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Antimicrobial Agents and Chemotherapy, July 1998, p. 1862-1865, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Enhanced Bioavailability of Itraconazole in
Hydroxypropyl
-Cyclodextrin Solution versus Capsules in
Healthy Volunteers
Joseph A.
Barone,1,*
Bruce L.
Moskovitz,2
Joseph
Guarnieri,2
Alan E.
Hassell,2
John L.
Colaizzi,1
Robert H.
Bierman,1 and
Lois
Jessen1
Rutgers
The State University of New Jersey,
Piscataway,1 and
Janssen Research
Foundation, Titusville,2 New Jersey
Received 7 July 1997/Returned for modification 24 December
1997/Accepted 6 April 1998
 |
ABSTRACT |
The bioavailabilities and bioequivalences of single 200-mg doses of
itraconazole solution and two capsule formulations were evaluated in a
crossover study of 30 male volunteers. The two capsule formulations
were bioequivalent. The bioavailabilities of the solutions itraconazole
and hydroxyitraconazole were 30 to 33% and 35 to 37% greater,
respectively, than those of either capsule. However, the maximum
concentrations of the drug in plasma (Cmax),
the times to Cmax, and the terminal half-lives
were comparable for all three formulations. These data indicate that
the bioavailabilities of itraconazole and hydroxyitraconazole are
enhanced when administered as an oral solution instead of capsules.
| |
TEXT |
Itraconazole (ITR) (Sporanox;
Janssen Pharmaceutica, Titusville, N.J.) is a broad-spectrum triazole
agent available for the treatment of histoplasmosis, blastomycosis,
onychomycosis, and amphotericin B-refractory aspergillosis (7, 8,
10, 15, 19, 20, 27). ITR is highly effective in vitro against
Candida albicans and other Candida species,
including many resistant to fluconazole (1, 4). To achieve
maximum absorption, the ITR capsule formulation should be taken with
food and in the presence of an acidic gastric environment (2, 14,
20).
An oral solution formulation of ITR (Sporanox oral solution [SOS])
containing hydroxypropyl-
-cyclodextrin is approved and has greater
bioavailability when given in the fasted state than in the nonfasted
state to healthy volunteers (3). Previously, single 100-mg
doses of two formulations of ITR capsules (F05 and F12) were found to
be bioequivalent (18). The objectives of the present trial
were to compare the pharmacokinetics of these two capsule formulations
when given at the recommended therapeutic dose (200 mg/day) and to
determine the bioavailabilities of ITR and its active metabolite,
hydroxyitraconazole (OH-ITR), by comparing SOS with both capsule
formulations.
Patients.
Healthy male volunteers at least 18 years of age
who were nonsmokers and who weighed within 10% of the
normal body weights for their heights were eligible for study
inclusion. Patients could have no clinically significant abnormalities
on physical examination or in blood counts, biochemistries, or
urinalyses, and a negative urine drug screen was required.
Patients with a significant concurrent illness, a history of
barbiturate, amphetamine, or narcotic abuse, an inability to swallow
capsules, or a history of hypersensitivity to imidazole or azole
compounds or who had participated in an investigational study or used
an investigational drug within the previous month were not entered.
Institutional review board approval was obtained and each subject gave
written informed consent before entry.
Study design.
This was an open-label, single-dose, crossover
study with three phases separated by 2-week washout intervals. Patients
were randomized to one of six sequence groups (F05-F12-SOS,
F05-SOS-F12, F12-F05-SOS, F12-SOS-F05, SOS-F05-F12, or
SOS-F12-F05) and received one of the following three treatments
with 200 ml of water during each phase: formula F05 (two 100-mg ITR
capsules), formula F12 (two 100-mg ITR capsules), or SOS (20 ml,
containing 200 mg of ITR).
Physical examinations and clinical laboratory tests (hematologies,
biochemistries, urinalyses, and urine drug screens) were performed
within 2 weeks of the start of dosing and again at the 96-h blood
sampling for phase 3 (end of study). Subjects were admitted to the
study unit the evening before dosing. No food or beverages (except
water) were permitted after midnight. In the morning, subjects received
a standard breakfast (fried egg and bacon, toast with butter and jam,
whole milk, orange juice, and banana) followed immediately by the study
medication; subjects were not permitted to drink until 2 h after
dosing or to eat until 4 h after dosing. Patients remained at the
study site through the 36-h blood collection and then returned for the
48-, 72-, and 96-h blood collections. No medications except analgesics
were permitted during the study. Adverse events (AEs) were monitored by
nondirected interviews conducted before each dosing and at 4, 12, 24, 72, and 96 h after each dosing. Information included date of
onset, duration, intensity, frequency, action taken, relationship to
study medication, and outcome.
