Effect of coadministered ketoconazole, a strong cytochrome P450 3A4 enzyme inhibitor, on the pharmacokinetics of ciclesonide and its active metabolite desisobutyryl-ciclesonide.
OBJECTIVE
Cytochrome P450 (CYP) 3A4 isoenzyme has been identified in vitro as the key enzyme to metabolize desisobutyryl-ciclesonide (des-CIC), the pharmacologically active metabolite of the inhaled corticosteroid ciclesonide. This pharmacokinetic drug-drug interaction study was conducted to confirm this major metabolic pathway in vivo by using the strong CYP3A4 inhibitor ketoconazole, and to assess the effect of ketoconazole on the pharmacokinetics of ciclesonide and des-CIC.


METHODS
Fourteen healthy adults participated in this open-label, nonrandomized, fixed sequence, two-period, repeated-dose pharmacokinetic study. During the first 7-day treatment period, the subjects orally inhaled ciclesonide 320 microg once daily. During the second 7-day treatment period, the subjects continued with the same dose of orally inhaled ciclesonide and concomitantly received oral ketoconazole 400 mg once daily. Pharmacokinetic profiles for ciclesonide and des-CIC were obtained on day 7 of each study period.


RESULTS
For the parent compound, ciclesonide, no changes in the pharmacokinetic parameter estimates--the area under the serum concentration-time curve during the dosage interval (AUC(tau)), maximum serum concentration (C(max)) and time to reach the C(max)--were observed. In contrast, the AUC(tau) and C(max) of des-CIC increased approximately 3.5-fold and 2-fold under the influence of the CYP3A4 inhibitor ketoconazole.


CONCLUSIONS
The CYP3A4 pathway is the major pathway for biotransformation of the active metabolite of ciclesonide in humans. While elimination of des-CIC was reduced by strong CYP3A4 inhibitor coadministration in vivo, activation of the parent compound ciclesonide to des-CIC was not affected. Dose adjustment is not necessary when ciclesonide needs to be coadministered with ketoconazole, because the potency of an inhaled corticosteroid is mediated by topical concentrations in the lung and because ciclesonide has a very low potential to produce systemic adverse effects.
Böhmer
Gabriele M
GM
Department of Clinical Pharmacology, University Hospital of Tübingen, Tübingen, Germany. gabriele.boehmer@med.uni-tuebingen.de
Drollmann
Anton
A
Gleiter
Christoph H
CH
Nave
Rüdiger
R
D000328:Adult; D018926:Anti-Allergic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000009:adverse effects / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001711:Biotransformation; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011282:Pregnenediones / Q000009:adverse effects / Q000493:pharmacokinetics*
D018926:Anti-Allergic Agents; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D011282:Pregnenediones; C494355:desisobutyrylciclesonide; D001189:Aryl Hydrocarbon Hydroxylases; C422408:CYP3A43 protein, human; D007654:Ketoconazole; C120481:ciclesonide