Dosing recommendations based on population pharmacokinetics of tacrolimus in Mexican adult patients with kidney transplant

Abstract

The aim of this study was to perform a population pharmacokinetic analysis of tacrolimus in Mexican adult kidney transplant patients to analyse the influence of clinical and genetic covariates to propose a dosage regimen. Kidney transplant patients (>18 years old) receiving oral tacrolimus treatment were included in the current study. The population pharmacokinetic model was built using a one‐compartment model and the First Order Conditional Estimation method with Interaction (FOCEI via NONMEM v.7.3.). A total of 600 tacrolimus trough blood concentrations from 52 kidney transplant patients were analysed. Tacrolimus clearances were 26, 18.8 and 12.3 L/h, for patients with genetic polymorphisms CYP3A5*1*1, *1*3 and *3*3, respectively. The influence of haematocrit was inversely related to tacrolimus clearance, following an allometric power function. Total volume of distribution was 604 L. Interindividual variability associated with tacrolimus clearance and distribution volume for the final model was 33 and 63%, respectively, with a residual error of 2.5 ng/mL. Relative bioavailability was calculated between generic formulations A (0.53) and B (1) of tacrolimus. Internal validation was performed through bootstrap analysis to evaluate the stability of the final model; external validation was performed in a new group of patients (n = 13) to estimate residual errors on basic (57.8%) and final (34.8%) models. Finally, stochastic simulations were performed to propose a dosage regimen based on haematocrit, CYP3A5 genotype and generic formulation of tacrolimus. A stable and predictive population pharmacokinetic model of tacrolimus was developed for Mexican adult kidney transplant patients; additionally, the proposed dosage regimen of tacrolimus should be prospectively validated.

Population pharmacokinetic analysis and dosing guidelines for tacrolimus co‐administration with Wuzhi capsule in Chinese renal transplant recipients

“…The final results showed that only CYP3A5*3 had a significant association with TAC PK. It was found that the CL/F of TAC in CYP3A5 variants CYP3A5*1/*1 and *1/*3 is 1.18‐fold higher than that of the CYP3A5variants CYP3A5*3/*3, which was in consistent with the research results of Resendiz‐Galvan JE et al, 28 who studied 52 Mexican adult kidney transplant patients.…”

Important lack of difference in tacrolimus and mycophenolic acid pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients

“…By restricting the systematic review to population PK models that included haematocrit as continuous covariate in the CL/F model, results were similar (median and percentage coefficient of variation (CV%)) to those see in our study (Table 4). 10,30–40 This literature comparison also supported wider between‐subject variability (BSV) in CL/F in the Aboriginal group, with the CV% BSV the widest amongst these study cohorts.…”

Improving prediction of tacrolimus concentration using a combination of population pharmacokinetic modeling and machine learning in chinese renal transplant recipients

“…The two-compartment model is commonly utilized as a structural model for PPK studies in patients following an intense sampling strategy ( Zhu et al, 2014 ; Riva et al, 2023 ). Conversely, the single-compartment model is the most frequently employed PPK model based on conventional TDM data ( Reséndiz-Galván et al, 2019 ; Teng et al, 2022 ). Approximately 60% and 40% of published models are one- and two-compartment models, respectively.…”