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

• Published in: Antimicrobial agents and chemotherapy Vol. 62; no. 4
• Main Authors: Zhao, Miao, Lepak, Alexander J, VanScoy, Brian, Bader, Justin C, Marchillo, Karen, Vanhecker, Jamie, Ambrose, Paul G, Andes, David R
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.04.2018
• Subjects: Candida; Candidiasis; Experimental Therapeutics; Candida; pharmacodynamics; APX001
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02542-17

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 ( = 5), ( = 5), and ( = 4). MIC values ranged from 0.002 to 0.03 mg/liter for , from 0.008 to 0.06 mg/liter for , and from 0.004 to 0.03 mg/liter for 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 ( ) values of 0.46 to 15.6 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC ) 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 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 ( AUC /MIC) was the PK/PD index that best correlated with efficacy (coefficient of determination [ ] = 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 and a 96-h study duration with and The dose required to achieve 50% of the maximum effect (ED ) and stasis AUC/MIC targets were as follows: for , 3.67 ± 3.19 and 20.60 ± 6.50, respectively; for , 0.38 ± 0.21 and 1.31 ± 0.27, respectively; and for , 7.14 ± 4.54 and 14.67 ± 8.30, respectively. The present studies demonstrated and APX001A and APX001 potency, respectively, against , , and These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints. The identification of a lower AUC/MIC ratio target for suggests that species-specific susceptibility breakpoints should be explored.