Abstract
The optimum trough concentration of voriconazole for clinical response and safety is controversial. The objective of this review was to determine the optimum trough concentration of voriconazole and evaluate its relationship with efficacy and safety. 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-off value were included. We set the trough concentration cut-off value 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 infection-related mortality, all-cause mortality, rate of successful treatment and rate of prophylaxis failure. The safety outcomes included incidents of hepatotoxicity, neurotoxicity and visual disorders. 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 neurotoxicity was significantly increased with trough concentrations >4.0 and >5.5 mg/L. 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.
Highlights
Deep mycoses are serious infections associated with a high mortality
Owing to the limited number of studies, we only evaluated publication bias at the trough concentration cut-off level of 1 mg/L for treatment success (10 studies)
Differences in assay methods across studies may lead to differences in precision of the voriconazole result and differences in the timing of clinical outcome assessment may lead to lack of reliability in the results across studies. This meta-analysis demonstrated that 0.5 mg/L is the lower limit of the target voriconazole trough concentration during treatment
Summary
Deep mycoses are serious infections associated with a high mortality. No randomized trials have evaluated the target trough concentration of voriconazole in deep mycoses. Numerous observational studies have recommended lowest voriconazole concentration cut-off values, including 0.25,9 1,10 1.2,11 1.5,12 1.7,13 214 and 2.2 mg/L.15. A guideline authored by two Japanese societies and published in 2013 recommended a voriconazole target trough concentration of 1 –2 mg/L for efficacy and a trough concentration .4 – 5 mg/L as a critical concentration for potentially attributable elevated liver function tests,[16] which was primarily based on a meta-analysis of Numerous observational studies have recommended lowest voriconazole concentration cut-off values, including 0.25,9 1,10 1.2,11 1.5,12 1.7,13 214 and 2.2 mg/L.15 A guideline authored by two Japanese societies and published in 2013 recommended a voriconazole target trough concentration of 1 –2 mg/L for efficacy and a trough concentration .4 – 5 mg/L as a critical concentration for potentially attributable elevated liver function tests,[16] which was primarily based on a meta-analysis of
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