Trough Concentration Of Itraconazole And Its Relationship With Efficacy And Safety: A Systematic Review And Meta-Analysis

Objectives: The optimum trough concentration of itraconazole for clinical response and safty is controversial. The objective of this systematic review and meta-analysis was to determine the optimum trough concentration of itraconazole and evaluate its relationship with efficacy and safety.Methods: We searched PubMed, EMBASE, Web of Science, the Cochrane Library, Clinical-Trials. gov, and three Chinese literature databases (CNKI, WanFang, and CBM). We included observational studies that compared clinical outcomes below or above the trough concentration cut-off value which we set as 0.25, 0.5, and 1.0 mg/L. The efficacy outcomes were rate of successful treatment, rate of prophylaxis failure and invasive fungal infection (IFI)-related mortality. The safety outcomes included incidents of hepatotoxicity and other adverse events.Results: The study included a total of 29 studies involving 2,346 patients. Our meta-analysis showed that compared with itraconazole trough concentrations (C-trough) of >= 0.25 mg/L, levels of <0.25 mg/L significantly increased the incidence of IFI for prophylaxis (RR = 3.279, 95% confidence interval [CI] 1.73-6.206). Moreover, the success rate of treatment decreased significantly at a cut-off level of 0.5 mg/L (RR = 0.396, 95% CI 0.176-0.889). An itraconazole trough level of 1.0 mg/L was associated with hepatotoxicity and other adverse events in a review of many studies.Conclusion: An itraconazole trough concentration of 0.25 mg/L should be considered as the lower threshold for prophylaxis, and a target concentration of 0.5 mg/L should be the lower limit for effective treatment. A trough level of 1.0 mg/L is associated with increased hepatotoxicity and other adverse events (using High Performance Liquid Chromatography [HPLC]).