Only one nasal spray antihistamine is currently marketed in the U.S. and there is limited information available on systemic levels of antihistamines administered via the nasal versus the oral routes. A model was developed to characterize epinastine systemic exposure after nasal administration and then compare and evaluate it to previously modeled data for a 20 mg tablet for potential therapeutic effectiveness due to known systemic exposure. A total of 420 plasma samples were utilized from the PK subset of SAR subjects (12M, 18F) participating in a Phase 2, randomized, double-blind, placebo-controlled study assigned to either epinastine nasal spray 0.05% or 0.1% (0.14 mg/dose or 0.28 mg/dose). The data from Day 1, 196 samples from 28 subjects, were analyzed using the WinNonlin® program according to a one-compartment model with first-order absorption and elimination. In addition, the final PK model was evaluated for fit to the Day 14 observed exposure. A one-compartment model with Levenberg modification best fit the data and the following noncompartmental parameters were generated for Cmax, Tmax and AUC for the 0.14 mg and 0.28 mg doses respectively: 0.205 ± 0.023, 0.459 ± 0.042 ng/mL; 65 ± 7, 84 ± 9 min; 129 ± 22, 269 ± 73 min.ng/mL (mean±SE). A PK model for epinastine was established and confirms that systemic exposure from intranasal dosages at 0.14 mg and 0.28 mg is linear, reaches steady state by Day 3 and based on Cmax and AUC is minimally 58-fold below the 20 mg oral dose modeling. Thus, the effectiveness of epinastine delivered as a nasal solution is due to local activity and not systemic exposure.

Purpose: To investigate the safety and efficacy of diquafosol tetrasodium, a P2Y(2) receptor agonist that stimulates fluid and mucin secretion on the ocular surface, as a novel topical treatment of dry eye disease.Methods: Subjects with dry eye (n = 527) were evaluated in a randomized, double-masked, parallel-group trial comparing 24 weeks of treatment with 2 concentrations of diquafosol (1% and 2%) versus placebo instilled 4 times daily. Corneal staining, conjunctival staining, Schirmer tests, and subjective symptoms of dry eye were evaluated. Use of artificial tears was permitted as necessary.Results: Subjects treated with 2% diquafosol had significantly lower corneal staining scores compared with placebo at the 6-week, primary efficacy time point (P < 0.001), and superiority continued throughout the 24-week study. Reductions in corneal staining were observed as early as after 2 weeks of treatment, were maintained throughout the 24-week study, and were observed to worsen slightly (toward baseline) when diquafosol treatment was discontinued (week 25). Results for conjunctival staining were consistent with those observed for corneal staining. Schirmer scores at week 6 were significantly higher with diquafosol treatment than with placebo (P less than or equal to 0.030). The percentage of subjects with clearing of foreign body sensation (score of 0) was higher at week 6 in subjects treated with 2% diquafosol (21%) compared with placebo (15%), but the difference did not achieve significance (P = 0.193). Significant differences in favor of diquafosol were observed for clearing of foreign body sensation and for worst symptom in secondary data analyses.Conclusion: Diquafosol tetrasodium was well tolerated and was superior to placebo (vehicle) in reducing corneal staining and in relieving certain patient symptoms. Diquafosol has a favorable risk/benefit profile in a broad spectrum of patients with dry eye disease and is a novel topical treatment of dry eye.