The pharmacokinetics of itraconazole in animals and man: an overview

Heykants, J.; Michiels, M.; Meuldermans, W.; Monbaliu, J.; Lavrijsen, K.; Peer, A. van; Levron, J.C.; Woestenborghs, R.; Cauwenbergh, G.

Recent trends in the discovery, development and evaluation of antifungal agents: 223-249

1987

Itraconazole is a triazole antifungal agent with pronounced lipophilic properties. This physicochemical property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the more hydrophilic agent, ketoconazole. The pharmacokinetics of itraconazole in animals and man are characterized by a good oral absorption, an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination halflife of about one day in man and a biotransformation into a large number of (antifungal) inactive metabolites. Unlike most other antifungal drugs, itraconazole does not interfere with mammalian drug metabolizing enzymes, minimizing the risk of interaction with concomitantly administered drugs and suggesting a lower risk for hepatic reactions. These pharmacokinetic properties of itraconazole may contribute to the higher efficacy and improved safety of this drug in animal models and in patients with various mycotic infections.

Recent
Trends
in
the
Discovery,
Development
and
Evaluation
of
Antifungal
Agents.
R.A.
Fromtling
(Ed.)
Copyright
©
1987,
J.R.
Prous
Science
Publishers,
S.A.
THE
PHARMACOKINETICS
OF
ITRACONAZOLE
IN
ANIMALS
AND
MAN:
AN
OVERVIEW
J.
Heykants',
M.
Michiels',
W.
Meuldermans',
J.
Monbaliu',
K.
Lauri,
senl,
A.
Van
Peer',
J.C.
Levron
3
,
R.
Woesten-
borghs'
and
G.
Cauwenbergh
2
Departments
of
Drug
Metabolism
and
Pharmacokinetics
1
and
Clinical
Research
2
,
Janssen
Pharmaceutica,
B-2340
Beerse,
Belgium
and
Laboratoires
Janssen
3
,
Aubervilliers,
France
ABSTRACT
Itraconazole
is
a
triazole
antifungal
agent
with
pronounced
lipophilic
pro-
perties.
This
physicochemical
property
determines
to
a
large
extent
the
phar-
macokinetics
of
itraconazole
and
differentiates
it
from
the
more
hydrophilic
agent,
ketoconazole.
The
pharmacokinetics
of
itraconazole
in
animals
and
man
are
characterized
by
a
good
oral
absorption,
an
extensive
tissue
distribu-
tion
with
tissue
concentrations
many
times
higher
than
in
plasma,
a
relatively
long
elimination
half-life
of
about
one
day
in
man
and
a
biotransforma-
tion
into
a
large
number
of
(antifungal)
inactive
metabolites.
Unlike
most
other
antifungal
drugs,
itraconazole
does
not
interfere
with
mammalian
drug
metabolizing
enzymes,
minimizing
the
risk
of
interaction
with
concomitantly
administered
drugs
and
suggesting
a
lower
risk
for
hepatic
reactions.
These
pharmacokinetic
properties
of
itraconazole
may
contribute
to
the
higher
efficacy
and
improved
safety
of
this
drug
in
animal
models
and
in
patients
with
various
mycotic
infections.
KEY
WORDS:
Itraconazole
-
Kinetics
-
Distribution
-
Metabolism
-
Animals
-
Man
Address
all
correspondence
to:
Dr.
J.
Heykants,
Department
of
Drug
Metabolism
and
Pharmacokinetics,
Janssen
Pharmaceutica,
B-2340
Beerse
(Belgium).
223
224
J.
HEYKANTS
ET
AL.
INTRODUCTION
After
the
imidazole
drugs
miconazole
and
ketoconazole,
the
triazole
derivative
itraconazole
is
the
third
member
of
the
Janssen
family
of
azole
antifungal
agents.
Their
therapeutic
use
in
the
treatment
of
fungal
infec-
tions
is
different
and,
to
a
certain
extent,
complementary.
Besides
a
dif-
ferent
activity
spectrum,
this
may
be
related
to
differences
in
physicochemical
as
well
as
pharmacokinetic
properties.
The
aim
of
this
review
is
to
highlight
the
pharmacokinetics
of
itraconazole
in
animals
and
man
and
to
compare,
where
possible,
the
pharmacokinetics
of
itraconazole
with
those
of
ketoconazole.
As
itraconazole
is
still
under
development,
published
data
on
the
pharmacokinetics
of
the
drug
are
scarce.
Therefore,
reference
is
made
mainly
to
unpublished
research
reports.
PHYSICOCHEMICAL
PROPERTIES
Itraconazole
is
an
extremely
weak
base
(pKa
=
3.7),
which
is
only
ionized
at
low
pH
(e.g.,
in
gastric
juice)
and
virtually
not
at
physiological
pH.
In
comparison
with
the
imidazole
antifungals
miconazole
and
ketoconazole,
the
basicity
of
itraconazole
is
nearly
three
orders
of
magnitude
smaller.
