Tolerability and Pharmacokinetic Properties of Ciprofloxacin Dry Powder for Inhalation in Patients With Cystic Fibrosis: A Phase I, Randomized, Dose-Escalation Study

Abstract Background Inhaled antibacterial agents are used to manage chronic pulmonary infections in cystic fibrosis (CF) and non-CF bronchiectasis. However, established nebulized preparations impose a substantial time burden on patients. A dry powder formulation of ciprofloxacin for inhalation (ciprofloxacin DPI) has been developed using PulmoSphere™ (Novartis, Pharma AG, Basel, Switzerland) technology (administered using a T-326 inhaler) to maximize antibacterial activity and convenience. Objective This study investigated the tolerability and pharmacokinetic properties of multiple-dose once-daily and twice-daily ciprofloxacin DPI in adults with CF. Methods A Phase I, randomized, single-blind, placebo-controlled, dose-escalation study in patients with CF (median age 29.0 years [19–40]), stable pulmonary status, and chronic Pseudomonas aeruginosa colonization. Sequential cohorts received ciprofloxacin DPI 32.5 mg qd (1 capsule for inhalation; n = 6), 65 mg qd (2 capsules for inhalation; n = 6), or 32.5 mg (n = 6) bid for 7 days. Each group was placebo controlled. Results Twenty-five patients were enrolled (12 men; median age, 29.0 years [range, 19–40 years]; 6, 6, 6, and 7 patients in the ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid and placebo groups, respectively). No serious treatment-emergent adverse events or clinically relevant changes in tolerability parameters, including lung function measurements, were reported. Twenty-one patients (ciprofloxacin, n = 17; placebo, n = 4) experienced 29 mild drug-related treatment-emergent adverse events, including bitter taste (ciprofloxacin, 17 patients; placebo, 2) and bronchospasm (ciprofloxacin, 3; placebo, 2). Ciprofloxacin DPI was absorbed rapidly after inhalation. Systemic exposure to ciprofloxacin was low and comparable between single and multiple dosing in all 3 dose groups, suggesting an absence of substantial drug accumulation. The geometric mean AUCs after the last dose were 0.383, 1.472, and 0.781 mg · h/L with ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. The range of geometric mean t½ in plasma was 3.4 to 9.5 hours. Sputum concentrations of ciprofloxacin were high, with substantial variability. Geometric mean ciprofloxacin concentrations (%CV) in induced sputum were 57.7 (118.2), 177.5 (53.4), and 149.7 (249.7) mg/L 0.75 hours after the last dose of ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. Conclusions Ciprofloxacin DPI was well tolerat