In Vivo Pharmacokinetics and Pharmacodynamics of APX001 against Candida spp. in a Neutropenic Disseminated Candidiasis Mouse Model

摘要

APX001 is the prodrug of APX001A, which is a first-in-class small molecule with a unique mechanism of action that inhibits the fungal enzyme Gwt1 in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The goal of the present study was to determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy in the murine disseminated candidiasis model for Candida albicans (n = 5), C. glabrata (n = 5), and C. auris (n = 4). MIC values ranged from 0.002 to 0.03 mg/liter for C. albicans, from 0.008 to 0.06 mg/liter for C. glabrata, and from 0.004 to 0.03 mg/liter for C. auris. Plasma APX001A pharmacokinetic measurements were performed in mice after oral administration of 4, 16, 64, and 256 mg/kg of body weight APX001. Single-dose pharmacokinetic studies exhibited maximum plasma concentration (C-max) values of 0.46 to 15.6 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC(0-inf)) values of 0.87 to 70.0 mg . h/liter, and half-lives of 1.40 to 2.75 h. A neutropenic murine disseminated candidiasis model was utilized for all treatment studies, and drug dosing was by the oral route. Dose fractionation was performed against C. albicans K1, with total doses ranging from 4 to 1,024 mg/kg/day of APX001 fractionated into regimens of dosing every 3, 6, 8, and 12 h for a 24-h treatment duration. Nonlinear regression analysis was used to determine which PK/PD index best correlated with efficacy on the basis of the reduction in the number of CFU/kidney at 24 h. The 24-h free-drug AUC/MIC ratio (fAUC(0-24)/MIC) was the PK/PD index that best correlated with efficacy (coefficient of determination [R-2] = 0.88). Treatment studies with the remaining strains utilized regimens of 1 to 256 mg/kg of APX001 administered every 6 h for a 24-h duration with C. albicans and a 96-h study duration with C. glabrata and C. auris. The dose required to achieve 50% of the maximum effect (ED50) and stasis fAUC/MIC targets were as follows: for C. albicans, 3.67 +/- 3.19 and 20.60 +/- 6.50, respectively; for C. glabrata, 0.38 +/- 0.21 and 1.31 +/- 0.27, respectively; and for C. auris, 7.14 +/- 4.54 and 14.67 +/- 8.30, respectively. The present studies demonstrated in vitro and in vivo APX001A and APX001 potency, respectively, against C. albicans, C. glabrata, and C. auris. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints. The identification of a lower AUC/MIC ratio target for C. glabrata suggests that species-specific susceptibility breakpoints should be explored.