The
partition
coefficient
of
itraconazole
in
the
n-octanol/water
system
(log
P
=
5.66)
is
similar
to
that
of
miconazole
(log
P
=
5.22),
but
nearly
100
times
higher
than
for
ketoconazole
(log
P
=
3.73).
These
differences
in
lipophilicity
may
have
pharmacokinetic
consequences
too,
especially
in
terms
of
plasma
protein
binding
and
tissue
distribution.
The
solubility
of
itraconazole
is
practically
nil
in
water
and
diluted
acidic
solutions
(less
than
5
µg/ml).
Only
in
polar
organic
solvents
(e.g.,
dimethyl
sulphoxide)
or
in
acidified
polyethylene
glycols
(PEG),
can
concentrations
exceeding
10
mg/mI
be
obtained.
The
latter
solvent
system
was
successfully
applied
in
the
preparation
of
acceptable
formulations
containing
itraconazole
dissolved
in
a
matrix
of
acidified
high-molecular
PEGs.
Aqueous
solutions
of
itraconazole
at
5
mg/m1
could
be
prepared
by
addition
of
5
0
10
dimethyl-fl-
cyclodextrin
and
three
equivalents
of
methanesulphonic
acid.
Such
solu-
tions
were
used
in
pharmacokinetic
studies
in
laboratory
animals
and
as
reference
formulations
in
bioavailability
studies.
ASSAY
METHODS
According
to
the
physicochemical
properties
of
itraconazole
(high
molecular
weight,
low
volatility
and
favorable
UV-absorption
characteristics),
a
high-
performance
liquid
chromatographic
(HPLC)
method
was
selected
for
the
measurement
of
the
drug
in
biological
samples
(21).
Itraconazole
and
the
structurally
related
internal
standard
were
extracted
from
buffered
(pH
7.8)
PHARMACOKINETICS
OF
ITRACONAZOLE
225
plasma
or
tissue
homogenate
(1:4,
w/v)
using
a
heptane-isoamyl
alcohol
(98.5:1.5)
mixture,
back-extracted
into
0.05
M
sulphuric
acid
and
finally,
after
alkalinization
of
the
acid
phase,
re-extracted
with
the
same
solvent
mixture.
The
organic
layer
was
evaporated
to
dryness
and
the
residue,
reconstituted
in
the
elution
solvent,
was
submitted
to
HPLC
analysis.
Separations
were
achieved
using
a
reversed-phase
column,
packed
with
5
Am
particle-sized
RSiL
C
18
HL
and
0.05
°lo
diethylamine
in
water:
acetonitrile
(40:60)
as
an
elution
solvent.
Peaks
of
itraconazole
and
the
internal
stan-
dard
were
quantified
by
UV-monitoring
at
wavelengths
of
254
or
263
nm.
Ultimate
sample
concentrations
were
calculated
by
determining
the
peak
area
ratios
of
itraconazole
to
the
internal
standard,
and
by
comparing
these
ratios
with
standard
curves
obtained
after
analysis
of
calibration
samples
in
blank
plasma
or
tissues.
For
quantification
of
lower-concentrated
samples,
peak
height
ratios
were
used
as
well.
Extracts
were
very
pure
and
no
interfering
peaks
were
encountered.
A
detection
limit
of
about
1
ng/ml
of
plasma
could
be
achieved,
provided
that
2
ml
samples
were
submitted
to
the
procedure.
The
accuracy
(
0
7o
relative
error)
and
reproducibility
(°lo
C.V.)
were
below
5%
at
itraconazole
con-
centrations
exceeding
10
ng/MI
and
less
than
10%
for
lower
concentrations.
The
method
has
been
applied
to
pharmacokinetic
studies
in
experimental
animals
and
man.
A
bioassay
has
been
developed
for
itraconazole
based
on
the
agar
diffu-
sion
method
with
Candida
albicans
as
the
test
organism
(J.
Van
Cutsem,
personal
communication).
As
the
detection
limit
of
the
bioassay
was
in
the
order
of
50
ng/ml,
the
method
was
used
for
therapeutic
monitoring
in
pa-
tients
and
not
in
pharmacokinetic
studies.
Most
of
the
absorption,
distribution,
metabolism
and
excretion
(ADME)
studies
in
experimental
animals
and
the
metabolism
study
in
healthy
volunteers
were
performed
by
using
specifically
labelled
3
H-itraconazole
(Fig.
1)
(18).
The
specific
activity
of
the
batches
used
in
the
various
studies
ranged
from
29
to
300
µCi/mg.
The
radiochemical
and
metabolic
stability
of
3
H-itraconazole
proved
to
be
excellent.
N
'N
)
CI
CH2
/
\
Cl
0
CH3
0
0
/ \
N
N
I
\
N
-
CH
-CH2
-CH3
N
Figure
1
Structure
of
itraconazole
(R
51211)
and
position
of
the
tritium
label
(1).
10,
5
PL
A
SM
A
CON
C
EN
TRA
TIO
N,
p
g
/rn
i
2
-
1-
0.5
-
0.2
-
0.1--
J
0.05
226
J.
HEYKANTS
ET
AL.
