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

Elst, Kim C. M. van der; Brouwers, Charlie H. S.; Heuvel, Edwin R. van den; Wanrooy, Marjolijn J. P. van; Uges, Donald; Werf, Tjip S. van der; Kosterink, Jos G. W.; Span, L. F. R.; Alffenaar, Jan‐Willem C.

doi:10.1097/ftd.0000000000000235

Cited by 30 publications

(19 citation statements)

References 43 publications

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“…The large number of early levels in this study, however, may help explain the higher proportion of sub-therapeutic levels. When looking at posaconazole levels reported in other studies, the rate of not achieving optimal plasma concentrations varied widely from 20% [ 29 ] to 90% [ 30 ]; however, a majority of the studies report percentages in the range of 20–50% [ 6 , 7 , 21 , 31 – 34 ]. It can be difficult to compare percentages of therapeutic drug measurements across studies due to the differing therapeutic threshold cut-offs, TDM practices, and patient populations at each site.…”

Section: Discussionmentioning

confidence: 99%

“…For both voriconazole and posaconazole, the relationship between efficacy and drug exposure has been established [ 7 , 10 , 11 ]. A voriconazole plasma level of 1.0–5.5 or 1.0–6.0 μg/ml is generally recommended as the goal range for improved outcomes and minimized toxicities [ 11 , 12 ], and a threshold of >0.5–0.7 μg/ml has been recommended as a therapeutic posaconazole concentration [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Voriconazole and posaconazole therapeutic drug monitoring: a retrospective study

Schoeppler

Jaeger

et al. 2017

Ann Clin Microbiol Antimicrob

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BackgroundTherapeutic drug monitoring (TDM) aims to minimize the clinical impact of posaconazole and voriconazole pharmacokinetic variability. However, its benefits on clinical outcomes are still being defined. Additionally, TDM data are limited for posaconazole IV and delayed-release tablet formulations among specific patient populations, including critically ill. The aim of this study was to determine the percentage of therapeutic posaconazole and voriconazole drug levels across all formulations in a real-world clinical setting and elucidate factors affecting attainment of target concentrations.MethodsThis study was a retrospective cohort study conducted at the University of Colorado Hospital between September 2006 and June 2015 that evaluated patients who received posaconazole or voriconazole TDM as part of routine care.ResultsVoriconazole (n = 250) and posaconazole (n = 100) levels were analyzed from 151 patients. Of these, 54% of voriconazole and 69% of posaconazole levels were therapeutic. For posaconazole, 14/38 (37%), 28/29 (97%) and 27/33 (82%) levels were therapeutic for the oral suspension, IV, and delayed-release tablet, respectively. Intravenous and delayed-release tablet posaconazole were 20 fold (p < 0.01) and sevenfold (p = 0.002) more likely than the oral suspension to achieve a therapeutic level. Subsequent levels were more likely to be therapeutic after dose adjustments (OR 3.31; 95% CI 1.3–8.6; p = 0.02), regardless of timing of initial non-therapeutic level. In a multivariable logistic regression analysis, no characteristics were independently predictive of therapeutic voriconazole levels and only absence of H2RA/PPI use was independently predictive of therapeutic posaconazole levels. There was no correlation between survival and therapeutic drug levels for either voriconazole (p = 0.67) or posaconazole (p = 0.50).ConclusionsA high percentage of drug levels did not achieve TDM targets for voriconazole and posaconazole oral suspension, supporting the need for routine TDM for those formulations. The utility of TDM for the IV and delayed-release tablet formulations of posaconazole is less apparent.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Voriconazole and posaconazole therapeutic drug monitoring: a retrospective study

Schoeppler

Jaeger

et al. 2017

Ann Clin Microbiol Antimicrob

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“…24,30 ; the newer oral delayed release tablet formulation has substantially better, and more reliable, absorption than earlier formulations 39,40 A series of studies have shown a relationship between posaconazole levels and efficacy. 54,57,58 While these studies varied in their rigor with respect to TDM methods and definitions of efficacy, the body of data has led to recommendations of target steady-state trough posaconazole concentrations of > 700 ng/mL for prophylaxis and, provisionally, >1250 ng/mL for treatment of invasive fungal disease. 54,59 In a recent study, Cornely et al found that 90% of adult patients taking the newer delayed release tablets for prophylaxis of fungal infections had steady-state trough levels >700 ng/mL and there was no correlation between drug levels and adverse events.…”

Section: Isavuconazonium Sulfatementioning

confidence: 99%

New facets of antifungal therapy

et al. 2016

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Invasive fungal infections remain a major cause of morbidity and mortality in immunocompromised patients, and such infections are a substantial burden to healthcare systems around the world. However, the clinically available armamentarium for invasive fungal diseases is limited to 3 main classes (i.e., polyenes, triazoles, and echinocandins), and each has defined limitations related to spectrum of activity, development of resistance, and toxicity. Further, current antifungal therapies are hampered by limited clinical efficacy, high rates of toxicity, and significant variability in pharmacokinetic properties. New antifungal agents, new formulations, and novel combination regimens may improve the care of patients in the future by providing improved strategies to combat challenges associated with currently available antifungal agents. Likewise, therapeutic drug monitoring may be helpful, but its present use remains controversial due to the lack of available data. This article discusses new facets of antifungal therapy with a focus on new antifungal formulations and the synergistic effects between drugs used in combination therapy.

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“…Previous studies on the use of posaconazole in LTx-patients have mostly been conducted with POS-Liq alone, or included only a small subpopulation of LTx-patients. [28][29][30][31] Our study shows that both posaconazole formulations are a safe and effective option for the prophylaxis of IFIs in LTx-patients. With regards to the treatment of IFIs, POS-Tab appears to be the superior formulation.…”

Section: Discussionmentioning

confidence: 62%

Posaconazole liquid vs tablet formulation in lung transplant recipients

Stelzer

Weber

Ihle

et al. 2017

Mycoses

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Posaconazole is an extended-spectrum triazole antifungal used in the treatment and prophylaxis of Aspergillus infections. It is available as oral suspension (POS-Liq) and delayed-release tablets (POS-Tab). The aim of this longitudinal, retrospective study was to compare the clinical effectiveness, toxicity and pharmacokinetics of POS-Liq vs POS-Tab in lung transplant recipients (LTx-recipients), who were treated with both formulations subsequently. Twenty-four consecutive LTx-recipients with 191 documented posaconazole trough levels (PTLs) for POS-Liq or POS-Tab were included. The administered daily doses were 300 mg for POS-Tab and 600 mg (prophylaxis) or 800 mg (therapy) for POS-Liq. Target PTLs were ≥700 ng/mL (prophylaxis) and ≥1250 ng/mL (therapy). The overall prophylactic and therapeutic response rates were 78% and 67%, respectively. No cases of hepatotoxicity or QT-prolongation were observed with either formulation. The achieved target PTLs were tripled under POS-Tab compared to POS-Liq with fewer risk factors for sub-therapeutic PTLs. Concomitant administration of POS-Tab significantly reduced the tacrolimus concentration-to-dose ratio (P = .001). We suggest the use of POS-Tab is appropriate for prophylaxis and therapy of Aspergillus infections in LTx-recipients, since POS-Tab displayed more reliable PTLs with no added adverse events. However, we recommend regular drug monitoring for POS-Liq and for therapy with POS-Tab and that immunosuppressant levels are monitored closely when the posaconazole formulation is switched.

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

Cited by 30 publications

References 43 publications

Voriconazole and posaconazole therapeutic drug monitoring: a retrospective study

Voriconazole and posaconazole therapeutic drug monitoring: a retrospective study

New facets of antifungal therapy

Posaconazole liquid vs tablet formulation in lung transplant recipients

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