Reduction of the inhibitory effect of ketoconazole on budesonide pharmacokinetics by separation of their time of administration.
BACKGROUND
Budesonide is a glucocorticosteroid used in the treatment of, for example, inflammatory bowel diseases, with a recommended once-daily morning dosing regimen. Ketoconazole is a potent inhibitor of the cytochrome P450 3A (CYP3A) activities and known to inhibit the elimination of drugs metabolized by CYP3A, including budesonide. It is of therapeutic interest to know whether the influence of ketoconazole can be reduced by administration on an occasion different in time to CYP3A substrates.


METHODS
Eight healthy men completed this randomized, open crossover study that comprised three different periods. In period 1, a single oral dose of 3 mg budesonide was given in the morning. In period 2, a 200-mg ketoconazole tablet was administered once daily in the morning on 4 consecutive days. On the fourth day, 3 mg budesonide was administered at the same time as the ketoconazole. In period 3, 200 mg ketoconazole was administered once daily in the evening on 4 consecutive days. On the fourth day, 3 mg budesonide was administered 12 hours before the ketoconazole. One-week washout periods separated the budesonide administrations.


RESULTS
The mean area under the plasma drug concentration-time curve [AUC(0-24)] for budesonide was increased by 6.5 times when it was given simultaneously with ketoconazole. When the administrations of the two drugs were separated by 12 hours, the mean AUC(0-24) for budesonide was increased by only 3.8 times.


CONCLUSIONS
This study shows that the capability of ketoconazole to inhibit the elimination of budesonide is significantly reduced (by 50%) by a 12-hour separation of the administration times.
Seidegård
J
J
Experimental Medicine, AstraZeneca R&D Lund, Sweden. Janeric.Seidegard@astrazeneca.com
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D019819:Budesonide / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004334:Drug Administration Schedule; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000494:pharmacology*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D012016:Reference Values; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D019819:Budesonide; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D007654:Ketoconazole