Tear Film Pharmacokinetics and Systemic Absorption Following Topical Administration of 1% Prednisolone Acetate Ophthalmic Suspension in Dogs

Abstract

The study aimed to determine the tear film pharmacokinetics following topical administration of 1% prednisolone acetate-assessing whether two drops would provide a superior kinetic profile compared to one drop-and to determine the fraction of an eye drop that reaches the systemic circulation in dogs. Two separate experiments were conducted in eight healthy Beagle dogs: (i) Instillation of 1 drop (35 µL) or 2 drops (70 µL) of 1% prednisolone acetate ophthalmic suspension in each eye, followed by tear collections with Schirmer strips from 0 to 720 min; (ii) Instillation of 1 or 2 drops of 1% prednisolone acetate in both eyes 4 times daily for 3 days, followed by blood collection 10-15 min after each topical administration on Day 3. Tear and blood samples were analyzed with high performance liquid chromatography to determine the levels of prodrug (prednisolone acetate), active metabolite (prednisolone) and total prednisolone (prednisolone total = prodrug + active metabolite). Prednisolone levels represented 10 and 72% of prednisolone total concentrations in tears and plasma, respectively, indicating a greater hydrolysis of prodrug in the blood vs. tear compartment. For eyes receiving one or two drops, tear film prednisolone total concentrations were high (∼3.1 mg/mL) immediately following topical administration but rapidly decreased by ∼45% at 1 min and ∼95% at 15 min. No differences were noted between 1 vs. 2 drops in tear film prednisolone total concentrations (including maximal concentration, C max) or residual drug levels in tears at any time point (P ≥ 0.097); however, instillation of 2 drops provided a higher average tear concentration (C avg) and overall drug exposure to the ocular surface (AUC last) over the 12-h sampling period (P = 0.009). Average plasma prednisolone total concentration represented ≤ 2% of the dose applied to the ocular surface, and did not differ significantly for dogs receiving 1 drop (17 ng/mL) or 2 drops (20 ng/mL) 4 times daily for 3 days (P = 0.438). In sum, topical corticotherapy is beneficial for inflammatory conditions of the canine anterior segment given the relatively high concentrations achieved in tears, although caution is warranted to prevent unwanted local or systemic adverse effects.

Kinetics and minimal inhibitory concentrations of ceftiofur in tear film following extended-release parenteral administration (Excede®) in dogs

“…Oral or parenteral administration of therapeutic drugs represent a promising tool for adjunct therapy of ocular surface diseases owing to several key advantages. While the ocular bioavailability of topical administration is poor given efficient washout by tears ( 1 – 3 ), parenteral administration could be considered as a form of sustained release at the ocular surface through lacrimal gland diffusion and conjunctival leakage ( 10 ). Further, systemic drug administration could help improve patient ( 27 ) and owner compliance, especially in cases of bacterial keratitis where multiple medications have to be applied as often as every 1–2 h ( 28 ).…”

“…Systemically administered medications can often serve as adjunctive therapy in the management of ocular surface diseases. Potential benefits of systemic therapy include ease of administration, improved owner/patient compliance, and possibly sustained drug levels when compared to topical instillation (due to rapid drug loss via nasolacrimal drainage, tear volume turnover, and mechanical forces from eyelid blinking) ( 1 – 3 ). Although promising, tear film levels are only described for select (oral or parenteral) medications in veterinary medicine such as doxycycline ( 4 – 6 ), minocycline, ( 7 ) pradofloxacin ( 6 ), famciclovir ( 8 ), voriconazole ( 9 ) and prednisone ( 10 ).…”

Albumin in Tears Modulates Bacterial Susceptibility to Topical Antibiotics in Ophthalmology

“…This discrepancy could be explained by differences in protein and drug concentrations in blood vs. tear fluid. Compared to blood, albumin concentrations are ~10–100-fold lower in tears ( 8 , 10 , 39 ) while drug concentrations are relatively higher in tears, especially after topical drug administration ( 26 , 40 ). Thus, albumin levels used in the present study (i.e., purposely selected to be relevant for the ocular surface) are likely to get saturated by the antibiotic molecules, rendering any excess drug to become unbound regardless of the drug's protein binding properties ( 33 ).…”

“…Contact time between the antibiotic and albumin is much longer in the in vitro setting (16–24 h incubation) than on the ocular surface (<30 min) ( 9 ). Topically administered medications are rapidly lost due to reflex blinking and efficient nasolacrimal drainage ( 18 , 26 ), with only ~55 and 5% of drug remaining in the tear film at 1 and 30 min following eyedrop administration ( 40 ). As such, reversibility in drug binding (i.e., bound drug becomes unbound and vice versa) ( 34 , 50 ) is likely to occur in vitro but is either absent or limited in the tear film.…”

Is it necessary to wait several minutes between applications of different topical ophthalmic solutions? A preliminary study with tropicamide eye drops in healthy dogs

“…At 1 and 5 min following eye drop administration, only about 54% and 17% of the applied drug is retained on the canine ocular surface 15 . Therefore, given the volume of the canine tear film (~65 µL), 16 the addition of a new eye drop (32 µL on average) is expected to dilute the residual drug concentration by 3‐fold.…”