Itraconazole Decreases the Clearance and Enhances the Effects of Intravenously Administered Methylprednisolone in Healthy Volunteers

Abstract

A possible interaction of itraconazole, a potent inhibitor of CYP3A4, with intravenously administered methylprednisolone, was examined. In this double-blind, randomized, two-phase cross-over study, 9 healthy volunteers received either 200 mg itraconazole or matched placebo orally once a day for 4 days. On day 4, a dose of 16 mg methylprednisolone as sodium succinate was administered intravenously. Plasma concentrations of methylprednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined up to 24 hr. itraconazole increased the total area under the plasma methylprednisolone concentration-time curve (AUC(0-m) 2.6-fold) (P<O.OOl), while the AUC (12-24) of methylprednisolone was increased 12.2-fold (P<O.OOl). The systemic clearance of methylprednisolone during the itraconazole phase was 40% of that during the placebo phase (P<O.Ol). The volume of distribution of methylprednisolone was not affected by itraconazole. The mean elimination half-life of methylprednisolone was increased from 2.1 5-0.3 hr to 4.820.8 hr (P<O.OOl) by itraconazole. The mean morning plasma cortisol concentration during the itraconazole phase, measured 24 hr after the administration of methylprednisolone, was only about 9% of that during the placebo phase (11.0?9.0 ndml versus 117249.2 ng/ml; P<O.OOl). In conclusion, itraconazole decreases the clearance and increases the elimination half-life of intravenously administered methylprednisolone, resulting in greatly increased exposure to methylprednisolone during the night time and in enhanced adrenal suppression. Care should be taken when itraconazole or other potent inhibitors of CYP3A4 are used concomitantly with methylprednisolone.Methylprednisolone, a glucocorticoid with immunosuppressive and antiinflammatory properties, is widely used as both oral and intravenous formulations. Glucocorticoids, including methylprednisolone, may cause adverse effects, particularly during long-term therapy.The triazole antifungal agent, itraconazole, is a potent inhibitor of CYP3A4, and it greatly increases plasma concentrations of many orally administered drugs which are metabolized by CYP3A4, such as midazolam, triazolam, buspirone, felodipine, and lovastatin Varhe r t al. 1994;Neuvonen et al. 1996;Jalava et al. 1997;Kivisto et al. 1997). In our recent study, itraconazole considerably increased the concentrations of oral methylprednisolone in plasma (Varis et al. 1998). However, there seems to be no data on the possible interaction of itraconazole with intravenous methylprednisolone. The aim of this study was therefore to examine to what extent itraconazole affects the pharmacokinetics and pharmacodynamics of intravenously administered methylprednisolone. Materials and MethodsFour female and six male volunteers (age range 19 to 22 years; weight range 45 to 80 kg) were enrolled into this study, after written Author for correspondence: Pertti J. Neuvonen, Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, FIN-00290 Helsinki, Finland (fax +358-9-4717 4039, e...

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.…”

Drug–drug interactions of antifungal agents and implications for patient care

“…ITZ inhibits the metabolism of oral and intravenous methylprednisolone, which results in two-to threefold increases in its C max , AUC 0-∞ and t ½ [63][64][65]. ITZ also increases intravenous and oral dexamethasone AUC 0-∞ by approximately three-and fourfold, respectively [65].…”

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

“…Toxicities reported in o4% of patients (peripheral neuropathy, fluid retention, gastrointestinal intolerance, elevated hepatic transaminases, rash, headache, tremor and sleep disturbance) have been found with high steady-state triazole levels in patients with chronic pulmonary aspergillosis [72,78]. In addition, an important drug-drug interaction exists between itraconazole and several corticosteroids, including oral or intravenous methylprednisolone and inhaled budesonide and fluticasone; the azole impairs metabolism of these exogenous glucocorticosteroids resulting in potential adrenal suppression, including overt Cushing syndrome [79][80][81][82][83][84][85][86][87]. It is, therefore, safer to use oral prednisone or prednisolone (neither of which has these interactions), or perhaps inhaled beclomethasone (which to date has not been shown to have an azole interaction but has also not been systematically studied in this regard), or ciclesonide (a prodrug with topical respiratory metabolism) [88], if using itraconazole or other triazoles in treating ABPA or SAFS.…”