Trough concentration of itraconazole and its relationship with efficacy and safety: a systematic review and meta-analysis

Abstract

ObjectivesThe 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.MethodsWe 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.ResultsThe study included a total of 29 studies involving 2,346 patients. Our meta-analysis showed that compared with itraconazole trough concentrations (Ctrough) 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.ConclusionAn 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]).

A novel highly bio‐available itraconazole formulation (SUBA®‐Itraconazole) for anti‐fungal prophylaxis in lung transplant recipients

“…However, further assessment of toxicity-particularly hepatotoxicity-would need to be considered as dose escalations continue. 22 Dose escalation may not be required as there is some evidence that levels of 0.25-0.50 mg/L are effective for prophylaxis, 25 and 82% of trough itraconazole concentrations with empiric dosing exceeded 0.25 mg/L in our study.…”

“…21 SUBA®-Itraconazole has demonstrated safety and efficacy for fungal prophylaxis in hematopoietic stem cell transplantation [22][23][24] with a target trough level of > 0.5 mg/L, although efficacy has also been noted at 0.25-0.50 mg/L. 25 No data is available on dose adjustment for calcineurin inhibitors in lung transplant recipients with SUBA®-itraconazole, though prior formulations of itraconazole have demonstrated the need for tacrolimus dose reductions of 50-75% to avoid toxicity. 14,[26][27][28] We introduced SUBA®-itraconazole for antifungal prophylaxis in our lung transplant centre in December 2016 as there was no comparator trial data in lung transplantation preferring one triazole over another, prior formulations of itraconazole showed efficacy, 5,13,14 pharmocokinetic data suggested improved bioavailability of the SUBA®-itraconazole formulation, and the cost of SUBA®-itraconazole was low compared to posaconazole.…”

Comparing posaconazole and itraconazole for antifungal prophylaxis in critically ill lung transplant recipients: Efficacy and plasma concentrations

“…Target attainment was defined as recommended by the British Society of Mycology and in accordance with the previously published literature. Trough concentrations of ≥500 µg/L for itraconazole 15,17,28,29 and of ≥700 µg/L for posaconazole were defined as target concentrations 3,15,20 …”

The role of antifungals in the management of patients with severe asthma

“…Inhibition by hepatic CYP3A4 by itraconazole may result in increased levels of corticosteroids including budesonide and fluticasone [9, 65–67 ]. A sub‐group of 27 patients in the FAST study was evaluated to address this interaction.…”