Compartmental pharmacokinetics and tissue distribution of the antifungal echinocandin lipopeptide micafungin (FK463) in rabbits

The plasma pharmacokinetics and tissue distribution of the novel antifungal echinocandin-like lipopeptide micafungin (FK463) were investigated in heal thy rabbits. Cohorts of three animals each received micafungin at 0.5, 1, a nd 2 mg/kg of body weight intravenously once daily for a total of 8 days. S erial plasma samples were collected on days I and 7, and tissue samples wer e obtained 30 min after the eighth dose. Drug concentrations were determine d by validated high-performance liquid chromatographic methods. Plasma drug concentration data were fit to a two-compartment pharmacokinetic model, an d pharmacokinetic parameters were estimated using weighted nonlinear least- square regression analysis. Micafungin demonstrated linear plasma pharmacok inetics without changes in total clearance and dose-normalized area under t he concentration-time curve from 0 It to infinity. After administration of single doses to the rabbits, mean peak plasma drug concentrations ranged fr om 7.62 mug/ml at 0.5 mg/kg to 16.8 mug/ml at 2 mg/kg, the area under the c oncentration-time curve from 0 to 24 h ranged from 5.66 to 21.79 mug.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, res pectively. No significant changes in pharmacokinetic parameters and no accu mulation was noted after multiple dosing. Mean tissue micafungin concentrat ions 30 min after the last of eight daily doses were highest in the lung (2 .26 to 11.76 mug/g), liver (2.05 to 8.82 mug/g), spleen (1.87 to 9.05 mug/g ), and kidney (1.40 to 6.12 mug/g). While micafungin was not detectable in cerebrospinal fluid, the concentration in brain tissue ranged from 0.08 to 0.18 mug/g. These findings indicate linear disposition of micafungin at dos ages of 0.5 to 2 mg/kg and achievement of potentially therapeutic drug conc entrations in plasma and tissues that are common sites of invasive fungal i nfections.