Inhalation of a Dry Powder Ciprofloxacin Formulation in Healthy Subjects: A Phase I Study

Abstract

BackgroundOral and intravenous formulations of ciprofloxacin have established efficacy and safety profiles in respiratory infections. A dry powder for inhalation (DPI) that uses Novartis’ PulmoSphere™ technology has been developed to deliver high concentrations of ciprofloxacin to the lung with low systemic exposure using a portable and convenient passive dry powder inhaler (Novartis’ T-326 inhaler).ObjectivesThe primary objective was to investigate the safety and tolerability of ciprofloxacin DPI in healthy male subjects, with a secondary objective to investigate the pharmacokinetics of ciprofloxacin after ciprofloxacin DPI administration.MethodsThis was a phase I, single-dose, single-site, randomized, single-blind, placebo-controlled, crossover study conducted in the hospital setting. Subjects were followed up for safety for approximately 2 weeks. Six healthy male subjects, aged 27–42 years with no history of pulmonary disease, repeated bronchitis or respiratory allergies were enrolled. In randomized order and separated by a 1-week washout period, subjects inhaled a single dose of ciprofloxacin DPI 32.5 mg or placebo from the T-326 inhaler. Primary safety parameters included vital signs, electrocardiogram, laboratory tests, adverse events and lung function (total specific resistance, thoracic gas volume and forced expiratory volume in 1 s). Plasma concentration–time data were used to calculate pharmacokinetic parameters.ResultsCiprofloxacin DPI was well tolerated with no clinically relevant adverse effects on lung function. Estimates of lung deposition derived from physiology-based pharmacokinetic modelling suggest that approximately 40 % of the total dose of ciprofloxacin DPI reached the trachea/bronchi and alveolar space. Systemic ciprofloxacin was detected soon after inhalation [peak concentration in plasma (Cmax) 56.42 μg/L, median time to Cmax 0.625 h], but total systemic exposure was minimal (area under the plasma concentration–time curve 354.4 μg·h/L). Terminal elimination half-life (9.5 h), apparent total clearance from plasma after non-intravenous administration (91.7 L/h) and apparent volume of distribution (1,262 L) data suggest that elimination from the respiratory tract was prolonged.ConclusionsIn healthy subjects, ciprofloxacin DPI was well tolerated, delivered ciprofloxacin to the lungs and resulted in minimal systemic exposure, allowing further investigation of its clinical use for the management of specific, chronic infections in pulmonary diseases.

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

“…As described previously (149), sputum concentrations following a dose of 100 mg dry powder were not significantly higher. The corresponding serum concentrations were negligibly low, with maximal concentrations of 0.08 and 0.3 mg/liter following the 50-mg and 100-mg doses, respectively.…”

“…The corresponding serum concentrations were negligibly low, with maximal concentrations of 0.08 and 0.3 mg/liter following the 50-mg and 100-mg doses, respectively. Low ciprofloxacin serum concentrations and a long half-life in sputum indicate minimal absorption and, thus, minimal systemic exposition following aerosolized delivery of ciprofloxacin (149). Ciprofloxacin sputum and ELF (151)(152)(153)(154)(155)(156).…”

Inhaled Antibiotics for Gram-Negative Respiratory Infections

“…The Pulmosphere DPI technology has also been applied to a zwitterionic betaine salt form of ciprofloxacin in a phase I study of healthy volunteers (188). Six male subjects were given a single dose of 32.5 mg of ciprofloxacin or placebo via a portable passive DPI.…”

A New Era of Pulmonary Delivery of Nano-antimicrobial Therapeutics to Treat Chronic Pulmonary Infections

“…Ciprofloxacin DPI was well tolerated in patients with minimal ciprofloxacin systemic adverse effects. 40% of the total dose was shown to reach the trachea/bronchi and alveolar space of the lungs, with the aim of increasing ciprofloxacin retention in the lung [180]. This formulation was successful in Phase I clinical trials in 2013 to evaluate the potential of ciprofloxacin DPI for mild to moderate COPD.…”