Pharmacokinetic Studies of Sustained-Release Depot of Dexamethasone in Beagle Dogs

Abstract

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.

Dexamethasone Intracanalicular Insert: A Review in Treating Post-Surgical Ocular Pain and Inflammation

“…NF-κB), ultimately leading to a decrease in inflammatory prostaglandins [ 7 ] Decreases inflammatory processes (e.g. oedema, recruitment of inflammatory cells, leakage of capillaries and fibrin deposition) [ 6 ] Pharmacokinetic properties of the dexamethasone intracanalicular insert Release properties Tapered release from dexamethasone 0.4 mg inserts occurred over 28 days (median 267 µg dexamethasone remaining in explanted inserts on day 7 and tapered to 0 µg/mL by day 28) in a canine model [ 34 ] Systemic absorption Very limited systemic absorption of dexamethasone occurred in humans (plasma samples from 5/16 healthy volunteers were below lower LOQ at all time points, C max was < 1 ng/mL) [ 35 ] Other properties of the dexamethasone intracanalicular insert Retention and clearance The insert was retained for 30 days in 90.4% of 530 pts across three phase III trials [ 9 ] Hydrolysis of the PEG polymer leads to degradation and clearance of the insert; removal via manual expression or irrigation with saline is not required [ 12 ] Ease of use Placement of the dexamethasone insert was deemed to be easy by investigators in 76.5% of pts across three phase III trials ( n = 541) [ 36 ] and, when required, removal was reported to be easy or moderately easy in all removals of dexamethasone ( n = 2) or placebo ( n = 7) inserts [ 9 ] The fluorescent insert was easily visualized by investigators in 94.0% of pts on day 2 (day 1 post-operation) and 83.3% of pts in phase III trials by day 30 [ 9 , 36 ] C max maximum plasma concentration, LOQ limit of quantification, PEG polyethylene glycol, pts patients …”

Thermal Pulsation with or without Dexamethasone Intracanalicular Insert for Meibomian Gland Dysfunction: A Prospective, Masked Trial

“…The DEX insert has several features to support this hypothesis. First, it provides short-term pulsed therapy with a diminishing dose over time to minimize complications related to IOP and cataract formation 54 , 55 and with minimal systemic absorption. 56 Second, it is preservative-free, which is important given the pro-inflammatory nature of preservatives in ophthalmic formulations and their adverse effects on ocular surface disease.…”

Evaluation of Same-Day versus Next-Day Implantation of Intracanalicular Dexamethasone for the Control of Postoperative Inflammation and Pain Following Cataract Surgery

“…The sustained-release insert described herein offers attributes that overcome the potential side effects and challenges of topical corticosteroid use. 20 , 21 Topical agents, which are instilled intermittently, inevitably lead to variability in drug concentration owing to the poor bioavailability of the agent. The insert’s intracanalicular location, with proximity to the ocular surface, purports to offer a superior bioavailability profile with improved consistency of drug concentration in contrast to topical administration.…”