Retrospective analysis of goal drug level attainment of posaconazole for invasive fungal infection prophylaxis in patients with acute myeloid leukemia pre- and post-switch to tablet formulation

Liebenstein, Tyler; Widmer, Kristin M; Fallon, Michael J.

doi:10.1177/1078155217722405

Cited by 16 publications

(6 citation statements)

References 12 publications

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“…These results are in line with several studies in patients with hematological/oncological underlying diseases reaching these targeted exposure ranges (Cornely et al, 2016;Cumpston et al, 2015;Jeong et al, 2016;Pham et al, 2016). Nevertheless, the rate of patients who achieved the targeted posaconazole serum levels at steady state is comparable to a study by Miceli et al (2015), but lower compared to other published data (Durani et al, 2015;Liebenstein et al, 2018). Another study by Chin et al reported a rate of only 44% of patients who reached stable posaconazole serum levels 1,000 mg/L in antifungal therapy, whereby outcome was unfortunately not reported (Chin et al, 2017).…”

Section: Discussionsupporting

confidence: 89%

Intravenous and tablet formulation of posaconazole in antifungal therapy and prophylaxis: A retrospective, non-interventional, multicenter analysis of hematological patients treated in tertiary-care hospitals

Heimann

Penack

Heinz

et al. 2019

International Journal of Infectious Diseases

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Objectives: Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness. Methods: We set up a web-based registry on www.ClinicalSurveys.net for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively. Results: Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 -03/2016 were observed. Median age was 58 years (range: 19 -77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 mg/L (IQR 573-1,498 mg/L) and 904 mg/L (IQR 728-1,550 mg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86%. The median overall duration of POS therapy was 18 days (IQR: 7 -23 days). Fourteen patients (48%) had progressive IFD under POS therapy, of these five patients (36%) died related to or likely related to IFD. Conclusions: Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species.

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Section: Discussionsupporting

confidence: 89%

Intravenous and tablet formulation of posaconazole in antifungal therapy and prophylaxis: A retrospective, non-interventional, multicenter analysis of hematological patients treated in tertiary-care hospitals

Heimann

Penack

Heinz

et al. 2019

International Journal of Infectious Diseases

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“…Oral absorption of POS oral suspension is affected by food and gastric pH. In contrast, POS tablets contain the active drug mixed with a pH‐sensitive polymer and this polymer releases the drug in the intestines, causing threefold increased exposures compared to POS oral suspension …”

Section: Introductionmentioning

confidence: 99%

“…In contrast, POS tablets contain the active drug mixed with a pH-sensitive polymer 10 and this polymer releases the drug in the intestines, causing threefold increased exposures compared to POS oral suspension. 11 Therapeutic drug monitoring (TDM) has been widely implemented to assess therapeutic efficacy of POS oral suspension but its usefulness is in a state of flux following the introduction of the new POS formulations specifically in the setting of prophylaxis. [12][13][14] Current guidelines recommend a Ctrough concentration of ≥0.7 mg/L for prophylaxis and >1.0 mg/L for primary and >1.25 mg/L for salvage therapy, 15 although these concentrations were determined independent of the susceptibility of the infecting pathogen.…”

Section: Introductionmentioning

confidence: 99%

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

Schauwvlieghe

Buil

Verweij

et al. 2019

Mycoses

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Summary Background Oral follow‐up therapy is problematic in moulds with reduced azole‐susceptibility, such as azole‐resistant Aspergillus fumigatus infection. Currently, only intravenous liposomal amphotericin B (L‐AmB) is advocated by guidelines for the treatment of azole‐resistant aspergillosis infections. Preclinical research indicates that high‐dose posaconazole (HD‐POS) might be a feasible option provided that high drug exposure (ie POS serum through levels >3 mg/L) can be achieved and is safe. Objectives To describe our experience with the use of oral HD‐POS as treatment strategies for patients infected with pathogens with a POS MIC close to the clinical breakpoint. Patients/Methods We review evidence supporting the use of HD‐POS and describe our experience on safety and efficacy in 16 patients. In addition, we describe the adverse events (AE) observed in 25 patients with POS concentrations at the higher end of the population distribution during treatment with the licensed dose. Results Sixteen patients were treated intentionally with HD‐POS for voriconazole‐resistant invasive aspergillosis (7/16), mucormycosis (4/16), salvage therapy for IA (4/16) and IA at a sanctuary site (spondylodiscitis) in 1. Grade 3‐4 AEs were observed in 6, and all of them were considered at least possibly related. Grade 3‐4 AEs were observed in 5 of the 25 patients with spontaneous high POS serum through levels considered at least possibly related using Naranjo scale. Conclusions High‐dose posaconazole is a treatment option if strict monitoring for both exposure and for AE is possible.

