<p>Comparative Assessment of Distribution Characteristics and Ocular Pharmacokinetics of Norvancomycin Between Continuous Topical Ocular Instillation and Hourly Administration of Eye Drop</p>

Abstract

Background: The aim of this study was to compare the distribution characteristics and ocular pharmacokinetics of norvancomycin (NVCM) in ocular tissues of the anterior segment between continuous topical ocular instillation and hourly administration of eye drop in rabbits. Methods: Sixty rabbits were randomly divided into two groups: continuous topical ocular instillation drug delivery (CTOIDD) group and eye drop (control) group. In the CTOIDD group, NVCM solution (50 mg/mL) was perfused to the ocular surface using the CTOIDD system at 2 mL/ h up to 10 h and the same solution was administered at one drop (50 μL) per hour for 10 h in the control group. Animals (N=6 per time-point per group) were humanely killed at 2, 4, 6, 10, and 24 h to analyze their ocular tissues and plasma. The concentrations of NVCM in the conjunctiva, cornea, aqueous humour, iris, ciliary body and plasma were measured by HPLC with photodiode array detector. The pharmacokinetic parameters were calculated by Kinetica 5.1. Results: The highest concentrations of NVCM for the CTOIDD group and control group were 2105.45±919.89 μg/g and 97.18±43.14 μg/g in cornea, 3033.92±1061.95 μg/g and 806.99 ±563.02 μg/g in conjunctiva, 1570.19±402.87 μg/g and 46.93±23.46 μg/g in iris, 181.94 ±47.11 μg/g and 15.38±4.00 μg/g in ciliary body, 29.78±4.90 μg/mL and 3.20±1.48 μg/mL in aqueous humour, and 26.89±5.57 μg/mL and 1.90±1.87 μg/mL in plasma, respectively. The mean NVCM levels significantly increased at all time-points in cornea, iris, and ciliary body (p<0.05) in the CTOIDD group. The AUC 0-24 values in the CTOIDD group were 27,543.70 μg•h/g in cornea, 32,514.48 μg•h/g in conjunctiva, 8631.05 μg•h/g in iris, 2194.36 μg•h/g in ciliary body and 343.9 μg•h/mL in aqueous humour, which were higher than for the eye drop group in all tissues. Conclusion: Since continuous instillation of NVCM with CTOIDD could reach significantly higher concentrations and was sustained for a longer period compared with hourly administration of eye drop, CTOIDD administered NVCM could be a possible method to treat bacterial keratitis.

Treatment of Severe Acute Bacterial Keratitis in Rabbits Using Continuous Topical Ocular Instillation with Norvancomycin

“…In our previous pharmacokinetic study, we used a CTOIDD system to deliver NVCM into the ocular surface to achieve a much higher drug concentration in the ocular tissue rapidly compared to hourly administration of eye drops in healthy rabbits. 17 In this current study, we explored the efficacy of CTOIDD of NVCM for treating severe acute bacterial keratitis infection with S. aureus . Rabbits with severe acute bacterial keratitis were treated with continuous instillation of NVCM solution (50 mg/mL) through CTOIDD for six hours per day in a one-week regimen.…”

“…The proximate end was closed, and the distal end connected with an auto-infusion pump. 17 General and topical anesthesia were the same as described in the “Induction of bacterial keratitis” subsection. The ring part was sutured to be fixed in the bulbar conjunctiva around the limbus ( Figure 2 ).…”

“…This device is characterized by automatic, controllable, and continuous instillation of drug solution to the ocular surface. 17 Norvancomycin (NVCM) is one of the glycopeptide antimicrobial agents, has similar antibacterial characteristics to vancomycin, and is an inexpensive alternative to vancomycin. 18–21 …”

“…In our previous pharmacokinetic study, we reported that the CTOIDD system provided higher concentrations of NVCM in nondiseased ocular tissues of rabbits compared to hourly administration of eye drops. 17 Thus, this study was designed to investigate the efficacy of NVCM through CTOIDD for treating severe acute bacterial keratitis infection with S. aureus in rabbits.…”