Voriconazole therapeutic drug monitoring including analysis of CYP2C19 phenotype in immunocompromised pediatric patients with invasive fungal infections

• Published in: European journal of clinical pharmacology Vol. 80; no. 11; pp. 1829 - 1840
• Main Authors: Resztak, Matylda, Zalewska, Paulina, Wachowiak, Jacek, Sobkowiak-Sobierajska, Agnieszka, Główka, Franciszek K.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-11-2024; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Children; Dosage; Drug dosages; Drug interaction; Fungal infections; Gene polymorphism; Genetic variability; Genotype & phenotype; Genotyping; Oral administration; Patients; Pediatrics; Pharmacokinetics; Pharmacology/Toxicology; Phenotypes; Population genetics; Population studies; Therapeutic drug monitoring; Voriconazole; Therapeutic drug monitoring; Trough concentration; Children; Genetic polymorphisms; Voriconazole
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-024-03752-z

Purpose
Therapeutic drug monitoring (TDM) of voriconazole (VCZ) should be mandatory for all pediatric patients with invasive fungal infections (IFIs). The narrow therapeutic index, inter-individual variability in VCZ pharmacokinetics, and genetic polymorphisms cause achieving therapeutic concentration during therapy to be challenging in this population.
Methods
The study included 44 children suffering from IFIs treated with VCZ. Trough concentrations (C
trough
) of VCZ ware determined by the HPLC-FLD method. Identification of the CYP2C19*2 and CYP2C19*17 genetic polymorphisms was performed by PCR–RFLP. The correlation between polymorphisms and VCZ C
trough
was analyzed. Moreover, the effect of factors such as dose, age, sex, route of administration, and drug interactions was investigated.
Results
VCZ was administered orally and intravenously at a median maintenance dosage of 14.7 mg/kg/day for a median of 10 days. The VCZ C
trough
was highly variable and ranged from 0.1 to 6.8 mg/L. Only 45% of children reached the therapeutic range. There was no significant association between C
trough
and dosage, age, sex, route of administration, and concomitant medications. The frequencies of variant phenotype normal (NM), intermediate (IM), rapid (RM) and ultrarapid metabolizers (UM) were 41%, 18%, 28%, and 13%, respectively. C
trough
of VCZ were significantly higher in NM and IM groups compared with RM, and UM groups.
Conclusion
The C
trough
of VCZ is characterized by inter-individual variability and a low rate of patients reaching the therapeutic range. The significant association exists in children between VCZ C
trough
and CYPC19 phenotype. The combination of repeated TDM and genotyping is necessary to ensure effective treatment.