Compartmental Pharmacokinetics and Tissue Distribution of the Antifungal Echinocandin Lipopeptide Micafungin (FK463) in Rabbits

Abstract

The plasma pharmacokinetics and tissue distribution of the novel antifungal echinocandin-like lipopeptide micafungin (FK463) were investigated in healthy rabbits. Cohorts of three animals each received micafungin at 0.5, 1, and 2 mg/kg of body weight intravenously once daily for a total of 8 days. Serial plasma samples were collected on days 1 and 7, and tissue samples were obtained 30 min after the eighth dose. Drug concentrations were determined by validated high-performance liquid chromatographic methods. Plasma drug concentration data were fit to a two-compartment pharmacokinetic model, and pharmacokinetic parameters were estimated using weighted nonlinear least-square regression analysis. Micafungin demonstrated linear plasma pharmacokinetics without changes in total clearance and dose-normalized area under the concentration-time curve from 0 h to infinity. After administration of single doses to the rabbits, mean peak plasma drug concentrations ranged from 7.62 g/ml at 0.5 mg/kg to 16.8 g/ml at 2 mg/kg, the area under the concentration-time curve from 0 to 24 h ranged from 5.66 to 21.79 g ⅐ h/ml, the apparent volume of distribution at steady state ranged from 0.296 to 0.343 liter/kg, and the elimination half-life ranged from 2.97 to 3.20 h, respectively. No significant changes in pharmacokinetic parameters and no accumulation was noted after multiple dosing. Mean tissue micafungin concentrations 30 min after the last of eight daily doses were highest in the lung (2.26 to 11.76 g/g), liver (2.05 to 8.82 g/g), spleen (1.87 to 9.05 g/g), and kidney (1.40 to 6.12 g/g). While micafungin was not detectable in cerebrospinal fluid, the concentration in brain tissue ranged from 0.08 to 0.18 g/g. These findings indicate linear disposition of micafungin at dosages of 0.5 to 2 mg/kg and achievement of potentially therapeutic drug concentrations in plasma and tissues that are common sites of invasive fungal infections.Micafungin (FK463) is a novel, semisynthetic antifungal echinocandin-like lipopeptide that inhibits the synthesis on 1,3␤-glucan, an essential polymeric polysaccharide in the cell wall of many pathogenic fungi (12, 24). As a class, the echinocandins lack mechanism-based toxicity and have an extended spectrum of antifungal activity without cross-resistance to existing antifungal agents (4,5,9,15,18). In vitro, micafungin has demonstrated potent and broad-spectrum fungicidal activity against clinically relevant Candida spp. and potent inhibitory activity against Aspergillus spp. (21, 23, 25). The compound displayed promising antifungal efficacy in murine models of disseminated candidiasis as well as disseminated and pulmonary aspergillosis (16,19,20) and is currently in advanced stages of clinical development (12).Little is still known, however, about the disposition of micafungin in plasma and tissues. Therefore, the purpose of this study was to assess the compartmental plasma pharmacokinetics and tissue distribution of micafungin at potentially therapeutic dosages in healthy laboratory animals. The inform...

Tissue Distribution after Intravenous Dosing of Micafungin, an Antifungal Drug, to Rats

“…[6][7][8][9] Maximum concentrations for all tissues examined as well as plasma were seen at the first sampling time (5 min) after intravenous administration, and the amount of micafungin in liver, kidney, and lung 5 min after dosing was estimated to be 10.7%, 2.9%, and 2.4% of the dose, respectively. Micafungin concentrations in liver, kidney, and lung 5 min after dosing (C 5 min ) were 1.15, 1.64, and 2.58-fold higher than the plasma concentration, and the AUC 0-∞ for these tissues were 1.61, 3.42, and 2.89-fold higher than that for plasma, respectively.…”

“…and Aspergillus spp., suggesting the achievement of potentially therapeutic drug concentrations in plasma and tissues that are common sites of invasive fungal infections. 7) Micafungin concentrations above the MIC 90 against the clinical isolates of Candida spp. and Aspergillus spp.…”

“…and Aspergillus spp. 7) However, there are few detailed studies on the tissue distribution kinetics of unchanged drug after an intravenous dose of micafungin in animals and humans.…”

“…2,5) It has been reported that micafungin exhibits linear pharmacokinetics after intravenous dosing to rats, mice, dogs, and rabbits, as well as humans. [6][7][8][9] The radioactivity after intravenous dosing of 14 C-labeled micafungin to male rats is widely distributed immediately and the radioactivity in tissues decreases almost in parallel with the radioactivity in plasma.…”

“…[6][7][8][9] The radioactivity after intravenous dosing of 14 C-labeled micafungin to male rats is widely distributed immediately and the radioactivity in tissues decreases almost in parallel with the radioactivity in plasma. 10) Unchanged micafungin concentrations in rabbit tissues, including the liver, kidney, lungs, and spleen, at near peak plasma concentrations 30 min after the last of multiple doses over eight days are several-fold in excess of the MIC 90 against the clinical isolates of Candida spp.…”