Pharmacokinetics And Metabolism - Itraconazole
General Pharmacokinetic Characteristics
Peak plasma concentrations are reached within 2.5 hours
following administration of the oral solution. 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
and AUC values 4 to 7-fold higher than those seen after a single dose.
Steady-state Cmax values of about 2 μg/ml are reached after oral
administration of 200 mg once daily. 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
Itraconazole is rapidly absorbed after administration of
the oral solution. Peak plasma concentrations of itraconazole are reached
within 2.5 hours following administration of the oral solution under fasting
conditions. The observed absolute bioavailability of itraconazole under fed
conditions is about 55% and increases by 30% when the oral solution is taken in
fasting conditions. Itraconazole exposure is greater with the oral solution
than with the capsule formulation 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.
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. Ã 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, PRECAUTIONS : DRUG INTERACTIONS and DOSAGE
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® Oral
Solution, monitor carefully and consider other treatment alternatives which may
include discontinuation of SPORANOX® Oral Solution administration.
(See BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS:
DRUG INTERACTIONS and ADVERSE REACTIONS: Post-marketing
Experience for more information.)
Seventeen cystic fibrosis
patients, ages 7 to 28 years old, were administered itraconazole oral solution
2.5 mg/kg b.i.d. for 14 days in a pharmacokinetic study. Sixteen patients
completed the study. Steady state trough concentrations > 250 ng/mL were
achieved in 6 out of 11 patients ≥ 16 years of age but in none of the 5
patients < 16 years of age. Large variability was observed in the
pharmacokinetic data (%CV for trough concentrations = 98% and 70% for ≥ 16
and < 16 years, respectively; %CV for AUC = 75% and 58% for ≥ 16 and
< 16 years, respectively). If a patient with cystic fibrosis does not respond
to SPORANOX® Oral Solution, consideration should be given to
switching to alternative therapy.
The oral bioavailability of hydroxypropyl-β-cyclodextrin
given as a solubilizer of itraconazole in oral solution is on average lower
than 0.5% and is similar to that of hydroxypropyl-βcyclodextrin alone.
This low oral bioavailability of hydroxypropyl-β-cyclodextrin is not
modified by the presence of food and is similar after single and repeated
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.
Isolates from several fungal species with decreased
susceptibility to itraconazole have been isolated in vitro and from patients
receiving prolonged therapy.
Candida krusei, Candida glabrata and Candida
tropicalis are generally the least susceptible Candida species, with
some isolates showing unequivocal resistance to itraconazole in vitro.
Itraconazole is not active against Zygomycetes (e.g., Rhizopus
spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium
spp., Scedosporium spp. and Scopulariopsis spp.
In systemic candidosis, if fluconazole-resistant strains
of Candida species are suspected, it cannot be assumed that these are
sensitive to itraconazole, hence their sensitivity should be tested before the
start of itraconazole therapy.
Several in vitro studies have reported that some fungal
clinical isolates, including Candida species, 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
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.
Activity In Vitro and In Vivo
Itraconazole has been shown to be active against most
strains of the following microorganism, both in vitro and in clinical
Susceptibility Testing Methods
(Applicable to Candida isolates from patients with
oropharyngeal or esophageal candidiasis)
The interpretive criteria and breakpoints for
itraconazole against Candida albicans are applicable to tests performed
using Clinical Laboratory and Standards Institute (CLSI) microbroth dilution
reference method M27A for MIC (partial inhibition endpoint) read at 48 hours.
Broth Microdilution Techniques
Quantitative methods are used to determine antifungal
minimum inhibitory concentrations (MICs). These MICs provide estimates of the
susceptibility of Candida spp. to antifungal agents. MICs should be
determined using a standardized procedure at 48 hours. Standardized procedures
are based on a microdilution method (broth)1,2 with standardized
inoculum concentrations and standardized concentrations of itraconazole powder.
