Optimal trough concentration of voriconazole with therapeutic drug monitoring in children: A systematic review and meta-analysis

Abstract

Objectives: This systematic review and meta-analysis was designed to determine the optimal trough concentration of voriconazole for children with invasive fungal infections (IFIs). Methods: We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and Japana Centra Revuo Medicina) for clinical studies describing the voriconazole trough concentration. We used stepwise cut-off values of 1.0e2.0 mg/L for efficacy and 3.0e6.0 mg/L for safety. The efficacy outcomes were treatment success and all-cause mortality, and the safety outcomes were hepatotoxicity, neurotoxicity and all-cause adverse events. Results: Nine studies involving 211 patients were included in the analysis. The probability of treatment success against IFIs was significantly increased at cut-off values of !1.0 mg/L (odds ratio [OR] ¼ 2.65, 95% confidence interval [CI] ¼ 1.20e5.87). Our analysis did not find any relationship between the trough concentration and survival. Concerning safety, the occurrence of any outcomes did not significantly differ according to the voriconazole trough concentrations at any cut-off value. However, in a subgroup analysis of Asian study locations, a significantly higher risk of hepatotoxicity was demonstrated at voriconazole trough cut-off values ! 3.0 mg/L (OR ¼ 8.40, 95% CI ¼ 1.36e51.92). Although a significant correlation between the voriconazole concentration and hepatotoxicity was evident in regression curve analysis, (y ¼ 0.1198e 0.2298x ), no correlation was demonstrated for neurotoxicity (y ¼ 0.3913e À0.008x ). Conclusion: Our findings suggest that the optimal trough concentration for increasing clinical success and minimizing hepatotoxicity during voriconazole therapy in children with IFIs, particularly for Asian populations, is 1.0e3.0 mg/L.

Recent Advances in Therapeutic Drug Monitoring of Voriconazole, Mycophenolic Acid, and Vancomycin: A Literature Review of Pediatric Studies

“…In this study, 211 children with hematologic disorders, solid organ transplantation, and from Asian and non-Asian countries were included. The authors found that the efficacy of IFIs treatment increases significantly with cutoff values of ≥1.0 mg/L [27].…”

“…High plasma concentration of VCZ might be associated with an increased risk of toxicity. As VCZ is well tolerated in children with a lower rate of adverse effects (AEs), toxicity targets have not been validated for this population so far [27]. However, several studies have reported the incidence of adverse drug reactions.…”

A Strategy for Hospital Pharmacists to Control Antimicrobial Resistance (AMR) in Japan

“…However, data on the target range of voriconazole concentrations in children are lacking because most studies are limited by small sample sizes and other factors. Hanai et al [ 74 ] used a similar approach to suggest that the target concentration range for voriconazole in children, particularly for Asian populations, is 1.0–3.0 μg/mL.…”

Voriconazole Use in Children: Therapeutic Drug Monitoring and Control of Inflammation as Key Points for Optimal Treatment

“…Approved in 2002 by the FDA, voriconazole is a broad-spectrum triazole antifungal agent that has become a mainstay of both primary and salvage treatment for invasive aspergillosis and candidiasis [1,[7][8][9][10][11][12][13][14]. Several publications, mainly in adults but also in children, suggest that therapeutic drug monitoring (TDM) improves the efficacy and safety of voriconazole [1,8,[15][16][17][18][19][20][21][22][23][24]. As between-subject differences in voriconazole plasma concentrations (PC) are more marked in children than in adults [25][26][27][28][29][30], monitoring of trough concentrations is particularly important in children to ensure optimal treatment.…”