Kamran Hosseini

Pharmacokinetic Comparisons of Bromfenac in DuraSite and Xibrom

PURPOSE The purpose of this study was to compare the ocular pharmacokinetics of experimental solutions of bromfenac in DuraSite(®) to Xibrom™ (bromfenac ophthalmic solution) 0.09%. METHODS The bromfenac content was measured in the aqueous humor of 84 Dutch Belted rabbits after a single dose of either 0.045% or 0.09% bromfenac in DuraSite in the left eye and the commercial preparation in the right eye. The drug content in the aqueous humor was measured at 0.5, 1, 2, 4, 8, 12, and 24  h after instillation. In a separate multi-dose study, rabbits received one drop of the 0.09% experimental or commercial preparation, 3 times daily for 14 days. For both experiments the drug content in ocular tissues was analyzed using liquid chromatography atmospheric pressure ionization tandem mass spectrometry. RESULTS In single-dose experiments, the concentration of bromfenac in the aqueous humor was higher with the experimental preparations than with the commercial solution. The area under the concentration-time curve of 0.045% and 0.09% bromfenac in DuraSite was ∼2 and 4-fold higher than that of commercial bromfenac ophthalmic solution, 0.09%. After multi-dose experiments, ocular tissue concentrations of bromfenac were ∼3 times higher for the experimental than for the commercial formulation. CONCLUSIONS The study demonstrates that the DuraSite topical drug delivery system can deliver bromfenac to various ocular tissues and attain considerably higher concentrations than the commercially available eye drop formulation. The higher aqueous concentration sustained with these experimental formulations could broaden the utility of bromfenac and/or reduce the currently approved dosing frequency of this drug.

Anti-inflammatory Activity of Azithromycin as Measured by Its NF-кB Inhibitory Activity

Growing data suggest that the antibiotic azithromycin mediates anti-inflammatory activity through the inhibition of the transcription factor NF-кB. The purpose of this study was to compare azithromycin’s anti-inflammatory potency with that of hydrocortisone and dexamethasone as measured in an activated NF-кB assay. Dose–response curves and the corresponding inhibitory potencies (IC50) of azithromycin, hydrocortisone, and dexamethasone were evaluated in a fluorescence assay using A549 cells. All three compounds inhibited TNFα stimulated NF-кB activity in a dose-dependent manner. IC50 values of azithromycin, hydrocortisone and dexamethasone were 56 µM, 2.6 nM, and 0.18 nM, respectively. Hydrocortisone was approximately 4 orders of magnitude more potent than azithromycin, while dexamethasone was approximately 14 times as potent as hydrocortisone. In relative terms the anti-inflammatory potency of azithromycin was about 4 orders of magnitude weaker than that of hydrocortisone.

Ocular Pharmacokinetics of AzaSite Xtra—2% Azithromycin Formulated in a DuraSite Delivery System

Purpose: The pharmacokinetics of a 2% ocular solution of azithromycin in DuraSite was evaluated in rabbits to determine whether the PK/PD parameters support a once-a-day for three-day therapeutic regimen against bacterial conjunctivitis. Materials and Methods: Mean levels of azithromycin were determined in tears, bulbar conjunctiva, cornea, and plasma following a single drop of 2% azithromycin. The levels were determined by HPLC-MS. Results: Concentrations of azithromycin peaked at 30 minutes. At the end of 24 hours, ocular tissue concentrations exceeded the MIC breakpoint for the most common causative pathogens of bacterial conjunctivitis by at least 7-fold. Conclusion: The PK/PD profile of 2% azithromycin suggests efficacy against common causative bacteria with just one dose per day for three days.