PHARMACOKINETIC
STUDIES
IN
ANIMALS
Pharmacokinetics
of
Itraconazole
and
Ketoconazole
in
the
Dog
_The
pharmacokinetics
of
itraconazole
and
ketoconazole
were
studied
in
Beagle
dogs
after
single
intravenous
administration
at
5
mg/kg
of
either
drug.
Itraconazole
was
given
in
a
dimethy1-0-cyclodextrin
solution
as
its
methanesulphonate
salt,
whereas
ketoconazole
was
dissolved
at
10
mg/ml
in
aqueous
6
0
7o
polyvinylpyrrolidone
adjusted
to
pH
4.2.
Plasma
levels
of
ketoconazole
were
determined
with
a
specific
HPLC
procedure
(2),
with
a
detection
limit
of
10
ng/ml.
Plasma
concentrations
of
ketoconazole
declined
monophasically
with
a
half-life
of
1.4
hr,
whereas
itraconazole
decayed
triexponentially
with
a
ter-
minal
half-life
of
51
hr
(Fig.
2).
The
apparent
volume
of
distribution
of
17
1/kg
for
itraconazole
was
almost
20
times
higher
than
that
for
ketoconazole
(0.87
I/kg),
indicative
of
a
more
extensive
distribution
to
the
tissues
for
itraconazole.
The
total
plasma
clearance
(CI)
of
itraconazole
(234
ml/kg/hr)
was
twice
lower
than
that
of
ketoconazole
(464
ml/kg/hr).
As
a
consequence
of
the
longer
terminal
half-life
of
itraconazole
(Fig.
2),
fluc-
tuations
between
peak
and
trough
steady-state
plasma
levels
for
the
same
dosing
interval
are
much
smaller
for
itraconazole
than
for
ketoconazole.
The
same
holds
true
for
the
antifungal
levels
at
the
site
of
infection.
PARAMETER
ITRACONAZOLE
(n=4)
KETOCONAZOLE
(n=3)
t
1
/
2
(h)
51
?
12
1.4
I'
0.5
Cl
(mi.
kg
-1
.
h
-1
)
234
?
37
466
±
104
V
d
(I.
kg
-1
1
17
±
1.6
0.87
t
0.08
AUC"..
(pg.h.m1
-1
)
21
±4.0
11
±
2.3
ITRACONAZOLE
KETOCONAZOLE
0.02
-
0.01—
r
e
0
8
1
I
6
24
3
'
2
40
48
56
1
6
'
4
7
I
2
80
88
96
HOURS
Figure
2
Mean
plasma
concentrations
and
pharmacokinetic
parameters
(mean
+SD)
of
itraconazole
and
ketoconazole
in
dogs
after
5
mg/kg
i.v.
of
either
drug.
PHARMACOKINETICS
OF
ITRACONAZOLE
227
Comparative
Oral
Absorption
and
Plasma
Kinetics
The
absorption
and
pharmacokinetics
of
single
oral
doses
of
itraconazole
have
been
studied
in
male
and
female
Wistar
rats,
male
albino
guinea
pigs,
female
New
Zealand
rabbits,
male
cats
and
male
and
female
Beagle
dogs.
Details
on
the
administered
doses
and
formulations
and
the
main
phar-
macokinetic
parameters
are
summarized
in
Table
1.
Peak
plasma
levels
of
itraconazole
were
obtained
within
1
to
4
hr
after
dosing.
Taking
into
account
differences
in
dose
levels,
peak
plasma
con-
centrations
for
a
10
mg/kg
dose
were
similar
in
all
species
studied:
approx-
imately
0.3
µg/ml
for
the
PEG
formulation
and
nearly
I
Ikg/m1
for
the
solu-
tion.
The
terminal
half-life
was
in
the
order
of
6
to
10
hr
in
male
rats,
guinea
pigs,
rabbits
and
cats.
In
female
rats,
the
half-life
was
twice
as
long
as
in
males.
The
longest
half-life
(44
to
58
hr)
was
observed
in
dogs
and
this
was
similar
to
that
after
intravenous
administration
(Fig.
2).
Comparison
of
the
areas
under
the
plasma
level
time
curves
(AUC)
corrected
for
dif-
ferences
in
dose
level,
demonstrated
a
cdmparable
systemic
absorption
of
itraconazole
from
the
distinct
PEG
formulations
in
the
guinea
pig,
rabbit,
cat
and
dog.
However,
as
shown
in
Table
1
for
rats
and
dogs,
administra-
tion
of
itraconazole
in
methyl-0-cyclodextrin
solution
markedly
enhanced
the
bioavailability
of
the
drug.
In
the
fasting
dog,
the
absolute
bioavailability
of
itraconazole
was
nearly
50°7o
for
the
solution
and
20
0
70
for
the
PEG
cap-
sules,
corresponding
to
a
relative
bioavailability
of
40
0
7o
for
the
PEG
for-
mulation.
A
similar
figure
was
found
in
fasting
volunteers
after
oral
ad-
ministration
of
the
PEG
capsules,
but
intake
of
this
formulation
with
a
meal
normalized
the
absorption
of
itraconazole
to
that
of
the
solution
(Fig.
12).
