Afshin Shafiee

In vivo ocular efficacy profile of mapracorat, a novel selective glucocorticoid receptor agonist, in rabbit models of ocular disease.

PURPOSE To compare the efficacy of mapracorat (formerly ZK-245186, and subsequently BOL-303242-X), a novel selective glucocorticoid receptor agonist (SEGRA), with that of dexamethasone (DEX) in rabbit models of ocular disease. The effects of topical BOL-303242-X and DEX on intraocular pressure (IOP) and body weight changes were also evaluated. METHODS Dry eye was induced by atropine sulfate administration and was treated with saline, BOL-303242-X (0.1%-1.0%), DEX (0.1%), Restasis 0.05% (Allergan, Inc., Irvine, CA), or Refresh Endura (Allergan, Inc.) three times per day for 7 to 8 days. For paracentesis studies, vehicle, BOL-303242-X (0.1%, 0.5%, and 1.0%), or DEX (0.1%) were repeatedly administered topically 3 hours before paracentesis and continued for 90 minutes afterward. For IOP and body weight measurements, right eyes of rabbits were topically treated with vehicle, BOL-303242-X (1.0% or 0.1%), or DEX (0.1%) four times per day for 6 weeks. RESULTS In the dry eye model, BOL-303242-X and DEX were fully efficacious, maintaining tear volume and tear breakup time (TBUT) at baseline levels. Although Restasis improved tear volume compared with vehicle, no changes were observed in TBUT. In the paracentesis study, BOL-303242-X and DEX improved ocular inflammation. BOL-303242-X reduced protein and PGE(2) levels. Finally, BOL-303242-X showed no effects on integrated IOP or body weight, whereas DEX significantly increased integrated IOP and prevented the increase of body weight observed in the vehicle-treated animals. CONCLUSIONS BOL-303242-X shows full anti-inflammatory efficacy (similar to DEX) in experimental models of dry eye and postoperative inflammation while demonstrating reduced effects in IOP and body weight. These data indicate that mapracorat, a SEGRA, shows efficacy similar to that of traditional steroids while exhibiting an improved side effect profile in IOP and muscle wasting.

Experimental determination and allometric prediction of vitreous volume, and retina and lens weights in Göttingen minipigs.

OBJECTIVES To determine the vitreous volume, and retinal and lens wet weights in male and female Göttingen minipigs of different age groups. PROCEDURES Vitreous, lens and retina were isolated from fresh minipig eyes. Vitreous volume, lens and retina weight were measured and allometric scaling was utilized to predict these parameters. RESULTS There were no gender differences in body weights or retina and lens weights in the three age groups examined in this study. For vitreous volumes, females had a significantly larger volume (approximately 10%-12%) than males in the 4-6 and 6-8 month, but not in the 8-11-month group. The mean body weight increased from 12.2 +/- 2.6 kg (4-6 months) to 19.4 +/- 4.0 kg (8-11 months). In the same period, the mean vitreous volume increased from 2.00 +/- 0.28 to 2.67 +/- 0.31 mL, while the mean retinal and lens weights increased from 114 +/- 22 to 126 +/- 17 mg, and from 298 +/- 26 to 392 +/- 15 mg, respectively. Allometric analysis between six species for vitreous volume and four species for lens weight covering a weight range of 260-fold was not able to estimate the vitreous volume, but it did predict the lens weight in 8-11 months minipigs. CONCLUSIONS Overall these measurements add important context to intraocular pharmacology studies, and will help in the improved design and interpretation of such experiments.

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.