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“…The prevalence of patients with posaconazole C avg or trough concentrations (C min ) of Ͻ700 ng/ml reported in observational TDM studies with posaconazole tablets varies widely. A number of early observational studies reported that between 0% and 10% of patients did not achieve C avg or C min above 700 ng/ml (21)(22)(23)(24)(25)(26)(27)(28)(29), similar to the phase III posaconazole registration trials (14,30). Other studies have reported rates of posaconazole C min below 700 ng/ml, ranging from 10% to 20% of patients (16,19,31,32).…”

Section: Discussionmentioning

confidence: 83%

Using State Transition Models To Explore How the Prevalence of Subtherapeutic Posaconazole Exposures Impacts the Clinical Utility of Therapeutic Drug Monitoring for Posaconazole Tablets and Oral Suspension

Lewis

Kontoyiannis

Viale

et al. 2019

Antimicrob Agents Chemother

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Therapeutic drug monitoring (TDM) has been recommended in guidelines for patients receiving posaconazole oral suspension, but its utility in patients receiving posaconazole tablet, which has an improved bioavailability, remains unclear. We used state transition models with first-order Monte Carlo microsimulation to re-examine the posaconazole exposure-response relationships reported in two phase III clinical trials (prophylaxis with posaconazole oral suspension, models 1 and 2) and a third multicenter observational TDM study (model 3). We simulated the impact of TDM-guided interventions to improve initial average posaconazole concentrations (Cavg) to reduce clinical failure (in models 1 and 2) and breakthrough invasive fungal disease (bIFD) in model 3. Simulations were then repeated using posaconazole tablet Cavg distributions in place of the oral suspension formulation. In all three models with posaconazole oral suspension, TDM interventions associated with maximal improvement in posaconazole Cavg reduced absolute rates of subtherapeutic exposures (Cavg < 700 ng/ml) by 25% to 49%. Predicted reductions in absolute clinical failure rates were 11% in model 1 and 6.5% in model 2 and a 12.6% reduction in bIFD in model 3. With the tablet formulation, maximally effective TDM interventions reduced subtherapeutic exposures by approximately 5% in all three models and absolute clinical failure rates by 3.9% in model 1 and 1.6% in model 2; there was a 1.6% reduction in bIFD in model 3. Our modeling suggests that routine TDM during prophylaxis with posaconazole tablets may have limited clinical utility unless populations with higher prevalence (>10%) of subtherapeutic exposures can be identified based on clinical risk factors.

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Retrospective analysis of goal drug level attainment of posaconazole for invasive fungal infection prophylaxis in patients with acute myeloid leukemia pre- and post-switch to tablet formulation

Abstract: Patients receiving posaconazole tablets attained significantly higher serum drug levels than those receiving suspension.

Cited by 16 publications

References 12 publications

Intravenous and tablet formulation of posaconazole in antifungal therapy and prophylaxis: A retrospective, non-interventional, multicenter analysis of hematological patients treated in tertiary-care hospitals

Intravenous and tablet formulation of posaconazole in antifungal therapy and prophylaxis: A retrospective, non-interventional, multicenter analysis of hematological patients treated in tertiary-care hospitals

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

Using State Transition Models To Explore How the Prevalence of Subtherapeutic Posaconazole Exposures Impacts the Clinical Utility of Therapeutic Drug Monitoring for Posaconazole Tablets and Oral Suspension

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