A randomized, double-masked, parallel-group, comparative study to evaluate the clinical efficacy and safety of 1% azithromycin–0.1% dexamethasone combination compared to 1% azithromycin alone, dexamethasone 0.1% alone, and vehicle in the treatment of subjects with blepharitis

Purpose To evaluate the clinical efficacy and safety of a 1% azithromycin–0.1% dexamethasone combination in DuraSite (“combination”) compared to 0.1% dexamethasone in DuraSite, 1% azithromycin in DuraSite, and vehicle in the treatment of subjects with blepharitis. Materials and methods This was a Phase III, double-masked, vehicle-controlled, four-arm study in which 907 subjects with blepharitis were randomized to combination (n=305), 0.1% dexamethasone (n=298), 1% azithromycin (n=155), or vehicle (n=149). Ten study visits were scheduled: screening visit, days 1 and 4 (dosing phase) and 15, and months 1–6 (follow-up phase). On day 1, subjects applied one drop of the study drug to the eyelid of the inflamed eye(s) twice daily, and continued with twice-daily dosing for 14 days. After completing 14 days of dosing, subjects were followed for 6 months for efficacy and safety. Results A total of 57 subjects (6.3%) had complete clinical resolution at day 15: 25 (8.2%), 17 (5.7%), 8 (5.2%), and 7 (4.7%) subjects in the combination-, 0.1% dexamethasone-, 1% azithromycin-, and vehicle-treatment groups, respectively. The combination was superior to 1% azithromycin and vehicle alone, but not to 0.1% dexamethasone alone. Mean composite (total) clinical sign and symptom scores improved in all four treatment groups during the post-treatment evaluation phase for the intent-to-treat population, but outcomes were superior when a drop containing 0.1% dexamethasone was utilized. Clinical response was noted as early as day 4, and persisted as long as 6 months. Most adverse events were considered mild in severity and not related to the study drug. Conclusion A higher percentage of subjects in the combination group achieved complete clinical resolution of the signs and symptoms of blepharitis at day 15 than with 1% azithromycin and vehicle, but outcomes were similar to treatment with 0.1% dexamethasone alone. The combination was well tolerated.

Noninvasive detection of ganciclovir in ocular tissue by Raman spectroscopy: Implication for monitoring of drug release

UNLABELLED Treatment of various pathological conditions in ophthalmology, such as cytomegalovirus (CMV) retinopathy and endophthalmitis, requires a local drug intervention rather than a systemic approach. Accurate knowledge of intraocular drug concentration can permit the ophthalmologist to maintain drug levels within the therapeutic levels necessary for an optimal prognosis, while preventing or minimizing toxicity associated with drug overdose. PURPOSE To develop a noninvasive/noncontact method for quantification of the local concentration of ganciclovir in the ocular media. METHODS An integrated CCD-based Raman spectroscopic system designed specifically for ophthalmic applications was used to noninvasively detect the presence of ganciclovir in the ocular media. Various known concentrations of ganciclovir were injected into the aqueous humor of rabbit eyes in a pilot study, in vivo. Raman spectra were then acquired by focusing an argon laser beam within the anterior chamber of the eye. The specific Raman signature of ganciclovir was assessed at several concentrations. RESULTS Spectral features unique to ganciclovir were identified and distinguished from those of ocular tissue. The amplitudes of the spectral peaks corresponding to ganciclovir exhibited a linear dependence on the local concentration of the drug in the anterior chamber of the eye. CONCLUSION Raman spectroscopy may offer an effective tool for the noninvasive assessment of the local concentration of ganciclovir in the ocular media. This technique offers the potential to determine both the amount and the rate of the drug release from implants designed to deliver antiviral drugs locally within the eye. The availability of such data could enable the ophthalmologist to improve treatment efficacy by avoiding premature or late surgical replacement of the implants.

Ocular pharmacokinetics of bimatoprost formulated in DuraSite compared to bimatoprost 0.03% ophthalmic solution in pigmented rabbit eyes

