T. Pene Dumitrescu,1 L. Santos,2 S. Hughes,3 A. Pereira,3 G. Young,3 E. Hussey,2 P. Charlton,2 S. Baptiste-Brown,4 J. S. Stuart,2 V. D. Schmith1; 1Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC, 2Stiefel, a GlaxoSmithKline Company, Research Triangle Park, NC, 3Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, United Kingdom, 4Clinical Pharmacology Sciences & Study Operations, GlaxoSmithKline, King of Prussia, PA
BACKGROUND: The main objective of this GSK funded study was to assess the PK of single dose [14C]UMEC in healthy subjects, following administration to axilla or palm, and estimate repeat dose exposure (QD) to bridge safety to the inhaled program. Very few studies with topically applied [14C] have been conducted to date. UMEC is a long acting muscarinic antagonist approved for COPD (inhaled), and currently in development for primary hyperhidrosis (topical).
METHODS: Subjects were assigned to 3 cohorts: unoccluded axilla [UA], occluded axilla [OA], or occluded palm [OP], and received a single dose of 1.85% [14C]UMEC solution (18 µCi) for 8 h. PK samples were collected up to 72 h. After 8 h, the formulation was washed off. [14C]UMEC plasma concentrations (Cp) were quantified by Accelerator Mass Spectrometry. Population PK modeling and simulations (M&S) were done in Phoenix NLME 1.3.
RESULTS: Cmax in OA was ~ 9x > than the Cmax in the UA cohort. The majority of the UA subjects had incomplete profiles, and all Cp in the OP cohort were nonquantifiable. Due to UMEC flip-flop PK, to distinguish between the elimination and absorption rate constant, Cp data from the OA were combined with IV data from a prior study. The data were best described by a two-compartment population model with linear elimination and sequential 0 and 1st order absorption processes. The CL was 45.2 L/h; Vcentral was 7.73 L; Vperi was 261 L; and CLintercomp was 39.4 L/h. The model parameter bias ranged from 2.1 to 30.1%. Simulated systemic exposure following QD doses to axilla was less than for the inhaled dosing, suggesting bridging to inhaled systemic safety is possible.
CONCLUSION: This unique study and M&S approach allows for bridging systemic safety data across routes of administration and supports the design of a shorter, combined phase IIa/b design.