Pharmacodynamic target evaluation of a novel oral glucan synthase inhibitor, SCY-078 (MK-3118), using an in vivo murine invasive candidiasis model

Abstract

Echinocandins inhibit the synthesis of β-1,3-D-glucan in Candida and are the first-line therapy in numerous clinical settings. Their use is limited by poor oral bioavailability, and they are available only as intravenous therapies. Derivatives of enfumafungin are novel orally bioavailable glucan synthase inhibitors. We performed an in vivo pharmacodynamic (PD) evaluation with a novel enfumafungin derivative, SCY-078 (formerly MK-3118), in a well-established neutropenic murine model of invasive candidiasis against C. albicans, C. glabrata, and C. parapsilosis. The SCY-078 MICs varied 8-fold. Oral doses of 3.125 to 200 mg/kg SCY-078 salt in sterile water produced peak levels of 0.04 to 2.66 μg/ml, elimination half-lives of 5.8 to 8.5 h, areas under the concentration-time curve from 0 to 24 h (AUC0-24 h) of 0.61 to 41.10 μg·h/ml, and AUC from 0 to infinity (AUC0-∞) values of 0.68 to 40.31 μg·h/ml. The pharmacokinetics (PK) were approximately linear over the dose range studied. Maximum response (Emax) and PK/PD target identification studies were performed with 4 C. albicans, 4 C. glabrata, and 3 C. parapsilosis isolates. The PD index AUC/MIC was explored by using total (tAUC) and free (fAUC) drug concentrations. The maximum responses were 4.0, 4.0, and 4.3 log10 CFU/kidney reductions for C. albicans, C. glabrata, and C. parapsilosis, respectively. The AUC/MIC was a robust predictor of efficacy (R2, 0.53 to 0.91). The 24-h PD targets were a static dose of 63.5 mg/kg, a tAUC/MIC of 500, and an fAUC/MIC of 1.0 for C. albicans; a static dose of 58.4 mg/kg, a tAUC/MIC of 315, and an fAUC/MIC of 0.63 for C. glabrata; and a static dose of 84.4 mg/kg, a tAUC/MIC of 198, and an fAUC/MIC of 0.40 for C. parapsilosis. The mean fAUC/MIC values associated with a 1-log kill endpoint against these species were 1.42, 1.26, and 0.91 for C. albicans, C. glabrata, and C. parapsilosis, respectively. The static and 1-log kill endpoints were measured relative to the burden at the start of therapy. The static and 1-log kill doses, as well as the total and free drug AUC/MIC PD targets, were not statistically different between species but were numerically lower than those observed for echinocandins. SCY-078 is a promising novel oral glucan synthase inhibitor against Candida species, and further investigation is warranted.

FIG 1

Plasma concentrations of SCY-078 after oral administration of single doses of 3.125, 12.5, 50, and 200 mg/kg in infected neutropenic mice. The PK parameters, including half-lives (T1/2), maximum plasma concentrations (Cmax), and areas under the concentration-time curve from 0 to infinity (AUC), are indicated. Each symbol represents the geometric mean ± standard deviation of the results determined for three mice.

FIG 2

In vivo dose-response curves for SCY-078 against C. albicans (A; 4 isolates), C. glabrata (B; 4 isolates), and C. parapsilosis (C; 3 isolates). Mice received one of a series of five 4-fold increasing doses of SCY-078 every 12 h over a 96-h treatment period. Each symbol represents the mean organism burden in the kidneys of three mice. The error bars represent the standard deviations. The dashed horizontal lines at 0 on the y axis represent the organism burden at the start of therapy. Symbols above the line represent net growth, whereas symbols below the line represent organism reduction, or killing, over the treatment period.

FIG 3

Relationship between SCY-078 AUC and AUC/MIC index using total drug concentrations (tAUC) and in vivo efficacy against four C. albicans (A), four C. glabrata (B), and three C. parapsilosis (C) isolates. The panels on the left show outcome relative to 24-h AUC drug concentrations alone, and those on the right include an assessment of the AUC/MIC. Mice received one of a series of five 4-fold increasing doses of SCY-078 every 12 h over a 96-h treatment period. Each symbol represents the mean organism burden in the kidneys of three mice. The dashed horizontal lines at 0 on the y axis represent organism burden at the start of therapy. Symbols above the line represent net growth, whereas symbols below the line represent organism reduction, or killing, over the treatment period. The best-fit line for the Hill equation and the coefficient of determination (R²) are shown for each group.

FIG 4

Relationship between SCY-078 AUC/MIC index using total (tAUC) and free (non-protein-bound, fAUC) drug concentrations and in vivo efficacy against C. albicans (4 isolates), C. glabrata (4 isolates), and C. parapsilosis (3 isolates). The panel on the left represents total drug concentrations, and the one on the right, free drug concentrations. Mice received one of a series of five 4-fold increasing doses of SCY-078 every 12 h over a 96-h treatment period. Each symbol represents the mean organism burden in the kidneys from three mice. The dashed horizontal lines at 0 on the y axis represent the organism burden at the start of therapy. Symbols above the line represent net growth, whereas symbols below the line represent organism reduction, or killing, over the treatment period. Also shown are the best-fit curves based on the Hill equation and the E_max, ED₅₀, slope (N), and coefficient of determination (R²).