Glycopyrronium tosylate (GT) 2.4% cloth is a once-daily topical anticholinergic available in the USA for the treatment of primary axillary hyperhidrosis in adult and pediatric patients 9 years of age and older. |
In a phase I study, systemic absorption of glycopyrronium and the rate of adverse events were lower with GT vs oral glycopyrrolate; in a population pharmacokinetic analysis using data from two phase II studies, the probability of having an anticholinergic adverse event with GT was related to plasma concentrations of glycopyrronium, which were generally low. |
Overall in these studies, there was limited absorption and a corresponding low risk of anticholinergic adverse events with proper GT administration, which is consistent with phase III clinical observations and highlights the importance of GT instructions for use, which include wiping each underarm once with the same cloth, washing hands with soap and water immediately after discarding the used cloth, and avoiding contact with the eyes. |
1 Introduction
2 Methods
2.1 Phase I PK Study
2.1.1 Study Design and Subjects
2.1.2 Blood Sample Collection and Analysis
2.1.3 Safety
2.2 Population PK Study
2.2.1 Study Design and Subjects
2.2.2 Blood Sample Collection and Analysis
2.2.3 Population PK Model Development
2.2.4 Safety and Efficacy
3 Results
3.1 Phase I PK Study
3.1.1 Subjects and Samples
Characteristics | Topical glycopyrronium tosylate Adult n = 11 | Topical glycopyrronium tosylate Pediatric n = 20 | Oral glycopyrrolate Adult n = 18 |
---|---|---|---|
Subjects | |||
Enrolled/completed | 11/11 | 20/20 | 18/18 |
Safety populationa | 11 | 20 | 18 |
PK evaluable populationb | 11 | 20c | 18 |
Age | |||
Mean (SD) | 26.0 (8.9) | 14.8 (1.6) | 44.0 (10.4) |
Median (min, max) | 23.0 (18, 49) | 15.0 (10, 17) | 46.5 (18, 58) |
Sex [n (%)] | |||
Male | 4 (36.4) | 7 (35.0) | 16 (88.9) |
Female | 7 (63.6) | 13 (65.0) | 2 (11.1) |
Race [n (%)] | |||
White | 9 (81.8) | 13 (65.0) | 9 (50.0) |
Black or African American | 2 (18.2) | 7 (35.0) | 8 (44.4) |
Other | 0 | 0 | 1 (5.6) |
Ethnicity [n (%)] | |||
Hispanic or Latino | 2 (18.2) | 0 | 2 (11.1) |
Not Hispanic or Latino | 9 (81.8) | 20 (100.0) | 16 (88.9) |
Weight (kg) | |||
Mean (SD) | 87.8 (27.7) | 67.2 (16.9) | 80.2 (9.8) |
Median (min, max) | 79.5 (61.7, 156.9) | 63.6 (46.3, 108.0) | 78.8 (66.7, 98.8) |
BMI (kg/m2) | |||
Mean (SD) | 29.4 (6.3) | 23.9 (5.6) | 27.2 (2.4) |
Median (min, max) | 29.5 (21.9, 40.0) | 22.2 (18.6, 40.8) | 27.8 (23.5, 30.8) |
3.1.2 Pharmacokinetics
PK parameter | Topical glycopyrronium tosylate Adult | Topical glycopyrronium tosylate Pediatric | Oral glycopyrrolatea Adult | ||
---|---|---|---|---|---|
2.4% | 2.4% | 1 mg/q8h | 2 mg/q8h | 3 mg/q8h | |
Day 5 of 5 | Day 5 of 5 | Day 5 of 15 | Day 10 of 15 | Day 15 of 15 | |
Cmax (ng/mL) | n = 11 | n = 20 | n = 18 | n = 18 | n = 18 |
Mean ± SD | 0.08 ± 0.04 | 0.07 ± 0.06 | 0.15 ± 0.12 | 0.23 ± 0.11 | 0.38 ± 0.19 |
Median (min, max) | 0.08 (0.02, 0.15) | 0.04 (0, 0.25) | 0.12 (0.05, 0.54) | 0.22 (0.10, 0.42) | 0.34 (0.13, 0.89) |
AUC0–6h (ng h/mL) | n = 10 | n = 11 | n = 18 | n =8 | n = 18 |
Mean ± SD | 0.20 ± 0.14 | 0.18 ± 0.13 | 0.61 ± 0.44 | 0.98 ± 0.41 | 1.57 ± 0.64 |
Median (min, max) | 0.14 (0.09, 0.57) | 0.15 (0, 0.50) | 0.49 (0.20, 2.01) | 1.03 (0.44, 1.70) | 1.51 (0.64, 2.85) |
