A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Sporanox Pharmacology, Pharmacokinetics, Studies, Metabolism - Itraconazole Capsules
Sporanox Pharmacology, Pharmacokinetics, Studies, Metabolism - Itraconazole Capsules
CLINICAL PHARMACOLOGY
Mode of Action
In vitro studies have demonstrated that itraconazole inhibits
the cytochrome P-450-dependent
synthesis of ergosterol,
which is a vital component
of fungal cell membranes.
Pharmacokinetics and Metabolism
NOTE: The plasma
concentrations reported below were measured by high performance
liquid chromatography
(HPLC) specific for
itraconazole. When itraconazole in plasma
is measured by a bioassay, values reported are approximately 3.3
times higher than those obtained by HPLC
due to the presence of the bioactive
metabolite, hydroxyitraconazole.
See Microbiology below.
The pharmacokinetics
of itraconazole after intravenous
administration and its absolute
oral bioavailability
from an oral solution
were studied in a randomized cross-over study using six healthy
male volunteers. The total
plasma clearance
averaged 381 ± 95 ml/min and the apparent volume of distribution
averaged 796 ± 185 l. The observed absolute oral bioavailability
of itraconazole was 55%.
The oral bioavailability
of itraconazole is maximal when Sporanox (itraconazole capsules)
is taken with a full meal. The pharmacokinetics
of itraconazole were studied using six healthy
male volunteers who received,
in a cross-over design, single 100 mg
doses of itraconazole as a polyethylene
glycol capsule, with
or without a full meal. The same six volunteers also received 50
mg or 200 mg with a full
meal in a cross-over design.
In this study, only itraconazole
plasma concentrations
were measured. Presented in the table (TABLE 1) below are the respective
pharmacokinetic parameters for itraconazole:
TABLE 1
| |
50 mg |
100 mg |
100 mg |
200 mg |
| |
(fed) |
(fed) |
(fasted) |
(fed) |
| Cmax (ng/ml) |
45 ± 16 |
132 ± 67 |
38 ± 20 |
289 ± 100 |
| Tmax (hours) |
3.2 ± 1.3 |
4.0 ± 1.1 |
3.3 ± 1.0 |
4.7 ± 1.4 |
| AUC0-(ng°h/ml) |
567 ± 264 |
1899 ± 838 |
722 ± 289 |
5211 ± 2116 |
|
Values are means ± standard
deviation
|
Doubling the Sporanox dose
results in approximately a three-fold increase in the itraconazole
plasma concentrations.
Values given in the table
(TABLE 2) below represent data from a cross-over pharmacokinetics
study in which 27 healthy
male volunteers each took
a single 200 mg dose
of Sporanox with or without a full meal:
TABLE 2
| |
Itraconazole |
Hydroxyitraconazole |
| |
Fed |
Fasted |
Fed |
Fasted |
| Cmax (ng/ml) |
239 ± 85 |
140 ± 65 |
397 ± 103 |
286 ± 101 |
| Tmax (hours) |
4.5 ± 1.1 |
3.9 ± 1.0 |
5.1 ± 1.6 |
4.5 ± 1.1 |
| AUC0-¥(ng°h/ml) |
3423 ± 1154 |
2094 ± 905 |
7978 ± 2648 |
5191 ± 2489 |
| t½ (hours) |
21 ± 5 |
21 ± 7 |
12 ± 3 |
12 ± 3 |
|
Values are means ± standard
deviation
|
Absorption of itraconazole under fasted conditions in individuals
with relative or absolute
achlorhydria, such as patients
with AIDS or volunteers
taking gastric acid
secretion suppressors
(e.g., H2inhibitors), was increased when Sporanox
was administered with a cola beverage. Eighteen males with AIDS
received single 200 mg doses
of Sporanox under fasted conditions with 8 ounces of water
or 8 ounces of a cola beverage in a crossover
design. The absorption
of itraconazole was increased when Sporanox was coadministered with
a cola beverage with AUC0-24 and Cmax increasing
75 ± 121% and 95 ± 128%, respectively. Thirty healthy
males received single 200 mg
doses of Sporanox under fasted conditions either 1) with water;
2) with water, after ranitidine 150 mg
b.i.d. for 3 days; or
3) with cola, after ranitidine 150 mg
b.i.d. for 3 days. When
Sporanox was administered after ranitidine pretreatment, itraconazole
was absorbed to a lesser extent than when Sporanox was administered
alone, with decreases in AUC0- 24 and Cmaxof
39 ± 37% and 42 ± 39%, respectively. When Sporanox
was administered with cola after ranitidine pretreatment, itraconazole
absorption was comparable
to that observed when Sporanox was administered alone.
Steady-state concentrations were reached within 15 days following
oral doses of 50-400 mg daily.
