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. Conclusion 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. Clinical Pharmacology & Therapeutics (2000) 68 , 13–17; doi: 10.1067/mcp.2000.106895