The MIC values should be interpreted according to the criteria provided in
Criteria for Itraconazole1,2
||Broth Microdilution MIC* (μg/mL) at 48 Hours
|| ≤ 0.125
||0.25 - 0.5
|| ≥ 1
|* A report of “Susceptible”
indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. The intermediate
category implies that an infection due to the isolate may be appropriately
treated in the body sites where the drugs are physiologically concentrated or
when a high dosage of drug is used. The resistant category implies that
isolates are not inhibited by the usually achievable concentrations of the
agent with normal dosage schedules and clinical efficacy of the agent against
the isolate has not been reliably shown in treatment studies. The intermediate category
is sometimes called Susceptible-Dose Dependent (SDD) and both categories are
equivalent for itraconazole.
test procedures require the use of quality control organisms to control the
technical aspects of the test procedures. Standard itraconazole powder should
provide the following range of values noted in the table below.
NOTE: Quality control microorganisms are specific strains of
organisms with intrinsic biological properties relating to resistance
mechanisms and their genetic expression within fungi; the specific strains used
for microbiological control are not clinically significant.
Acceptable Quality Control
Ranges for Itraconazole to be used in Validation of Susceptibility Test Results1,2
||Broth Microdilution MIC (μg/mL) at 48 Hours
|Candida krusei ATCC 6258
|† ATCC is the registered
trademark of the American Type Culture Collection.
Two randomized, controlled
studies for the treatment of oropharyngeal candidiasis have been conducted
(total n=344). In one trial, clinical response to either 7 or 14 days of
itraconazole oral solution, 200 mg/day, was similar to fluconazole tablets and
averaged 84% across all arms. Clinical response in this study was defined as
cured or improved (only minimal signs and symptoms with no visible lesions).
Approximately 5% of subjects were lost to follow-up before any evaluations
could be performed. Response to 14 days therapy of itraconazole oral solution
was associated with a lower relapse rate than 7 days of itraconazole therapy.
In another trial, the clinical response rate (defined as cured or improved) for
itraconazole oral solution was similar to clotrimazole troches and averaged
approximately 71% across both arms, with approximately 3% of subjects lost to
follow-up before any evaluations could be performed. Ninety-two percent of the
patients in these studies were HIV seropositive.
In an uncontrolled, open-label study of selected patients
clinically unresponsive to fluconazole tablets (n=74, all patients HIV
seropositive), patients were treated with itraconazole oral solution 100 mg
b.i.d. (Clinically unresponsive to fluconazole in this study was defined as
having received a dose of fluconazole tablets at least 200 mg/day for a minimum
of 14 days.) Treatment duration was 14-28 days based on response. Approximately
55% of patients had complete resolution of oral lesions. Of patients who
responded and then entered a follow-up phase (n=22), all relapsed within 1
month (median 14 days) when treatment was discontinued. Although baseline
endoscopies had not been performed, several patients in this study developed
symptoms of esophageal candidiasis while receiving therapy with itraconazole
oral solution. Itraconazole oral solution has not been directly compared to
other agents in a controlled trial of similar patients.
A double-blind randomized study (n=119, 111 of whom were
HIV seropositive) compared itraconazole oral solution (100 mg/day) to
fluconazole tablets (100 mg/day). The dose of each was increased to 200 mg/day
for patients not responding initially. Treatment continued for 2 weeks
following resolution of symptoms, for a total duration of treatment of 3-8
weeks. Clinical response (a global assessment of cured or improved) was not
significantly different between the two study arms, and averaged approximately
86% with 8% lost to follow-up. Six of 53 (11%) itraconazole-treated patients
and 12/57 (21%) fluconazole-treated patients were escalated to the 200 mg dose
in this trial. Of the subgroup of patients who responded and entered a
follow-up phase (n=88), approximately 23% relapsed across both arms within 4
1. Clinical and Laboratory Standards Institute (CLSI). Reference
Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved
Standard-Third Edition. CLSI document M27-A3. Clinical and Laboratory Standards
Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898,
2. Clinical and Laboratory Standards Institute (CLSI). Reference
Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Fourth
Informational Supplement. CLSI document M27-S4. Clinical and Laboratory
Standards Institute, 940 West Valley Road, Suite 2500, Wayne, Pennsylvania
19087 USA, 2012.