Evaluation of an alternative posaconazole prophylaxis regimen in haematological malignancy patients receiving concomitant stress ulcer prophylaxis

Ross, Ashley; Slain, Douglas; Cumpston, Aaron; Bryant, Alexander M.; Hamadani, Mehdi; Craig, Michael

doi:10.1016/j.ijantimicag.2012.09.001

Cited by 14 publications

(14 citation statements)

References 14 publications

(52 reference statements)

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“…C ss values of Ͻ500 ng/ml were reported in several cases with this regimen by various authors (in 79.6% of cases [16], in 76.2% of cases [17], and in 44% of cases [18]). Likewise, when considering the threshold of 700 ng/ml, even higher percentages of cases with subtherapeutic C ss values were reported (in 85.2% of cases [16], in 90.5% of cases [17], in 70.3% of cases [19], in 48% of cases [20], and in 20% of cases [21]). Of note, it should not be overlooked that most of those studies considered either patients taking posaconazole alone or those taking it concomitantly with PPIs or with H 2 antagonists (22), which are known to impair the posaconazole absorption rate.…”

Section: Discussionmentioning

confidence: 66%

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

Cojutti

Candoni

Simeone

et al. 2013

Antimicrob Agents Chemother

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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 ...

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Section: Discussionmentioning

confidence: 66%

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

Cojutti

Candoni

Simeone

et al. 2013

Antimicrob Agents Chemother

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“…The most commonly used time point is serum trough concentrations. For purposes of our analysis, we chose to evaluate 4-hour concentrations in our tablet patients, to remain consistent with our previous reports of the suspension formulation [9, 15] and allow direct comparison between the two groups. Considering the long half-life of posaconazole, we do not expect to see significant variations between these time points, but there is limited data to describe this variability.…”

Section: Discussionmentioning

confidence: 99%

“…Substantial differences in absorption and bioavailability between these two formulations may result in variability in serum posaconazole concentrations. As demonstrated in several studies, bioavailability and gastrointestinal absorption of PCZ-susp are variable and affected by factors such as concomitant acid suppression therapy and enteral intake [4–9]. In contrast, PCZ-tab has demonstrated improved oral bioavailability.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Serum Posaconazole Concentrations in Patients with Hematological Malignancies Receiving Posaconazole Suspension Compared to the Delayed-Release Tablet Formulation

Belling

Kanate

Shillingburg

et al. 2017

Leukemia Research and Treatment

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Posaconazole (PCZ) is frequently used for prophylaxis against invasive fungal infections (IFI) in patients undergoing induction chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Posaconazole is commercially available as an oral suspension (PCZ-susp) and as a delayed-release tablet (PCZ-tab). Differences in absorption and bioavailability between these formulations may result in variability in serum posaconazole concentrations. The primary objective of this retrospective analysis was to compare attainment of goal serum posaconazole steady state concentrations (Css) ≥ 700 ng/ml in patients with AML/MDS undergoing induction chemotherapy receiving PCZ-susp 600–800 mg per day (N = 118) versus PCZ-Tablet 300 mg twice daily for one day, followed by 300 mg daily (N = 64). Sixty-two patients (97%) in the PCZ-tab group compared to 20 patients (17%) in the PCZ-susp group achieved goal Css (P < 0.0001). Median posaconazole serum Css was 1,665 ng/ml (522–3,830 mg/ml) in the PCZ-tab group versus 390 ng/ml (51–1,870 ng/ml) in the PCZ-susp group (P < 0.0001). There was no difference in hepatotoxicity, QTc prolongation, or breakthrough IFI. Patients receiving PCZ-tab were significantly more likely to achieve goal Css and demonstrated higher Css versus patients receiving PCZ-susp. Prospective studies are needed to assess the potential correlation of serum concentrations with efficacy and toxicity.

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“…Oral formulations of PCZ are commercially available as a suspension (PCZ-susp) and as delayed-release tablets (PCZ-tab) (1). Several studies have shown that the gastrointestinal absorption and bioavailability of PCZ-susp are unpredictable and dependent on various factors, including food intake and concomitant acid suppressants (2)(3)(4)(5)(6)(7). Due to its superior oral bioavailability, the PCZ-tab can be administered without regard to food intake and seems less likely to be affected by concomitant acid-suppressing medications (8)(9)(10)(11).…”

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confidence: 99%

Superior Serum Concentrations with Posaconazole Delayed-Release Tablets Compared to Suspension Formulation in Hematological Malignancies

Cumpston

Caddell

Shillingburg

et al. 2015

Antimicrob Agents Chemother

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d Posaconazole (PCZ), approved for prophylaxis against invasive fungal disease in high-risk patients, is commercially available orally as a suspension formulation (PCZ-susp) and as a delayed-release tablet (PCZ-tab). We evaluated the serum steady-state concentrations (C ss ) of PCZ stratified by the administered formulation for antifungal prophylaxis in patients with myeloid malignancies (n ‫؍‬ 150). The primary outcome was the attainment rate of the target C ss of >700 ng/ml. Secondary outcomes included toxicity assessment (hepatotoxicity and corrected QT [QTc] interval prolongation) and breakthrough fungal infections. Patients who received the PCZ-susp (n ‫؍‬ 118) or PCZ-tab (n ‫؍‬ 32) and had PCZ C ss assessment after at least 7 days of therapy were eligible. The median C ss in the PCZ-susp group was 390 ng/ml (range, 51 to 1,870 ng/ml; mean, 436 ng/ml) compared to 1,740 ng/ml (range, 662 to 3,350 ng/ml; mean, 1,781 ng/ml) in the PCZ-tab group (P < 0.0001). The percentages of patients achieving the target goal of >700 ng/ml were 17% versus 97%, respectively (P < 0.0001). Hepatotoxicity (grade 2 or higher) occurred in 1 patient in each group. QTc interval measurements were available for 32 patients in the PCZ-susp group and for 12 patients in the PCZ-tab group, and prolonged intervals of grade 2 or higher were noted in 9% (n ‫؍‬ 3) and 17% (n ‫؍‬ 2), respectively (P ‫؍‬ 0.6). Breakthrough fungal infections in the PCZ-susp and PCZ-tab groups were 7% (n ‫؍‬ 8) and 3% (n ‫؍‬ 1), respectively (P ‫؍‬ 0.68). We conclude that the use of PCZ-tab was associated with higher C ss and with the probability of achieving therapeutic goals without worsening of adverse effects. P osaconazole (PCZ) is a triazole antifungal agent that is approved for invasive fungal disease prophylaxis in high-risk patients. Oral formulations of PCZ are commercially available as a suspension (PCZ-susp) and as delayed-release tablets (PCZ-tab) (1). Several studies have shown that the gastrointestinal absorption and bioavailability of PCZ-susp are unpredictable and dependent on various factors, including food intake and concomitant acid suppressants (2-7). Due to its superior oral bioavailability, the PCZ-tab can be administered without regard to food intake and seems less likely to be affected by concomitant acid-suppressing medications (8-11).PCZ concentrations follow dose-dependent pharmacokinetics at steady state with saturation of absorption of the PCZ-susp occurring at 800 mg/day (12). The current guidelines recommend as a goal steady-state concentrations (C ss ) of Ն700 ng/ml in the prophylaxis setting (13). Comparative studies evaluating the PCZsusp and the newer PCZ-tab are not available. Herein, we report a retrospective analysis comparing the serum concentrations of the two formulations. MATERIALS AND METHODSPatient population. For this study, 152 consecutive patients with acute myelogenous leukemia (AML) or high-grade myelodysplastic syndrome (MDS) who were admitted to the inpatient hematologic malignancy service at West Virginia Unive...

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Evaluation of an alternative posaconazole prophylaxis regimen in haematological malignancy patients receiving concomitant stress ulcer prophylaxis

Cited by 14 publications

References 14 publications

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

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

Evaluation of Serum Posaconazole Concentrations in Patients with Hematological Malignancies Receiving Posaconazole Suspension Compared to the Delayed-Release Tablet Formulation

Superior Serum Concentrations with Posaconazole Delayed-Release Tablets Compared to Suspension Formulation in Hematological Malignancies

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