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. 2022 Jul 22:13:869939.
doi: 10.3389/fphar.2022.869939. eCollection 2022.

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

Xiao Chen  1 , Dongdong Wang  1 , Feng Zheng  1 , Xiaowen Zhai  2 , Hong Xu  3 , Zhiping Li  1
Affiliations

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

Xiao Chen et al. Front Pharmacol. .

Abstract

The present study aimed to explore the population pharmacokinetics and initial dose optimization of tacrolimus in children with severe combined immunodeficiency (SCID) undergoing hematopoietic stem cell transplantation (HSCT). Children with SCID undergoing HSCT treated with tacrolimus were enrolled for analysis. Population pharmacokinetics of tacrolimus was built up by a nonlinear mixed-effects model (NONMEM), and initial dose optimization of tacrolimus was simulated with the Monte Carlo method in children weighing <20 kg at different doses. A total of 18 children with SCID undergoing HSCT were included for analysis, with 130 tacrolimus concentrations. Body weight was included as a covariable in the final model. Tacrolimus CL/F was 0.36-0.26 L/h/kg from body weights of 5-20 kg. Meanwhile, we simulated the tacrolimus concentrations using different body weights (5-20 kg) and different dose regimens (0.1-0.8 mg/kg/day). Finally, the initial dose regimen of 0.6 mg/kg/day tacrolimus was recommended for children with SCID undergoing HSCT whose body weights were 5-20 kg. It was the first time to establish tacrolimus population pharmacokinetics in children with SCID undergoing HSCT; in addition, the initial dose optimization of tacrolimus was recommended.

Keywords: hematopoietic stem cell transplantation; initial dose optimization; population pharmacokinetics; severe combined immunodeficiency; tacrolimus.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Model evaluation. (A) Goodness-of-fit plots of the model, (B) distribution of weighted residuals for the model, and (C) observation/individual predictions/population predictions vs. time. │iWRES│, the absolute value of weighted residuals of the individual.
FIGURE 2
FIGURE 2
Individual plots. ID, patient ID number; DV, measured concentration value; IPRED, individual predictive value; PRED, population predictive value.
FIGURE 3
FIGURE 3
Tacrolimus CL/F and concentration simulation. (A) CL/F of tacrolimus in SCID undergoing HSCT. (B) Pediatric patients weighing 5 kg. (C) Pediatric patients weighing 10 kg. (D) Pediatric patients weighing 15 kg. (E) Pediatric patients weighing 20 kg.
FIGURE 4
FIGURE 4
Probability to achieve the target concentrations.
See this image and copyright information in PMC

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