Trough concentration of voriconazole and its relationship with efficacy and safety: A systematic review and meta-analysis

Objectives: The optimum trough concentration of voriconazole for clinical response and safety is controversial. The objective of this reviewwas to determine the optimum trough concentration of voriconazole and evaluate its relationship with efficacy and safety. Methods: MEDLINE, EMBASE, ClinicalTrials.gov, the Cochrane Library and three Chinese literature databases were searched. Observational studies that compared clinical outcomes below and above the trough concentration cut-offvaluewere included. We set the trough concentration cut-offvalue for efficacy as 0.5, 1.0, 1.5, 2.0 and 3.0 mg/L and for safety as 3.0, 4.0, 5.0, 5.5 and 6.0 mg/L. The efficacy outcomes were invasive fungal infectionrelated mortality, all-cause mortality, rate of successful treatment and rate of prophylaxis failure. The safety outcomes included incidents of hepatotoxicity, neurotoxicity and visual disorders. Results: A total of 21 studies involving 1158 patients were included. Compared with voriconazole trough concentrations of >0.5 mg/L, levels of <0.5 mg/L significantly decreased the rate of treatment success (risk ratio=0.46, 95% CI 0.29-0.74). The incidence of hepatotoxicity was significantly increased with trough concentrations >3.0, >4.0,>5.5 and >6.0 mg/L. The incidence of neurotoxicitywas significantly increased with trough concentrations >4.0 and >5.5 mg/L. Conclusions: A voriconazole level of 0.5 mg/L should be considered the lower threshold associated with efficacy. A trough concentration >3.0 mg/L is associated with increased hepatotoxicity, particularly for the Asian population, and >4.0 mg/L is associated with increased neurotoxicity.