Prolonged exposure to loteprednol etabonate in human tear fluid and rabbit ocular tissues following topical ocular administration of Lotemax gel, 0.5%.

PURPOSE: A new gel formulation containing loteprednol etabonate (LE), a C-20 ester corticosteroid used to treat ocular inflammation, was developed to provide increased retention on the ocular surface for improved drug delivery to intraocular tissues. This investigation evaluated concentrations of LE in tear fluid following topical instillation of LE gel to humans and the ocular and systemic pharmacokinetics of LE following administration to rabbits. METHODS: LE ophthalmic gel 0.5% was administered as a single topical dose to human volunteers (n=12) and Dutch Belted rabbits (n=40). In the human study, tear sampling was performed at 6, 9, 12, and 24 h after instillation. In the rabbit study, tears and ocular tissues were collected from 5 min through 24 h postdose. Serial blood samples were collected from one cohort of rabbits for plasma analysis. Concentrations of LE were determined by high performance liquid chromatography tandem mass spectrometry. RESULTS: In humans, LE was detected in tears at all the time points assessed with mean concentrations of 114 µg/g at 6 h declining to 2.41 µg/g at 24 h postdose. In rabbits, LE was detected in all ocular tissues within 5 min after dosing. Maximum concentrations of LE were achieved within 0.5 h and were highest in tear fluid (1560 µg/g), followed by bulbar conjunctiva (4.03 µg/g), cornea, (2.18 µg/g), iris/ciliary body (0.162 µg/g), and aqueous humor (0.0138 µg/mL). LE remained measurable in all ocular tissues through 24 h with the exception of aqueous humor. In contrast, plasma levels of LE were low with no detectable levels after 4 h. CONCLUSIONS: The gel formulation of LE provided prolonged exposure to LE on the ocular surface, with measurable levels in tears through 24 h in both humans and rabbits, for delivery of LE to anterior segment tissues, as evidenced by sustained levels of LE in rabbit conjunctiva, cornea, and iris/ciliary body.

Efficacy and safety of loteprednol etabonate 0.5% gel in the treatment of ocular inflammation and pain after cataract surgery.

PURPOSE: To examine the efficacy and safety of a new gel formulation loteprednol etabonate 0.5% in the treatment of inflammation and pain after cataract surgery. SETTING: Seventeen United States clinical sites. DESIGN: Prospective double-masked parallel-group study. METHODS: Patients with anterior chamber cell (ACC) grade 2 or higher after cataract surgery were randomized to loteprednol etabonate 0.5% gel or vehicle 4 times a day for 14 days. Primary outcome measures included the proportion of patients with complete resolution of ACC and grade 0 (no) pain on postoperative day 8. Safety measures included adverse events, intraocular pressure (IOP), visual acuity, biomicroscopy and funduscopy findings, and tolerability (ocular symptoms and drop comfort). RESULTS: The intent-to-treat population included 406 patients (203 per treatment). On day 8, 30.5% of patients in the loteprednol etabonate group and 16.3% of patients in the vehicle group had complete resolution of ACC, whereas 72.9% and 41.9%, respectively, had grade 0 pain (both P<.001). Significant treatment differences for complete resolution of ACC and grade 0 pain favoring loteprednol etabonate were also found on day 15 and day 18. One patient in each treatment group had a significant increase in IOP (≥ 10 mm Hg). Analyses of pain, photophobia, and tearing favored loteprednol etabonate at different time points beginning on day 3. More than 85% of patients in each treatment group reported no discomfort on drop instillation. CONCLUSION: Loteprednol etabonate gel 0.5% was efficacious and safe in treating postoperative inflammation and pain. FINANCIAL DISCLOSURE: Dr. Rajpal is a consultant to Bausch & Lomb, Inc., Allergan, Inc., and Alcon Laboratories, Inc. Dr. Siou-Mermet and Ms. Erb are employees of Bausch & Lomb, Inc. Dr. Roel has no financial or proprietary interest in any material or method mentioned.

Loteprednol etabonate gel 0.5% for postoperative pain and inflammation after cataract surgery: results of a multicenter trial.

