Bioavailability of a small unilamellar low-clearance liposomal amikacin formulation after extravascular administration

Amikacin in small, low-clearance liposomes (MiKasome(R)) has prolonged plas ma and tissue residence and in vivo activity against extracellular infectio ns, including Klebsiella pneumonia and Pseudomonas endocarditis. Small lipo somes may cross endothelial barriers, and enter the systemic circulation af ter extravascular administration. We compared the systemic bioavailability (F) of low-clearance liposomal amikacin in rats following intravenous (i.v. ), intraperitoneal (i.p.), intramuscular (i.m.) and subcutaneous (s.c.) inj ection (20 mg/kg) and intratracheal (i.t.) instillation (10 mg/kg). Drug-co ntaining liposomes were extensively absorbed after i.p. (F=87-146%) and i.t . (F=64%) administration, with maximum amikacin plasma concentrations of 17 1 mu g/ml at 9h and 80 mu g/ml at 18 h, respectively. Absorption was slower and less extensive following s.c. (plasma T-max: 20.3 mu g/ml at 48 h) and i.m. (plasma T-max: 49.6 mu g/ml at 19 h) injection, but a significant fra ction (12-27%) of the liposomes was absorbed. The plasma AUCs of liposomal amikacin exceeded the AUC of conventional i.v. amikacin by at least 25-fold for all routes. Amikacin AUCs in regional lymph nodes exceeded plasma AUCs by 4-fold after s.c. and i.m. injection of liposomal amikacin. AUCs in tis sues surrounding the injection sites were 20- and 191-fold higher than plas ma AUCs after i.m. and s.c. injection, respectively. Thus, small low-cleara nce liposomes produced sustained levels of liposome-encapsulated amikacin i n plasma, local tissues and lymph nodes after extravascular administration, suggesting applications in perioperative prophylaxis, pneumonias and intra lesional therapy as well as sustained systemic delivery of encapsulated dru gs.