title: Clinical pharmacology of alcaftadine, a novel antihistamine for the prevention of allergic conjunctivitis.
abstract: OBJECTIVE
  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.
authors.affiliation: Johnson&Johnson PRD, Beerse, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Bohets
authors.forename: Claude
authors.initials: C
authors.lastname: McGowan
authors.forename: Geert
authors.initials: G
authors.lastname: Mannens
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schroeder
authors.forename: Kimberly
authors.initials: K
authors.lastname: Edwards-Swanson
authors.forename: Aron
authors.initials: A
authors.lastname: Shapiro
mesh_terms: D000293:Adolescent; D000328:Adult; D001552:Benzazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D003233:Conjunctivitis, Allergic / Q000517:prevention & control*; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D006633:Histamine Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D011485:Protein Binding
chemical_list: D001552:Benzazepines; D065607:Cytochrome P-450 Enzyme Inhibitors; D006633:Histamine Antagonists; D007093:Imidazoles; C557708:alcaftadine