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Bioavailability of a small unilamellar low-clearance liposomal amikacin formulation after extravascular
R M Fielding1, L Moon-McDermott, R O Lewis
1Biopharmaceutics Group, NeXstar Pharmaceuticals, Inc., Boulder, CO 80301, USA. biopharm@worldnet.att.net
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 (20 mg/kg) and intratracheal (i.t.) instillation (10 mg/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 171 micrograms/ml at 9 h and 80 micrograms/ml at 18 h, respectively. Absorption was slower and less extensive following s.c. (plasma Tmax: 20.3 micrograms/ml at 48 h) and i.m. (plasma Tmax: 49.6 micrograms/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.
Insights
Small liposomes carrying amikacin (MiKasome) show extended presence in plasma and tissues, offering potential for treating infections. Extravascular administration, like intraperitoneal and intratracheal routes, resulted in significant systemic bioavailability.
Area of Science:
- Pharmacology and Pharmaceutics
- Drug Delivery Systems
- Nanomedicine
Background:
- Amikacin in small, low-clearance liposomes (MiKasome) demonstrates prolonged plasma and tissue residence.
- This formulation exhibits in vivo activity against extracellular infections like Klebsiella pneumonia and Pseudomonas endocarditis.
- Small liposomes possess the ability to traverse endothelial barriers and enter systemic circulation post-extravascular administration.
Purpose of the Study:
- To compare the systemic bioavailability (F) of low-clearance liposomal amikacin in rats.
- To evaluate absorption following various administration routes: intravenous (i.v.), intraperitoneal (i.p.), intramuscular (i.m.), subcutaneous (s.c.), and intratracheal (i.t.).
Main Methods:
- Liposomal amikacin was administered via i.v., i.p., i.m., s.c. (20 mg/kg), and i.t. (10 mg/kg) routes in rats.
- Plasma and tissue concentrations of amikacin were measured over time.
- Systemic bioavailability (F) and pharmacokinetic parameters like AUC and Tmax were calculated.
Main Results:
- Extensive absorption (F = 87-146% for i.p., F = 64% for i.t.) was observed after i.p. and i.t. administration.
- Slower, less extensive absorption occurred with s.c. (12-27% absorbed) and i.m. routes.
- Plasma AUCs of liposomal amikacin were at least 25-fold higher than conventional i.v. amikacin across all routes.
- Amikacin AUCs in lymph nodes and surrounding tissues were significantly elevated after s.c. and i.m. injections.
Conclusions:
- Small, low-clearance liposomes achieve sustained amikacin levels in plasma, local tissues, and lymph nodes after extravascular administration.
- This suggests potential applications in perioperative prophylaxis, pneumonia treatment, and intralesional therapy.
- The formulation facilitates sustained systemic delivery of encapsulated amikacin.