PURPOSE: Loteprednol etabonate (LE) is approved by the US FDA in a suspension and ointment form (0.5%) for the treatment of postoperative ocular inflammation. This study examined the gel formulation of LE, an improved, nonsettling formulation with a lower preservative level and a more physiologic pH. PATIENTS AND METHODS: This multicenter, double-masked, parallel-group, vehicle-controlled study randomized patients aged ≥18 years with postoperative anterior chamber cell (ACC) ≥ grade 2 following uncomplicated cataract surgery to either LE gel or vehicle four times a day for 14 days. Primary efficacy end points included the proportion of patients with complete resolution of ACC and grade 0 (no) pain by postoperative day 8. Secondary efficacy end points included complete resolution and change from baseline in ACC and flare (individual and combined), and grade 0 pain at each visit. Safety end points included treatment-emergent adverse events, ocular symptoms, changes in intraocular pressure (IOP) and visual acuity, and biomicroscopy and funduscopy findings. RESULTS: A total of 407 patients were randomized to treatment (n = 206, LE gel; n = 201, vehicle). At day 8, 31.1% (64) of LE-treated patients and 13.9% (28) of vehicle-treated patients had complete resolution of ACC (P < 0.001), and 75.7% (156) of LE-treated patients and 45.8% (92) of vehicle-treated patients had grade 0 pain (P < 0.001). Secondary efficacy end points also favored LE gel. Fewer patients treated with LE gel required rescue medication (10.7% versus 42.3%) prior to day 15, and fewer had an ocular adverse event (16.0% versus 28.9%, P = 0.002). No drug-related adverse effects were reported more than once in the LE group. Mean IOP decreased in both treatment groups; one patient in the LE group demonstrated a clinically significant increase (≥10 mm Hg) in IOP that was not considered drug-related. Visual acuity and funduscopy findings were similar between treatments. CONCLUSION: LE gel 0.5% was efficacious and safe in treating postoperative inflammation and pain in this clinical study.

A multicentre, double-masked, randomized, controlled trial assessing the effect of oral supplementation of omega-3 and omega-6 fatty acids on a conjunctival inflammatory marker in dry eye patients.

PURPOSE: To determine whether oral supplementation with omega-3 and omega-6 fatty acids can reduce conjunctival epithelium expression of the inflammatory marker human leucocyte antigen-DR (HLA-DR) in patients with dry eye syndrome (DES). METHODS: This 3-month, double-masked, parallel-group, controlled study was conducted in nine centres, in France and Italy. Eligible adult patients with mild to moderate DES were randomized to receive a placebo containing medium-chain triglycerides or treatment supplement containing omega-3 and omega-6 fatty acids, vitamins and zinc. Treatment regimen was three capsules daily. Impression cytology (IC) was performed at baseline and at month 3 to assess the percentage of cells expressing HLA-DR and to evaluate fluorescence intensity, an alternate measure of HLA-DR. Dry eye symptoms and objective signs were also evaluated. Analyses were performed on the full analysis set (FAS) and per-protocol set (PPS). RESULTS: In total, 138 patients were randomized; 121 patients with available IC were included in the FAS, and of these, 106 patients had no major protocol deviations (PPS). In the PPS, there was a significant reduction in the percentage of HLA-DR-positive cells in the fatty acids group (p = 0.021). Expression of HLA-DR as measured by fluorescence intensity quantification was also significantly reduced in the fatty acids group [FAS (p = 0.041); PPS (p = 0.017)]. No significant difference was found for the signs and symptoms, but there was a tendency for improvement in patients receiving the fatty acids treatment. CONCLUSION: This study demonstrates that supplementation with omega-3 and omega-6 fatty acids can reduce expression of HLA-DR conjunctival inflammatory marker and may help improve DES symptoms.

Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans.

PURPOSE: Studies were conducted to evaluate the ocular penetration and systemic exposure to besifloxacin, a fluoroquinolone antibiotic, following topical ocular administration to animals and humans. METHODS: Besifloxacin ophthalmic suspension (0.6%) was administered as a topical ocular instillation to pigmented rabbits, cynomolgus monkeys, and human subjects. At predetermined intervals after dosing, samples of ocular tissues and plasma were collected and analyzed for besifloxacin levels using HPLC/MS/MS methods. RESULTS: Besifloxacin demonstrated good ocular penetration in rabbits and monkeys, with rapid absorption and sustained concentrations observed in anterior ocular tissues through 24 h after a single administration. Maximum besifloxacin concentrations in conjunctiva, cornea, and aqueous humor of monkeys were 6.43 microg/g, 2.10 microg/g, and 0.796 microg/mL, respectively, after a single topical dose, and concentrations declined in these tissues with an apparent half-life of 5-14 h. Following a single topical ocular administration to humans, the maximum besifloxacin concentration in tears was 610 microg/g with concentrations decreasing to approximately 1.6 microg/g at 24 h. The resulting pharmacokinetic parameters for besifloxacin in human tears were evaluated relative to the MIC(90) values (microg/mL) for besifloxacin against Streptococcus pneumoniae (0.125), Staphylococcus aureus (0.25), Staphylococcus epidermidis (0.5), and Haemophilus influenzae (0.06). Following a single topical administration, the C(max)/MIC(90) ratios for besifloxacin in human tears were > or =1,220, and the AUC((0-24))/MIC(90) ratios were > or =2,500 for these relevant ocular pathogens. Following repeated 3-times daily (TID) topical ocular administration to human subjects with clinically diagnosed bacterial conjunctivitis, maximum besifloxacin concentrations in plasma were less than 0.5 ng/mL, on average. CONCLUSIONS: Taken together, the results of the current investigation provide a PK/PD-based rationale that supports the use of besifloxacin for the safe and effective treatment of ocular infections.