Toxicities and pharmacokinetics of subconjunctival injection of liposomal amphotericin B

Abstract

The toxicity of conventional formulations of amphotericin B deoxycholate (AmB(DOC)) limits its clinical applications. To reduce the toxicity of AmB(DOC), lipid formulations of amphotericin B (AmB) have been developed and clinically applied. In the present study, we evaluated the ocular toxicity and pharmacokinetics of subconjunctival injection of liposomal AmB. Subconjunctival injection of either AmB(DOC) (containing 1.5 mg of AmB and 1.2 mg of deoxycholate), deoxycholate (1.2 mg), or liposomal amphotericin B (L-AmB) (containing 1.5 mg of AmB and lipids) was given to white New Zealand rabbits. After 24 hours, toxicities of the drugs were evaluated by slit lamp and histologically. To evaluate the pharmacokinetics of subconjunctival injection of L-AmB, the concentration of the drug in the cornea was evaluated at 4, 12, 24, and 48 hours after subconjunctival injection of L-AmB, with or without corneal epithelial removal. Subconjunctival injection of AmB(DOC) or deoxycholate alone induced severe corneal and conjunctival edema, with necrosis and infiltration of inflammatory cells. In contrast, subconjunctival injection of L-AmB induced only mild inflammation near the injection site. The concentration of AmB injected in eyes with intact corneal epithelium was 4.93-2.49, 0.63-0.31, 0.15-0.07 microg/g at 4, 12, and 24 hours respectively after the injection of L-AmB. When injected in eyes after corneal epithelial removal, the concentration of AmB was 19.7-9.87, 2.49-1.25, and 1.25-0.63 microg/g at 4, 12, and 24 hours after injection respectively Subconjunctival injection of L-AmB has reduced ocular toxicities and gives satisfactory concentrations in corneal stroma compared with conventional AmB(DOC). Subconjunctival injection of L-AmB will be a choice of treatment for mycotic keratitis.