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

作者：Xiaolin Liu, Yan-Ping Guan, Ying Wang, Ke Huang, Fulin Jiang, Jian Wang, Q. Yu, Kaifeng Qiu, Min Huang, Junyan Wu, Dun‐hua Zhou, Guo-Ping Zhong, Xiaoxia Yu · 发表于：Frontiers in Pharmacology · 年份：2022 · DOI：10.3389/fphar.2022.891648 · 被引用次数：10 · 研究领域：Renal Transplantation Outcomes and Treatments、Pharmacological Effects and Toxicity Studies、HIV/AIDS drug development and treatment

Background: 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. Methods: A retrospective analysis was performed on 86 pediatric HSCT patients who received tacrolimus intravenously or orally. A total of 578 tacrolimus trough concentrations (C0) were available for pharmacokinetic analysis using a non-linear mixed-effects modeling method. Demographic and clinical data were included and assessed as covariates via the stepwise method. Bayesian estimators were used to devise pediatric dosage regimens that targeted C0 of 5–15 ng mL−1. Results: 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−1 (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 (n = 24) with CYP3A5 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 i...