Remarkably efficient inhaled antifungal monotherapy for invasive pulmonary aspergillosis: Figure 1–

Hilberg, Ole; Andersen, Charlotte Uggerhøj; Henning, Ole; Lundby, Tim; Mortensen, Jann; Bendstrup, Elisabeth

doi:10.1183/09031936.00163511

Cited by 39 publications

(36 citation statements)

References 10 publications

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“…The finding of roughly 8 times higher concentrations in ELF than in plasma after oral administration are consistent with the results of a previous study in human beings after intravenous administration . However, due to the effectiveness of the inhaled 40‐mg dose that was previously observed , it was expected that the concentrations of voriconazole in ELF after inhalation would be closer to the ELF concentrations after oral ingestion. Even though there was a tendency for the ELF/plasma ratio to be higher after inhalation, it was not significant.…”

Section: Discussionsupporting

confidence: 91%

Voriconazole Concentrations in Plasma and Epithelial Lining Fluid after Inhalation and Oral Treatment

Andersen

Sønderskov

Bendstrup

et al. 2017

Basic Clin Pharma Tox

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Adverse effects can compromise oral voriconazole treatment of pulmonary aspergillosis. Inhaled low-dose voriconazole may be an alternative treatment. In this study, six patients inhaled 40 mg voriconazole b.i.d. for 2 days, and six patients ingested 400 and 200 mg orally b.i.d. on day one and two, respectively. Blood samples were collected after the first inhalation, and bronchial alveolar lavage fluids and blood samples were collected for measurements of voriconazole 12 hr after the last administration. The concentration of voriconazole in epithelial lining fluid (ELF) was calculated by the urea dilution method. Voriconazole concentrations were detectable in plasma 15 min. after inhalation and declined at 30 and 60 min. Twelve hours after the last dose, median (95% CI) plasma voriconazole concentration was 8 (4-26) ng/mL in the inhalation group and 1224 (535-2341) ng/mL in the oral group (p < 0.0001). In ELF, median concentration was 190 (55-318) ng/mL and 8827 (4369-35172) ng/mL, respectively (p < 0.0001). Median ELF/plasma concentration ratio was 21 (6-63) in the inhalation group and 8 (3-20) in the oral group (p = 0.2). In conclusion, voriconazole is rapidly absorbed into the systemic circulation after inhalation. There was a non-significant trend towards a higher ELF/plasma concentration ratio in the inhalation group compared to the oral group.

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Section: Discussionsupporting

confidence: 91%

Voriconazole Concentrations in Plasma and Epithelial Lining Fluid after Inhalation and Oral Treatment

Andersen

Sønderskov

Bendstrup

et al. 2017

Basic Clin Pharma Tox

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“…As a clinical strategy, topical treatment of the lung is advantageous over oral or intravenous therapy because it delivers high concentrations of an antifungal agent directly to the site of infection and avoids unfavorable systemic side effects. The benefits of inhaled administration for the treatment of invasive pulmonary aspergillosis have been shown in numerous studies involving amphotericin B, itraconazole, and voriconazole (30–32). …”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Antifungal Profile of a Novel and Long-Acting Inhaled Azole, PC945, on Aspergillus fumigatus Infection

Colley¹,

Alanio

Kelly

et al. 2017

Antimicrob Agents Chemother

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The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tightly binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [IC50s], 0.23 μM and 0.22 μM, respectively) with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032 to >8 μg/ml, while those of voriconazole ranged from 0.064 to 4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth yielded IC50 (determined based on optical density [OD]) values of 0.0012 to 0.034 μg/ml, whereas voriconazole (0.019 to >1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (with MICs ranging from 0.0078 to 2 μg/ml), including Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae (1 or 2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945 and then washed, PC945 was found to be absorbed quickly into both target and nontarget cells and to produce persistent antifungal effects. Among temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at 14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.

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“…Moreover, the molecule is retained within the lung, resulting in low systemic exposure after oral and face mask nebulization in a phase 1 study (NCT02715570) (40) (in preparation). Although patients have been treated with voriconazole by nebulization successfully (27), it required frequent dosing at extremely high doses due to its short duration of action in the lung and rapid systemic exposure after nebulization (27,28). Voriconazole's short pharmacodynamic duration of action in the lung relative to PC945 probably contributed to the relative antifungal activities seen here, where a once daily regimen was used.…”

Section: Discussionmentioning

confidence: 93%

“…Tolman and colleagues have demonstrated that prophylaxis with an aerosolized aqueous intravenous formulation of voriconazole significantly improved survival and limited the extent of invasive disease, as assessed by histopathology, in an invasive pulmonary murine model (26). In human studies, aerosolization of voriconazole showed beneficial effects but it required frequent and high doses as voriconazole was not optimised as an inhaled medicine (27,28).…”

Section: Introductionmentioning

confidence: 99%

Antifungal effects of PC945, a novel inhaled triazole, onCandida albicans-infected immunocompromised mice

Nishimoto

Ito

Kimura

et al. 2020

Preprint

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Although Candida spp. are frequently detected in fungal cultures of respiratory secretions, their presence is normally assumed to reflect benign colonization. However, there is growing evidence that Candida spp. are involved in the pathogenesis of respiratory diseases such as bronchiectasis and asthma. The aim of this study is to investigate the in vitro and in vivo effects of a novel antifungal triazole, PC945, optimised for topical delivery, against C. albicans. In temporarily neutropenic, immunocompromised mice, C. albicans (529L [ATCC®MYA4901™] strain), inoculated intranasally, induced acute lung injury and death, associated with higher fungal burden and cytokine induction in the lung. PC945 saline suspension, dosed intranasally once daily, starting one day post candida inoculation, dose-dependently (0.56 ~ 14 μg/mouse) improved survival rate and inhibited fungal load in the lung on Day 5 post inoculation. These effects by PC945 were 7 ~ 25-fold more potent than those of voriconazole, despite being of similar in vitro antifungal activity versus this strain. Furthermore, extended prophylaxis with low dose PC945 (0.56 μg/mouse) was found to inhibit fungal load more potently than the shorter treatment regimens, suggesting antifungal effects of PC945 accumulated on repeat dosing. In addition, antifungal susceptibility testing on 88 candida isolates (C. albicans, C. parapsilosis, C. tropicalis, C. lucitaniae, C. glabrata, C. guilliermondii) revealed that PC945 has potent effects on Candida species broadly. Thus, PC945 has the potential to be a novel topical therapy for the treatment of C. albicans pulmonary infection in humans.

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Remarkably efficient inhaled antifungal monotherapy for invasive pulmonary aspergillosis: Figure 1–

Cited by 39 publications

References 10 publications

Voriconazole Concentrations in Plasma and Epithelial Lining Fluid after Inhalation and Oral Treatment

Voriconazole Concentrations in Plasma and Epithelial Lining Fluid after Inhalation and Oral Treatment

In Vitro and In Vivo Antifungal Profile of a Novel and Long-Acting Inhaled Azole, PC945, on Aspergillus fumigatus Infection

Antifungal effects of PC945, a novel inhaled triazole, onCandida albicans-infected immunocompromised mice

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