Significantly improved pharmacokinetics enhances in vivo efficacy of APX001 against echinocandin and multidrug resistant Candida isolates in a mouse model of invasive candidiasis [PublishAheadOfPrint]

APX001 is a first-in-class, intravenous and orally available broad-spectrum antifungal agent in clinical development for the treatment of life-threatening invasive fungal infections. The half-life of APX001A, the active moiety of APX001, is significantly shorter in mice than in humans (1.4 – 2.75 h in mice vs 2 – 2.5 days in humans), making exploration of efficacy in mouse models difficult. With pre-treatment of 1-aminobenzotriazole (ABT), a non-specific cytochrome P450 inhibitor, greatly increased plasma exposure of APX001A was observed in different mice strains of both genders. As a consequence, 26 mg/kg APX001 plus ABT sterilized kidneys in mice infected with C. albicans, while APX001 alone at the same dosage only resulted in a modest 0.2 log₁₀ CFU/g burden reduction relative to vehicle control. In the presence of ABT, two days of once daily dosing APX001 at 26 mg/kg also demonstrated significant in vivo efficacy in the treatment of C. glabrata infections in mice. Potent kidney burden reduction was achieved in not only mice infected with either a susceptible strain or echinocandin and multidrug resistant strains. In contrast, the standard of care micafungin was not ineffective in treating infections caused by these resistant C. glabrata isolates.

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