependent factors in CL pl /F and K m in our study. This may be attributed to progressive CYP3A enzyme activity recovery in the intestine and liver, and steroid dose tapering after transplantation.…”

Numerical Optimization of Prednisolone–Tacrolimus Loaded Ultraflexible Transethosomes for Transdermal Delivery Enhancement; Box–Behnken Design, Evaluation, Optimization, and Pharmacokinetic Study

“…Additionally, the presence of ethanol in TETSMs improves drug penetration through the minute holes created in the stratum corneum as a result of fluidization by enhancing the lipids fluidity and decreasing the density of the lipid bilayer [11]. Moreover, the addition of TAC to TETSMs gel formulations resulted in higher pharmacokinetic parameters of PRED, as TAC is previously reported to increase corticosteroids accumulation [45]. These findings support the fact that transdermal delivery bypasses first-pass metabolism for many active ingredients including corticosteroids.…”

Population pharmacokinetics and initial dose optimization of tacrolimus in children with severe combined immunodeficiency undergoing hematopoietic stem cell transplantation

“…For example, Zhou et al (2021) reported initial dosage optimization of tacrolimus in pediatric patients with thalassemia major undergoing hematopoietic stem cell transplantation based on population pharmacokinetics, without azoles included as final covariates. Teng et al (2022) reported population pharmacokinetics of tacrolimus in Chinese adult liver transplant patients, without azoles included as final covariates. Chen et al reported that wuzhi capsule dosage affects tacrolimus elimination in adult kidney transplant recipients, as determined by a population pharmacokinetics analysis, without azoles included as final covariates (Lizhi .…”