Pharmacokinetic determinations.
During each of the three
crossover phases, 10-ml blood samples were obtained immediately prior
to dosing (time zero) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48,
72, and 96 h after dosing. Blood was collected in heparinized
tubes, centrifuged within 1 h of sampling, pipetted into labeled
containers, and stored at 
20°C. The frozen plasma samples were
sent to Janssen Research Foundation, where they were analyzed for
concentrations of ITR and OH-ITR by high-performance liquid
chromatography by the method of Woestenborghs et al.
(30). The limits of quantification were 1 ng/ml for ITR and
2.5 ng/ml for OH-ITR. The relative errors of the assay method were +9%
at 1 ng/ml and +0.2% at 500 ng/ml.
The following pharmacokinetic parameters were evaluated for ITR and
OH-ITR: the maximum concentration of the drug in plasma (Cmax), the time to Cmax
(Tmax), the terminal half-life
(t1/2), the area under the plasma
concentration-time curve from 0 to 96 h postdose
(AUC0-96), and the area under the plasma
concentration-time curve from 0 to 
(AUC0-
). The
t1/2 was computed as ln 2/, where is the
elimination rate constant determined by linear regression of the
terminal points of the log-linear plasma concentration-time curves.
AUCs were calculated via trapezoidal summation.
Statistical analysis.
SAS version 5.16 was used for all data
calculations and statistical analyses. Demographic data were compared
with a one-way analysis of variance for continuous variables and a
chi-square test for categorical variables. Pharmacokinetic data were
analyzed with an analysis of variance model appropriate for a
three-treatment, three-period crossover design. Pairwise comparisons
were carried out with t tests on the least-squares means.
All P values were based on two-sided tests, with alpha equal
to 0.05.
In order to determine bioequivalences, 90% confidence intervals (CI)
were computed for each pharmacokinetic parameter for
each pair of
formulations (
25). If the 90% CI of the test formulation
was completely contained in the range of 80 to 120% of the reference
formulation, the two formulations were considered bioequivalent
for
that pharmacokinetic parameter.
Thirty subjects were enrolled and all completed the study. Five
subjects were randomized to each of the six sequence groups,
which were
comparable for demographic variables. The study population
had a mean
age of 24 years (range, 19 to 34) and a mean weight
of 167 lb (range,
130 to 206).
Plasma ITR concentrations.
The bioequivalences of the three
formulations are illustrated in Fig. 1. SOS and F05 were
bioequivalent with regard to Cmax, Tmax, and t1/2 (Table
1). SOS and F12 also were
bioequivalent with regard to Cmax,
Tmax, and t1/2 (Table
2).
Bioavailability, as measured by the AUC
0-96 and
AUC
0-, was greater for SOS than for either capsule
formulation.
The AUC
0-96 and AUC
0- were
30.7 and 30.4% higher,
respectively, for SOS than for F05. The
AUC
0-96 and AUC
0- for SOS were also higher
(32.7 and 31.4%, respectively) than those
for F12. The two capsule
formulations were bioequivalent with
regard to all parameters.
Plasma OH-ITR concentrations.
Overall, mean plasma OH-ITR
concentrations were substantially higher than ITR concentrations with
both capsule formulations and with SOS. As with ITR, the mean AUCs for
OH-ITR were similar for F05, F12, and SOS from 0 to 96 h postdose
(Fig. 2). SOS and F05 were bioequivalent
with regard to Cmax,
Tmax, and t1/2 but not
with regard to AUC0-96 and AUC0- (Table 3). The overall systemic exposure to
OH-ITR was enhanced with SOS (compared to the exposure with F05) based
on the AUC0-96 and AUC0-, which were 37.3 and 37.4% higher, respectively. SOS and F12 were bioequivalent with
regard to Cmax, Tmax, and t1/2, but the AUC0-96 and
AUC0- were higher (34.9 and 34.8%, respectively) for
SOS (Table 4). The two capsule formulations were bioequivalent with regard to all parameters.
Treatment sequence and phase effects.
For both ITR and OH-ITR,
there were no significant differences among the six sequences with
regard to carryover effects (P 
0.31) or phase
effects.
