Clinical pharmacology of alcaftadine, a novel antihistamine for the prevention of
allergic conjunctivitis.
Author(s): Bohets H, McGowan C, Mannens G, Schroeder N, Edwards-Swanson K, Shapiro A.
Affiliation(s): Johnson&Johnson PRD, Beerse, Belgium.
Publication date & source: 2011, J Ocul Pharmacol Ther. , 27(2):187-95
PURPOSE: In this report, we characterize the in vitro pharmacokinetic properties
of a new antihistamine, alcaftadine. In addition, we report results from phase 1
studies of several ophthalmic formulations of alcaftadine and examine the
pharmacokinetic properties of one formulation in detail.
METHODS: In vitro pharmacology employed a human liver microsome assay combined
with index substrates or inhibitors for specific cytochromes. Metabolic fate of
(14)C-alcaftadine was determined by high-performance liquid chromatography-based
separation of parent compound from metabolites. Plasma protein binding was
determined by equilibrium dialysis using (3)H-labeled alcaftadine and
(3)H-labeled alcaftadine carboxylic acid metabolite. Relative tolerability
(comfort) of 4 concentrations and 3 formulations of alcaftadine ophthalmic
solution was assessed in 2 double-masked, randomized, placebo-controlled,
contralateral studies in which formulations were compared to Tears Naturale II
(placebo) in normal adult subjects. Data analysis focused on the mean differences
in subject-reported drop comfort scores (within each dose level, at each time
point) and compared the study-treatment eye with the placebo eye.
Pharmacokinetics of alcaftadine 0.25% ophthalmic solution were determined in an
open-label, single-center study after a single bilateral dose and after 7 days of
once-a-day bilateral doses in healthy subjects 18-55 years old.
RESULTS: Alcaftadine is not significantly metabolized by microsomal cytochromes,
but it is rapidly converted to the carboxylic acid metabolite by one or more
cytosolic enzymes. Neither the parent compound nor its carboxylic acid metabolite
displayed significant plasma protein binding. Over a range of formulations and
concentrations (0.05%-0.5%), alcaftadine was well tolerated and subjects reported
little or no discomfort or taste perversion in any treatment group.
Pharmacokinetic studies showed that both the parent compound and the carboxylic
acid metabolite reach peak serum levels within minutes of administration and fall
below detectable levels within 3 h of dosing.
CONCLUSIONS: Based upon pharmacokinetic and phase 1 studies, the novel
antihistamine alcaftadine is an appropriate drug for use as an ophthalmic
formulation for prevention and treatment of ocular allergic conditions such as
allergic conjunctivitis (alcaftadine ophthalmic solution 0.25% was recently
approved for use by the FDA). Topical administration of alcaftadine 0.25%
ophthalmic solution was well tolerated and had an acceptable safety profile.
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