Pharmacodynamics of Isavuconazole in a Dynamic
            <i>In Vitro</i>
            Model of Invasive Pulmonary Aspergillosis

Box, Helen; Livermore, Joanne; Johnson, Adam; McEntee, Laura; Felton, Timothy; Whalley, Sarah; Goodwin, Jonathan; Hope, William

doi:10.1128/aac.01364-15

Cited by 27 publications

(29 citation statements)

References 18 publications

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“…Modest postantifungal effect was observed but should not be relied upon to enhance efficacy. The findings of this study were substantiated by an in vitro model of invasive pulmonary aspergillosis …”

Section: Methodssupporting

confidence: 56%

Isavuconazonium sulfate: a triazole prodrug for invasive fungal infections

et al. 2016

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Objective To review the place in therapy of isavuconazole, the active metabolite of isavuconazonium sulfate, via a review of the available literature on drug chemistry, spectrum of activity, pharmacokinetic/pharmacodynamic profile and trials assessing clinical efficacy and safety. Methods Relevant data, original research articles and reviews, were gathered primarily through the use of a PubMed database search. The search was conducted without date restrictions in order to collect both historical and recent data regarding isavuconazole. Key findings Isavuconazole is a triazole currently approved not only for use in invasive aspergillosis and mucormycosis but also has demonstrable activity against Candida species and other common fungal pathogens. This drug has features which make it more clinically appealing compared to other azoles with similar indications. In specific, isavuconazole does not require a cyclodextrin vehicle due to its water solubility, and at present, does not require therapeutic drug monitoring. Moreover, isavuconazole has displayed improved safety and tolerability compared to voriconazole. Available data from Phase III clinical trials shows isavuconazole to be a possible therapeutic option to currently available therapies for which it is approved; however, clinical conclusions should be reserved until results have been published and more data from clinical use is reported. Conclusions Isavuconazole is a new triazole with broad-spectrum antifungal activity including invasive aspergillosis and mucormycosis.

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Section: Methodssupporting

confidence: 56%

Isavuconazonium sulfate: a triazole prodrug for invasive fungal infections

et al. 2016

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“…Isavuconazole in vitro demonstrates superior hyphal growth inhibition and MICs against Aspergillus fumigatus in comparison to those of voriconazole (10)(11)(12)(13)(14). However, there is a paucity of laboratory animal data for isavuconazole against Aspergillus spp.…”

mentioning

confidence: 99%

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

Petraitis

Petraitienė

Moradi

et al. 2016

Antimicrob Agents Chemother

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We studied the pharmacokinetics and efficacy of the broad-spectrum triazole isavuconazole for the treatment of experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. Treatment started 24 h after endotracheal administration of Aspergillus fumigatus inoculum; study subjects included rabbits receiving orally administered prodrug isavuconazonium sulfate (BAL8557) equivalent to active moiety isavuconazole (ISA; BAL4815) at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg (of body weight)/day, with an initial loading dose of 90 mg/kg (ISA90), and untreated rabbits (UC). There were significant concentration-dependent reductions of residual fungal burden (log CFU/gram) and of organism-mediated pulmonary injury, lung weights, and pulmonary infarct scores in ISA40-and ISA60-treated rabbits in comparison to those of UC (P < 0.001). ISA20-treated (P < 0.05), ISA40-treated, and ISA60-treated (P < 0.001) rabbits demonstrated significantly prolonged survival in comparison to that of UC. ISA40-and ISA60-treated animals demonstrated a significant decline of serum (1¡3)-␤-D-glucan levels (P < 0.05) and galactomannan indices (GMIs) during therapy following day 4 in comparison to progressive GMIs of UC (P < 0.01). There also were significantly lower concentration-dependent GMIs in bronchoalveolar lavage (BAL) fluid from ISA40-and ISA60-treated rabbits (P < 0.001). There was a direct correlation between isavuconazole plasma area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) and residual fungal burdens in lung tissues, pulmonary infarct scores, and total lung weights. In summary, rabbits treated with isavuconazole at 40 and 60 mg/kg/day demonstrated significant dose-dependent reduction of residual fungal burden, decreased pulmonary injury, prolonged survival, lower GMIs in serum and BAL fluid, and lower serum (1¡3)-␤-D-glucan levels.

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“…PK/PD studies are used to describe the impact of antifungal agents on microbial growth in relation to both antimicrobial potency and drug exposure profile, the latter aspects of which are typically determined by organism susceptibility (MIC) and the combination of PK characteristics and dosing schedule . The PK/PD bridging studies will help define the highest MIC that can be treated with the current isavuconazole regimen and inform dosage and schedule selection against each fungus by Monte Carlo simulation . However, in Desai and Townsend's studies of patients with hepatic or renal impairment, they only calculated the PK of isavuconazole in these subjects .…”

Section: Discussionmentioning

confidence: 99%

“…5 The PK/PD bridging studies will help define the highest MIC that can be treated with the current isavuconazole regimen and inform dosage and schedule selection against each fungus by Monte Carlo simulation. 19 However, in Desai and Townsend's studies of patients with hepatic or renal impairment, they only calculated the PK of isavuconazole in these subjects. 7,8 Thus, we utilized PK/PD analysis combining the PK of isavuconazole and PD (MIC distribution of Aspergillus spp.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Analysis of Isavuconazole Against Aspergillus spp. and Candida spp. in Healthy Subjects and Patients With Hepatic or Renal Impairment by Monte Carlo Simulation

Zheng

Zhu

et al. 2018

The Journal of Clinical Pharma

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The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study is to evaluate the efficacy of various isavuconazole dosing regimens for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp. Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamics (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (AUC/MIC) targets of isavuconazole. A clinically recommended dosage regimen of isavuconazole (200 mg qd) obtained high cumulative fraction of response values of > 90% for all subjects against A. fumigatus, A. flavus, A. nidulans, A. terreus, A. versicolor, C. parapsilosis and C. tropicalis. For patients with mild or moderate hepatic impairment, the dosage should be halved only when treating invasive fungal infections caused by C. albicans, C. parapsilosis or C. tropicalis. However, dose adjustment is unlikely to be required in mild to severe renal impairment patients because all cumulative fraction of response values were similar to those of comparing with healthy subjects. Notably, all isavuconazole dosing regimens were not effective against C. glabrata and C. krusei in all subjects. These PK/PD-based simulations rationalize and optimize the dosage regimens of isavuconazole for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp.

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Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis

Cited by 27 publications

References 18 publications

Isavuconazonium sulfate: a triazole prodrug for invasive fungal infections

Isavuconazonium sulfate: a triazole prodrug for invasive fungal infections

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

Pharmacokinetic/Pharmacodynamic Analysis of Isavuconazole Against Aspergillus spp. and Candida spp. in Healthy Subjects and Patients With Hepatic or Renal Impairment by Monte Carlo Simulation

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