Initial Dosage Optimization of Tacrolimus in Pediatric Patients With Thalassemia Major Undergoing Hematopoietic Stem Cell Transplantation Based on Population Pharmacokinetics

Abstract

Background: Hematopoietic stem cell transplantation (HSCT) is an effective treatment for hematological disorders. Tacrolimus is widely used after HSCT, but it has highly interindividual variable pharmacokinetics. Population pharmacokinetics (PPK) researches of tacrolimus in children with β-thalassemia major (β-TM) undergoing HSCT are insufficient. Objective: To establish a PPK model of tacrolimus in children with β-TM and optimize initial dosing regimen for achieving target concentration of 5 to 15 ng/mL. Methods: Data on patients aged <18 years were retrospectively collected from January 2017 to December 2018. PPK analysis and Monte Carlo simulations were performed using nonlinear mixed-effects modeling. Results: A data set of 55 patients with 332 concentrations was included. A 2-compartment model could best describe the pharmacokinetics of tacrolimus. The body surface area and gender were significant covariates in the final model. The typical value of clearance, the distribution volume of the central room, the distribution volume of the peripheral room, and the intercompartmental clearance were 5.05L/h, 4.33L, 155L, and 6.22L/h, respectively. The optimal initial dosing regimen of 0.03, 0.04, 0.05, 0.06, and 0.10 mg/kg were appropriate for female children with a weight (WT) of 50 to 10 kg. The regimen of 0.04, 0.05, 0.06, 0.07, and 0.12 mg/kg is suitable for male children with a WT of 50 to 10 kg. The probability of target attainment (PTA) of each regimen reached 91%. Conclusion and Relevance: A stable PPK model of tacrolimus was established. The proposed dosage regimen reached a good PTA, which could provide a reference for tacrolimus therapy.

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

“…Tacrolimus is a first-line agent for GVHD prevention and has been routinely employed to stop rejection of HSCT [15][16][17][18]. However, tacrolimus has a narrow therapeutic range; the use of high concentrations seems to be related to toxicity, while lower concentrations are related to an acute rejection's increased risk (23).…”

“…HSCT may adjust superoxide generation, making neutrophil function within normal range and improvement in inflammatory progression (14). However, HSCT patients must take tacrolimus, a potent immunosuppressant, for a prolonged period to prevent transplant rejection (15)(16)(17)(18). In addition, voriconazole, a second-generation triazole with potent broad-spectrum antifungal activity, is used for prophylaxis against invasive fungal disease (IFD), which is a major cause of morbidity and mortality in pediatric patients after HSCT (19,20).…”

Effects of Posaconazole on Tacrolimus Population Pharmacokinetics and Initial Dose in Children With Crohn’s Disease Undergoing Hematopoietic Stem Cell Transplantation

“…It has been reported that HSCT significantly improves the quality of life of CD patients, and 50% of CD patients who underwent HSCT achieved complete healing of the mucosa and clinical remission ( Lindsay et al, 2017 ; Lopez-Garcia et al, 2017 ; Ruiz et al, 2020 ). However, for HSCT patients, long-term tacrolimus treatment is necessary to prevent rejection ( Gao and Ma, 2019 ; Ishiwata et al, 2020 ; Soskind et al, 2020 ; Zhou et al, 2020 ). Similarly, posaconazole is also needed for the prevention of invasive fungal disease (IFD) in HSCT patients ( Busca et al, 2016 ; Zhang et al, 2017 ).…”

Population Pharmacokinetic Model Development of Tacrolimus in Pediatric and Young Adult Patients Undergoing Hematopoietic Cell Transplantation

“…Tacrolimus PK variability is particularly important to consider in the pediatric population given the differences in absorption, distribution, metabolism and excretion among children of various sizes and at different stages of development ( Kearns et al, 2003 ). Given the known variability in PK of tacrolimus in pediatric patients, several recently published studies have described pediatric-specific population pharmacokinetic (PopPK) models along with their associated dosing guides ( Wallin et al, 2009 ; Andrews et al, 2018 ; Wang et al, 2020 ; Zhou et al, 2021 ). Zhou et al developed a model within a subpopulation of children undergoing HCT for β-thalassemia ( Zhou et al, 2021 ).…”

“…Given the known variability in PK of tacrolimus in pediatric patients, several recently published studies have described pediatric-specific population pharmacokinetic (PopPK) models along with their associated dosing guides ( Wallin et al, 2009 ; Andrews et al, 2018 ; Wang et al, 2020 ; Zhou et al, 2021 ). Zhou et al developed a model within a subpopulation of children undergoing HCT for β-thalassemia ( Zhou et al, 2021 ). Wang et al and Wallin et al described similar models where a one-compartment model best described the dataset and allometrically scaled weight improved approximations of clearance (Cl) and volume of distribution (Vd) ( Wallin et al, 2009 ; Wang et al, 2020 ).…”