title: Lung deposition and pharmacokinetics of nebulized cyclosporine in lung transplant patients.
abstract: BACKGROUND
  Inhaled cyclosporine (CsA) is being investigated as a prophylaxis for lung transplant rejection. Lung deposition and systemic exposure of nebulized CsA in lung transplant patients was evaluated as part of the Phase 3 cyclosporine inhalation solution (CIS) trial (CYCLIST).
  
  
  METHODS
  Ten patients received 300 mg of CIS (62.5 mg/mL CsA in propylene glycol) admixed with 148 MBq of Tc-DTPA (technetium-99m bound to diethylenetriaminepentaacetic acid) administered using a Sidestream(®) disposable jet nebulizer. Deposition was assessed using a dual-headed gamma camera. Blood samples were collected over a 24-hr time period after aerosol dosing and analyzed for CsA levels. A pharmacokinetic analysis of the resulting blood concentration versus time profiles was performed.
  
  
  RESULTS
  The average total deposited dose was 53.7 ± 12.7 mg. Average pulmonary dose was 31.8 ± 16.3 mg, and stomach dose averaged 15.5 ± 11.1 mg. Device performance was consistent, with breathing maneuvers influencing dose variation. Predose coaching with five of 10 patients reduced stomach deposition (22.6 ± 11.2 vs. 8.3 ± 5.2 mg; p=0.03). Blood concentrations declined quickly from a maximum of 372 ± 140 ng/mL to 15.3 ± 9.7 ng/mL at 24 hr post dose. Levels of AUC(0-24) [area under the concentration vs. time curve from 0 to 24 hr] averaged 1,493 ± 746 ng hr/mL. On a three times per week dose regimen, this represents <5% of the weekly systemic exposure of twice per day oral administration.
  
  
  CONCLUSIONS
  Substantial doses of CsA can be delivered to the lungs of lung transplant patients by inhaled aerosol. Systemic levels are small relative to typical oral CsA administration.
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh , Pittsburgh, PA 15213.
authors.forename: T E
authors.initials: TE
authors.lastname: Corcoran
authors.forename: R
authors.initials: R
authors.lastname: Niven
authors.forename: W
authors.initials: W
authors.lastname: Verret
authors.forename: S
authors.initials: S
authors.lastname: Dilly
authors.forename: B A
authors.initials: BA
authors.lastname: Johnson
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000336:Aerosols; D000368:Aged; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery*; D016040:Lung Transplantation; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D009820:Ohio; D010414:Pennsylvania; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D016284:Technetium Tc 99m Pentetate; D016896:Treatment Outcome
chemical_list: D000336:Aerosols; D007166:Immunosuppressive Agents; D019275:Radiopharmaceuticals; D016572:Cyclosporine; D016284:Technetium Tc 99m Pentetate
keywords: aerosol deposition; inhaled cyclosporine; lung transplant