Drug-drug interaction of phenytoin sodium and methylprednisolone on voriconazole: a population pharmacokinetic model in children with thalassemia undergoing allogeneic hematopoietic stem cell transplantation

Yun Wu; Lu-Lu Niu; Ya-Yun Ling; Si-Ru Zhou; Tian-Min Huang; Jian-Ying Qi; Dong-Ni Wu; Rong-da Cai; Ting-Qing Wu; Yang Xiao; Taotao Liu

doi:10.1007/s00228-024-03795-2

Drug-drug interaction of phenytoin sodium and methylprednisolone on voriconazole: a population pharmacokinetic model in children with thalassemia undergoing allogeneic hematopoietic stem cell transplantation

Eur J Clin Pharmacol. 2024 Dec 23. doi: 10.1007/s00228-024-03795-2. Online ahead of print.

Authors

Yun Wu^#¹, Lu-Lu Niu^#¹, Ya-Yun Ling², Si-Ru Zhou¹, Tian-Min Huang¹, Jian-Ying Qi¹, Dong-Ni Wu¹, Rong-da Cai¹, Ting-Qing Wu¹, Yang Xiao¹, Taotao Liu³

Affiliations

¹ Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
² Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
³ Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China. liutaotao@gxmu.edu.cn.

^# Contributed equally.

PMID: 39714727
DOI: 10.1007/s00228-024-03795-2

Abstract

Purpose: Voriconazole (VRC) is recommended for the prevention and treatment of invasive fungal infections in children undergoing hematopoietic stem cell transplantation (HSCT). It demonstrates nonlinear pharmacokinetics (PK) and exhibits substantial inter- and intraindividual variability. Phenytoin sodium (PHT) and methylprednisolone (MP) are commonly used in the early stages of HSCT to prevent epilepsy and graft-versus-host disease. Drug-drug interactions between VRC and these medications represent a significant concern in HSCT recipients. This study aims to investigate the effects of coadministration with PHT, MP, and other covariates on VRC metabolism in children with thalassemia (TM) undergoing allogeneic HSCT (Allo-HSCT) using population pharmacokinetics (PPK) and to recommend the optimal dosage regimen for this unique group.

Methods: A total of 237 samples from 57 children with TM undergoing Allo-HSCT were collected. Non-linear mixed effects modeling and Monte Carlo simulation (MCS) were applied for PPK analysis and for optimizing VRC dosing, respectively.

Results: The VRC data were characterized by a two-compartment model with linear elimination and first-order absorption. All parameters were incorporated in allometric scaling form, with PHT and MP significantly influencing VRC clearance. The MCS revealed a negative correlation between the children's body weight (ranging from 10 to 40 kg) and the required dose. When PHT was co-administered, approximately three times the regular dose of VRC was required. In contrast, when MP was administered together, the dose needed to be increased by 12.5-50%.

Conclusion: The proposed regimen improved the probability of target attainment for VRC and may serve as a reference for the individualized administration of VRC in clinical practice.

Keywords: Allogeneic hematopoietic stem cell transplantation; Children; Drug–drug interaction; Population pharmacokinetics; Thalassemia; Voriconazole.

Grants and funding

(No. 2021JJA140122)./the Natural Science Foundation of Guangxi, China