Pharmacokinetics and Concentration-Dependent Efficacy of Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis

Petraitis, Vidmantas; Petraitienė, Rūta; Moradi, Patriss W.; Strauss, Gittel E.; Katragkou, Aspasia; Kovanda, Laura; Hope, William; Walsh, Thomas J.

doi:10.1128/aac.02665-15

Cited by 40 publications

(18 citation statements)

References 27 publications

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“…Little data are available to support TDM for ISA, even if TDM may be informative in cases of treatment failure, drug-drug interaction [21], or suspected toxicity [5,32,36]. Our bioassay confirmed the exposure-efficacy relationship for ISA, both on A. fumigatus and C. paraspilosis, consistent with previous results obtained in vivo (both in an animal model [18] and humans [17]) and in vitro [19]. Conversely, the most comprehensive study conducted to date on patients treated with ISA and followed by TDM did not show any relationship between ISA exposure and its efficacy or safety [20].…”

Section: Discussionsupporting

confidence: 89%

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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Section: Discussionsupporting

confidence: 89%

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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“…Isavuconazole in vitro demonstrates superior hyphal growth inhibition and MICs against A. fumigatus in comparison to the hyphal growth inhibition and MICs of voriconazole (28)(29)(30)(31). The pharmacodynamics and efficacy of isavuconazole as a single agent were explored in a model of IPA in neutropenic mice by Lepak and colleagues (32), in a model of disseminated aspergillosis in immunocompetent mice by Seyedmousavi et al (33), and in a model of invasive pulmonary aspergillosis in persistently neutropenic rabbits (14,34).…”

Section: Figmentioning

confidence: 99%

Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis

Petraitis

Petraitienė

McCarthy

et al. 2017

Antimicrob Agents Chemother

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Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in immunocompromised patients. We hypothesized that simultaneous inhibition of biosynthesis of ergosterol in the fungal cell membrane and (1→3)-β-d-glucan in the cell wall, respectively, by the antifungal triazole isavuconazole (ISA) and the echinocandin micafungin (MFG) may result in improved outcomes in experimental IPA in persistently neutropenic rabbits. Treatments included ISA at 20 mg/kg of body weight/day (ISA20), 40 mg/kg/day (ISA40), and 60 mg/kg/day (ISA60); MFG at 2 mg/kg/day (MFG2); combinations of ISA20 and MFG2, ISA40 and MFG2, and ISA60 and MFG2; and no treatment (untreated controls [UC]). The galactomannan index (GMI) and (1→3)-β-d-glucan levels in serum were measured. The residual fungal burden (number of CFU per gram) was significantly reduced in ISA20-, ISA40-, ISA60-, ISA20-MFG2-, ISA40-MFG2-, and ISA60-MFG2-treated rabbits compared with that in MFG2-treated or UC rabbits ( < 0.01). Measures of organism-mediated pulmonary injury, lung weights, and pulmonary infarct score were lower in ISA40-MFG2-treated rabbits than in rabbits treated with ISA40 or MFG2 alone ( < 0.01). Survival was prolonged in ISA40-MFG2-treated rabbits in comparison to those treated with ISA40 or MFG2 alone ( < 0.01). These outcome variables correlated directly with significant declines in GMI and serum (1→3)-β-d-glucan levels during therapy. The GMI correlated with measures of organism-mediated pulmonary injury, lung weights ( = 0.764; < 0.001), and pulmonary infarct score ( = 0.911; < 0.001). In summary, rabbits receiving combination therapy with isavuconazole and micafungin demonstrated a significant dose-dependent reduction in the residual fungal burden, decreased pulmonary injury, prolonged survival, a lower GMI, and lower serum (1→3)-β-d-glucan levels in comparison to rabbits receiving isavuconazole or micafungin as a single agent.

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“…However, the two higher doses of ISA (40 and 60 mg/kg/day were significantly better than both voriconazole (15 mg/kg) and controls [50]. Box et al [51] conducted an in vitro pharmacodynamic study of ISA for invasive pulmonary aspergillosis by using a dynamic model of the human alveolus (consisting of a cellular bilayer of human pulmonary arterial endothelial cells and human alveolar epithelial cells against A. fumigatus isolates (MICs 1 --4 µg/ml)).…”

Section: In Vivo Studiesmentioning

confidence: 75%

The ‘cephalosporin era’ of triazole therapy: isavuconazole, a welcomed newcomer for the treatment of invasive fungal infections

Chitasombat¹,

Kontoyiannis²

2015

Expert Opinion on Pharmacotherapy

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ISA is a new broad spectrum triazole antifungal for the treatment of invasive fungal disease available as oral and intravenous formulations, and the ability to be administered as a once-daily regimen. ISA has broad-spectrum in vitro activity, favorable pharmacokinetic profile, and good tolerability. ISA may be considered for primary treatment for a vast variety of invasive fungal infections. Further study of ISA given as prophylaxis, combination, or salvage therapy is warranted.

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Pharmacokinetics and Concentration-Dependent Efficacy of Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis

Cited by 40 publications

References 27 publications

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

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

Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis

The ‘cephalosporin era’ of triazole therapy: isavuconazole, a welcomed newcomer for the treatment of invasive fungal infections

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