The relationship between the success rate of empirical antifungal therapy with intravenous itraconazole and clinical parameters, including plasma levels of itraconazole, in immunocompromised patients receiving itraconazole oral solution as prophylaxis: a multicenter, prospective, open-label, observational study in Korea

Abstract

To identify the role of therapeutic drug monitoring of itraconazole (ITZ) in the setting of empirical antifungal therapy with intravenous (IV) ITZ, we performed a multicenter, prospective study in patients with hematological malignancies who had received antifungal prophylaxis with ITZ oral solution (OS). We evaluated the plasma levels of ITZ and hydroxy (OH) ITZ both before initiation of IV ITZ and on days 5-7 of IV ITZ. A total of 181 patients showed an overall success rate of 68.0 %. Prolonged baseline neutropenia and accompanying cardiovascular comorbidity were significantly associated with poor outcomes of the empirical antifungal therapy (P = 0.005 and P = 0.001, respectively). A significantly higher trough plasma level of OH ITZ per body weight was found in the patients who achieved success with empirical antifungal therapy (P = 0.036). There were no significant correlations between plasma concentrations of ITZ/OH ITZ (baseline or trough levels) and toxicities. Seven patients had a discontinuation of ITZ therapy due to toxicity. This study demonstrated that IV ITZ as empirical antifungal therapy was effective and therapeutic drug monitoring was helpful to estimate the outcome of empirical antifungal therapy in patients receiving antifungal prophylaxis with ITZ OS. To predict the outcome of empirical antifungal therapy with IV ITZ, we should evaluate baseline clinical characteristics and also perform the therapeutic drug monitoring of both ITZ and OH ITZ.

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

“… 16 , 17 A guideline 21 and other observational studies 18 , 19 suggested 0.5–1.0 mg/L as itraconazole trough concentration. Patients with C trough of 1.0 mg/L were associated with a high level of clinical response according to Kim et al’s 2014 study 20 and others. 40 Therefore, we established the stepwise cut-off values for itraconazole efficacy and safety as 0.25, 0.5, and 1.0 mg/L.…”

“…However, numerous observational studies have concluded minimum itraconazole level cut-off values, including 0.25, 16 , 17 0.5, 18 , 19 and 1.0 mg/L. 20 A 2014 guideline from the British society for medical mycology recommended an itraconazole trough concentration of 0.5–1.0 mg/L to prevent and treat IFI, 21 which was based on some observational studies 22 – 30 and a previous meta-analysis in 2003. 31 This guideline also proposed an increased incidence of toxicity at higher itraconazole concentrations citing two studies which quantified itraconazole concentrations.…”

Comparison of long‐term and short‐term administration of itraconazole for primary antifungal prophylaxis in recipients of allogeneic hematopoietic stem cell transplantation: a multicenter, randomized, open‐label trial

“…The efficacy of ITCZ has been proven to be associated with a sufficient serum concentration . After 4 doses of 200‐mg IV solution of ITCZ, trough serum concentrations of ITCZ and hydroxyitraconazole in normal volunteers were reported 687 ± 146 ng/mL and 1263 ± 109 ng/mL, respectively .…”

Repurposing Drugs in Oncology (ReDO)—itraconazole as an anti-cancer agent

“…Overall there is a high-degree of inter and intra-patient variability in plasma concentrations, with differences influenced by drug formulation (oral solution or tablets), changes in kinetics during long-term treatments, interactions with food intake, and other medications and changes in pathological status of patients. It is generally recommended, therefore, that for long-term treatment patients be regularly monitored for plasma levels [ 6 , 12 , 13 ].…”