For ITR
Tmaxs, the means were 4.9, 4.8, and
5.1 h for phases 1, 2, and 3, respectively (
P = 0.06). For OH-ITR
Tmaxs, the means
were 5.3, 5.3, and 5.9 h for phases 1, 2, and 3, respectively
(
P = 0.08). These differences were not statistically
significant
and were not considered clinically meaningful.
Safety.
Of the 30 subjects who completed the study, 2 (7%)
had one AE each, neither of which resulted in study discontinuation.
One subject had a mild rash that began on the first day of SOS dosing and one subject reported mild headache that occurred the day after the
first dose of F05. Both AEs resolved within 1 day, did not recur, and
were judged to be possibly related to the study medication. No
clinically significant changes from baseline in vital signs or
laboratory parameters were observed.
The results of our study demonstrate that the bioavailability of ITR,
as measured by the AUC, is enhanced with SOS. For ITR,
bioavailability
was 30 to 33% greater for SOS than for both capsule
formulations,
while the mean
Cmaxs,
Tmaxs, and
t1/2s were
comparable
for all three formulations. For OH-ITR, overall systemic
exposure
was also higher (35 to 37%) for SOS than for both capsule
formulations,
and all three formulations had similar mean
Cmaxs,
Tmaxs, and
t1/2s.
Capsule formulations F05 and F12 were bioequivalent. Mean peak plasma
ITR concentrations were achieved within approximately
5 h after a
200-mg dose of each capsule formulation. Peak concentrations
of OH-ITR
were higher, with longer
Tmaxs and shorter
t1/2s. These
data are consistent with those
reported by Hardin et al. (
14)
for oral ITR capsules (200 mg/day).
ITR absorption from solid-dose forms is variable and can be enhanced by
administration with food and in the presence of an
acidic gastric
environment (
2,
12,
14,
26,
29). SOS
has been shown to
produce significantly higher plasma ITR levels
in animal studies
(
16,
17), and when SOS is administered in
the fasting state,
the bioavailability of ITR is enhanced compared
with that obtained with
capsules (
3).
Taken together, these data indicate that ITR has greater
bioavailability in the form of SOS and may be effectively administered
in that form without food, unlike ITR capsules. This has important
implications for immunocompromised patients who are unable to
take
solid-dose forms or are unable to take medications with food
(
5). Studies have found SOS to be at least as effective as
fluconazole tablets and clotrimazole troches in the treatment
of
oropharyngeal and esophageal candidiasis in immunocompromised
patients,
including those who are human immunodeficiency virus
positive (
13,
21,
28). SOS has also been shown to be effective
for
fluconazole-refractory oropharyngeal candidiasis in human
immunodeficiency virus-positive patients (
11,
22) and as
antifungal
prophylaxis in bone marrow autograft patients and in
patients
receiving chemotherapy for acute myeloid leukemia (
23,
24).
No clear association between plasma ITR concentrations and clinical
outcomes has been reported; however, data suggesting that
undetectable
plasma ITR concentrations are more often associated
with therapeutic
failure exist. In a study of ITR therapy for
aspergillosis
(
9), higher mean trough concentrations were found
among
patients who had a response by 3 months than among those
with stable
diseases or treatment failures. No complete or partial
responders had
undetectable plasma ITR concentrations. Additionally,
Cartledge et al.
(
6) showed that SOS achieves higher plasma
ITR and OH-ITR
concentrations than does the capsule in AIDS patients
and that this is
associated with improved efficacy.
In conclusion, the present study demonstrates that the
Cmaxs,
Tmaxs, and
t1/2s for ITR and OH-ITR in the SOS formulation
and
the two capsule formulations are similar. However, the
bioavailabilities
of ITR and OH-ITR are significantly enhanced
with SOS. Its effectiveness,
coupled with ease of administration and
enhanced ITR bioavailability,
supports the use of SOS in
immunocompromised patients.
| |
ACKNOWLEDGMENTS |
This study was supported by Janssen Pharmaceutica.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: College of
Pharmacy, RutgersThe State University of New Jersey, William Levine
Hall, Frelinghuysen Rd., Piscataway, NJ 08855-0789. Phone: (732)
445-3285. Fax: (732) 445-2533. E-mail:
jbarone{at}rci.rutgers.edu.
| |
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Antimicrobial Agents and Chemotherapy, July 1998, p. 1862-1865, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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