title: Inhalation of a dry powder ciprofloxacin formulation in healthy subjects: a phase I study.
abstract: BACKGROUND
  Oral 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).
  
  
  OBJECTIVE
  The 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.
  
  
  METHODS
  This 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.
  
  
  RESULTS
  Ciprofloxacin 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 (C(max)) 56.42 μg/L, median time to C max 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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Bayer Pharma AG, Clinical Pharmacology, Bldg 470, Room 219, 42096 Wuppertal, Germany. heino.stass@bayer.com
authors.forename: Heino
authors.initials: H
authors.lastname: Stass
authors.forename: Johannes
authors.initials: J
authors.lastname: Nagelschmitz
authors.forename: Stefan
authors.initials: S
authors.lastname: Willmann
authors.forename: Heinz
authors.initials: H
authors.lastname: Delesen
authors.forename: Abhishek
authors.initials: A
authors.lastname: Gupta
authors.forename: Sybille
authors.initials: S
authors.lastname: Baumann
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002939:Ciprofloxacin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D058995:Dry Powder Inhalers; D006207:Half-Life; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D016037:Single-Blind Method; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin