Purpose: To examine the pharmacokinetic characteristics of sustained-release dexamethasone depots in two separate canine studies.Methods: Dexamethasone depots loaded with a clinically representative (0.4 mg) dose (DEXTENZA™; Ocular Therapeutix) or an elevated (0.7 mg) dose were inserted into the canaliculi of beagle eyes (n = 37 and n = 34, respectively). Tear fluid was collected for pharmacokinetic analysis of dexamethasone in both studies at predetermined time points. Explanted 0.4 mg depots were collected weekly to measure remaining drug level. Clinical observations and ophthalmic examinations were performed in both studies at each visit.Results: The 0.4 mg depots released a median 308 μg by day 15 and tapered to complete drug release by day 28. Median dexamethasone tear fluid concentrations in the 0.4 mg study group decreased from 2,805 ng/mL at day 7 to 0 ng/mL on day 28. Median dexamethasone tear fluid concentrations in the 0.7 mg study group decreased from 4,370 ng/mL at 6 h post insertion to 830 ng/mL on day 35. Mean ± standard deviation intraocular pressures in the 0.4 and 0.7 mg study groups were 20.7 ± 2.8 and 19.0 ± 4.1 mmHg at baseline, respectively, and demonstrated no meaningful change (20.5 ± 3.0 and 20.6 ± 2.9 mmHg, respectively) over the studies' durations. No ocular toxicities were attributed to the dexamethasone depot.Conclusion: Sustained-release dexamethasone produced no identifiable ocular toxicity in this animal model, and pharmacokinetics demonstrated a sustained and tapered drug release over 28 days at a 0.4 mg dose and exceeded 35 days at a 0.7 mg dose.

Ocular Therapeutix.

No abstract

Aim: Despite advances in cataract surgery, postoperative ocular inflammation and pain occurs. To address compliance issues with topical corticosteroid administration, a hydrogel-based dexamethasone insert was developed for intracanalicular administration. The objective is to understand the anatomy to best administer the insert and learn how the anatomy and hydrogel properties help retain the insert in the canaliculus over time. Materials & methods: Human cadavers (n = 5) were dissected to assess dimensions of punctum and canaliculus as part of drug discovery and development. Results & conclusions: Mean measures for punctal diameter was 0.5 ± 0 mm and vertical canaliculi length was 2.4 ± 0.5 mm and width was 1.6 ± 0.5 mm. Vertical canalicular width was larger than the punctal opening, a critical understanding for placing and retaining intracanalicular inserts.

Intracanalicular dexamethasone insert is a resorbable sustained-release polyethylene glycol-based hydrogel insert delivering a 0.4 mg tapered dose of dexamethasone for up to 30 days to the ocular surface. It is FDA-approved for treating inflammation and pain after ocular surgery. It has also been studied for ocular surface diseases such as allergic conjunctivitis. This study assessed the plasma pharmacokinetic (PK) parameters of dexamethasone following intracanalicular insertion. Patients and Methods: Study subjects (N=16) were healthy adults. A dexamethasone insert was unilaterally placed into the canaliculus, and blood samples were obtained for analysis 1 hour prior to insertion and 1, 2, 4, 8, 16, 24 hours and 4, 8, 15, 22 and 29 days after insertion. Safety analyses included slit lamp and dilated fundus examinations, best corrected visual acuity, intraocular pressure (IOP) and adverse events (AEs). Results: Plasma results were below the lower limit of quantitation (LLOQ) at all time points in five subjects (31.3%). Among subjects with quantifiable plasma concentrations, C max was <1 ng/mL (range, 0.05 to 0.81 ng/mL), AUC 0-last ranged from 0.13 to 7.18 h•ng/mL, and T max ranged from 4.0 to 163.0 hours. Mean (SD) IOP increased from 16.3 (1.4) mmHg at baseline to 19.3 (3.2) at Day 22 but returned to baseline after treatment. No changes occurred in dilated fundus, punctum, or visual acuity examinations. Conclusion:The dexamethasone 0.4 mg insert results in minimal systemic exposure following intracanalicular administration.