Open-Label Study of Absorption and Clearance of 1% Voriconazole Eye Drops

Abstract

h Twenty participants undergoing elective cataract surgery received 1% voriconazole eye drops (1 drop per eye) either 20, 40, 60, or 80 min before surgery. Median voriconazole concentrations of 1.9 to 3.2 mg/liter in aqueous humor samples were attained over the first 80 min, which were higher than in vitro MIC 90 values for typical fungi that cause keratitis. Fungal keratitis remains one of the most difficult-to-treat corneal infections and accounts for approximately 50% of infectious keratitis cases in developing countries (1). The filamentous fungi Aspergillus and Fusarium spp. are the two most frequently encountered causative pathogens (2).Voriconazole is increasingly used as a first-line treatment for ocular fungal infections (3) given its excellent in vitro activity against a wide variety of keratitis isolates (4), including less common fungi (e.g., Curvularia and Acremonium spp.). Topically administered 1% and 2% voriconazole eye drops have been documented to achieve good intraocular penetration in noninflamed (5, 6) and inflamed eyes (7). However, the voriconazole concentrations observed in the aqueous humor samples of patients receiving 2% voriconazole eye drops (6) were similar to that reported for the 1% voriconazole eye drops (5) when the same dosing frequency was used (i.e., total of four once-hourly doses). This suggests that increasing the concentration of voriconazole eye drops from 1% to 2% does not result in higher voriconazole concentrations in the aqueous humor of noninflamed human eyes. The extent of voriconazole clearance from the eye after topical administration might have been the key factor behind this observation, but this issue has largely remained unexplored, except in a recent ocular kinetic study by Senthilkumari et al. (8); therefore, data on this remain limited. The availability of such data is important for optimizing the dosing of voriconazole eye drops. Accordingly, we investigated the change in voriconazole concentrations in the aqueous humor of human eyes over time after topical administration of 1% voriconazole eye drops.Between April 2009 and April 2011, participants who were Ն18 years old and were scheduled for elective cataract surgery at the Royal Victorian Eye and Ear Hospital (RVEEH) were recruited. Excluded were subjects with a history of inflammation of the eye (uveitis) to undergo surgery, with a history of kidney or liver failure, who were breastfeeding, pregnant, or trying to conceive, who had an allergy to voriconazole or benzalkonium chloride, or who were using medications known to interact with voriconazole. Written informed consent was obtained from participants prior to enrollment. The study was approved by the ethics committees of RVEEH and Monash University.One-percent voriconazole eye drops were prepared aseptically from Vfend injections as previously described (6). All eye drops were stable for at least 14 weeks when stored at 2 to 8°C (9). Consenting participants each received a single drop (50 l) of 1% voriconazole to the eye to undergo surgery 20 min (a...

Administration of 1% topical voriconazole drops was effective and safe in the treatment of refractory otomycosis without tympanic membrane perforation

“…14 Although there are still no topical voriconazole agents, 1% or 2% voriconazole, which is prepared by mixing voriconazole powder and sterile water, has been proven effective and safe in the treatment of fungal keratitis. 15,16…”

Evaluation of voriconazole anti-Acanthamoeba polyphaga in vitro activity, rat cornea penetration and efficacy against experimental rat Acanthamoeba keratitis

“…20 Accordingly, corneal voriconazole concentrations were found to be equivalent, after a regimen of eye drops every 2 h, to that in the aqueous humour of humans, 20 and elevated aqueous humour concentrations were rapidly obtained after eye instillation in humans. 18 In topically treated rats, plasma concentrations were close to those in healthy horses 21 and presumably lower than those associated with adverse side effects in humans. 22 Owing to ethical constraints, one eye of each rat was infected.…”

“…In an AK rat model, topical and oral voriconazole doses were determined according to previous studies in humans. 18 Eye-drop treatment from day 7 p.i. reduced AK lesion worsening from day 7 to day 14 p.i.…”

Drug reservoir function of voriconazole impregnated human amniotic membrane: An in vitro study

“…[ 25 ] Topically administered 1% voriconazole eye drops have been documented to achieve good intraocular penetration in non-inflamed and inflamed eyes. [ 23 26 27 28 ] It is evident from these studies that 1% voriconazole eye drops offered sufficient voriconazole concentrations in the aqueous humor which is above the MIC 90 (0.06 – 8 mg/L) for most fungal species. [ 29 ] However, a large filamentous fungal susceptibility study using ocular isolates from keratitis cases in South India showed that MIC 90 of voriconazole for the Fusarium isolates were in the range of 0.13 to >64 mg/ml as compared to natamycin whereas the in vitro activity of voriconazole against A. flavus isolates were in the range of 0.13 -8 mg/ml.…”