Pharmacokinetics and safety of AZD9668, an oral neutrophil elastase inhibitor, in healthy volunteers and patients with COPD.

Objective: To establish the pharmacokinetics (PK), tolerability and safety profile of AZD9668, an oral inhibitor of neutrophil elastase (NE), an enzyme implicated in the signs, symptoms and disease progression in NE-driven respiratory diseases via its role in the inflammatory process, mucus overproduction and lung-tissue damage.

Methods: PK and safety/tolerability profile of AZD9668 were studied in 107 healthy Caucasian and Japanese volunteers and 18 patients with COPD in three double-blind, randomized, placebo-controlled studies with single and multiple exposure to AZD9668 for up to 14 days. Ex vivo zymosan-stimulated NE activity in whole blood was also assessed as a surrogate pharmacodynamic measure.

Differences in endogenous esterification and retention in the rat trachea between budesonide and ciclesonide active metabolite.

The airway retention of inhaled glucocorticosteroids (GCs) depends largely on their lipophilicity. Inhaled budesonide (BUD) becomes highly lipophilic reversibly by the formation of esters acting as a reservoir of active BUD. Ciclesonide (CIC) was also reported to form esters after hydrolysis to active metabolite (CIC-AM).