4
3-
E
-
on
a_
2-
-
to
tn
IQ
}
O
0
O
Rat
•
Rabbit
A
Cat
✓
Dog
{
0
20
4
p
0
60
80
100
1
20
DOSE
(mg/kg)
Figure
3
Average
steady-state
plasma
concenvations
(C
ss
)
of
itraconazole
in
four
animal
species
after
repeated
oral
administration.
o
fi.
a
T
N
1'4
00
'1
V
13
S
I
N
VN
A3
H
'f
Table
I
Pharmacokinetic
parameters
(mean
+SD)
of
itraconazole
in
various
animal
species
(M
=
male,
F=
female)
after
single
oral
administration
at
5
or
10
mg/kg
either
in
solution
or
in
a
PEG-capsule
Parameter
Rat
Guinea
pig
Rabbit
Cat
Dog
4M
4F
6M
2F
2M
3M/3
F
4M
Dose
(mg/kg)
10
10
5
5
10
10 10
Formulation
CyD-solution
1
CyD-solution
PEG-solution
PEG-solution
PEG-capsule
PEG-capsule
CyD-solution
C
max
(µg/m1)
0.67
+0.26
1.04
+
0.10
0.14+0.09
0.17
0.24
0.33
+0.16
0.90+0.08
T
max
(h)
I
1
2
4
2
3
2
t
1
/
2
(h)
6.5
15
9.5
7.3
9.9
2
58
+16
44
+14
AUC,
(µg.h/m1)
6.4
13.6
1.3
2.2
3.3
3.6+
1.5
8.7
+
0.6
CyD-solution:
dimethy1-13-cyclodextrin
solution
of
itraconazole
2
Estimated
to
24
hr
20
-
10-
5
Adrenal
Liver
Kidney
Lung
Plasma
Brain
2
-
0.5
E
0.2
-
0.1,
0.05:
0.02-
0.01
Adrenal
Kidney
Plasma
Brain
Liver
Lung
PHARMACOKINETICS
OF
ITRACONAZOLE
229
Steady-state
plasma
levels
of
itraconazole
were
also
measured
in
rats,
rabbits,
cats
and
dogs
at
daily
doses
varying
from
2.5
to
122
mg/kg
(Fig.
3).
The
duration
of
treatment
was
11
days
for
rabbits,
2
weeks
for
rats,
3
weeks
for
cats
and
3
months
for
dogs.
The
drug
was
administered
by
gavage
of
the
PEG
solution
or
capsules
to
rabbits,
cats
and
dogs
and
ad-
mixed
in
the
feed
(dissolved
in
a
PEG
matrix)
to
rats.
Steady
state
was
reach-
ed
within
2
to
4
days
in
rats
and
rabbits
and
within
3
weeks
in
dogs.
Average
steady-state
levels
increased
proportionally
with
the
dose
in
rats,
rabbits
and
dogs
(Fig.
3)
and
values
were
consistent
with
those
predictable
from
single
dose
kinetics
(Table
1).
Hence,
the
kinetics
of
itraconazole
remained
linear
even
at
doses
many
times
higher
than
therapeutic
doses
in
patients.
Tissue
Distribution
in
Rats
and
Dogs
The
distribution
of
itraconazole
was
studied
in
male
and
female
rats
after
single
oral
doses
of
3
H-itraconazole
(10
mg/kg),
either
by
quantitative
measurement
of
the
tissue
concentrations
of
radioactivity
and
of
unchang-
ed
itraconazole,
or
by
whole
body
autoradiography
(WBA).
The
labelled
drug
was
given
in
a
dimethy1-0-cyclodextrin
solution.
Itraconazole
was
absorbed
rather
rapidly
from
the
gastrointestinal
tract.
In
most
tissues,
peak
radioactivity
concentrations
were
attained
within
2-4
hr
after
dosing
(Fig.
4).
Highest
levels
were
seen
in
the
adrenal
gland
and
the
Jiver.
Peak
amounts
in
the
liver,
persisting
between
0.5
and
4
hr,
represented
on
average
11
0
70
of
the
administered
dose.
Remarkably
high
radioactivity,
amounting
to
about
15
times
the
corresponding
plasma
con-
centration,
was
observed
in
the
perirenal
fat
(Fig.
5).
In
most
other
tissues
TR
UD
100
7
50
F.
100-
50
p
g
-eq
/m
l
or
g
OF
WET
TISSUE
20
10—
S
2
-
I,
0.5
0.2
-
0.1
-
0.05
0.02
-
0.01—
0
8
16
24
32
40
48
56
64
72
0
8
16
24
32
40
48
56
64
72
HOURS
HOURS
Figure
4
Tissue
concentrations
of
radioactivity
(TR)
and
of
unchanged
drug
(UD)
in
male
Wistar
rats
after
an
oral
10
mg/kg
dose
of
3
1-1-itraconazole
in
solution.
230
J.
HEYKANTS
ET
AL.
