Posaconazole prophylaxis in neutropenic patients with hematological malignancies: limits in clinical practice

Abstract

Posaconazole (PSZ) is being used for prophylaxis in hematological patients who are at high risk for invasive fungal disease (IFD), but absorption limitations have been reported. Our objective was to assess both the feasibility and the efficacy of PSZ prophylaxis in clinical practice. From March 2010 to September 2010, all patients admitted to our unit for chemotherapy for acute leukemia or hematopoietic stem cell transplantation received optimized PSZ prophylaxis 200 mg four times daily with cola soda. PSZ trough concentrations (Cmin) were monitored at days 5, 7, 14, and 21. The incidence of IFDs was determined and compared to that of a historical control group. Thirty-five consecutive patients were prospectively included. PSZ prophylaxis was interrupted for 29% of them at day 14 and 51% of them at day 21. The main limitations were impracticality of oral feeding (29%) and occurrence of suspected IFDs (23%). PSZ median Cmin were 0.47, 0.40, 0.24, 0.36 μg/mL at days 5, 7, 14, and 21, respectively. Eighty percent of patient results were lower than the target Cmin of 0.5 μg/ml on day 14, the higher-risk period associated with neutropenia. Four probable breakthrough IFDs (11%) were diagnosed in 2010; no clear association between PSZ Cmin and occurrence of infection was observed. The incidence of IFDs was unchanged (historical control group: 9.7%; P = 0.72). Implementation of systematic PSZ prophylaxis did not significantly decrease the incidence of IFDs at our center. PSZ interruptions related to mucositis and too low Cmin were the main limitations to its use.

Efficacy of antifungal prophylaxis with oral suspension posaconazole during induction chemotherapy of acute myeloid leukemia

“…Our observation of possible IFD in 21 % of patients correlates well with recently published data (Bourdelin et al 2014;Peterson et al 2013). The detection of aspergillus antigen by serum galactomannan assay was not implemented in our routine diagnostic procedure and might result in a lower frequency of possible IFD.…”

“…Posaconazole has been approved for antifungal prophylaxis in AML and MDS patients who are treated with intensive induction chemotherapy because of a reduced frequency of breakthrough fungal infections and even an increase in survival as compared to fluconazole and itraconazole (Cornely et al 2007). Nevertheless, the results of this randomized clinical trial could not be reproduced by all consecutive observational or even prospective analyses (Bertz et al 2014;Bourdelin et al 2014). This might be due to the uncertain bioavailability of posaconazole because of several factors that influence its absorption.…”

“…Furthermore, a high rate of suspected IFD reflecting 23 % of the investigated cohort resulted in an unchanged frequency (11 %) of probable IFD in 35 prospectively analyzed patients as compared to a historical control group (Bourdelin et al 2014).…”

Hyperlipidemia Alters the Pharmacokinetics of Posaconazole and Vincristine Upon Co-Administration in Rats

“…Triazole antifungals including fluconazole, voriconazole, itraconazole, and posaconazole (PSZ) are among the common measures taken for the prophylaxis and treatment of invasive fungal infections [18, 40]. Posaconazole is widely used as prophylactic therapy in hematopoietic stem cell transplant recipients with graft-vs.-host disease, or in individuals with hematological malignancies experiencing prolonged neutropenia as a result of intensive chemotherapy [3, 18, 22]. …”

Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis

“…All 28 [ 9 , 11 , 12 , 14 , 15 , 20 , 21 , 31 – 52 ] studies, with 1930 enrolled patients, contributed to our systematic analysis of the relationship between posaconazole plasma concentration and rate of clinical prophylaxis success. Twenty participating studies [ 9 , 11 , 14 , 15 , 32 – 39 , 41 , 43 – 48 , 50 ], with 1043 patients, provided outcomes of interest at a cut-off value of 0.5 mg/L; and 15 studies [ 9 , 12 , 20 , 21 , 31 , 34 , 35 , 40 , 42 , 43 , 45 , 47 – 49 , 51 , 52 ], with 1098 patients, provided data at a cut-off value of 0.7 mg/L.…”