Safety and pharmacokinetics of multiple-dose ciprofloxacin dry powder for inhalation in patients with moderate or severe COPD

Introduction: Many patients with COPD are chronically colonized with bacteria and could benefit from long-term antibacterial therapy. Ciprofloxacin dry powder for inhalation (DPI) is an investigational PulmoSphere™ formulation for pulmonary delivery of ciprofloxacin. Aim: To investigate the safety, tolerability and PK of ciprofloxacin DPI in patients with COPD. Methods: In a randomized, phase I, single-blind, parallel-group study, adults with GOLD stage II or III COPD received 32.5 mg or 48.75 mg ciprofloxacin (50 mg, 75 mg ciprofloxacin DPI, respectively) or matching placebo as a single dose on Day 0 and 12 and bid on Days 2–11. Results: Patients received 32.5 mg (n=6) or 48.75 mg (n=9 including 3 who replaced drop-outs) ciprofloxacin, or placebo (n=4). There were no severe or serious AEs; most AEs were mild in severity. There were treatment-related AEs in 4, 8 and 1 patients in the 32.5 mg and 48.75 mg ciprofloxacin and placebo groups, respectively. Three patients discontinued (48.75 mg ciprofloxacin) due to AEs: moderate treatment-related dyspnoea (n=1); infectious diseases (n=2). Day 0 geometric mean plasma ciprofloxacin AUC was 0.532 mg*h/l and 0.727 mg*h/l, and AUC 0 –last in induced sputum was 1190 mg*h/l and 2010 mg*h/l, for the 32.5 mg and 48.75 mg groups, respectively. Ciprofloxacin sputum concentrations were highly variable; geometric mean induced sputum C max :plasma C max ratios ranged 1650–10,600. Conclusions: Ciprofloxacin DPI was well tolerated over 12 days9 treatment in patients with moderate or severe COPD. High sputum concentrations contrasted with low systemic exposure.