Cilofungin (LY121019) shows nonlinear plasma pharmacokinetics and tissue penetration in rabbits.

We studied the plasma pharmacokinetics and tissue penetration of cilofungin (LY121019), a new echinocandin antifungal compound, by intermittent and continuous infusion in rabbits. Following a single intravenous dose of 50 mg/kg of body weight, the maximum concentration in plasma was 297 +/- 39 micrograms/ml, the area under the curve was 30.1 +/- 6.7 micrograms.h/ml, clearance was 30 +/- 10 ml/min/kg, volume of distribution was 0.85 +/- 0.23 liters/kg, half-life in distribution phase was 3.7 +/- 0.2 min (first 12 min postdose), and half-life in elimination phase was 12.9 +/- 0.7 min. When rabbits received cilofungin by continuous infusion (CI) at 10 mg/kg/h over 6 days, sustained concentrations in plasma of 290 +/- 56 micrograms/ml were seen, more than 50-fold higher than predicted if kinetics were linear. Similarly, at 5 mg/kg/h, high levels were also obtained. Such elevated levels in plasma would not have been predicted from the pharmacokinetic characteristics of cilofungin given as a single intravenous dose. Further pharmacokinetic study at several rates of CI suggested that cilofungin elimination follows Michaelis-Menten kinetics. Simultaneous cilofungin levels in plasma and tissue were then determined for rabbits receiving six intravenous, intermittent doses (ID) of cilofungin at 15 mg/kg every 4 min and for rabbits receiving CI as described above. After ID, the mean of the ratios of cilofungin levels in tissue to those in plasma were highest for liver and bile but very low for cerebrum and cerebellum. After CI, ratios were as much as 89 times higher than for ID and significantly greater in the brain, choroid, kidney, and bile (P less than 0.05). We conclude that following a single dose of cilofungin, the compound is rapidly cleared via first-order kinetics and does not penetrate into the central nervous system, whereas following CI, cilofungin exhibits nonlinear saturable kinetics, is slowly cleared, and significantly penetrates into central nervous system tissues.