50
-
20
-
10
—
0.5
-
0.2
-
0.1-
0.05
-
Brain
Lung
Liver
KidneyAdrenal
Muscle
Skin
Fat
Figure
5
Tissue/plasma
concentration
ratios
of
radioactivity
at
peak
time
after
oral
administration
of
3
H-
itraconazole
(10
mg/kg,
white
bars)
or
3
H-ketoconazole
(20
mg/kg,
shaded
bars)
to
male
Wistar
rats.
radioactivity
levels
were
about
two
to
five
times
higher
than
corresponding
plasma
levels.
Only
in
the
brain,
were
levels
markedly
lower
than
in
plasma
(Fig.
4
and
5).
Brain
radioactivity
in
the
male
rat
was
mainly
due
to
un-
changed
drug.
In
the
other
tissues
the
fraction
of
unchanged
itraconazole
was
similar
to
that
found
in
plasma
throughout
the
investigational
period.
Consequently,
parent
drug
and
radiolabelled
metabolites
disappeared
from
tissues
at
a
similar
rate
as
from
plasma
(Fig.
4).
Differences
in
distribution
characteristics
between
itraconazole
and
ketoconazole
are
clearly
demonstrated
in
Figure
5,
which
represents
tissue
to
plasma
ratios
of
radioactivity
at
peak
time
for
both
3
H-labelled
drugs
in
male
Wistar
rats.
Most
striking
differences
are
seen
for
the
lung,
the
skin
and,
due
to
the
more
lipophilic
properties
of
itraconazole,
in
the
fat.
Data
obtained
with
WBA
(14)
illustrate
these
quantitative
results.
As
shown
in
Figure
6,
highest
radioactivity
was
seen
in
the
liver
and
the
adrenal,
more
distinctly
in
the
cortical
zone.
Passage
through
the
blood-brain
bar-
rier
and,
for
pregnant
rats,
through
the
placental
barrier
was
very
limited.
This
was
evidenced
by
the
lowest
levels
of
radioactivity
at
any
time
point
in
the
brain
and
fetal
tissues.
A
remarkably
high
concentration
persisted
in
the
vaginal
tissue
and
more
explicitly
in
the
vaginal
fluid
(Fig.
7).
A
quan-
titative
study
of
the
distribution
of
itraconazole
in
the
pregnant
Wistar
rat
TISSU
E
/
PLASMA
CON
CENTRA
TIO
N
RAT
IO
V
m
PHARMACOKINETICS
OF
ITRACONAZOLE
231
bf
m
b)
St
•
p1
i‘t1
'111
)
Figure
6
Autoradiogram
from
a
pregnant
Wistar
rat
(18th
day
of
gestation),
24
hours
after
oral
administra-
tion
of
3
H-itraconazole
at
10
mg/kg.
Abbreviations:
a:
adrenal;
b:
brain;
bf:
brown
fat
(hibernating
gland);
F:
fetus;
f:
fat;
H:
heart;
h:
pituitary
gland;
i:
intestine;
K:
kidney;
L:
lung;
I:
liver;
m:
muscle;
pl:
placenta;
S:
salivary
glands;
s:
spleen;
St:
stomach;
T:
thymus.
(at
the
18'
day
of
gestation)
confirmed
these
findings.
Fetal
levels
of
radioac-
tivity,
maximal
at
about
4
hr
after
dosing,
were
three
times
less
than
in
the
maternal
plasma
and
even
eight
times
less
than
in
the
placenta.
These
findings
and
the
fact
that
only
0.4%
of
the
maternal
dose
could
be
recovered
from
the
combined
fetuses
indicate
a
restricted
transfer
of
itraconazole
through
the
placenta.
R
R
‘...
,
v
'
•
.i...
--
.
I
..
..-,,-
'
,
.
ur
.-..
.0,.
,
..,
.
.
M
P
1
Figure
7
Detail
of
an
autoradiogram
(enlargement:
5x)
showing
the
distribution
of
radioactivity
in
the
vagina
of
a
pregnant
Wistar
rat
(18th
day
of
gestation),
24
hours
after
oral
administration
of
3
H-itraconazole
at
10
mg/kg.
Additional
abbreviations.
M:
mammary
gland;
u:
urinary
bladder;
ur:
ureter;
ut:
uterus;
v:
vagina.
\\\\\\\\\\NA
p.
Liver
Skin
Pancreas
Kidney
Heart
Muscle
Stomach
Lung
Brain
Plasma
232
HEYKANTS
ET
AL.
Tissue
levels
of
itraconazole
were
also
measured
in
rats
after
subchronic
treatment
at
9,
32
and
121
mg/kg/day,
with
the
drug
dissolved
in
a
PEG
matrix
admixed
in
the
feed
(15).
For
the
low
dose
level,
tissue
concentra-
tions
were
similar
to
those
observed
after
single
dosing
at
10
mg/kg,
in-
dicating
that
no
undue
accumulation
occurred
on
subchronic
administra-
tion.
For
the
higher
dose,
drug
concentrations
in
tissues
increased
propor-
tionally
to
those
in
plasma.
Throughout
the
post-dosing
period,
tissue
to
plasma
concentration
ratios
remained
constant,
indicative
of
a
similar
elimination
rate
from
tissues
as
from
plasma.
