Lower oropharyngeal deposition of inhaled ciclesonide via hydrofluoroalkane metered-dose inhaler compared with budesonide via chlorofluorocarbon metered-dose inhaler in healthy subjects.
OBJECTIVE
Inhaled corticosteroids may cause oropharyngeal side effects if deposited in the oropharynx in active form. Ciclesonide, an inhaled corticosteroid with low glucocorticoid receptor affinity, is activated primarily in the lung by esterases to an active metabolite, desisobutyryl-ciclesonide (des-CIC), with high glucocorticoid receptor affinity. We studied oropharyngeal deposition of ciclesonide, des-CIC, and budesonide.


METHODS
In an open-label, randomized, two-treatment (administered in sequence), five-period study, 18 healthy subjects received 800 microg (ex-valve) inhaled ciclesonide via a hydrofluoroalkane-pressurized, metered-dose inhaler followed by 800 microg budesonide (Pulmicort) by a chlorofluorocarbon-pressurized, metered-dose inhaler (four puffs of 200 microg each, ex-valve) or vice versa. Oropharyngeal cavity rinsing was performed immediately, or 15, 30, 45, or 60 min after inhalation (one rinsing per study period), and the solutions were analyzed using liquid chromatography with tandem mass spectrometric detection.


RESULTS
Ciclesonide and budesonide were detected in most oropharyngeal wash samples. Maximal concentration of each inhaled corticosteroid was reached immediately post-inhalation; maximal concentrations of ciclesonide and des-CIC were 30% and 0.67%, respectively, of budesonide. Oropharyngeal deposition of ciclesonide and budesonide decreased rapidly within 15 min post-inhalation, and less rapidly thereafter. Less than 10% of the residual ciclesonide in the oropharynx was converted to des-CIC. The molar dose-adjusted amount of des-CIC was 4% of budesonide (P < 0.0001). There were no significant adverse events.


CONCLUSIONS
Oropharyngeal deposition of des-CIC was more than one order of magnitude lower than that of budesonide when administered by the respective metered-dose inhalers. This may explain the low frequency of oropharyngeal side effects of ciclesonide in clinical studies.
Nave
Ruediger
R
ALTANA Pharma AG, Byk-Gulden-Str. 2, 78467, Konstanz, Germany. ruediger.nave@altanapharma.com
Zech
Karl
K
Bethke
Thomas D
TD
D000280:Administration, Inhalation; D000328:Adult; D019540:Area Under Curve; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics; D019819:Budesonide / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D017402:Chlorofluorocarbons / Q000737:chemistry; D002853:Chromatography, Liquid / Q000379:methods; D005260:Female; D005466:Fluorocarbons / Q000737:chemistry; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D036501:Metered Dose Inhalers; D008875:Middle Aged; D009960:Oropharynx / Q000378:metabolism*; D011282:Pregnenediones / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*
D001993:Bronchodilator Agents; D017402:Chlorofluorocarbons; D005466:Fluorocarbons; D011282:Pregnenediones; D019819:Budesonide; C120481:ciclesonide