Comparative pharmacokinetics of amphotericin B after single- and multiple-dose administration of G-ABCD and conventional amphotericin B deoxycholate to rats.

Abstract Objectives G-ABCD is a biosimilar product of amphotericin B colloidal dispersion (ABCD). This study was designed to systematically examine the plasma pharmacokinetics (PK) and tissue distribution of G-ABCD in rats, using DAmB as a positive control. Methods Male Sprague-Dawley rats received single dose or 14 doses of G-ABCD (1.0, 2.0 or 5.0 mg/kg) or the conventional micellar formulation amphotericin B deoxycholate (DAmB, 1.0 mg/kg) via intravenous injection. Plasma and tissue samples were obtained for analysis of amphotericin B concentration by liquid chromatography-tandem mass spectrometry. Results After single dose administration of 1 mg/kg, G-ABCD resulted in significantly lower plasma Cmax (1536 vs 5256 ng/mL) and AUC0-∞ (3972 vs 7006h·ng/mL) of non-complexed amphotericin B (N-AMB) than DAmB. G-ABCD was associated with quicker distribution but slower elimination of amphotericin B than DAmB. Amphotericin B concentration reached steady state after 7 doses of G-ABCD. After multiple doses of 1 mg/kg, G-ABCD showed lower peak level and longer half-life of amphotericin B in plasma than DAmB. G-ABCD treatment in rats was associated with relatively higher distribution to liver and spleen, but reduced amphotericin B delivery to kidneys, the major target organ of toxicity. Conclusion These results suggest that G-ABCD provides flatter but more lasting plasma level of amphotericin B and lower kidney burden in rats than DAmB.