Tissue
levels
in
dogs
were
measured
24
hr
after
the
last
dose
of
a
12-month
chronic
toxicity
experiment
at
doses
of
5,
20
or
80
mg/kg
provided
daily
in
a
PEG
capsule
formulation.
Except
for
the
brain,
itraconazole
tissue
levels
were
higher
than
corresponding
levels
in
plasma
(Fig.
8).
The
highest
concentration,
26
times
the
plasma
level,
was
found
in
the
perirenal
fat.
Tissue
levels
of
up
to
10
times
higher
than
the
plasma
levels
occurred
in
the
liver,
skin
and
pancreas.
Moderately
high
levels
were
seen
in
the
lung,
kidney
and
muscle.
Tissue
to
plasma
concentration
ratios
were
dose-
independent,
demonstrating
that
no
undue
accumulation
occurred
in
any
particular
tissue
after
long-term
administration
of
itraconazole
at
very
high
doses.
TISSUE
/
PLASMA
CONCENTRATION
RATIO
4.1
O
O
O
O
\N.
Fat
Figure
8
Tissue/plasma
concentration
ratios
of
itraconazole
in
the
dog
after
12
months
of
daily
treatment
at
doses
of
5,
20
or
80
mg/kg.
Means
of
the
three
dose
levels
are
given
at
24
hours
after
the
last
dose.
PHARMACOKINETICS
OF
ITRACONAZOLE
233
Excretion
and
Metabolism
in
Rats
and
Dogs.
Comparison
with
Man
EXCRETION
IN
URINE
AND
FECES
This
was
studied
after
a
single
oral
dose
of
3
H-itraconazole
in
male
and
female
Wistar
rats
(10
mg/kg)
(12),
in
male
Beagle
dogs
(2.5
mg/kg)
and
in
male
volunteers
(100
mg).
As
shown
in
Table
2,
the
excretion
of
radioactivity
in
male
rats
was
very
rapid
and
com-
plete
within
a
few
days
after
dosing.
The
excretion
in
urine
amounted
to
only
7.2
0
7o
of
the
dose.
In
female
rats,
the
excretion
was
somewhat
slower
than
in
males,
and
the
contribution
of
urine
was
even
smaller
(4.5°7o).
The
excretion
in
dogs
was
much
slower:
one
week
after
dosing
excretion
of
the
radioactivity
in
urine
amounted
to
16.7
0
70
and
that
in
feces
to
65
0
70.
In
humans,
the
contribution
of
the
urinary
excretion
was
much
larger
(35.2
0
7o)
than
in
rats
and
dogs.
The
total
excretion
in
humans
amounted
to
90
0
7o
at
one
week
after
-
dosing.
BILIARY
EXCRETION
IN
RATS
After
a
single
oral
dose
of
10
mg/kg
3
H-
itraconazole,
the
biliary
excretion
of
the
radioactivity
was
more
abundant
in
male
rats
than
in
females
(12).
In
male
rats,
a
maximal
biliary
excretion
rate
of
3.2
0
7o
of
the
dose
per
hour
was
reached
at
3
hr
after
dosing,
whereas
in
female
rats,
the
biliary
excretion
rate
showed
no
clear
maximum
and
rang-
ed
between
0.6
and
0.9°7o
per
hour
from
1
to
24
hr
after
dosing.
The
elimina-
tion
half-life
of
the
biliary
radioactivity
was
longer
in
female
rats
(30
hr)
than
in
males
(20
hr).
Total
biliary
excretion
was
63
0
7o
and
43%
of
the
dose
in
male
and
female
rats,
respectively.
Table
2
Excretion
of
the
radioactivity
(as
a
%
of
the
administered
dose,
mean
+
SD)
with
the
urine
and
feces
of
rats,
dogs
and
humans
(M
=
male,
F=
female)
after
a
single
oral
dose
of
3
H-itraconazole
Sample
+
time
interval
(days)
Rat
10
mg/kg
Dog
2.5
mg/kg
Man
100
mg
5M
5F
3M
3M
Urine
0-1
d
5.9
+1.3
2.0
+
0.5
6.4+
0.7
22.1+3.2
1-2
d
1.0
+0.3
1.3
*
0.2
4.5*
3.2
7.2+1.0
2-4
d
0.26
+0.06
1.0
+
0.4
3.5*
0.8
4.3
+
0.7
4-7
d
0.08
+
0.02
0.27+
0.16
2.2+
0.6
1.6
+
0.1
Urine
0-7
d
7.2
+1.5
4.5
+
0.4
16.7+
4.2
35.2
*
2.5
Feces
0-1
d
74.7
+4.7
57.7
+10.9
38.5+20.6
9.7
*
8.9
1-2
d
13.2
±4.2
•
21.9
+
4.0
24.7
*
9.7
2-4
d
2.1
+0.9
13.1
*
5.0
20.4
+
12.4
14.4+5.2
4-7
d
0.24+0.06
2.0
+
1.5
5.7±
2.4
5.3+3.4
Feces
0-7
d
90.3
+1.6
94.8
+
1.8
64.5+
8.9
54.1
±2.5
Total
0-7
d
97.5
+1.3
99.3
+
1.7
81.3
+
11.5
89.3
+
0.4
234
J.
