APX001 Pharmacokinetic/Pharmacodynamic Target Determination againstAspergillus fumigatusin anIn VivoModel of Invasive Pulmonary Aspergillosis
ABSTRACTAPX001, the prodrug of APX001A, is a first-in-class antifungal agent that has a potent activity againstAspergillus 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. fumigatusisolates. 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 byA. fumigatusquantitative 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 [R2] = 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. Exposure-response 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 demonstratedin vitroandin vivoAPX001A/APX001 potency againstA. fumigatus. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints.