Ocular Distribution of Intravenously Administered Lipid Formulations of Amphotericin B in a Rabbit Model

Abstract

Little is known about the ocular penetration of amphotericin B (AMB) and its lipid formulations, the current drug of choice in fungal endophthalmitis. The ocular distribution of AMB lipid complex (ABLC), liposomal AMB (L-AMB), and AMB deoxycholate (D-AMB) was studied in a rabbit model. D-AMB (1 mg/kg of body weight/day), ABLC (5 mg/kg/day), or L-AMB (5 mg/kg/day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7 consecutive days after induction of unilateral uveitis by intravitreal injection of endotoxin. AMB concentrations in aqueous humor, vitreous humor, and plasma were determined by high-pressure liquid chromatography 16 h after administration of a single dose or 24 h after the last of seven doses. After single-dose administration, L-AMB achieved at least eightfold-higher AMB concentrations in the aqueous of inflamed eyes than ABLC or D-AMB (1.21 ؎ 0.58 g/ml versus 0.14 ؎ 0.04 and 0.11 ؎ 0.09 g/ml, respectively). At that time point no drug was detectable in the vitreous. After 7 days of treatment, the concentration of AMB in the vitreous was higher after treatment with L-AMB (0.47 ؎ 0.21 g/ml) than after treatment with ABLC (0.27 ؎ 0.18 g/ml) and D-AMB (0.16 ؎ 0.04 g/ml). Similarly, AMB concentration in the aqueous was higher after repeated doses of L-AMB (0.73 ؎ 0.43 g/ml) than after repeated doses of ABLC (0.03 ؎ 0.02 g/ml) or D-AMB (0.13 ؎ 0.06 g/ml). No AMB was detected in noninflamed eyes. Following systemic administration, AMB distribution to the eye is inflammation dependent and occurs sequentially, first to the aqueous and then to the vitreous. Compared to D-AMB and ABLC, L-AMB reaches higher drug concentrations in both ocular compartments.Fungal endophthalmitis is a sight-threatening infection that is often difficult to treat. Intravenous amphotericin B (AMB), with or without additional 5-flucytosine, is considered the treatment of choice for severe systemic fungal infections and is often used as adjuvant treatment for intraocular infections caused by a wide range of fungi (24). The usefulness of this polyene, however, is limited by a number of adverse reactions (26), particularly its dose-limiting nephrotoxicity (12, 23). Renal insufficiency in association with azotemia, renal tubular acidosis, and impaired urinary concentrating capacity resulting in electrolyte imbalance often leads to dose reduction or premature discontinuation of the drug (5, 10). The lipid formulations of AMB now available for clinical use may offer therapeutic advantages. Due to their reduced nephrotoxicity and different pharmacodynamic properties, higher doses of the parent compound may be delivered to infected tissues (3, 17, 29).The exact mechanism responsible for the reduced toxicity of the lipid formulations is not yet known. A recent publication suggests that it may be related to lower concentrations of free AMB found in plasma after administration of lipid-associated AMB. The exposure to free and protein-bound AMB in subjects treated with liposomal AMB (L-AMB) was found to be approximat...

Ocular penetration of caspofungin in a rabbit uveitis model

“…On the contrary, caspofungin levels were lower in both aqueous and cornea than at the same interval after single-dose administration. This may be due to a decreasing intensity of LPS-induced uveitis over time in spite of the fact that higher endotoxin doses were used in the multiple-dose study [10]. There is no evidence that in the absence of fungal infection caspofungin may directly influence the host's immune response and thus modulate the intensity of, e.g., iatrogenic uveitis.…”

Tissue Penetration of Antifungal Agents

“…Penetration of AmBd into both the aqueous and vitreous of the infected eye was higher in the patient with rhinofacial disease and extensive retinal inflammation (fluid/serum concentration ratio of 0.4) than in the second patient, who had minimal retinal inflammation (ratio of 0.06). Penetration of all formulations of amphotericin B into the eyes of rabbits is also enhanced by inflammation (124,125,249). Indeed, amphotericin B is not detected in noninflamed eyes, even after multiple dosing of AmBd, ABLC, or L-AMB (16,124,125).…”

“…Penetration of all formulations of amphotericin B into the eyes of rabbits is also enhanced by inflammation (124,125,249). Indeed, amphotericin B is not detected in noninflamed eyes, even after multiple dosing of AmBd, ABLC, or L-AMB (16,124,125). Consequently, intracameral injection is the favored delivery route for these agents in patients with severe keratomycosis or endophthalmitis.…”

Interpretation of drug concentrations in an alternative matrix: the case of meprobamate in vitreous humor

“…To complete this descriptive study and to confirm the hypothesis concerning the transport mechanism of meprobamate through the blood-VH barrier, it could be interesting to conduct experimental studies as it has already been performed for ophthalmic drugs [26,27]. Since each drug has its own pharmacological and physicochemical properties, these results may not be transposable: other molecules should be studied with the same objectives before their VH concentrations can be interpreted.…”