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 (prednisolonetotal = prodrug + active metabolite). Prednisolone levels represented 10 and 72% of prednisolonetotal 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 prednisolonetotal 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 prednisolonetotal concentrations (including maximal concentration, Cmax) or residual drug levels in tears at any time point (P ≥ 0.097); however, instillation of 2 drops provided a higher average tear concentration (Cavg) and overall drug exposure to the ocular surface (AUClast) over the 12-h sampling period (P = 0.009). Average plasma prednisolonetotal 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.
Highlights
Administered corticosteroid is a common practice in human and veterinary ophthalmology [1, 2]
The present study describes the tear film pharmacokinetics of topical 1% prednisolone acetate and estimates the fraction of the drug that is absorbed into the systemic circulation of dogs
The study did not solely report the active metabolite but instead focused on the overall drug concentration as it better represents the amount of drug that is available for diffusion into the eye or absorption into the systemic circulation; the majority of esterase activity that converts prednisolone acetate to prednisolone is located in ocular tissues and not the tear compartment [17]
Summary
Administered corticosteroid is a common practice in human and veterinary ophthalmology [1, 2]. Multiple formulations of ocular corticosteroids are commercially available, and the choice is often dictated by the properties of the specific drug and associated formulation; in practice, 1% prednisolone acetate is often considered superior to other formulations (e.g., betamethasone phosphate, dexamethasone alcohol, or disodium phosphate) as the acetate derivative of the steroid provides superior penetration in the cornea and anterior chamber [1, 3, 4]. Despite well-documented benefits of topical prednisolone acetate for various ocular disorders, the basic pharmacokinetics (PK) of the drug has yet to be elucidated. This knowledge would help clinicians optimize frequency of administration and better understand the potential toxicity associated with topical corticotherapy at a local and systemic level [1, 2]. Prednisolone acetate is a prodrug that requires ester hydrolysis to obtain the active metabolite prednisolone [14]; further, prednisolone acetate is a suspension and not a solution, a formulation that could theoretically increase the retention time on the ocular surface as drug particles are sequestered in the conjunctival cul-de-sac [15, 16]
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