Purpose To compare the aqueous humor (AH) and iris-ciliary body (ICB) concentration of bimatoprost in rabbit eyes treated with ISV-215 (0.03% bimatoprost formulated in DuraSite) with the marketed product bimatoprost 0.03% ophthalmic solution. Methods The left eye of rabbits received a single topical instillation of either ISV-215 (n = 32 eyes) or bimatoprost 0.03% (n = 32 eyes). At predetermined time points, levels of bimatoprost and bimatoprost acid in the AH and the ICB were quantified by HPLC-MS/MS. Results Both bimatoprost and bimatoprost acid were detected in the AH and the ICB within 15 minutes of dosing. Bimatoprost acid concentrations in both compartments were markedly higher than bimatoprost. There was a statistically significant (P < 0.01) increase in the concentration of the prodrug in the AH and its acid form in the ICB in animals treated with ISV-215 compared to bimatoprost 0.03%. In the ISV-215-treated rabbit eyes, the highest concentrations of bimatoprost and bimatoprost acid were in the ICB and AH, respectively, while in the bimatoprost 0.03%-treated eyes, no differences in the drug content of the selected ocular tissues were observed. Conclusions Bimatoprost 0.03% formulated in DuraSite has superior ocular distribution and area under the curve compared to bimatoprost 0.03% in rabbit eyes. This improvement in the pharmacokinetic parameters of ISV-215 may provide us with a better platform to optimize a bimatoprost formulation that offers the same degree of efficacy in lowering intraocular pressure and improved therapeutic index in glaucomatous patients by lessening the ocular side effects associated with long-term use of topical prostaglandin F2α analogs.

Aqueous Humor Penetration of Ketorolac Formulated in DuraSite or DuraSite 2 Delivery Systems Compared to Acular LS in Rabbits

PURPOSE To evaluate the ocular penetration of ISV-304 (ketorolac tromethamine) formulated in DuraSite(®) or DuraSite(®) 2 compared to Acular LS(®) (0.4% ketorolac ophthalmic solution) in rabbits. METHODS The left eye of rabbits received a single topical instillation of either ISV-304 (0.2% and 0.4% ketorolac) in DuraSite, ISV-304 (0.2% and 0.4% ketorolac) in DuraSite 2, or Acular LS. At predetermined time points, aqueous humor (AH) levels of ketorolac were measured by HPLC-MS/MS, and Cmax, Tmax, and AUC0.25-24h were determined. RESULTS The highest mean concentration of ketorolac was achieved in ISV-304 (0.4%) formulated in DuraSite 2 with a Cmax value of 1889 ± 884 ng/mL, compared to Cmax values for ISV-304 (0.4%) formulated in DuraSite (1212 ± 435 ng/mL) or Acular LS (275 ± 83 ng/mL). ISV-304 (0.2%) formulations also achieved higher AH Cmax values (801 ± 205 ng/mL and 1077 ± 415 ng/mL) compared to Acular LS. There was a significant increase in drug exposure in the ISV-304 (0.4%) formulated in DuraSite 2 or DuraSite formulations with AUC0.25-24h values 6836 ng/mL*h and 5684 ng/mL*h, respectively, compared to Acular LS with an AUC0.25-24h value of 1424 ng/mL*h. ISV-304 (0.2%) formulations also had high AUC0.25-24h values (3241 ng/mL*h and 4490 ng/mL*h), which were a 2.3-3.2-fold increase over the Acular LS AUC0.25-24h value. CONCLUSIONS DuraSite and DuraSite 2 delivery systems markedly improved the ketorolac ocular pharmacokinetic parameters in rabbits. DuraSite formulations may lessen the side effects associated with topical nonsteroidal anti-inflammatory drug use by maintaining efficacy with a reduced dosing regimen and reduced active ingredient.

A randomized double-masked study to compare the ocular safety, tolerability, and efficacy of bromfenac 0.075% compared with vehicle in cataract surgery subjects