AUC0–24h (ng h/mL) | n = 7 | Not determinedb | n = 18 | n = 18 | n = 18 |
Mean ± SD | 0.88 ± 0.57 | Not determinedb | 2.12 ± 1.47 | 3.50 ± 1.5 | 5.50 ± 2.19 |
Median (min, max) | 0.79 (0.37, 1.93) | Not determinedb | 1.74 (0.70, 6.84) | 3.53 (1.49, 5.94) | 5.34 (2.21, 9.81) |
Tmax (h) | n = 11 | n = 19 | n = 18 | n = 18 | n = 18 |
Mean ± SD | 3.18 ± 4.41 | 1.76 ± 1.53 | 2.39 ± 0.99 | 2.86 ± 1.60 | 2.19 ± 1.10 |
Median (min, max) | 1.0 (0, 10) | 1.50 (0, 6) | 2.50 (1.00, 4.00) | 2.75 (0.50, 6.00) | 2.00 (0.50, 4.00) |
T1/2 (h) | n = 14 | n = 11 | n = 12 | ||
Mean ± SD | Not determinedc | Not determinedc | 2.59 ± 0.65 | 2.80 ± 0.48 | 2.76 ± 0.88 |
Median (min, max) | Not determinedc | Not determinedc | 2.64 (1.78, 4.16) | 2.92 (1.98, 3.60) | 2.53 (1.62, 4.52) |
Comparison | Cmax (ng/mL) | AUC0–6h (ng h/mL) | AUC0–24h (ng h/mL) | |
---|---|---|---|---|
Adult | Pediatric | Pediatric | Adult | |
GT pediatric day 5 vs GT adult day 5 | ||||
Geometric mean ratio (90% CI) for pediatric [test]/adult [reference] | 0.64 (0.37, 1.10) | 0.87 (0.54, 1.4) | Not determineda | |
GT day 5 vs oral glycopyrrolate day 5 | ||||
Geometric mean ratio (90% CI) for GT [test]/oral glycopyrrolate [reference] | 0.55 (0.38, 0.80) | 0.35 (0.22, 0.55) | 0.28 (0.19, 0.43) | 0.41 (0.26, 0.65) |
GT day 5 vs oral glycopyrrolate day 10 | ||||
Geometric mean ratio (90% CI) for GT [test]/oral glycopyrrolate [reference] | 0.34 (0.25, 0.48) | 0.22 (0.14, 0.34) | 0.16 (0.11, 0.23) | 0.23 (0.16, 0.34) |
GT day 5 vs oral glycopyrrolate day 15 | ||||
Geometric mean ratio (90% CI) for GT [test]/oral glycopyrrolate [reference] | 0.21 (0.15, 0.29) | 0.13 (0.09, 0.20) | 0.10 (0.07, 0.15) | 0.15 (0.10, 0.21) |
3.1.3 Safety
Topical glycopyrronium tosylate N = 31 | Oral glycopyrrolate n = 18 | |||
---|---|---|---|---|
Adult n = 11 | Pediatric n = 20 | Total n = 31 | ||
TEAEs [n (%)] | 2 (18.2) | 3 (15.0) | 5 (16.1) | 7 (38.9) |
Dry mouth | 0 | 0 | 0 | 3 (16.7) |
Headache | 2 (18.2) | 2 (10.0) | 4 (12.9) | 1 (5.6) |
Nocturia | 0 | 0 | 0 | 2 (11.1) |
Chest pain | 0 | 0 | 0 | 1 (5.6) |
Hypoesthesia | 0 | 0 | 0 | 1 (5.6) |
Nasal dryness | 0 | 0 | 0 | 1 (5.6) |
Cough | 0 | 1 (5.0) | 1 (3.2) | 0 |
Laceration | 0 | 1 (5.0) | 1 (3.2) | 0 |
Rhinorrhea | 0 | 1 (5.0) | 1 (3.2) | 0 |
TEAE by severity [n (%)] | ||||
Mild Moderate Severe | 2 (18.2) 0 0 | 3 (15.0) 0 0 | 5 (16.1) 0 0 | 7 (38.9) 0 0 |
Treatment-related TEAE [n (%)] | 0 | 0 | 0 | 5 (27.8) |
Serious TEAEs [n (%)] | 0 | 0 | 0 | 0 |
TEAE leading to discontinuation [n (%)] | 0 | 0 | 0 | 0 |
3.2 Population PK Study
3.2.1 Subjects and Samples
Demographics and characteristics | Pop PK database N = 108 | Pop PK AE and PD database N = 137 |
---|---|---|
Age | ||
Mean (SD) | 32.6 (11.6) | 32.8 (11.2) |
Median (min, max) | 29.5 (18, 72) | 30.0 (18, 72) |
Sex [n (%)] | ||
Male | 60 (55.6) | 73 (53.3) |
Female | 48 (44.4) | 64 (46.7) |
Race [n (%)] | ||
Caucasian | 94 (87.0) | 121 (88.3) |
Black | 10 (9.3) | 12 (8.8) |
Asian | 1 (0.9) | 1 (0.7) |
Other | 3 (2.8) | 3 (2.2) |
Weight (kg) | ||
Mean (SD) | 84.1 (22.6) | 83.4 (22.2) |
Median (min, max) | 82.1 (45.4, 152) | 80.7 (45.4, 153) |
BMI (kg/m2) | ||
Mean (SD) | 28.4 (6.2) | 28.0 (6.0) |
Median (min, max) | 28.2 (17.2, 46.8) | 27.2 (17.2, 46.8) |