Alternative Drug Delivery for Patients Undergoing Cataract Surgery as Demonstrated in a Canine Model

Abstract

Purpose: (1) To determine ketorolac concentrations in selected ocular tissues following the intracameral administration of phenylephrine and ketorolac injection 1%/0.3% (OMIDRIA^®) delivered in irrigation solution during lens replacement surgery in beagle dogs. (2) To compare the ketorolac initial dose and resultant concentrations from the above study to those achieved in aqueous and vitreous by topical administration in patients undergoing cataract surgery or vitrectomy, respectively.

Methods: Lens replacement surgery with phacoemulsification was performed in 20 female beagle dogs. A fixed combination of phenylephrine and ketorolac injection 1%/0.3% was diluted 125-fold into the balanced salt solution and delivered intracamerally during the phacoemulsification procedure. Ketorolac concentration was determined by liquid chromatography/mass spectrometry.

Results: Concentrations of ketorolac when administered by the intracameral route in the dosing solution in dogs were found to be considerably higher in both aqueous and vitreous compared to what is achieved with topical dosing in patients.

Conclusions: Adequate therapeutic concentrations of ketorolac in aqueous and vitreous humor were achieved even at 10 h postdose. Critical concentrations in the aqueous that envelopes the iris/ciliary body, which are sites of prostaglandin E₂ synthesis, and the vitreous are not achieved by topical dosing in clinical studies after the surgery, but are by direct intracameral dosing as determined in this study. Based on these studies and clinical data, phenylephrine and ketorolac injection 1%/0.3% delivered during surgery as an irrigation solution may preclude the need for topically administered pre- and postoperative NSAIDs.

Keywords: NSAIDs; anti-inflammatory; cataract surgery; ketorolac; topical dosing.

FIG. 1.

Decline of ketorolac over a 10-h period after intracameral dosing with phenylephrine/ketorolac delivered in irrigation solution in lens replacement surgery in dogs. This figure shows the ketorolac concentration in ng ± SEMs at 0, 2, 6, 8, and 10 h of aqueous, iris/ciliary body, vitreous, choroid/RPE, and retina following lens implantation surgery in dogs after dosing with phenylephrine/ketorolac, delivered in irrigation solution. The final concentrations were 0.008% phenylephrine and 0.00024% ketorolac. In addition, the concentrations required to inhibit COX-1 and COX-2 by 50% are shown based on results using human recombinant COX-1 and COX-2. This suggests that sufficient levels of ketorolac are present in these tissues to inhibit both isoforms of COX-1 and COX-2 at time points studied. RPE, retinal pigment epithelium; SEM, standard error of the mean.

FIG. 2.

Ketorolac concentrations in aqueous humor at 2, 6, and 10 h after dosing with 0.008% phenylephrine and 0.00024% ketorolac compared with topical dosing. This figure shows concentrations of aqueous humor expressed as mean ng/mL ± SEM for time points 2, 6, 8, and 10 h after lens implantation surgery in dogs (4 samples/time point) using 0.008% phenylephrine and 0.00024% ketorolac delivered intracamerally through the irrigation solution. The next set of values (red bars) shows topical dosing (clinical study) at 1 and 6 h after dosing. This results in adequate concentrations to completely inhibit COX-1 (>90% inhibition) at these time points. As shown (green bars), topical dosing also achieves adequate aqueous levels before surgery. However, determinations with topical dosing followed by cataract surgery revealed a substantial loss of ketorolac, which was insufficient to inhibit COX-1 or COX-2^13,14 (human recombinant COX-1 and COX-2) bringing into question whether this is reflected in tissue levels such as in the iris/ciliary body as well.

FIG. 3.

Vitreous concentrations of ketorolac following dosing during lens replacement surgery in dogs and comparison with concentrations achieved by topical dosing. This figure shows ketorolac concentrations in the vitreous after dosing with 0.008% phenylephrine and 0.00024% ketorolac in irrigation solution during lens replacement surgery in dogs. Topical dosing 4 times with 0.4% ketorolac 3 days before vitrectomies did not achieve concentrations in the vitreous to significantly inhibit COX-1 or COX-2, suggesting that beneficial effects of ketorolac in patients in preventing cystoid macular edema are likely due to its effects in the anterior segment. These findings in this study were also extended to other NSAIDs, including bromfenac and nepafenac (amfenac). None of these drugs achieved inhibition exceeding 50% of PGE₂ concentrations in the published studies (results not shown). NSAIDs, nonsteroidal anti-inflammatory drugs.