Aqueous Humor Concentrations of Topically Administered Caspofungin in Rabbits

Abstract

Background: The echinocandin caspofungin (CAS) is a novel antifungal drug with fungicidal in vitro activity against all Candida spp., which are the most frequent cause of fungal keratitis. Penetration of CAS through the cornea into the aqueous humor after topical administration was investigated. Methods: A CAS solution with a concentration of 7 mg/ml was applied onto each rabbit’s cornea. Drug application after corneal epithelium abrasion was processed in different time intervals: single application with aqueous humor sampling after 1 and 2 h. In addition, after continuous application of CAS every 30 min, aqueous humor concentrations of CAS after 1, 2 and 5 h were analyzed by liquid-chromatography tandem mass spectrometry. Results: Topical administration of CAS without corneal epithelium abrasion resulted in no detectable amounts of the drug in the aqueous humor. However, with corneal abrasion, after a single application, levels of 2.16 ± 1.57 μg/ml (n = 6) were reached after 1 h and then decreased to 1.76 ± 0.88 μg/ml (n = 2) after 2 h. After serial application every 30 min, the following intracameral levels of CAS were detected: after 1 h, 2.11 ± 1.09 μg/ml (n = 6); after 2 h, 4.94 ± 1.80 μg/ml (n = 5), and after 5 h, 3.45 ± 2.11 μg/ml (n = 6). Conclusion: In the aqueous humor, therapeutic drug levels can be reached that cover the MICs of most fungi after epithelial abrasion. To achieve a sustained high level of CAS as an effective antifungal therapy for corneal keratitis, CAS should be administered topically every 30 min after removal of the corneal epithelium.

Penetration of Topically Administered 0.5-Percent Caspofungin Eye Drops into Human Aqueous Humor

“…This study is the first to demonstrate that topically administered caspofungin penetrates into uninflamed human eyes, in contrast to results from previous animal studies (10,23). The difference could be due to the use of a more sensitive analytical assay (limit of quantification [LOQ], 10 ng/ml) (17) than that used in the earlier study (LOQ, 50 ng/ml) (10).…”

“…While the concentrations observed were below the MIC 90 for most fungal species (15,23), topical caspofungin may still be useful for fungal keratitis. Disruption of the corneal surface or inflammation in rabbit models has resulted in higher caspofungin concentrations in aqueous humor after systemic or topical administration (10,23). As the cornea is the primary site of infection in keratitis, high corneal concentrations of antifungal agents are desirable.…”

“…Compounds of Ͼ500 Da experience difficulty penetrating the intact corneal epithelium after topical administration due to frictional force that reduces diffusion (16). While the concentrations observed were below the MIC 90 for most fungal species (15,23), topical caspofungin may still be useful for fungal keratitis. Disruption of the corneal surface or inflammation in rabbit models has resulted in higher caspofungin concentrations in aqueous humor after systemic or topical administration (10,23).…”

“…Caspofungin has activity against a wide range of fungi, with MIC 90 values ranging from 60 to 2,000 ng/ml (15,23). Caspofungin eye drops are effective for treatment of fungal keratitis in rabbits (11,18) and have good penetration into animal eyes with inflammation or previous corneal abrasion (10,23).…”

“…Caspofungin eye drops are effective for treatment of fungal keratitis in rabbits (11,18) and have good penetration into animal eyes with inflammation or previous corneal abrasion (10,23). Clinically, caspofungin is administered mostly intravenously (1,4,6,9,19,20) or intravitreally (24) for ocular mycosis.…”