Superior Serum Concentrations with Posaconazole Delayed-Release Tablets Compared to Suspension Formulation in Hematological Malignancies

Abstract

d Posaconazole (PCZ), approved for prophylaxis against invasive fungal disease in high-risk patients, is commercially available orally as a suspension formulation (PCZ-susp) and as a delayed-release tablet (PCZ-tab). We evaluated the serum steady-state concentrations (C ss ) of PCZ stratified by the administered formulation for antifungal prophylaxis in patients with myeloid malignancies (n ‫؍‬ 150). The primary outcome was the attainment rate of the target C ss of >700 ng/ml. Secondary outcomes included toxicity assessment (hepatotoxicity and corrected QT [QTc] interval prolongation) and breakthrough fungal infections. Patients who received the PCZ-susp (n ‫؍‬ 118) or PCZ-tab (n ‫؍‬ 32) and had PCZ C ss assessment after at least 7 days of therapy were eligible. The median C ss in the PCZ-susp group was 390 ng/ml (range, 51 to 1,870 ng/ml; mean, 436 ng/ml) compared to 1,740 ng/ml (range, 662 to 3,350 ng/ml; mean, 1,781 ng/ml) in the PCZ-tab group (P < 0.0001). The percentages of patients achieving the target goal of >700 ng/ml were 17% versus 97%, respectively (P < 0.0001). Hepatotoxicity (grade 2 or higher) occurred in 1 patient in each group. QTc interval measurements were available for 32 patients in the PCZ-susp group and for 12 patients in the PCZ-tab group, and prolonged intervals of grade 2 or higher were noted in 9% (n ‫؍‬ 3) and 17% (n ‫؍‬ 2), respectively (P ‫؍‬ 0.6). Breakthrough fungal infections in the PCZ-susp and PCZ-tab groups were 7% (n ‫؍‬ 8) and 3% (n ‫؍‬ 1), respectively (P ‫؍‬ 0.68). We conclude that the use of PCZ-tab was associated with higher C ss and with the probability of achieving therapeutic goals without worsening of adverse effects. P osaconazole (PCZ) is a triazole antifungal agent that is approved for invasive fungal disease prophylaxis in high-risk patients. Oral formulations of PCZ are commercially available as a suspension (PCZ-susp) and as delayed-release tablets (PCZ-tab) (1). Several studies have shown that the gastrointestinal absorption and bioavailability of PCZ-susp are unpredictable and dependent on various factors, including food intake and concomitant acid suppressants (2-7). Due to its superior oral bioavailability, the PCZ-tab can be administered without regard to food intake and seems less likely to be affected by concomitant acid-suppressing medications (8-11).PCZ concentrations follow dose-dependent pharmacokinetics at steady state with saturation of absorption of the PCZ-susp occurring at 800 mg/day (12). The current guidelines recommend as a goal steady-state concentrations (C ss ) of Ն700 ng/ml in the prophylaxis setting (13). Comparative studies evaluating the PCZsusp and the newer PCZ-tab are not available. Herein, we report a retrospective analysis comparing the serum concentrations of the two formulations. MATERIALS AND METHODSPatient population. For this study, 152 consecutive patients with acute myelogenous leukemia (AML) or high-grade myelodysplastic syndrome (MDS) who were admitted to the inpatient hematologic malignancy service at West Virginia Unive...

Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses

“…PCZ was associated with a rate of proven or probable breakthrough IFIs of only 2%, which was comparable to the low rates of breakthrough infections seen in registry and real-life data with both the PCZ suspension and PCZ tablets (2,15). The types of organisms implicated in the breakthrough IFIs were few in number and representative of the types of pathogens typically seen in high-risk hematological malignancy patients.…”

Visual Hallucinations Associated with High Posaconazole Concentrations in Serum

“…Although central nervous system (CNS) toxicity has not previously been reported with posaconazole, this observation may reflect the low levels achieved with the oral suspension combined with its low CNS penetration (7,10). However, newer formulations result in significantly higher posaconazole concentrations in serum (11), particularly in patients with low body mass (12). Use of posaconazole tablets can result in serum concentrations above the range that has been well …”

New facets of antifungal therapy

“…39,40 The delayed release oral tablet is considered a more reliable option for the prophylaxis or treatment of IFIs. Studies have suggested that the posaconazole oral tablet has higher azole plasma levels 41 , better absorption 42 , and improved bioavailability 43 than that of oral suspension. Furthermore, an intravenous formulation of posaconazole was developed and FDA-approved in 2014 for patients who are unable to take oral medications.…”