title: Itraconazole comedication increases systemic levels of inhaled fluticasone in lung transplant recipients.
abstract: BACKGROUND
  After lung transplantation (LTx), inhaled corticosteroids may be prescribed and at the same time prophylaxis against fungal infections with itraconazole is common. In our center, the addition of inhaled fluticasone propionate to systemic immunosuppression resulted in clinical Cushing's syndrome in 4 lung transplant recipients on itraconazole comedication.
  
  
  OBJECTIVE
  The current study was undertaken to compare systemic levels of inhaled fluticasone in patients with and without concomitant itraconazole therapy.
  
  
  METHODS
  The single-center, prospective controlled study was performed in the LTx program in Zurich, Switzerland. Twenty stable recipients, 1-7 years after LTx, on a prednisone maintenance dose (5-7.5 mg/day) gave informed consent and were assigned to 2 groups: (A) without itraconazole comedication and (B) currently on itraconazole, being continued during the study period. The patients of both groups started inhalation of 1 mg fluticasone propionate twice daily for 14 days with a powder disc inhaler. Plasma fluticasone levels were measured before the start of the study and on day 14.
  
  
  RESULTS
  Fluticasone levels before starting the treatment were below the detection limit in all 17 patients (7 in group A and 10 in group B) adhering to the study protocol. Baseline characteristics (underlying disease, age at LTx, time since LTx, FEV(1)) were comparable between the 2 groups. On study day 14, plasma fluticasone levels had increased to detectable levels in all patients (A: 273 +/- 124 pg/ml, B: 701 +/- 131 pg/ml), i.e. to significantly higher (p = 0.038) concentrations in patients on itraconazole.
  
  
  CONCLUSIONS
  Itraconazole comedication substantially increases systemic levels of inhaled fluticasone, most likely by inhibiting the cytochrome P450 3A4 enzyme system and thus the clearance of fluticasone. Accumulation of fluticasone can result in increased systemic effects and therefore comedication has to be taken into consideration when inhaled fluticasone is prescribed.
authors.affiliation: Division of Pulmonary Medicine and Lung Transplant Program, University Hospital, Zurich, Switzerland.
authors.forename: Rahel
authors.initials: R
authors.lastname: Naef
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmid
authors.forename: Markus
authors.initials: M
authors.lastname: Hofer
authors.forename: Stefan
authors.initials: S
authors.lastname: Minder
authors.forename: Rudolf
authors.initials: R
authors.lastname: Speich
authors.forename: Annette
authors.initials: A
authors.lastname: Boehler
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000935:Antifungal Agents / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D000068298:Fluticasone; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume / Q000187:drug effects; D006084:Graft Rejection; D006801:Humans; D017964:Itraconazole / Q000627:therapeutic use*; D008172:Lung Diseases, Fungal / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016040:Lung Transplantation; D008875:Middle Aged; D011446:Prospective Studies; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome
chemical_list: D000730:Androstadienes; D000935:Antifungal Agents; D001993:Bronchodilator Agents; D017964:Itraconazole; D000068298:Fluticasone