Pharmacokinetics And Metabolism
General Pharmacokinetic Characteristics
Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 μg/mL, 1.1 μg/mL and 2.0 μg/mL after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 mL/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.
Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of itraconazole is about 55%.
The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole) Capsules are taken immediately after a full meal. Absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases. (see DRUG INTERACTIONS.) Absorption of itraconazole under fasted conditions in these subjects is increased when SPORANOX® Capsules are administered with an acidic beverage (such as a non-diet cola). When SPORANOX® Capsules were administered as a single 200-mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H2-receptor antagonist, itraconazole absorption was comparable to that observed when SPORANOX® Capsules were administered alone. (see DRUG INTERACTIONS.)
Itraconazole exposure is lower with the Capsule formulation than with the Oral Solution when the same dose of drug is given. (see WARNINGS)
Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (>700 L), suggesting extensive distribution into tissues. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma.
Itraconazole is extensively metabolized by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of itraconazole.
Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose.
As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as 1 week after start of treatment – for at least six months after the end of a 3-month treatment period.
Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg oral dose of itraconazole was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as CrCl 50-79 mL/min), moderate (defined in this study as CrCl 20-49 mL/min), and severe renal impairment (defined in this study as CrCl <20 mL/min) were similar to that in healthy subjects (range of means 42-49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function. Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. (see PRECAUTIONS and DOSAGE AND ADMINISTRATION.)
Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose of itraconazole as capsule. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37±17 hours vs. 16±5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole. (see CONTRAINDICATIONS, DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION.)
Decreased Cardiac Contractility
When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX® Capsules, SPORANOX® should be discontinued. (see BOX WARNING, CONTRAINDICATIONS, WARNINGS, DRUG INTERACTIONS and ADVERSE REACTIONS: Post-Marketing Experience for more information.)
Mechanism Of Action
In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.
Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, and Trichophyton species (See INDICATIONS AND USAGE: Description of Clinical Studies).
Susceptibility Testing Methods
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.
Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy.
Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
Several in vitro studies have reported that some fungal clinical isolates with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed.
Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown.
Description Of Clinical Studies
Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.
Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.
Histoplasmosis In HIV-Infected Patients
Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.
Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.
Onychomycosis Of The Toenail
Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX® Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).
Onychomycosis Of The Fingernail
Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX® Capsules b.i.d., followed by a 3-week period without SPORANOX®, which was followed by a second 1-week pulse of 200 mg of SPORANOX® Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed.