Limited Systemic Exposure with Topical Glycopyrronium Tosylate in Primary Axillary Hyperhidrosis

Abstract

Background: Glycopyrronium tosylate (GT; Qbrexza^® [glycopyrronium] cloth, 2.4%) is a topical anticholinergic approved (USA) for primary axillary hyperhidrosis in patients aged ≥ 9 years.

Objective: The objective of this study was to compare the pharmacokinetics and safety of GT to oral glycopyrrolate (phase I study) and assess the relationship between glycopyrronium pharmacokinetics and anticholinergic-related adverse events or efficacy with population pharmacokinetics using data from two phase II studies.

Methods: In the phase I study, study staff applied GT to axillae of patients with primary axillary hyperhidrosis (aged 9-65 years) once daily (5 days); oral glycopyrrolate was administered to healthy adults (aged 18-65 years) every 8 hours (15 days). In the phase II studies (NCT02016885 [20 December, 2013], NCT02129660 [2 May, 2014]), adults with primary axillary hyperhidrosis applied topical glycopyrronium (0.8-3.2%) or vehicle to axillae once daily (4 weeks). Pharmacokinetic and adverse event data were collected in all studies.

Results: Glycopyrronium pharmacokinetic parameters were similar between adult and pediatric patients treated with GT; there was no evidence of accumulation. Systemic absorption of glycopyrronium was lower with GT vs oral glycopyrrolate. No anticholinergic-related adverse events occurred with GT in the phase I study, while dry mouth and nasal dryness occurred with oral glycopyrrolate; anticholinergic adverse events occurred in the phase II studies. In the population pharmacokinetic analysis, frequency/severity of anticholinergic-related adverse events increased with higher glycopyrronium concentration; no relationship was observed between efficacy and pharmacokinetic measures.

Conclusions: These studies indicate limited absorption of GT compared to oral glycopyrrolate and a low risk of anticholinergic adverse events with proper GT administration when following instructions for use (wipe each underarm once with same cloth, wash hands, avoid ocular contact).

Fig. 1

Phase I study design. Study staff administered all the study drug. Topical glycopyrronium tosylate (GT; 2.4%) was applied to each axilla once daily. Because of the oral glycopyrrolate titration schedule (1.0 mg/8 h, then increased by 1.0-mg increments every 5 days to a maximum of 3.0 mg/8 h if no dose-limiting side effects), the oral glycopyrrolate arm was 17 days long whereas the GT arm, which did not involve titration, was 7 days long. Pediatric patients (included only in the GT arm; age 9 to < 18 years) had a modified pharmacokinetic (PK) sampling schedule to comply with guidelines for safe volumes of blood sampling; no pre-dose samples were collected in pediatric subjects on days 2, 3, and 4. In case of early termination, the safety follow-up telephone call occurred 2 days after early termination

Fig. 2

Population pharmacokinetic study: probability of anticholinergic adverse events (frequency). Shading denotes the 95% confidence interval; patients randomized to vehicle were assigned a value of “0” for glycopyrronium exposure. CI confidence interval, C_max maximum plasma concentration

Fig. 3

Population pharmacokinetic study: probability of anticholinergic adverse events (severity). Shading denotes the 95% confidence interval. CI confidence interval, C_max maximum plasma concentration