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Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of Inhaled Once-Daily Umeclidinium in Healthy Adults Deficient in CYP2D6 Activity: A Double-Blind, Randomized Clinical Trial.


Clin Drug Investig. 2013 Jul 24;


Authors: Cahn A, Mehta R, Preece A, Blowers J, Donald A


Abstract

BACKGROUND: Umeclidinium is a new, long-acting, muscarinic receptor antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). In vitro cell culture data suggest that up to 99 % of umeclidinium is potentially metabolized by cytochrome P450 2D6 (CYP2D6), but without a definitive human metabolism radiolabel study, the extrapolation of in vitro to in vivo is only an estimate.

OBJECTIVE: The objective of this study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of umeclidinium in patients with normal and deficient CYP2D6 metabolism.

METHODS: This was a randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled single and repeat doses (for 7 days) of umeclidinium. The study took place at a single clinical site, at which subjects remained throughout the study. Healthy volunteers (HVTs) who were normal CYP2D6 metabolizers (HVT-NMs) [n = 20] and poor CYP2D6 metabolizers (HVT-PMs) [n = 16] participated in the study. The subjects received umeclidinium (100-1,000 μg) and placebo as single and repeat doses. The primary outcome measurements were protocol-defined safety and tolerability endpoints.

RESULTS: Thirteen subjects in each population reported adverse events (AEs); none were considered serious. No clinically significant abnormalities in vital signs, lung function, haematology, biochemistry, 12-lead electrocardiograms (ECGs) or 24-h Holter ECGs were attributable to the study drug. There were no differences in plasma and urine pharmacokinetics between populations: the plasma area under the concentration-time curve over the dosing interval (from 0 to 24 h for the once-daily drug) [AUCτ (ng·h/mL)] and the maximum plasma concentration [Cmax (ng/mL)] ratios (with 90 % confidence intervals [CIs]) following repeat dosing with 500 μg umeclidinium for HVT-PMs (as compared with HVT-NMs) were 1.03 (0.79-1.34) and 0.80 (0.59-1.08), respectively; the cumulative amount of the unchanged drug excreted into the urine at 24 h (Ae24) [ng] ratio was 1.01 (0.82-1.26). Following repeat dosing with umeclidinium 1,000 μg, the plasma AUCτ [ng·h/mL] and Cmax (ng/mL) ratios (with 90 % CIs) were 1.33 (0.98-1.81) and 1.07 (0.76-1.51); the urine Ae24 (ng) ratio was 1.47 (1.15-1.88). Similar ratios for urine and plasma were observed following single and repeat-dose regimens.

CONCLUSION: Umeclidinium has favourable safety and pharmacokinetic profiles in both HVT-NM and HVT-PM populations.

PMID: 23881566 [PubMed - as supplied by publisher]