title: Ciprofloxacin Dry Powder for Inhalation in Patients with Non-Cystic Fibrosis Bronchiectasis or Chronic Obstructive Pulmonary Disease, and in Healthy Volunteers.
abstract: BACKGROUND
  Ciprofloxacin dry powder for inhalation (Ciprofloxacin DPI) is in development as long-term intermittent therapy to reduce the frequency of acute exacerbations in non-cystic fibrosis bronchiectasis (NCFB) patients with respiratory bacterial pathogens. There is no approved therapy in this indication. Reliable, reproducible lung deposition is a prerequisite for inhaled drugs.
  
  
  METHODS
  In this phase I study, six patients with NCFB, six with chronic obstructive pulmonary disease (COPD), and 12 healthy volunteers (HVs), received one dose of99mTc-Ciprofloxacin DPI 32.5 mg to assess pulmonary drug deposition by quantitative scintigraphy.81mKrypton ventilation scans were performed to map lung contours. Systemic exposure as mediated by absorption in the lung was measured using the charcoal block method. HVs ingested activated charcoal orally (20 g before and 2 × 10 g after inhalation) to block gastrointestinal absorption of drug swallowed during inhalation. Indirect determination of pulmonary drug deposition was based on plasma and urine pharmacokinetic (PK) data.
  
  
  RESULTS
  Scintigraphic data revealed high, reproducible lung deposition in all participants (intrapulmonary deposition relative to nominal dose, mean [standard deviation; range]: NCFB, 53% [11%; 38%-64%]; COPD, 51% [10%; 34%-61%]; HVs, 51% [7%; 40%-64%] to 53% [8%; 44%-70%]). Similar ratios of central-to-peripheral airway deposition were seen across groups. Systemic exposure to ciprofloxacin was low. Relative bioavailability of Ciprofloxacin DPI was reduced by ∼60% after charcoal block, suggesting that systemic exposure was mainly caused by uptake via the lung. Lung deposition of 30% was estimated from PK data, but this may be an underestimation due to drug clearance from the lung and transintestinal secretion. Adverse events were no more frequent or severe in patients with lung diseases versus HVs, and no clinically relevant influence on vital signs or lung function was observed.
  
  
  CONCLUSIONS
  This study supports the continued development of Ciprofloxacin DPI in NCFB patients with respiratory bacterial pathogens.
authors.affiliation: 1 Bayer Pharma AG , Clinical Pharmacology, Wuppertal, Germany .
authors.forename: Heino
authors.initials: H
authors.lastname: Stass
authors.affiliation: 1 Bayer Pharma AG , Clinical Pharmacology, Wuppertal, Germany .
authors.forename: Johannes
authors.initials: J
authors.lastname: Nagelschmitz
authors.affiliation: 2 Inamed GmbH , Gauting, Germany .
authors.forename: Dominik
authors.initials: D
authors.lastname: Kappeler
authors.affiliation: 2 Inamed GmbH , Gauting, Germany .
authors.forename: Knut
authors.initials: K
authors.lastname: Sommerer
authors.affiliation: 2 Inamed GmbH , Gauting, Germany .
authors.forename: Claudius
authors.initials: C
authors.lastname: Kietzig
authors.affiliation: 3 Chrestos Concept GmbH & Co. KG, Ratingen, Germany .
authors.forename: Boris
authors.initials: B
authors.lastname: Weimann
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D001987:Bronchiectasis / Q000188:drug therapy*; D016022:Case-Control Studies; D002939:Ciprofloxacin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D058995:Dry Powder Inhalers; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin
keywords: COPD; Ciprofloxacin DPI (dry powder for inhalation); NCFB; charcoal block; chronic obstructive pulmonary disease; lung deposition; non-cystic fibrosis bronchiectasis; scintigraphy