The Effect of Corneal Thickness on Ocular Drug Penetration Yossi Yatziv MD1, Michael Regenbogen1, Moshe Lazar MD1 The authors have no financial interest in the subject matter of this poster 1. Department of Ophthalmology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv Israel

INTRODUCTION The Ocular Hypertension Treatment Study (OHTS), a large, multicenter randomized investigation, showed that topical ocular hypotensive medication was effective in delaying or preventing the onset of primary open angle glaucoma (POAG) in individuals with elevated intraocular pressure (IOP) (1). This study examined several risk factors for the development of POAG in individuals with ocular hypertension (OHT): among these parameters was central corneal thickness (CCT) which was found to be a powerful predictor for the development of POAG (2). Brandt et al (3) investigated the relation between CCT and the IOP response to topical ocular hypotensive medication in an OHTS population. The authors concluded that individuals with thicker corneas had smaller measured IOP responses to ocular hypotensive medication than those with normal or thin corneas. One of the proposed mechanisms by which CCT might influence the measured response was limitation of penetration of topical drugs in thicker corneas via mechanical or enzymatic mechanisms.

The degree of corneal penetration by topical medication can be measured either directly or indirectly. Two studies investigated the effect of corneal thinning on the penetration of topical tropicamide. Both studies used indirect methods to determine the degree of drug penetration into the eye; dilating drops were instilled onto the eye and degree of pupil dilation was used as an indirect indicator of drug penetration. (4,5). In the current study, we applied a direct method; in eyes of patients before cataract surgery CCT was measured and topical vancomycin at the beginning of the operation a small amount of anterior chamber fluid was aspirated and then analyzed for vancomycin concentration. The aim of this study was to examine if a correlation exists between the CCT and the degree of vancomycin penetration into the eye.

MATERIALS AND METHODS This prospective study included 66 eyes of 66 patients undergoing cataract surgery in our department. Prior to surgery all subject underwent complete ocular examination, on the day of surgery, CCT was measured using ultrasonic pachymetry. In addition to the routine application of topical mydriatics (tropicamide 0.5% , phenylephrine Hcl 10%), about 30 minutes prior to entering the operation room three drops of topical Vancomycin 50 mg/ml were instilled in the eye one every 10 minutes and after the last drop the patient was taken to surgery.

Before beginning surgery 0. 1-0 Before beginning surgery 0.1-0.3 ml of aqueous humor was aspirated from the anterior chamber using a 1 cc syringe with a 25 gauge needle. The patients then proceeded to undergo standard cataract operation. The aspirated fluid was analyzed for vancomycin concentration.

METHODS- Stataistics Association between vancomycin and several clinical factors was assesses using Pearson correlation coefficient for continuous variables (age ,CCT and time ) and two-sample t-test for binary variables (gender, eye side). Multiple linear regression analyses were performed including age gender eye and time to determine whether there was an independent effect of CCT on vancomycin, after controlling for all other factors.

RESULTS The 66‑patient cohort included 34 (52%) females and 32 (48%) males whose mean age was 73.8 years (range 40-95). The average time between the first drop instilled and the aspiration of the anterior chamber fluid was 30.1 minutes (range: 24-60 minutes) The mean CCT as measured by ultrasound pachymetry was 541.2  (range: 458-635). The concentration of Vancomycin in the aqueous humor was measured in 57 of the 66 eyes. In 9 eyes the measurement was cancelled due to insufficient amount of fluid. The mean Vancomycin concentration measured was 0.234 mcg/ml (range 0-0.80). When comparing the penetration of Vancomycin into the anterior chamber with the central corneal thickness measured by ultrasound pachymetry applying a regression analysis- no correlation between the two parameters was found (Graph 1).

Correlation between corneal thickness as measured by ultrasound and vancomycin concentration in the anterior chamber. 450 500 550 600 650 0.0 0.3 0.6 0.9 Vancomycin (mcg/ml)) CCT p=0.936

DISCUSSION The impact of corneal thickness has become a focus of interest and research in the field of intraocular pressure and glaucoma over the past few years. It has become common practice to measure CCT in OHT patients as an integral part of glaucoma risk assessment. Moreover, recent studies suggest that individuals with thicker corneas are more resistant to topical antihypertensive treatment (3), but the pathogenetic mechanism responsible for this remains unclear.

DISCUSSION It is known that the corneal epithelium and stroma are major influences in drug penetration. Several studies investigated the influence of the change in corneal thickness and the degree of drug penetration among individuals before and after refractive corneal thinning procedures (4,5). Their findings were inconsistent.

DISCUSSION To the best of our knowledge, this is the first investigation measuring the correlation between the CCT and the penetration of a topical drug measured directly. As shown in graph 1, penetration of vancomycin is not influenced by the corneal thickness as measured by ultrasound pachymetry. As seen in our results the degree of drug penetration varies considerably between the subjects, the thickness of the cornea is not a factor influencing the penetration of topical applied vancomycin drops into the anterior chamber. We suspect that other various physiological or environmental reasons are responsible for this variation but this remains to be investigated.

BIBLIOGRAPHY Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:701-713. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:714-720. Brandt JD, Beiser JA, Gordon MO, et al., Ocular Hypertension Treatment Study (OHTS) Group. Central corneal thickness and measured IOP response to topical ocular hypotensive medication in the Ocular Hypertension Treatment Study. Am J Ophthalmol 2004;138:717-722. 4. Nemet A, Morad Y. Does photorefractive keratectomy alter the effect of topical medications? Ophthalmologica 2002;216:430-433. 5. Chung HS, Feder RS. Pupil response to tropicamide following laser in situ keratomileusis. J Cataract Refract Surg 2005;31:553-556.