Efficacy and Pharmacokinetics of Fosmanogepix (APX001) in the Treatment of Candida Endophthalmitis and Hematogenous Meningoencephalitis in Nonneutropenic Rabbits.

ABSTRACT

Candida endophthalmitis is a serious sight-threatening complication of candidemia that may occur before or during antifungal therapy. Hematogenous Candida meningoencephalitis (HCME) is also a serious manifestation of disseminated candidiasis in premature infants, immunosuppressed children, and immunocompromised adults. We evaluated the antifungal efficacy and pharmacokinetics of the prodrug fosmanogepix (APX001) in a rabbit model of endophthalmitis/HCME. Manogepix (APX001A), the active moiety of prodrug fosmanogepix, inhibits the fungal enzyme Gwt1 and is highly active in vitro and in vivo against Candida spp., Aspergillus spp., and other fungal pathogens. Plasma pharmacokinetics of manogepix after oral administration of fosmanogepix on day 6 at 25, 50, and 100 mg/kg resulted in maximum concentration of drug in plasma (Cmax) of 3.96 ± 0.41, 4.14 ± 1.1, and 11.5 ± 1.1 µg/ml, respectively, and area under the concentration-time curve from 0 to 12 h (AUC0-12) of 15.8 ± 3.1, 30.8 ± 5.0, 95.9 ± 14 µg·h/ml, respectively. Manogepix penetrated the aqueous humor, vitreous, and choroid with liquid-to-plasma ratios ranging from 0.19 to 0.52, 0.09 to 0.12, and 0.02 to 0.04, respectively. These concentrations correlated with a significant decrease in Candida albicans burden in vitreous (>101 to 103 log CFU/g) and choroid (>101 to 103 log CFU/g) (P ≤ 0.05 and P ≤ 0.001, respectively). The aqueous humor had no detectable C. albicans in treatment and control groups. The tissue/plasma concentration ratios of manogepix in meninges, cerebrum, cerebellum, and spinal cord were approximately 11, which correlated with a >102 to 104 decline of C. albicans in tissue versus control (P ≤ 0.05). Serum and cerebrospinal fluid (CSF) (1→3)-ß-d-glucan levels demonstrated significant declines in response to fosmanogepix treatment. These findings provide an experimental foundation for fosmanogepix in treatment of Candida endophthalmitis and HCME and derisk the clinical trials of candidemia and invasive candidiasis.