Pharmacokinetics and safety results from the Phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease

Cornely, Oliver A.; Robertson, Michael; Haider, Shariq; Grigg, Andrew; Geddes, Michelle; Aoun, Mickaël; Heinz, Werner; Raad, Issam; Schanz, Urs; Meyer, Ralf G.; Hammond, Sarah P.; Mullane, Kathleen M.; Ostermann, Helmut; Ullmann, Andrew J.; Zimmerli, Stefan; Iersel, M.L.P.S. van; Hepler, Deborah A.; Waskin, Hetty; Kartsonis, Nicholas A.; Maertens, Johan

doi:10.1093/jac/dkx263

Cited by 62 publications

(42 citation statements)

References 23 publications

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“…Very recently, PK and safety results from a phase 3 study of IV POS in patients at risk for invasive fungal disease were published. Six per cent of the patients had a steady‐state concentration between >2.5 and ≤3.65 mg/L without signs of toxicity . In a retrospective analysis of 64 patients receiving POS tablet as prophylaxis, median POS steady‐state concentrations of 1.67 mg/L (0.52‐3.83 mg/L) were documented.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Intravenous doses above 300 mg were not investigated. The exposure of these two new formulations still shows substantial interpatient variability [31][32][33][34].…”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

“…Posaconazole exposure after administration of the oral suspension in healthy volunteers is about two to three times higher compared to hematological patients [42]. The steadystate exposures of posaconazole after administration of the delayed-release tablet or intravenous formulation are similar in patients with AML/MDS/HSCT, but are significantly higher than exposures achieved through administration of the suspension [32,34,[75][76][77]. The variability in posaconazole average concentration (C avg ) upon administration of the oral suspension in patients with AML/MDS/HSCT is relatively high, ranging from 57 to 68% [75,76].…”

Section: Posaconazole Descriptive Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Posaconazole

Chen

Krekels

Verweij

et al. 2020

Drugs

109

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Posaconazole is typically used for preventing invasive yeast and mold infections such as invasive aspergillosis in high-risk immunocompromised patients. The oral suspension was the first released formulation and many pharmacokinetic and pharmacodynamic studies of this formulation have been published. Erratic absorption profiles associated with this formulation were widely reported. Posaconazole exposure was found to be significantly influenced by food and many gastrointestinal conditions, including pH and motility. As a result, low posaconazole plasma concentrations were obtained in large groups of patients. These issues of erratic absorption urged the development of the subsequently marketed delayed-release tablet, which proved to be associated with higher and more stable exposure profiles. Shortly thereafter, an intravenous formulation was released for patients who are not able to take oral formulations. Both new formulations require a loading dose on day 1 to achieve high posaconazole concentrations more quickly, which was not possible with the oral suspension. So far, there appears to be no evidence of increased toxicity correlated to the higher posaconazole exposure achieved with the regimen for these formulations. The higher systemic availability of posaconazole for the delayed-release tablet and intravenous formulation have resulted in these two formulations being preferable for both prophylaxis and treatment of invasive fungal disease. This review aimed to integrate the current knowledge on posaconazole pharmacokinetics, pharmacodynamics, major toxicity, existing resistance, clinical experience in special populations, and new therapeutic strategies in order to get a clear understanding of the clinical use of this drug.

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“…Over the past few years, the therapeutic arsenal for invasive fungal infections (IFI) has expanded, especially for triazole antifungals. In addition to oral suspension, two new galenic formulations of posaconazole (POS) have been recently approved, consisting of a delayed‐release tablet and a powder for intravenous infusion . A new drug, isavuconazole (ISA), which is the active moiety of the water‐soluble prodrug isavuconazonium sulfate, is available in oral and intravenous forms for the treatment of mucormycosis and invasive aspergillosis .…”

Section: Introductionmentioning

confidence: 99%

“…The new tablet formulation makes it possible to reach higher POS C min values than for the oral suspension . This greater POS C min could theoretically result in a greater risk of side effects, although no study has yet clearly highlighted increased toxicity with the POS tablet formulation . Hence, no upper threshold for the POS C min has yet been proposed, even if some authors have suggested that dose reduction could be feasible for at least half of patients .…”

Section: Introductionmentioning

confidence: 99%

Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

Willeman¹,

Tonini²,

Garnaud

et al. 2019

Fundamemntal Clinical Pharma

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Therapeutic drug monitoring (TDM) of antifungal triazole was recommended, except for isavuconazole (ISA) whose target trough concentrations (Cmin) need to be specified. Concerning posaconazole (POS), tablet formulation results in higher exposure but no upper Cmin threshold has been yet proposed. We aimed to investigate the pharmacokinetic–pharmacodynamic relationship of POS and ISA, using a bioassay approach as surrogate marker of antifungal activity, in order to refine the therapeutic Cmin of both antifungals. A bioassay using a cellulose disk diffusion method was performed to determine the growth inhibition zone (GIZ) of POS and ISA on Aspergillus fumigatus and Candida parapsilosis (ISA only). GIZs of plasma from patients undergoing TDM for POS (n = 136) or ISA (n = 40) were determined. GIZs of plasma patients and antifungal Cmin were highly correlated for ISA (A. fumigatus: ρ = 0.942, P < 0.0001; C. parapsilosis: ρ = 0.949, P < 0.0001) and POS (ρ = 0.922, P < 0.0001), and these relationships were represented with a Michaelis–Menten model. Based on this modeling, the recommended thresholds of 0.7, 1, and 1.25 mg/L for the POS Cmin corresponded to 50.1, 55.2, and 59.1% of the maximal GIZ, respectively. We propose an upper threshold of 4.8 mg/L for the POS Cmin and a lower threshold of 2.0 mg/L for the Cmin of ISA, as they respectively corresponded to concentrations leading to 90% and 50% of the maximal GIZ on A. fumigatus. The determination of antifungal activity using this bioassay allowed refining target Cmin of POS and ISA, especially the upper threshold of POS (4.8 mg/L) and the lower threshold of ISA (2.0 mg/L).

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Pharmacokinetics and safety results from the Phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease

Abstract: ClinicalTrials.gov, NCT01075984.

Cited by 62 publications

References 23 publications

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

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

Pharmacokinetics and Pharmacodynamics of Posaconazole

Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

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