HEYKANTS
ET
AL.
The
enterohepatic
circulation
of
the
biliary
metabolites
of
itraconazole
was
investigated
by
a
study
of
their
biliary
excretion
in
doubly
cannulated
«acceptor»
rats,
receiving
a
continuous
intraduodenal
infusion
of
bile
from
simply
cannulated
«donor»
rats
which
had
been
dosed
orally
with
10
mg/kg
3
H-itraconazole.
In
male
rats,
about
half
of
the
biliary
radioactivity
was
-
subjected
to
an
enterohepatic
circulation;
in
females
only
25%.
METABOLITE
PATTERN
AND
METABOLIC
PATHWAYS
The
mass
balance
of
the
metabolites
in
the
excreta
was
studied
by
reversed-phase
HPLC
with
on-line
radioactivity
detection
and
direct
injection
of
urine
and
bile
samples
and
injection
of
methanolic
extracts
of
feces.
The
major
urinary
and
fecal
metabolites
were
isolated
and
purified
by
a
combination
of
liquid-liquid
extraction,
reversed-phase
HPLC
and
HPLC
on
a
—N(CH
3
)
2
column.
They
were
then
subjected
to
characterization
by
HPLC
co-chromatography
with
reference
compounds
and
by
mass
spectrometry
(electron
impact,
desorp-
tion
chemical
ionization
and
thermospray)
(12).
Itraconazole
was
metaboliz-
ed
extensively
into
a
very
large
number
of
metabolites
(more
than
30)
in
the
three
species.
The
metabolite
pattern
was
qualitatively
similar
in
the
three
species,
but
quantitative
differences
were
observed.
Because
of
the
very
complex
chemical
structure
of
the
itraconazole
molecule,
a
large
number
of
possible
phase
I
metabolic
pathways
can
be
postulated
(Fig.
9),
the
combination
of
which
gives
rise
to
a
very
large
number
of
metabolites.
More
than
20
urinary
metabolites
could
be
detected
in
the
three
species.
All
of
them
were
relatively
low
molecular
weight
metabolites
(<500),
miss-
ing
the
triazole
and
dichlorophenyl
moieties.
The
main
urinary
metabolite
in
male
rats
and
male
dogs
was
identified
as
2[44442,3-
dihydro-2-(1-methylpropy1)-3-oxo-4H-1,2,4-triazol-4-yllphenyl]-1-
piperazinyliphenoxylacetic
acid
(R
61465)
(Fig.
10),
resulting
from
a
'diox-
olane
scission
in
combination
with
aliphatic
oxidation
and
decarboxylation.
rE
—N
N
,
N
)
Oxidative
-
- f
-deatkytation
CH2
Oxidative
dioxolane
scission
CI
oxidative
dehalogenation
Aromatic
hydroxylation
Aliphatic
CH3
oxidation
/
0
i
1
I
)'-1
,
,ItCH
-CH2-CH3
N
I
\
Oxidative
\=-N
14-
dealkyla.ion
Triazotone
scission
/ \
CI
0
o
H
2
4
0
Oxidative
O
dealkylation
/ \
N
N
/
\
Piper
a
zi
ne
oxidation
(
•
or
-scission)
Figure
9
Possible
metabolic
pathways
for
itraconazole
in
animals
and
man.
PHARMACOKINETICS
OF
ITRACONAZOLE
235
HOOC
-
CH
-
2
/ \
N
N
LJ
/
\
CH
3
0
I
)-N-CH-
CH
CH
3
2
N
1
N
Figure
JO
Chemical
structure
of
R
61465,
the
main
urinary,
biliary
and
fecal
metabolite
in
male
rats,
and
the
main
urinary
metabolite
in
male
dogs.
The
other
urinary
metabolites
mainly
resulted
from
combinations
of
ox-
idative
degradation
of
the
piperazine
ring,
N-dealkylation
of
the
1-methylpropyl
moiety
and
N-acetylation
or
N-formylation.
R
61465
was
also
the
main
biliary
metabolite
in
male
rats,
accounting
for
9%
of
the
dose;
moreover,
it
was
the
main
metabolite
subjected
to
enterohepatic
circula-
tion.
The
smaller
biliary
excretion
of
the
radioactivity
as
well
as
the
smaller
enterohepatic
circulation
in
female
rats
with
respect
to
that
in
males
was
caused
partly
by
the
much
smaller
relatWe
amount
of
R
61465
formed
in
females.
No
parent
drug
could
be
detected
either
in
bile
or
in
urine.
In
the
feces,
unchanged
itraconazole
accounted
for
22°7o
of
the
dose
in
male
rats,
for
29%
in
female
rats
and
for
26
0
70
in
male
dogs.
A
clearly
smaller
relative
amount
of
the
dose
was
excreted
as
the
parent
drug
with
the
feces
of
three
volunteers,
viz.
3.2,
5.8
and
18.3%,
respectively.
