Effects of voriconazole on population pharmacokinetics and optimization of the initial dose of tacrolimus in children with chronic granulomatous disease undergoing hematopoietic stem cell transplantation

Abstract

Background: This study aimed to explore the effects of voriconazole on population pharmacokinetics and optimization of the initial dose of tacrolimus in children with chronic granulomatous disease (CGD) undergoing hematopoietic stem cell transplantation (HSCT).Methods: Thirty-four children with CGD undergoing HSCT were assessed to establish a population pharmacokinetic model (PPM) using the non-linear mixed effect. Tacrolimus concentrations were simulated by the Monte Carlo method in children weighing <25 kg at different doses.Results: In the final model, weight and concomitant use of voriconazole were included as covariates. With the same weight, the relative value of tacrolimus clearance was 1:0.388 in children not taking voriconazole: children taking voriconazole. Compared with children not taking voriconazole, the measured tacrolimus concentrations were all higher in children taking voriconazole (P<0.01); however, these were not corrected by dose or body weight for concentration differences. Thus, we simulated the tacrolimus concentrations using different body weights (5-25 kg) and different dose regimens (0.1-0.8 mg/kg/day) for the same body weight and dose. Tacrolimus concentrations in children taking voriconazole were higher than those in children not taking voriconazole (P<0.01). Also, in children with CGD undergoing HSCT who were not taking voriconazole, the initial dose regimen of 0.5 mg/kg/day was recommended for body weights of 5-10 kg, and 0.4 mg/kg/day was recommended for body weights of 10-25 kg. In children with CGD undergoing HSCT who were taking voriconazole, an initial dose regimen of 0.3 mg/kg/day was recommended for body weights of 5-25 kg. Conclusions:We established, for the first time, a PPM of tacrolimus in children with CGD undergoing HSCT in which voriconazole significantly increased tacrolimus concentrations. In addition, the initial dose of tacrolimus in children with CGD undergoing HSCT was recommended.

Effects of Voriconazole Exposure on the Pharmacokinetics of Tacrolimus in Lung Transplantation Patients, Based on Therapeutic Drug Monitoring Data

“…For example, a similar population pharmacokinetic study was also conducted in pediatric hematopoietic stem cell transplantation with voriconazole used as a covariate. 8 Other studies were mostly simple comparisons of the dose, concentration, or effectiveness of tacrolimus between groups, whether combined with voriconazole or not. [5][6][7][8][9][10] Therefore, there is still a lack of an accurate quantitative relationship between voriconazole exposure and a tacrolimus PK model.…”

“…8 Other studies were mostly simple comparisons of the dose, concentration, or effectiveness of tacrolimus between groups, whether combined with voriconazole or not. [5][6][7][8][9][10] Therefore, there is still a lack of an accurate quantitative relationship between voriconazole exposure and a tacrolimus PK model. A more detailed PK model is helpful to illustrate this quantitative relationship and provide a basis for the optimization of a combined tacrolimus and voriconazole dose regimen after lung transplantation.…”

“…In other patient populations, there are also only a few studies on the effect of voriconazole on the blood concentrations of tacrolimus. For example, a similar population pharmacokinetic study was also conducted in pediatric hematopoietic stem cell transplantation with voriconazole used as a covariate 8 . Other studies were mostly simple comparisons of the dose, concentration, or effectiveness of tacrolimus between groups, whether combined with voriconazole or not 5–10 .…”

External evaluation of a population pharmacokinetic model of tacrolimus after hematopoietic stem cell transplantation in children with thalassemia

“…None of the published models could meet evaluation standers of this test, probably because the patients of these models were children diagnosed as pernicious hematologic diseases, Crohn's disease, combined de ciency syndrome, and chronic granulomatous disease [18][19][20][21][22], therefore couldn't describe our patients' pharmacokinetic characteristics adequately. Pediatrics with β-TM received blood transfusions treatment since the onset of disease, with the prolongation of disease and frequent blood transfusions, regular iron removal treatment also fails to prevent iron deposition in liver of these children, leaving them to suffer varying degrees of impaired liver function, which may result to a different ability to metabolize TAC compared with children have other hematological disorders.…”

Therapeutic effect and rebound evaluation of dapagliflozin on glycated hemoglobin (HbA1c) in type 1 diabetes mellitus patients

“…The goodness-of-fit plots of the model (observations vs. predictions and observations/predictions vs. time), individual plots, and conditional weighted residual (CWRES) vs. time/ population predictions/individual predictions were used to estimate the final model, where CWRES values in the range of -3 to 3 represented a good prediction of the model (Chen et al, 2021;Chen et al, 2022). In addition, the medians and 2.5-97.5% results from bootstrap (n = 1,000) were used to compare with final model parameters.…”