ALTERED TISSUE DISTRIBUTION AND ELIMINATION OF AMIKACIN ENCAPSULATED IN UNILAMELLAR, LOW-CLEARANCE LIPOSOMES (MIKASOME(R))

Purpose. Amikacin in small unilamellar liposomes (MiKasome(R)) has pro longed plasma residence (half-life > 24hr) and sustained efficacy in G ram-negative infection models. Since low-clearance liposomes may be su bject to a lower rate of phagocytic uptake, we hypothesized this formu lation may enhance amikacin distribution to tissues outside the mononu clear phagocyte system. Methods. Rats received one intravenous dose (5 0 mg/kg) of conventional or liposomal amikacin. Amikacin was measured for ten days in plasma, twelve tissues, urine and bile. Results. Lipos omal amikacin increased and prolonged drug exposure in all tissues. Ti ssue half-lives (63-465 hr) exceeded the plasma half-life (24.5 hr). P eak levels occurred within 4 hours in some tissues, but were delayed 1 -3 days in spleen, liver, lungs and duodenum, demonstrating the import ance of characterizing the entire tissue concentration vs. time profil e for liposomal drugs. Predicted steady-state tissue concentrations fo r twice weekly dosing were >100 mu g/g. Less than half the liposomal a mikacin was recovered in tissues and excreta, suggesting metabolism oc curred. Amikacin was not detected in plasma ultrafiltrates. Tissue-pla sma partition coefficients (0.2-0.8 in most tissues) estimated from ti ssue-plasma ratios at T-max were similar to those estimated from tissu e AUCs. Conclusions. Low-clearance liposomal amikacin increased and pr olonged drug residence in all tissues compared to conventional amikaci n. The long tissue half-lives suggest liposomal amikacin is sequestere d within tissues, and that an extended dosing interval is appropriate for chronic or prophylactic therapy with this formulation.