Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects

Abstract

Aims Itraconazole is a potent inhibitor of CYP3A4 activity and is often used in combination with corticosteroids. Since the latter are partly metabolized by CYP3A4, we studied the interaction between itraconazole, prednisone and methylprednisolone in healthy male subjects. Methods The effects of 4 days administration of oral itraconazole (400 mg on the ®rst day then 200 mg day x1 for 3 days) on the pharmacokinetics of prednisolone after a single oral dose of prednisone (60 mg) and the pharmacokinetics of methylprednisolone after single oral dose of methylprednisolone (48 mg) were studied in 14 healthy male subjects in a two-period cross-over trial. Plasma cortisol concentrations were determined as a pharmacodynamic index. Results Itraconazole increased the mean area under the methylprednisolone concentration-time curve from 2773 ng ml x1 h to 7011 ng ml x1 h (P<0.001) and the elimination half-life from 3.2 h to 5.5 h (P<0.001). The pharmacokinetics of prednisolone were unchanged. Cortisol concentrations at 24 h were lower after administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 ng ml x1 vs 109 ng ml x1 , P<0.001). Conclusions Itraconazole increased methylprednisolone concentrations markedly with enhanced suppression of endogenous cortisol secretion, but had no effect on prednisolone pharmacokinetics. The pharmacokinetic interaction between methylprednisolone and itraconazole is probably related to inhibition of hepatic CYP3A4 activity by itraconazole.

Pharmacokinetic Assessment of Drug‐Drug Interactions of Isavuconazole With the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults

“…Similar findings have been reported for itraconazole and prednisolone coadministration 12. By contrast, voriconazole has demonstrated weak inhibition of prednisolone metabolism.…”

Impact of Fluconazole Prophylaxis on Cortisol Levels in Critically Ill Surgical Patients

“…A case report has described a liver transplant patient on prednisone therapy who developed Addisonian crisis after fluconazole was discontinued (42), presumably due to increased prednisone metabolism following the reversal of P450 enzyme suppression by fluconazole (42). Itraconazole, another triazole, has been shown to decrease the clearance of methylprednisolone and prolong methylprednisolone's inhibition of adrenal steroid synthesis (21,45), although it does not itself appear to cause adrenal dysfunction (32). Fluconazole (and newer triazoles) may exert the same effects, given its similar structure and mechanism of action.…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…163 No inhibition of NTCP or BSEP. 170 CYP3A4 inhibition will affect metabolism of a variety of drugs to increase their levels (e.g., BU, 171 dexamethasone, 172 midazolam, 173 ciclosporin, 174 tacrolimus, 174 methyl-prednisolone 175 ) or the levels of their metabolites. (e.g., CY 47 ).…”