Article

Population pharmacokinetics of cyclosporine in Chinese children receiving hematopoietic stem cell transplantation

Authors: Tai-feng Li1, Lei Hu2, Xiao-lu Ma3, Lin Huang2, Xue-mei Liu2, Xing-xian Luo2, Wan-yu Feng2, Chun-fu Wu1
1 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China
2 Department of Pharmacy, Peking University People’s Hospital, Beijing 100044, China
3 Department of Emergency, Peking University People’s Hospital, Beijing 100044, China
Correspondence to: Wan-yu Feng: renminyaojike@sina.com, Chun-fu Wu: wucf@syphu.edu.cn,
DOI: 10.1038/s41401-019-0277-x
Received: 10 April 2019
Accepted: 23 June 2019
Advance online: 24 July 2019

Abstract

Cyclosporine (CsA) is characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability, particularly in juvenile patients. The aims of this study were to build a population pharmacokinetic model of CsA in Chinese children with hematopathy who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to identify covariates affecting CsA pharmacokinetics. A total of 86 Chinese children aged 8.4 ± 3.8 years (range 1.1–16.8 years) who received allo-HSCT were enrolled. Whole blood samples were collected before allo-HSCT. Genotyping was performed using an Agena MassARRAY system. A total of 1010 trough plasma concentration values of CsA and clinical data were collected. The population pharmacokinetic model of CsA was constructed using nonlinear mixed-effects modeling (NONMEM) software. The stability and performance of the final model were validated using bootstrapping and normalized prediction distribution errors. We showed that a one-compartment model with first-order elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL) and volume of distribution (V) were 42.3 L/h and 3100 L, respectively. Body weight, postoperative days, CYP3A4*1 G genotype, estimated glomerular filtration rate and coadministration of triazole antifungal drugs were identified as significant covariates for CL. Weight and postoperative days were significant covariates for the V of CsA. Our model can be adopted to optimize the CsA dosing regimen for Chinese children with hematopathy receiving allo-HSCT.
Keywords: cyclosporine; population pharmacokinetic model; hematopoietic stem cell transplantation; Chinese children

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