In vivo pharmacodynamic evaluation of the novel nystatin derivative BSG005 in the invasive candidiasis and invasive pulmonary aspergillosis mouse models

Abstract

Nystatin, a polyene, is one of the oldest antifungal drugs with wide in vitro potency. BSG005 is a novel, chemically modified, nystatin-like molecule in development for systemic therapy. We evaluated the pharmacokinetic/pharmacodynamic (PK/PD) relationships and target exposures using in vivo invasive pulmonary aspergillosis (IPA) and invasive candidiasis (IC) infection models for BSG005 against common fungal pathogens including Aspergillus fumigatus, Candida albicans, Candida auris, and Candida glabrata. For each species group, three to four strains were selected. Minimum inhibitory concentration (MIC) testing was done by Clinical Laboratory Standards Institute (CLSI) methods. Single-dose kinetics for BSG005 were performed at four dose levels. The immunosuppressed mouse IPA model was used for A. fumigatus studies. For all Candida studies, we utilized the neutropenic disseminated candidiasis model. We used quantitative PCR to enumerate Aspergillus in the lung and colony forming units (CFU) counts for Candida in the kidney. Treatment results were evaluated based on both area under the concentration-time curve (AUC)/MIC and maximum plasma concentration (C_max)/MIC exposures. The BSG005 MIC was 1 mg/L against all strains. Escalating doses of BSG005 resulted in increased effect and, in general, the dose-response curves within each species were concordant. The median 96-h AUC/MIC associated with net stasis was lowest at 6.08 for C. glabrata. Increasing exposures were needed for same outcome for C. auris at 18.7, C. albicans at 29.3, and A. fumigatus at 102.4. C_max/MIC targets for the four groups were 0.22, 0.48, 0.60, and 1.41. BSG005 demonstrated potent activity against a variety of fungal pathogens in the neutropenic mouse models. C_max/MIC PK/PD targets were numerically lower than other polyene studies using the same infection models.

Keywords: Aspergillus; BSG-005; Candida; PK/PD; polyene.

Fig 1

Single-dose plasma concentration-time pharmacokinetic curves for BSG005. Four different doses of BSG005 that varied by fourfold concentrations on a milligram per kilogram basis were administered to mice by IP route. Groups of three mice were sampled at each time point. Each symbol represents the mean ± SD for three animals.

Fig 2

BSG005 dose-response curves for each A. fumigatus strain (A). Each symbol is the mean and standard deviation from four treated mice at each dose level. The horizontal dashed line represents net stasis of burden from the start of therapy. Points above the dashed line are net growth and those below the dashed line represent net decrease in burden. PK/PD regression analysis for AUC/MIC (B) and C_max/MIC (C). Each symbol is the mean from four mice. The curve is the best-fit line based on the sigmoid maximum effect (E_max) model. Also shown is the E_max, 50% maximal effect (ED50), slope of the curve (N), and strength of relationship based on coefficient of determination (R²).

Fig 3

BSG005 dose-response curves for C. albicans (A), C. glabrata (B), and C. auris (C). Each symbol is the mean and standard deviation from four treated mice at each dose level. The horizontal dashed line represents net stasis of burden from the start of therapy. Points above the dashed line are net growth and those below the dashed line represent net decrease in burden.

Fig 4

PK/PD regression analysis for AUC/MIC and C_max/MIC for C. albicans (A and B), C. glabrata (C and D), and C. auris (E and F). Each symbol is the mean and standard deviation from four mice. The solid curve is the best-fit line based on the sigmoid maximum effect (E_max) model. The 95% CI is represented by the dashed lines. Also shown is the E_max, 50% maximal effect (ED50), slope of the curve (N), and strength of relationship based on coefficient of determination (R²).