Factors Affecting Voriconazole Trough Concentration and Optimal Maintenance Voriconazole Dose in Chinese Children

Abstract

Voriconazole is a triazole antifungal agent commonly used for the treatment and prevention of invasive aspergillosis (IA). However, the study of voriconazole's use in children is limited. The present study was performed to explore maintenance dose to optimize voriconazole dosage in children and the factors affecting voriconazole trough concentration. This is a non-interventional retrospective clinical study conducted from 1 January 2016 to 31 December 2020. The study finally included 94 children with 145 voriconazole trough concentrations. The probability of achieving a targeted concentration of 1.0–5.5 µg/mL with empiric dosing increased from 43 (45.3%) to 78 (53.8%) after the TDM-guided adjustment. To achieve targeted concentration, the overall target maintenance dose for the age group of less than 2, 2 to 6, 6 to 12, and 12 to 18 years old was approximately 5.71, 6.67, 5.08 and 3.31 mg·kg−1/12 h, respectively (p < 0.001). Final multivariate analysis found that weight (p = 0.019), dose before sampling (p < 0.001), direct bilirubin (p < 0.001), urea nitrogen (p = 0.038) and phenotypes of CYP2C19 were influencing factors of voriconazole trough concentration. These factors can explain 36.2% of the variability in voriconazole trough concentration. Conclusion: In pediatric patients, voriconazole maintenance doses under the target concentration tend to be lower than the drug label recommended, but this still needs to be further studied. Age, body weight, dose, direct bilirubin, urea nitrogen and phenotypes of CYP2C19 were found to be influencing factors of voriconazole concentration in Chinese children. The influence of these factors should be taken into consideration during voriconazole use.

Impact of extracorporeal membrane oxygenation on voriconazole plasma concentrations: A retrospective study

“…Similar to the results of many previous studies (Dolton et al, 2012;Zhao et al, 2021a;Zhao Y. C et al, 2021), the linear regression model found that voriconazole trough concentration is significantly affected by the dose before sampling.…”

“…Since the metabolism of voriconazole is regulated by liver enzymes ( Zhong et al, 2018 ), its overexposure may occur in patients with liver damage. Published studies demonstrated that reduced voriconazole elimination is significantly associated with impaired liver function, as indicated by elevated alanine transaminase ( Zhao et al, 2021b ), aspartate transaminase ( Li et al, 2017 ), direct bilirubin ( Zhao Y. C et al, 2021 ) and international normalized ratio levels ( Zhao et al, 2021a ).…”

Pharmacogenomics and adverse effects of anti‐infective drugs in children

“…Voriconazole is a broad-spectrum antifungal agent commonly used for . 8 These different phenotypes can affect the blood concentration of voriconazole in children, [30][31][32] and the adverse events associated with it, with higher concentrations resulting in a relatively higher incidence of adverse reactions. 9,33 The main adverse reactions associated with voriconazole are photosensitivity and abnormal liver function.…”

Optimization of Voriconazole Dosing Regimens Against Aspergillus Species and Candida Species in Pediatric Patients After Hematopoietic Cell Transplantation: A Theoretical Study Based on Pharmacokinetic/Pharmacodynamic Analysis

“…14,15 Of these, CYP2C19 polymorphisms are considered a key determinant of the wide pharmacokinetic (PK) variability of VRC. 16 Low levels of exposure to VRC may result in treatment failure, whereas high levels of exposure may result in adverse neurological effects, hepatotoxicity, and visual impairment. [17][18][19] Therefore, the dosing schedule for VRC should be optimized to maximize the best therapeutic effect and minimize the occurrence of adverse effects.…”

“…However, VRC has a narrow therapeutic range and complex nonlinear pharmacokinetics; furthermore, multiple factors are known to be associated with the pharmacokinetics of VRC, including age, body weight, liver function, and genetic polymorphisms of the cytochrome P450 (CYP) 2C19 enzyme, all of which complicate the successful therapeutic use of VRC in the pediatric population 14,15 . Of these, CYP2C19 polymorphisms are considered a key determinant of the wide pharmacokinetic (PK) variability of VRC 16 . Low levels of exposure to VRC may result in treatment failure, whereas high levels of exposure may result in adverse neurological effects, hepatotoxicity, and visual impairment 17–19 .…”