AUTHOR=Liu Xiao-Lin , Guan Yan-Ping , Wang Ying , Huang Ke , Jiang Fu-Lin , Wang Jian , Yu Qi-Hong , Qiu Kai-Feng , Huang Min , Wu Jun-Yan , Zhou Dun-Hua , Zhong Guo-Ping , Yu Xiao-Xia 

TITLE=Population Pharmacokinetics and Initial Dosage Optimization of Tacrolimus in Pediatric Hematopoietic Stem Cell Transplant Patients

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.891648

DOI=10.3389/fphar.2022.891648

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> There is a substantial lack of tacrolimus pharmacokinetic information in pediatric hematopoietic stem cell transplant (HSCT) patients. This study aimed to develop population pharmacokinetics (PopPK) of tacrolimus in pediatric HSCT patients and to devise model-guided dosage regimens.</p><p><bold>Methods:</bold> A retrospective analysis was performed on 86 pediatric HSCT patients who received tacrolimus intravenously or orally. A total of 578 tacrolimus trough concentrations (C<sub>0</sub>) were available for pharmacokinetic analysis using a non-linear mixed-effects modeling method. Demographic and clinical data were included and assessed as covariates <italic>via</italic> the stepwise method. Bayesian estimators were used to devise pediatric dosage regimens that targeted C<sub>0</sub> of 5–15 ng mL<sup>−1</sup>.</p><p><bold>Results:</bold> A one-compartment model with first-order absorption adequately described the tacrolimus pharmacokinetics. Clearance (CL), volume of distribution (V), and typical bioavailability (F) in this study were estimated to be 2.42 L h<sup>−1</sup> (10.84%), 79.6 L (16.51%), and 19% (13.01%), respectively. Body weight, hematocrit, post-transplantation days, and caspofungin and azoles concomitant therapy were considered significant covariates for tacrolimus CL. Hematocrit had a significant impact on the V of tacrolimus. In the subgroup cohort of children (<italic>n</italic> = 24) with <italic>CYP3A5</italic> genotype, the clearance was 1.38-fold higher in CYP3A5 expressers than in non-expressers. Simulation indicated that the initial dosage optimation of tacrolimus for intravenous and oral administration was recommended as 0.025 and 0.1 mg kg<sup>−1</sup> d<sup>−1</sup> (q12h), respectively.</p><p><bold>Conclusion:</bold> A PopPK model for tacrolimus in pediatric HSCT patients was developed, showing good predictive performance. Model-devised dosage regimens with trough tacrolimus concentrations provide a practical strategy for achieving the therapeutic range.</p>