Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections: Analysis of 343 courses [PublishAheadOfPrint]

Background: Posaconazole is the preferred mold-active azole for prophylaxis against invasive fungal infection (IFI) in patients with hematologic malignancy (HM). Delayed release tablet and intravenous formulations of posaconazole have recently become available, but clinical data are limited. We sought to examine the real-world pharmacokinetics and prophylactic effectiveness of the new formulations of posaconazole given as prophylaxis in patients with HM.

Methods: A retrospective cohort of all consecutive adult inpatients with HM who received ≥3 days of posaconazole as tablet or intravenous from 12/1/2013-12/31/2015 for primary IFI prophylaxis at MD Anderson Cancer center. Clinical information were collected and correlated with low posaconazole serum levels (<700ng/mL). Rates of invasive fungal infections as well as safety events were assessed.

Results: 1,321 courses of posaconazole were administered at MD Anderson Cancer Center during the study time period, with 343 patient courses assessed for prophylactic safety and effectiveness. Seventy-nine patient (23%) courses had posaconazole serum levels available for interpretation. Acute myelogenous leukemia was the primary malignancy (62%) with 20% of all patients having previously received a stem cell transplant. Median posaconazole level was 1,380ng/ml (IQR 864-1860). A low posaconazole level (< 700ng/mL) was observed in 14 (18%) of patients. Proven or probable breakthrough IFI occurred in 8 patients (2%), 6 of whom had posaconazole TDM performed, all with levels above 700ng/mL. Overall, 19% of patients experienced grade 3/4 liver injury, primarily manifesting as hyperbilirubinemia and correlated with a serum level >1,830.

Conclusions: Although hepatotoxicity in a small percentage of patients is of concern, posaconazole tablets appeared to be generally safe and effective. As all breakthrough IFI in whom TDM was performed occurred in patients with levels >700ng/mL and a PCZ level >1,830ng/mL correlated with grade 3/4 liver toxicity, further studies are needed to assess the role of therapeutic drug monitoring.

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