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Antimicrob Agents Chemother. 2019 Jan 22. pii: AAC.02372-18. doi: 10.1128/AAC.02372-18. [Epub ahead of print]

APX001 Pharmacokinetic/Pharmacodynamic Target Determination against Aspergillus fumigatus in an in vivo Model of Invasive Pulmonary Aspergillosis.

Author information

1
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
2
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA.
3
William S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA.
4
Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
5
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA dra@medicine.wisc.edu.

Abstract

APX001, the prodrug of APX001A, is a first-in-class antifungal agent that has a potent activity against Aspergillus fumigatus. The goal of current study was to determine the pharmacodynamic (PD) index and target of APX001 in an immunocompromised murine model of invasive pulmonary aspergillosis against 6 A. fumigatus isolates. Minimum effective concentration (MEC) values ranged from 0.03 to 0.06 mg/liter. Dose fractionation was performed against isolate AF293 using total doses of APX001 ranging from 81 to 768 mg/kg/day fractionated into every 3-, 6-, and 8- hourly regimens over a 96-h treatment duration. Efficacy was assessed by A. fumigatus quantitative PCR (qPCR) of conidial equivalents from lung homogenates. Nonlinear regression analysis using the Hill equation demonstrated that the 24h AUC/MEC ratio was the PK/PD index that best correlated with efficacy (coefficient of determination [lsqb]R2[rsqb] = 0.79). Treatment studies with the remaining strains utilized regimens of 40 to 1536 mg/kg of APX001 administered every 3 h for a 96-h duration. Exposure-response relationships for all strains were similar and the median free drug AUC/MEC PK/PD targets for stasis and 1-log kill endpoint were 47.6 and 89.4, respectively. The present studies demonstrated in vitro and in vivo APX001A/APX001 potency against A. fumigatus These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints.

PMID:
30670426
DOI:
10.1128/AAC.02372-18

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