Values given in the table
below (TABLE 3) are data at steady-state from a pharmacokinetics
study in which 27 healthy male volunteers took 200 mg
Sporanox b.i.d. (with
a full meal) for 15 days:
TABLE 3
| |
Itraconazole |
Hydroxyitraconazole |
| Cmax (ng/ml) |
2282 ± 514 |
3488 ± 742 |
| Cmin (ng/ml) |
1855 ± 535 |
3349 ± 761 |
| Tmax (hours) |
4.6 ± 1.8 |
3.4 ± 3.4 |
| AUC0-12h (ng°h/ml) |
22569 ± 5375 |
38572 ± 8450 |
| t½ (hours) |
64 ± 32 |
56 ± 24 |
|
Values are means ± standard
deviation
|
Results of the pharmacokinetics
study suggest that itraconazole may undergo saturation
metabolism with multiple
dosing.
Itraconazole is extensively metabolized by the liver
into a large number of metabolites, including hydroxyitraconazole,
the major metabolite. Fecal excretion of the parent
drug varies between 3-18%
of the dose. Renal excretion of the parent
drug is less than 0.03%
of the dose. About 40% of the dose is excreted as inactive metabolites
in the urine. No single excreted
metabolite represents more than 5% of a dose. The main
metabolic pathways are oxidative scission of the dioxolane ring,
aliphatic oxidation
at the 1-methylpropyl substituent, N- dealkylation of this
1-methylpropyl substituent, oxidative degradation
of the piperazine
ring and triazolone scission.
Plasma concentrations of itraconazole in subjects with renal
insufficiency were comparable to those obtained in healthy
subjects. The effect
of hepatic impairment on the plasma
concentration
of itraconazole is unknown. It is recommended that plasma
concentrations of itraconazole in patients with hepatic impairment
be carefully monitored.
The plasma protein
binding of itraconazole is 99.8% and that of hydroxyitraconazole
is 99.5%. Itraconazole is not removed by hemodialysis.
In animal studies, itraconazole
is extensively distributed into lipophilic tissues. Concentrations
of itraconazole in fatty tissues, omentum, liver, kidney and skin
tissues are 2-20 times the corresponding
plasma concentrations.
Aqueous fluids such as
cerebrospinal
fluid and saliva
contain negligible amounts of the drug.
Microbiology
Itraconazole exhibits in vitro activity
against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma
duboisii, Aspergillus
flavus, Aspergillus
fumigatus and Cryptococcus neoformans. Itraconazole also
exhibits varyingin vitro activity against Sporothrix schenckii,Trichophyton
spp., Candida albicans and Candida
spp. The bioactive
metabolite, hydroxyitraconazole,
has not been evaluated againstHistoplasma capsulatum and
Blastomyces dermatitidis.Correlation between in vitro
minimum inhibitory concentration
(MIC) results and clinical
outcome has yet to be
established for azole antifungal
agents.
Itraconazole administered orally was active in a variety
of animal models of fungal
infection using standard
laboratory strains
of fungi. Fungistatic activity has been demonstrated against disseminated
fungal infections caused by Blastomyces dermatitidis, Histoplasma
duboisii, Aspergillus
fumigatus, Coccidioides immitis, Cryptococcus
neoformans, Paracoccidioides
brasiliensis, Sporothrix schenckii, Trichophyton
rubrum and Trichophyton
mentagrophytes. Itraconazole administered at 2.5 mg/kg and 5.0
mg/kg via the oral
and parenteral routes increased survival
rates and sterilized organ
systems in normal and immunosuppressed guinea pigs with disseminated
Aspergillus fumigatus infections. Oral itraconazole administered
daily at 40 mg/kg and 80 mg/kg increased survival
rates in normal rabbits
with disseminated
disease and immunosuppressed rats with pulmonaryAspergillus fumigatus
infection, respectively. Itraconazole has demonstrated antifungal
activity in a variety
of animal models infected
with Candida albicans
and other Candida species.
In vivo studies suggest that the activity of amphotericin B may be suppressed
by azole antifungal therapy. As with other azoles, ketoconazole and itraconazole
inhibit 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.
Special Populations
Cystic Fibrosis: Seventeen cystic fibrosis patients, ages 7 to 28 years
old, were administered itraconazole oral solution 2.5 mg/kg bid for 14 days
in a pharmacokinetic study. Steady state trough concentrations > 250 ng/mL
were achieved in 7 out of 12 patients greater than 16 years of age but in none
of the 5 patients less than 16 years of age. Large variability was observed
in the pharmacokinetic data (%CV = 88% and 65% for > 16 and < 16 years,
respectively for trough concentrations). If a patient does not respond to SPORANOX
oral solution, consideration should be given to switching to alternative therapy.
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