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. Results: AZD9668 was well tolerated at single doses up to 150 mg and multiple doses up to 70 mg twice daily. PK were dose linear; median time to peak plasma concentration was reached at 0.5 - 1.5 hours and the short elimination half-life was consistent with twice daily dosing. Steady state was reached by Day 2 of twice daily dosing with negligible accumulation. Approximately 40% of AZD9668 was eliminated renally as unchanged compound. Ex vivo zymosan-stimulated inhibition of NE activity was dose-dependent, with maximal inhibition achieved at 60 mg. PK in Japanese volunteers were similar to those in Caucasians, and the PK in patients with COPD were similar to those in healthy volunteers. Conclusion: The PK profile of AZD9668 was established in Caucasian and Japanese healthy volunteers and in patients with COPD. It was well tolerated at doses expected to produce a pharmacodynamic effect.