Retrospective Comparison of Posaconazole Levels in Patients Taking the Delayed-Release Tablet versus the Oral Suspension

Abstract

While posaconazole prophylaxis decreases the risk of invasive fungal infection compared to fluconazole, low bioavailability of the oral-suspension formulation limits its efficacy. A new delayed-release tablet formulation demonstrated an improved pharmacokinetic profile in healthy volunteers. However, serum levels for the two formulations have not been compared in clinical practice. This study compared achievement of therapeutic posaconazole levels in patients taking the delayed-release tablet to those taking the oral suspension. This retrospective cohort study included 93 patients initiated on posaconazole between 2012 and 2014 and had at least one serum posaconazole level measured. The primary measure was the proportion of patients achieving an initial therapeutic level (>700 ng/ml). An initial therapeutic posaconazole level was seen in 29 of 32 (91%) patients receiving tablets and 37 of 61 (61%) patients receiving suspension (P ‫؍‬ 0.003). Among patients with a steady-state level measured 5 to 14 days after initiation, a therapeutic level was observed in 18 of 20 (90%) patients receiving tablets and 25 of 43 (58%) patients receiving suspension (P ‫؍‬ 0.01). In these patients, the median posaconazole level of the tablet cohort (1655 ng/ml) was twice that of the suspension cohort (798 ng/ml) (P ‫؍‬ 0.004). In this cohort study, the improved bioavailability of delayed-release posaconazole tablets translates into a significantly higher proportion of patients achieving therapeutic serum levels than in the cohort receiving the oral suspension. The results of this study strongly support the use of delayed-release tablets over suspension in patients at risk for invasive fungal infection. Despite the approval of posaconazole for this indication, the oral suspension has limited bioavailability, particularly when decreased oral intake, mucositis, gastrointestinal graft-versus-host disease (GVHD), or diarrhea is present (3). Given that subtherapeutic posaconazole levels may be associated with breakthrough IFIs (4) and decreased likelihood of successful treatment (5), a new delayed-release (DR) tablet formulation with higher oral bioavailability (6) holds promise. In fact, a phase 3 trial reports that over 99% of patients with hematologic malignancies receiving DR tablets achieved levels of Ͼ500 ng/ml (7). Aside from a crossover study of 12 leukemia patients (8), clinical practice data comparing serum concentrations of the two posaconazole formulations have not been reported.The primary objective of this study was to compare steadystate levels of serum posaconazole in patients taking DR posaconazole tablets to those taking oral suspension to determine if the pharmacokinetic advantage of DR tablets observed in healthy volunteers and clinical trials translates to a higher rate of therapeutic serum concentrations in clinical practice. MATERIALS AND METHODSStudy population. This study was approved by the institutional review board at Mayo Clinic. All patients who were initiated on posaconazole and had a serum posaconazole leve...

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).…”

Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children

“…We did not find a significant relationship between age and posaconazole CL/F, which could be owing to the fact that our youngest patient was 6 months old, whereas rapid pharmacokinetic maturation tends to occur in the neonatal to early infant age group [12]. The gastro-resistant tablet formulation has been widely reported to have improved bioavailability over the suspension [21][22][23][24]. In addition, suspension bioavailability has previously been reported to be saturable in adults [25][26][27][28], although we are not aware of this relationship having previously been modelled using the population approach.…”

Posaconazole Plasma Concentrations on Days Three to Five Predict Steady-State Levels

“…3B) and 0.868 mg · h/liter (95% CI, 0.743 to 0.993 mg · h/liter) for predicting satisfactory PPCs at late steady state. This is the largest study to date that explores pre-steady-state (11). In contrast to what was done in our study, a significant proportion of patients in the study by Durani et al received PCZ delayed-release tablets, which may not only explain the higher PPCs obtained in that study but also indicate that accumulation of PCZ may be an important factor in patients with very high PPCs at pre-steady state.…”

“…(1)(2)(3)(4)(5)(6) and is currently approved for antifungal prophylaxis in patients with prolonged neutropenia and in patients with acute graft-versus-host diseases (GVHDs) after hematopoietic stem cell transplantation (HSCT) (7)(8)(9)(10). PCZ is available as an oral suspension and lately also as a delayed-release tablet formulation and an intravenous formulation (11)(12)(13). Due to the potentially lower costs and easier intake than for the delayed-release tablet, the oral suspension remains in use for antifungal prophylaxis (14).…”