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

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 of body weight/day fractionated into every 3-, 6-, and 8-h 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 24-h area under the concentration-time curve (AUC)/MEC ratio was the pharmacokinetic (PK)/PD index that best correlated with efficacy (coefficient of determination [R 2 ] ϭ 0.79). Treatment studies with the remaining strains utilized regimens of 40 to 1,536 mg/kg of APX001 administered every 3 h for a 96-h duration. Exposureresponse relationships for all strains were similar, and the median free drug AUC/MEC PK/PD targets for stasis and 1-log-kill endpoints 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.

11g, a Potent Antifungal Candidate, Enhances Candida albicans Immunogenicity by Unmasking β-Glucan in Fungal Cell Wall

“…The small molecule compound 11g reported in this paper is derived from the structure optimization of the published GPI biosynthesis inhibitors BIQ, G884, 10b, and E1210. It has been reported that all of these four compounds (BIQ, G884, 10b, and E1210) could inhibit the function of Gwt1p, the key enzyme in GPI synthesis pathway in fungi, and finally exhibit antifungal activity ( Tsukahara et al, 2003 ; Nakamoto et al, 2010 ; Hata et al, 2011 ; Mann et al, 2015 ; Zhao et al, 2018 , 2019 ). Therefore, we inferred that Gwt1p might be the target of 11g.…”

Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis

“…Manogepix, which has a novel mechanism of action different than that of the triazoles, echinocandins, and polyenes, has been shown to have broad in vitro activity against numerous pathogenic fungi, including Candida , Cryptococcus , Aspergillus , Fusarium , and Scedosporium species (15–19, 24). This in vitro activity has translated into in vivo efficacy of fosmanogepix in experimental models of candidiasis, cryptococcosis, coccidioidomycosis, aspergillosis, and scedosporiosis (20–22, 24, 28, 43). This therapeutic candidate has also previously been reported to have in vitro and in vivo activity against C.…”

“…This strategy has been successfully used in studies of invasive candidiasis caused by species other than C. auris, invasive aspergillosis, and invasive scedosporiosis (20, 22, 25, 26, 28). However, this was not done in the current study or in the others that evaluated the in vivo efficacy of fosmanogepix against invasive C.…”

Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance

“… 63 Polyene treatment for azole-resistant strains is suggested, but new-class agents, such as olorofim, which has US Food and Drug Administration breakthrough therapy designation, should be considered as alternatives, particularly if azole-resistant disease is documented. 64 The inositol acylase inhibitor, fosmanogepix, is in clinical trials for invasive aspergillosis, 65 and the oral triterpenoid beta-glucan inhibitor, ibrexafungerp, 66 is also in clinical trials for invasive aspergillosis and invasive candidiasis. Some of these drugs might be accessible on a named patient basis.…”