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

Abstract

Posaconazole is the preferred mold-active azole for prophylaxis against invasive fungal infections (IFIs) in patients with hematological malignancy. Delayedrelease 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 for patients with hematological malignancy. A retrospective cohort of all consecutive adult inpatients with hematological malignancy who received Ն3 days of tablet or intravenous posaconazole therapy for primary IFI prophylaxis at the M. D. Anderson Cancer Center between 1 December 2013 and 31 December 2015 was established. Clinical information was collected and correlated with low posaconazole serum levels (Ͻ700 ng/ml). Rates of IFIs and safety events were assessed. A total of 1,321 courses of posaconazole were administered at the M. D. Anderson Cancer Center during the study period, of which 343 courses were assessed for prophylactic safety and effectiveness. Seventy-nine patients (23%) had posaconazole serum level measurements available for interpretation. Acute myeloid leukemia was the primary malignancy (62%), with 20% of all patients having previously received a stem cell transplant. The median posaconazole level was 1,380 ng/ml (interquartile range, 864 to 1,860 ng/ml). Low posaconazole levels (Ͻ700 ng/ml) were observed for 14 patients (18%). Proven or probable breakthrough IFIs occurred in 8 patients (2%); posaconazole therapeutic drug monitoring (TDM) was performed for 6 of those patients, all with levels above 700 ng/ml. Overall, 19% of patients experienced grade 3 or 4 liver injury, manifesting primarily as hyperbilirubinemia and being correlated with serum levels of Ͼ1,830 ng/ml. Although hepatotoxicity in a small percentage of patients is of concern, posaconazole tablets appeared to be generally safe and effective. As all breakthrough IFIs for which TDM was performed occurred in patients with levels of Ͼ700 ng/ml, and a posaconazole level of Ͼ1,830 ng/ml was correlated with grade 3 or 4 liver toxicity, further studies are needed to assess the role of TDM.KEYWORDS posaconazole, hematological malignancy, prophylaxis, cancer, antifungal I nvasive fungal infections (IFIs) continue to be a significant cause of morbidity and death among patients with hematological malignancy (1). The triazole posaconazole (PCZ) has in vitro, preclinical, and clinical activities against a variety of yeasts and molds (2). Since its introduction 15 years ago, PCZ has been widely used for the prevention and treatment of IFIs in patients with leukemia and in hematopoietic stem cell

Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations

“…In addition, we found a positive association between age and POS C min in univariate analyses, which is in accordance with previous studies performed in hematological patients treated with POS-susp (7,17) or POS-tab (18). However, this association did not reach significance in multivariate analyses, suggesting that the influence of age on POS C min was dependent on another variable in our cohort.…”

“…Several studies reported CVs for the POS-tab C min , but comparing CV values is problematic since calculation methods of CV differ. Here, we used the method described by Bland (21) to calculate within-subject CV, whereas a different approach was used in other studies, i.e., the ratio between standard error and the mean POS C min in each patient (18,22). Finally, as explained above, we adjusted the POS C min for the POS dose in our cohort, which was not done in the other studies (18,22).…”

High‐dose posaconazole for azole‐resistant aspergillosis and other difficult‐to‐treat mould infections

“…20% of these patients developed liver injury, mostly hyperbilirubinemia but this is often multifactorial. More importantly, grade 3‐4 elevations in hepatic enzymes were only observed in 2% of the patients without pre‐existing liver injury with mostly spontaneous resolution despite treatment continuation . Thus, in the current literature, information about the toxicity of high POS serum concentrations is limited but no increase in the number of AEs was observed in patients with higher than average serum concentrations.…”

Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

“…Consequently, the upper C min limit that we propose for ISA must be interpreted with caution. Second, we propose upper limits for the POS and ISA C min , above which no gain of efficacy could be expected, but some adverse effects could occur at lower C min values [9,30,31,36]. Anyway, further studies with direct clinical outcomes (efficacy and safety) are required to confirm and validate the interest of such thresholds.…”

“…In the phase 3 study of the delayed-release tablet POS, C min from 0.5 to 3.75 mg/L was considered to be safe [1]. Moreover, recent studies failed to demonstrate any link between the POS C min and toxicity [12,14,30], even if some authors reported some cases of adverse events in patients with a POS C min > 1.8 mg/L [9,31,32]. Finally, although our results suggest that a gain of antifungal activity can be expected until a POS C min of 4.8 mg/L, additional research is needed to determine whether such POS exposure significantly improves efficacy without inducing toxicity.…”