Pharmacokinetic and pharmacodynamic profiling of generic amphotericin B colloidal dispersion in a rat model of invasive candidiasis

Abstract

Objectives: We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets of a biosimilar generic product of amphotericin B colloidal dispersion (G-ABCD) againstCandida albicans (MIC 1–2 μg/mL) in a rat model of invasive candidiasis (IC) to facilitate its precision administration. Methods: Single-dose plasma PKs of G-ABCD was studied in a rat IC model following intravenous administration at doses of 0.0625–10 mg/kg. Amphotericin B concentrations were determined and PK parameters were calculated based on the concentrations in plasma. The efficacy of G-ABCD was evaluated after single administration by the log reduction of CFU counts in kidney, liver, spleen and lung. The relationship between G-ABCD PK/PD index and log CFU reduction in kidney was calculated. Results: Following intravenous administration of G-ABCD at doses of 0.0625–10 mg/kg to rats, the maximum plasma concentration (Cmax) was 0.05–0.82 mg/L and the area under the concentration–time curve from 0 to 24 h (AUC0–24) was 0.50–5.29 mg h/L. G-ABCD showed potent antifungal activity against C. albicans C-13 with a maximum log CFU reduction of 2.1 in kidney. The mean AUC0–24/MIC target of G-ABCD against C. albicans was 0.97 for stasis, 1.40 for 1-log kill and 3.34 for 2-log kill, and the mean Cmax/MIC target was 0.063 for stasis, 0.097 for 1-log kill and 0.348 for 2-log kill. Conclusions: The antifungal effect of G-ABCD was potent and correlated with AUC0–24/MIC and Cmax/MIC in this rat model of IC. The results of this study provide data for optimising G-ABCD dosing regimens and breakpoints for antifungals.

Keywords

• Amphotericin B colloidal dispersion
• Rat model
• Invasive candidiasis
• Pharmacokinetic/pharmacodynamics
• PK/PD target