Bioavailability of a Small Unilamellar Low-Clearance Liposomal Amikacin Formulation after Extravascular Administration

Abstract

Amikacin in small, low-clearance liposomes (MiKasome®) has prolonged plasma and tissue residence and in vivo activity against extracellular infections, including Klebsiella pneumonia and Pseudomonas endocarditis. Small liposomes may cross endothelial barriers, and enter the systemic circulation after 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.) injection (20mg/kg) and intratracheal (i.t.) instillation (10mg/kg). Drug-containing liposomes were extensively absorbed after i.p. (F=87-146%) and i.t. (F=64%) administration, with maximum amikacin plasma concentrations of 171μg/ml at 9h and 80μg/ml at 18 h, respectively. Absorption was slower and less extensive following s.c. (plasma Tmax: 20.3μg/ml at 48 h) and i.m. (plasma Tmax: 49.6μg/ml at 19 h) injection, but a significant fraction (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 tissues surrounding the injection sites were 20- and 191-fold higher than plasma AUCs after i.m. and s.c. injection, respectively. Thus, small low-clearance liposomes produced sustained levels of liposome-encapsulated amikacin in plasma, local tissues and lymph nodes after extravascular administration, suggesting applications in perioperative prophylaxis, pneumonias and intralesional therapy as well as sustained systemic delivery of encapsulated drugs.