Antifungal Prophylaxis with Posaconazole in Patients with Acute Myeloid Leukemia: Dose Intensification Coupled with Avoidance of Proton Pump Inhibitors Is Beneficial in Shortening Time to Effective Concentrations

Abstract

Posaconazole is a second-generation triazole antifungal agent with a broad spectrum (1) that is currently licensed for prophylaxis in hematological patients at high risk of invasive fungal infections (2, 3).Rapid attainment of effective posaconazole concentrations during the neutropenic phase may be of paramount importance, considering that this is the most vulnerable period for mold infections in hematological patients (4). Unfortunately, the currently available oral formulation of posaconazole has an unpredictable pharmacokinetic behavior, and therapeutic drug monitoring (TDM) of trough plasma concentrations (C min ) is being increasingly advocated for guidance of appropriate drug exposure with posaconazole over time (5-7).As far as the therapeutic range for posaconazole is concerned, some authors suggest a C min of Ͼ500 ng/ml as a target threshold (8), whereas others found evidence to support a more conservative C min of Ͼ700 ng/ml (9), although a definitive threshold is still to be defined. Achievement of the desired threshold with the current posaconazole formulation is quite challenging, considering that several factors were shown to affect its absorption rate (10).Various strategies have been suggested in order to improve its oral bioavailability, among which avoidance of drugs altering gastric acidic pH, taking posaconazole with a high-fat meal, and increase of dose frequency are considered the most clinically relevant (11). Of note, these approaches are not always simultaneously feasible for the same patient, and what remains to be answered is the role that these approaches may have in shortening the time to therapeutically relevant concentrations in daily clinical practice.The aim of this study was to assess the relative influence that dose frequency and the presence or absence of cotreatment with proton pump inhibitors (PPIs) had on the time to a target C min of Ͼ700 ng/ml in a population of hematological patients who received posaconazole prophylaxis after induction chemotherapy for acute myeloid leukemia. MATERIALS AND METHODSStudy design. This was an observational study which involved adult patients with acute myeloid leukemia who underwent antifungal prophylaxis with posaconazole in the period between August 2009 and November 2010 after receiving induction chemotherapy at the hematologic clinic of our university teaching hospital. During this period, posaconazole prophylaxis was carried out with 2 dosing regimens at the physician's discretion, namely, 200 mg every 8 h (q8h) or 200 mg q6h, with the latter regimen usually being preferred in cases of very severe neutropenia. Concomitant use of PPIs was discouraged as much as possible.Only patients who had at least three subsequent C min assessments during the first 8 days of treatment according to our routine TDM program were considered feasible for this study. Blood samples for TDM were collected immediately before the morning administration and after centrifuged plasma samples were analyzed by means of a validated liquid chromatography-tandem mass ...

Pharmacologic and clinical evaluation of posaconazole

“…Because the posaconazole oral suspension formulation is more readily absorbed at a lower pH, proton pump inhibitors and cimetidine have been shown to decrease the area under the curve of posaconazole [7,43]. Other histamine H 2 receptor antagonists and antacids had no effect on the area under the curve.…”

How we treat invasive fungal diseases in patients with acute leukemia: the importance of an individualized approach

“…Different interactions with triazoles must be considered, 104 and consultation with a pharmacist is recommended. 1) Interactions in which triazoles affect other drugs, 108 requiring monitoring for clinical toxicity and toxic-range blood levels (eg, all-trans-retinoic acid, etoposide, vincristine, 109 ifosfamide, and cyclophosphamide).…”

“…105 Lower PPCs have been associated with increased IFDs. 104 Compared with oral posaconazole solution, a once-daily tablet significantly improves bioavailability. 106 Posaconazole is now available intravenously.…”

Subtherapeutic Posaconazole Exposure and Treatment Outcome in Patients With Invasive Fungal Disease

“…30 Furthermore, coadministration of posaconazole with a PPI or H 2 -antagonist had a negative effect on the posaconazole concentration, due to a reduced absorption secondary to a decrease in gastric acid production, and was in agreement with earlier studies. 11,12,14,15,31,32 Administration of the posaconazole oral suspension to patients who are unable to eat or use a PPI/H 2 -antagonist should therefore be avoided. The gastro-resistant tablet formulation of posaconazole that recently entered the market 33 or the intravenous formulation 34 that has recently been approved are more suitable for these patients.…”