A Novel Method for Studying the Pharmacokinetics of [(14) C]Umeclidinium After Application to the Axilla or Palm of Healthy Male Subjects.
Umeclidinium (UMEC), a long-acting muscarinic antagonist approved for chronic obstructive pulmonary disease (COPD), was investigated for primary hyperhidrosis as topical therapy. This study evaluated the pharmacokinetics, safety, and tolerability of a single dose of [(14) C]UMEC applied to either unoccluded axilla (UA), occluded axilla (OA), or occluded palm (OP) of healthy males. After 8 h the formulation was removed. [(14) C]UMEC plasma concentrations (Cp) were quantified by accelerator mass spectrometry. Occlusion increased systemic exposure by 3.8-fold. Due to UMEC absorption-limited pharmacokinetics, Cp data from the OA were combined with intravenous data from a phase I study. The data were described by a two-compartment population model with sequential zero and first-order absorption and linear elimination. Simulated systemic exposure following q.d. doses to axilla was similar to the exposure from the inhaled therapy, suggesting that systemic safety following dermal administration can be bridged to the inhaled program, and offering the potential for a reduced number of studies and/or subjects.
Clinical Pharmacology Modeling and Simulation, GSK, Research Triangle Park, North Carolina, USA.
T
T
Pene Dumitrescu
Stiefel, a GSK company, Research Triangle Park, North Carolina, USA.
L L
LL
Santos
Drug Metabolism and Pharmacokinetics, GSK, Ware, UK.
S C
SC
Hughes
Drug Metabolism and Pharmacokinetics, GSK, Ware, UK.
A I
AI
Pereira
Drug Metabolism and Pharmacokinetics, GSK, Ware, UK.
G C
GC
Young
Stiefel, a GSK company, Research Triangle Park, North Carolina, USA.
E
E
Hussey
Stiefel, a GSK company, Research Triangle Park, North Carolina, USA.
P
P
Charlton
Clinical Pharmacology Sciences & Study Operations, GSK, King of Prussia, Pennsylvania, USA.
S
S
Baptiste-Brown
Stiefel, a GSK company, Research Triangle Park, North Carolina, USA.
J S
JS
Stuart
R&D Projects Clinical Platforms and Sciences, QSci, GSK, Bangalore, India.
V
V
Vincent
Pharmaceutical Research Associates International Group, Zuidlaren, The Netherlands.
S P
SP
van Marle
Clinical Pharmacology Modeling and Simulation, GSK, Research Triangle Park, North Carolina, USA.
V D
VD
Schmith
D000280:Administration, Inhalation; D000328:Adult; D001365:Axilla / Q000502:physiology*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D003710:Demography; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D006225:Hand / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011812:Quinuclidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011851:Radioactivity
D002250:Carbon Radioisotopes; C573971:GSK573719; D011812:Quinuclidines