Purpose The aim of this study was to evaluate the safety, tolerability, and efficacy of a low-dose version of bromfenac 0.075% in DuraSite® (bromfenac 0.075%) compared with DuraSite® vehicle (vehicle) alone for the treatment of postoperative inflammation and ocular pain after cataract surgery. Methods A multicenter, double-masked, vehicle-controlled, parallel-group clinical trial of 240 subjects randomized in a 2:1 ratio to bromfenac 0.075% or vehicle was conducted. Subjects were dosed BID beginning 1 day before the cataract surgery, the day of surgery, and 14 days after surgery. A slit lamp biomicroscopy examination was performed to evaluate the signs of inflammation, including anterior chamber cells (ACC) and anterior chamber flare (ACF). The primary efficacy variable was the proportion of subjects with an ACC grade of 0 at Day 15. Secondary efficacy endpoints included the proportion of subjects who achieved a pain score of 0 at each postsurgical visual analog scale (VAS) assessment and the proportion of subjects with an ACF grade of 0 at Day 15. Results At Day 15, proportionally more subjects in the bromfenac 0.075% group than in the vehicle group had an ACC grade of 0 (57.1% vs 18.8%, respectively; P<0.001). At each of the postsurgical time points (Days 1, 8, 15, and 29), proportionally more bromfenac 0.075%-treated subjects (76.8%, 90.5%, 92.9%, and 85.1%, respectively) had no pain (a VAS score of 0) compared with the vehicle-treated subjects (48.2%, 38.8%, 42.4%, and 47.1%, respectively), and at each time point, these differences in proportions were statistically significant (P<0.001). More subjects in the bromfenac 0.075% group had complete ACF resolution (151/167; 90.4%) compared to those in the vehicle group (54/85; 63.5%). There were no new safety signals reported. Conclusion Bromfenac 0.075% in DuraSite is safe, well tolerated, and effective at reducing inflammation and preventing pain associated with cataract surgery.

In vivo OCT assessment of rabbit corneal hydration and dehydration

The knowledge of water content of the cornea (hydration level H) can provide crucial information for the assessment of corneal function. The correlation between the corneal thickness and its hydration enables us to estimate H indirectly by measuring changes in corneal thickness and scattering using OCT. The magnitude and axial distribution of the backscattering signal from the cornea yields additional information about the hydration gradient across the cornea. We present data on the effect of corneal hydration on its thickness and scattering in natural processes of de- and rehydration, as well as in stress tests with the use of glycerol-based dehydrating agent Ophthalgan. Our data demonstrate that scattering signal changes up to 50 times when corneal thickness varies from 60% to 200% of its normal state. The distribution of scattering intensity across the cornea also depends on the hydration level and gradient of the water distribution. Thus, OCT can provide a noninvasive and non-contact method for safe and fast measurement of thickness and optical properties of the cornea, and therefore, for estimation of corneal hydration level and corneal function.

Development and evaluation of a measure of patient-reported symptoms of Blepharitis

BackgroundBlepharitis is an ocular surface disease and chronic ophthalmic condition. This paper reports on the development of psychometric evaluation of a patient-reported measure of blepharitis symptoms.MethodsSelf-reports of 13 blepharitis symptoms collected in a Phase 3 multi-site, randomized, double-masked, 4-arm parallel group, clinical trial of 907 individuals with blepharitis (mean age = 62, range: 19–93; 57% female) were analyzed. Symptoms asked about were: eyes that itch; eyes that burn; eyelids feel heavy or puffy; feel like something is in your eye; dry eyes; gritty eyes; irritated eyes; eyes that tear or water; crusty eyes; flaking from your eyelids; eyelids that are stuck together; red eyes or eyelids; and debris like pieces of skin or dandruff in your eyes.ResultsCategorical factor analyses provided support for two multi-item symptom scales: Irritation (9 items, alpha = 0.88) and Debris (4 items, alpha = 0.85). Spearman-rank order correlations of the Irritation and Debris scales with the Ocular Surface Disease total score were 0.63 and 0.41, respectively (p’s < 0.001). Rank-order correlations between ratings of clinicians and self-reports of puffy eyes (r = 0.07, p < .05), red eyes (r = 0.12, p < .001), debris (r = 0.03, p > 0.05), and irritation (r = 0.47, p < .001).ConclusionsThis study provides support for the psychometric properties and construct validity of the Irritation and Debris scales for assessing symptoms of blepharitis. The associations between the self-reports and clinician ratings of 4 symptoms indicate substantial unique information in the new self-reported symptom items.Trial registrationThe trial was registered at ClinicalTrials.gov under the registry number NCT01408082.