26301 Pharmacokinetic analyses show limited systemic exposure with topical glycopyrronium tosylate

Abstract

GT is a topical anticholinergic approved (US) for primary axillary hyperhidrosis in patients ≥9 years. In a Phase 1 study, GT was applied by study staff once-daily to axillae of primary axillary hyperhidrosis patients (5 days); oral glycopyrrolate was administered to healthy adults every 8h (15 days; 1.0 mg then increasing by 1.0 mg/5 days). In the Phase 2 studies (NCT02016885, NCT02129660), primary axillary hyperhidrosis patients were randomized to topical glycopyrronium (0.8-3.2%) or vehicle applied to axillae once-daily (4 weeks). Pharmacokinetic parameters were similar between GT-treated adult and pediatric patients, with no evidence of accumulation. Systemic absorption of glycopyrronium was lower with GT vs oral glycopyrrolate. No anticholinergic-related adverse events (AEs) occurred with GT in the Phase 1 study, while dry mouth and nasal dryness occurred with oral glycopyrrolate; anticholinergic AEs occurred in the Phase 2 studies. In the population pharmacokinetic analysis, frequency/severity of anticholinergic-related AEs increased with higher glycopyrronium concentration; however, the mean (0.0985 μg/L [SD 0.213]) and median (0.026 μg/L [min, max [0, 1.67]) Cmax values were low. Mild AEs tended to occur at low concentrations, while the probability of moderate/severe AEs did not become appreciable (over 20%) until Cmax values of approximately 0.2 μg/L; most patients had glycopyrronium Cmax values <0.2 μg/L. No relationship was observed between efficacy and pharmacokinetic measures. These studies indicate limited absorption and low risk of anticholinergic AEs with proper GT administration, which underscores the importance of following instructions for use (wipe each underarm once with same cloth, wash hands, avoid ocular contact).