Significantly improved pharmacokinetics enhances in vivo efficacy of APX001 against echinocandin-and multidrug-resistant Candida isolates in a mouse model of invasive candidiasis

TY - JOUR

T1 - Significantly improved pharmacokinetics enhances in vivo efficacy of APX001 against echinocandin-and multidrug-resistant Candida isolates in a mouse model of invasive candidiasis

AU - Zhao, Yanan

AU - Lee, Min Hee

AU - Paderu, Padmaja

AU - Lee, Annie

AU - Jimenez-Ortigosa, Cristina

AU - Park, Steven

AU - Mansbach, Robert S.

AU - Shaw, Karen Joy

AU - Perlin, David S.

N1 - Publisher Copyright: © 2018 Zhao et al.

PY - 2018/10

Y1 - 2018/10

N2 - APX001 is a first-in-class, intravenous and orally available, broadspectrum antifungal agent in clinical development for the treatment of lifethreatening invasive fungal infections. The half-life of APX001A, the active moiety of APX001, is significantly shorter in mice than in humans (1.4 to 2.75 h in mice versus 2 to 2.5 days in humans), making the exploration of efficacy in mouse models difficult. After pretreatment with 1-aminobenzotriazole (ABT), a nonspecific cytochrome P450 inhibitor, greatly increased plasma APX001A exposure was observed in mice of different strains and of both genders. As a consequence, 26 mg/kg APX001 plus ABT sterilized kidneys in mice infected with Candida albicans, while APX001 alone at the same dose resulted in a modest burden reduction of only 0.2 log10 CFU/g, relative to the vehicle control. In the presence of ABT, 2 days of once-daily dosing with APX001 at 26 mg/kg also demonstrated significant in vivo efficacy in the treatment of Candida glabrata infections in mice. Potent kidney burden reduction was achieved in mice infected with susceptible, echinocandin-resistant, or multidrugresistant strains. In contrast, the standard of care (micafungin) was ineffective in treating infections caused by the resistant C. glabrata isolates.

AB - APX001 is a first-in-class, intravenous and orally available, broadspectrum antifungal agent in clinical development for the treatment of lifethreatening invasive fungal infections. The half-life of APX001A, the active moiety of APX001, is significantly shorter in mice than in humans (1.4 to 2.75 h in mice versus 2 to 2.5 days in humans), making the exploration of efficacy in mouse models difficult. After pretreatment with 1-aminobenzotriazole (ABT), a nonspecific cytochrome P450 inhibitor, greatly increased plasma APX001A exposure was observed in mice of different strains and of both genders. As a consequence, 26 mg/kg APX001 plus ABT sterilized kidneys in mice infected with Candida albicans, while APX001 alone at the same dose resulted in a modest burden reduction of only 0.2 log10 CFU/g, relative to the vehicle control. In the presence of ABT, 2 days of once-daily dosing with APX001 at 26 mg/kg also demonstrated significant in vivo efficacy in the treatment of Candida glabrata infections in mice. Potent kidney burden reduction was achieved in mice infected with susceptible, echinocandin-resistant, or multidrugresistant strains. In contrast, the standard of care (micafungin) was ineffective in treating infections caused by the resistant C. glabrata isolates.

KW - 1-aminobenzotriazole

KW - APX001

KW - APX001A

KW - Candida

KW - Efficacy

KW - Pharmacokinetics

UR - https://www.scopus.com/pages/publications/85053877343

U2 - 10.1128/AAC.00425-18

DO - 10.1128/AAC.00425-18

M3 - Article

C2 - 30012766

SN - 0066-4804

VL - 62

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 10

M1 - e00425

ER -