Abstract
Introduction: Umeclidinium (UMEC; GSK573719) is a new, long-acting muscarinic antagonist in development for treatment of chronic obstructive pulmonary disease (COPD).
Objectives: Evaluate the absorption, distribution, metabolism and elimination (ADME) of UMEC following single IV and oral doses of [14C]-UMEC.
Methods: This was an open-label, non-randomised ADME study of 6 healthy male subjects. There were two dosing periods: (1) a 65mcg IV dose of [14C]-UMEC (7.1mcCi) infused over 30min, and (2) a 1000mcg dose of [14C]-UMEC (50mcCi) administered orally. The dosing periods were separated by a washout of ≥28 days. Total radioactivity was measured in plasma, urine and faeces for 7–10 days following each dosing period.
Results: Following IV administration, the derived area-under-the-curve (0–∞) demonstrated that only ∼20% of total radioactivity in plasma was parent UMEC, suggesting the predominance of UMEC metabolites. The geometric mean volume of distribution of IV UMEC was 86L, suggestive of tissue compartmentation. By day 8, approximately 58% and 22% of IV UMEC-associated radioactivity was excreted in the faeces and urine, respectively. Oral UMEC is poorly absorbed with <1% of administered parent drug detected in plasma (all concentrations non-quantifiable). Following oral administration, total radioactivity in the faeces and urine was 92% and <1% of the administered oral UMEC dose respectively, confirming negligible gut absorption.
Conclusions: Oral UMEC bioavailability is negligible. Intravenous UMEC is mainly removed from plasma by metabolism and subsequent biliary secretion, and to a lesser extent by urinary excretion.
Funded by GSK (AC4112014; NCT01362257).
- © 2012 ERS