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

Abstract

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 <i>Candida albicans</i> (<i>n</i> = 5), <i>C. glabrata</i> (<i>n</i> = 5), and <i>C. auris</i> (<i>n</i> = 4). MIC values ranged from 0.002 to 0.03 mg/liter for <i>C. albicans</i>, from 0.008 to 0.06 mg/liter for <i>C. glabrata</i>, and from 0.004 to 0.03 mg/liter for <i>C. auris</i> 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 (<i>C</i>_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 <i>C. albicans</i> 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 (<i>f</i>AUC_0-24/MIC) was the PK/PD index that best correlated with efficacy (coefficient of determination [<i>R</i>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 <i>C. albicans</i> and a 96-h study duration with <i>C. glabrata</i> and <i>C. auris</i> The dose required to achieve 50% of the maximum effect (ED₅₀) and stasis <i>f</i>AUC/MIC targets were as follows: for <i>C. albicans</i>, 3.67 ± 3.19 and 20.60 ± 6.50, respectively; for <i>C. glabrata</i>, 0.38 ± 0.21 and 1.31 ± 0.27, respectively; and for <i>C. auris</i>, 7.14 ± 4.54 and 14.67 ± 8.30, respectively. The present studies demonstrated <i>in vitro</i> and <i>in vivo</i> APX001A and APX001 potency, respectively, against <i>C. albicans</i>, <i>C. glabrata</i>, and <i>C. auris.</i> These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints. The identification of a lower AUC/MIC ratio target for <i>C. glabrata</i> suggests that species-specific susceptibility breakpoints should be explored.