Absorption, Distribution, and Excretion of 14C-APX001 after Single-Dose Administration to Rats and Monkeys

Abstract

BackgroundAPX001 is a small-molecule therapeutic agent in clinical development for the treatment of invasive fungal infections (IFI).MethodsThe absorption, distribution and excretion profiles of [14C]APX001-derived radioactivity were determined in rats (albino and pigmented) and monkeys. Rats (some implanted with bile duct cannulae) were administered a single 100 mg/kg oral dose or a 30 mg/kg intravenous (IV) dose. Monkeys were administered a single 6 mg/kg IV dose. Samples of blood, urine, feces and bile, as well as carcasses, were collected through 168 hours after dosing. Samples were analyzed for total radioactivity content by liquid scintillation counting, and carcasses were analyzed by quantitative whole-body autoradiography.Results[14C]APX001-derived radioactivity was rapidly and extensively absorbed and extensively distributed to most tissues for both routes of administration in both species. In rats, tissues with the highest radioactivity Cmax values included bile, abdominal fat, reproductive fat, subcutaneous fat, and liver, but radioactivity was also detected in tissues associated with IFI, including lung, brain and eye. In monkeys, the highest Cmax values were in bile, urine, uveal tract, bone marrow, abdominal fat, liver, and kidney cortex. Liver and kidney were the tissues with highest radioactivity, but as in the rat, radioactivity was also detected in lung, brain and eye tissues. In pigmented rats, radiocarbon was densely distributed into pigmented tissue and more slowly cleared than from other tissues.Mean recovery of radioactivity in rats was approximately 95–100%. In bile duct-intact rats, >90% of radioactivity was recovered in feces. In cannulated rats, biliary excretion of radioactivity was the major route of elimination and accounted for 88.8% of the dose, whereas urinary and fecal excretion of radioactivity was minor and accounted for 2.56% and 5.42% of the dose, respectively. In monkeys, the overall recovery of radioactivity was 87.6%, and was eliminated in feces (49.8% of dose) and to a lesser extent in urine (20.6% of dose).ConclusionTogether, the results indicate that APX001-related radioactivity is extensively distributed to major tissues (including tissues relevant to IFI) in both rats and monkeys and cleared primarily by biliary/fecal excretion.Disclosures R. Mansbach, Amplyx Pharmaceuticals Inc.: Consultant, Consulting fee; K. J. Shaw, Amplyx Pharmaceuticals Inc.: Employee, Salary; M. R. Hodges, Amplyx Pharmaceuticals: Employee, Salary; S. Coleman, Covance Laboratories: Employee, Salary; M. E. Fitzsimmons, Covance Laboratories: Employee, Salary

In Vitro and In Vivo Evaluation of the Antifungal Activity of APX001A/APX001 against Candida auris

“…In the current model of disseminated C. auris infection, APX001 resulted in significantly better survival than anidulafungin. Both APX001 and anidulafungin demonstrated significant and equivalent decreases in kidney and lung CFU at 48 h. However, only APX001 demonstrated a reduction in brain CFU, a finding consistent with the brain penetration observed in 14 C-APX001 distribution studies where radioactivity was detected in tissues associated with invasive fungal infections ( 33 ). This contrasts with the poor CNS penetration observed for the echinocandins ( 30 ).…”

APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental Coccidioides immitis Pneumonia

“…APX001 has been shown to be effective in mouse models of Candida albicans (18, 22, 32), Candida auris (33), and Cryptococcus neoformans (17) infections, as well as Aspergillus and Fusarium infections (16). In addition to increased survival, a reduction in the colony counts of fungi in the lungs, kidneys, and brain tissues of infected mice has been observed, consistent with 14 C-APX001 studies that demonstrated wide tissue distribution in rats and monkeys, especially in tissues associated with invasive fungal infections (34). Notably, treatment with APX001 lead to a significant reduction in brain CFU in both a rabbit model of hematogenous C.…”

Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections

“…The absorption, distribution and excretion profiles of [ 14 C]FMGX-derived radioactivity were explored in rats using a single dose of 100 mg/kg PO or 30 mg/kg IV, whereas monkeys were administered a single 6 mg/kg IV dose [ 67 ]. Samples were analyzed for total radioactivity content by liquid scintillation counting, and carcasses were analyzed by quantitative whole-body autoradiography (QWBA).…”