Drug-drug interaction of phenytoin sodium and methylprednisolone on voriconazole: a population pharmacokinetic model in children with thalassemia undergoing allogeneic hematopoietic stem cell transplantation.
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引用次数: 0
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.
期刊介绍：
The European Journal of Clinical Pharmacology publishes original papers on all aspects of clinical pharmacology and drug therapy in humans. Manuscripts are welcomed on the following topics: therapeutic trials, pharmacokinetics/pharmacodynamics, pharmacogenetics, drug metabolism, adverse drug reactions, drug interactions, all aspects of drug development, development relating to teaching in clinical pharmacology, pharmacoepidemiology, and matters relating to the rational prescribing and safe use of drugs. Methodological contributions relevant to these topics are also welcomed.
Data from animal experiments are accepted only in the context of original data in man reported in the same paper. EJCP will only consider manuscripts describing the frequency of allelic variants in different populations if this information is linked to functional data or new interesting variants. Highly relevant differences in frequency with a major impact in drug therapy for the respective population may be submitted as a letter to the editor.
Straightforward phase I pharmacokinetic or pharmacodynamic studies as parts of new drug development will only be considered for publication if the paper involves
-a compound that is interesting and new in some basic or fundamental way, or
-methods that are original in some basic sense, or
-a highly unexpected outcome, or
-conclusions that are scientifically novel in some basic or fundamental sense.
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