Serum posaconazole levels among haematological cancer patients taking extended release tablets is affected by body weight and diarrhoea: single centre retrospective analysis

Abstract

The posaconazole extended release tablet formulation was developed to improve bioavailability relative to the oral suspension. Therapeutic drug monitoring has been used to optimise posaconazole dosing to achieve a target trough level ≥0.7 μg ml(-1). We retrospectively evaluated 28 patients with haematological malignancies who received posaconazole tablets for antifungal prophylaxis. Posaconazole serum trough levels were obtained 5 days after initiation of therapy. Mean trough level was 1.19 ± 0.63 μg ml(-1), and 71% achieved a trough level ≥0.7 μg ml(-1). Diarrhoea was associated with lower mean trough levels (0.65 ± 0.08 μg ml(-1) vs. 1.31 ± 0.13 μg ml(-1)), P = 0.002. Mean trough levels were lower in patients ≥90 kg (0.74 ± 0.09 μg ml(-1)) vs. <90 kg (1.32 ± 0.14 μg ml(-1)), P = 0.002 and in patients with body mass index (BMI) ≥30 (0.89 ± 0.13 μg ml(-1)) vs. BMI <30 (1.29 ± 0.14 μg ml(-1)), P = 0.05. Posaconazole delayed release tablets attain appropriate trough levels in most patients, but patients with a higher weight and those experiencing diarrhoea are more likely to have lower levels.

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

“…The tablet and intravenous formulations were approved on the basis of safety and pharmacokinetic data, with corresponding phase III data for the tablet formulation recently being published (9). To date, several small, single-center studies have reviewed the initial implementation of PCZ tablets, focusing mainly on pharmacokinetic endpoints (5,6,(10)(11)(12). In agreement with our early experience, those reports also have shown that PCZ tablets yield higher serum concentrations than the suspension formulation and appear to be safe (5).…”

“…In a study by Miceli et. al., obesity and diarrhea were associated with lower levels (10). Due to limitations with the retrospective nature of the study and medical record documentation, the impact of diarrhea was unfortunately not assessed in this study.…”

“…Multivariate analyses were planned a priori, but the small numbers of patients reaching the primary endpoints prevented any meaningful analyses from being completed. Because weight and BMI were shown previously to correlate with serum PCZ levels, these parameters were specifically correlated with serum PCZ levels using linear regression (10). CART analysis was used to determine what, if any, significant breakpoints existed for low serum PCZ levels and potential liver injury.…”

“…Whether there is a subset of patients who have low PCZ levels, despite the use of the new PCZ formulations, remains unclear. In one small study, a subgroup of patients with increased body weight and diarrhea were found to have PCZ levels of Ͻ700 ng/ml (10).…”

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 …”