The
major
fecal
metabolites
were
formed
by
aliphatic
oxidation
at
the
1-methylpropyl
substituent,
giving
rise
to
several
positional
isomers
and
diastereoisomers,
and
by
N-dealkylation
of
the
1-methylpropyl
moiety
and
triazolone
scission.
R
61465
was
the
main
fecal
metabolite
in
male
rats
(6.5
0
70
of
the
dose).
None
of
the
fecal
metabolites
accounted
for
more
than
10
0
70
of
the
dose
in
rats,
and
for
more
than
5
0
10
in
dogs
and
humans.
The
metabolic
pathways
of
itraconazole
were
partly
similar
to
those
of
ketoconazole,
e.g.,
dioxolane
scission
and
oxidative
degradation
of
the
piperazine
ring
(5).
However,
a
large
difference
in
the
biotransformation
of
these
two
antimycotics
was
the
very
rapid
oxidation,
scission
and
degrada-
tion
of
the
imidazole
ring
of
ketoconazole
in
contrast
with
the
metabolic
stability
of
the
1H-1,2,4-triazole
ring
of
itraconazole.
Although
the
number
of
possible
metabolic
pathways
is
much
larger
for
itraconazole
than
for
ketoconazole,
the
metabolic
stability
of
the
triazole
ring
most
probably
of-
fers
a
major
contribution
to
the
longer
elimination
half-life
of
itraconazole.
Antifungal
Activity
of
the
Metabolites
The
antifungal
activity
was
determined
by
a
bioassay
in
various
urine
samples
of
rats,
dogs
and
humans,
and
in
various
samples
of
rat
bile.
Only
in
some
dog
urine
samples
hydrolyzed
with
13-glucuronidase/arylsulphatase
236
1.
HEYKANTS
ET
AL.
and
in
one
rat
bile
sample
out
of
26,
could
slight
antifungal
activity
(near
the
detection
limit
of
the
bioassay)
be
detected.
This
confirmed
the
negligi-
ble
urinary
and
biliary
excretion
of
unchanged
itraconazole
and
proved
the
minimal
antifungal
activity
of
the
urinary
and
biliary
metabolites
of
itraconazole.
The
same
conclusions
had
been
drawn
previously
for
"
----
ketoconazole
(5).
Enzyme
Inhibition
and
Induction
Itraconazole,
when
added
in
vitro
to
suspensions
of
hepatic
microsomal
proteins
of
the
male
rat,
gave
rise
to
Type
II
difference
spectra,
indicative
of
a
ligand
interaction
of
the
drug
with
oxidized
cytochrome
P-450
(9).
In
a
comparative
study,
the
binding
of
miconazole,
ketoconazole
and
itraconazole
to
cytochromes
in
control,
phenobarbital-
or
3-methylcholanthrene-induced
microsomes
was
investigated
(9).
The
bind-
ing
of
itraconazole
to
rat
cytochrome
P-450
was
much
weaker
than
the
bind-
ing
of
the
other
antimycotics.
This
was
also
reflected
by
the
very
weak
inhibitory
properties
of
itraconazole
towards
microsomal
enzyme
activities,
viz.
aromatic
hydroxylation,
N-and
O-demethylation.
An
example
of
a
dose-
response
curve
for
the
inhibition
of
the
O-demethylase
activity
in
phenobarbital-induced
microsomes
by
the
antimycotics
is
shown
in
Figure
11.
The
1
50
values
for
miconazole
and
ketoconazole
were
5.8
AM
and
8.6
µM,
respectively,
whereas
for
itraconazole
only
a
13
0
7o
decrease
in
enzymatic
activity
was
observed
at
a
drug
concentration
of
10µM.
The
biochemical
basis
for
the
effects
of
the
antimycotics
on
mammalian
microsomal
enzyme
activities
probably
depends
on
a
direct
interaction
of
the
azole
nitrogen
with
100—
,
■
Miconazole
•
Ketoconazoie
♦
itraconazole
60-
40-
I
1
1
1
1
1
1
1
0.03
0.1
0.3
1
3
10
30
100
Drug
concentration
LuM1
Figure
11
Dose-response
curves
for
the
inhibition
of
O-demethylase
activity
in
phenobarbital-induced
microsomes
by
miconazole,
ketoconazole
or
itraconazole.
0
/0
o
f
co
n
tro
l
ac
t
iv
ity
0
PHARMACOKINET1CS
OF
ITRACONAZOLE
237
Table
3
Effects
of
oral
administration
of
a
high
dose
(160
mg/kg/day,
7
days)
of
miconazole,
ketoconazole
and
itraconazole
on
hepatic
parameters
in
male
Wistar
rats.
A
comparison
is
made
with
the
effect
of
sub-
chronic
administration
of
two
classical
inducers,
phenobarbital
(PB)
(60
mg/kg/day,
7
days)
and
3-methylcholanthrene
(3-MC)
(20
mg/kg/day,
7
days).
Results
represent
the
mean
+SD
of
four
(antimycotics)
or
six
(PB,
3-MC)
rats
Parameter
Miconazole
%
of
the
corresponding
control
Ketoconazole
Itraconazole
PB
3-MC
Relative
liver
weight
(g/100
g
body
weight)
125
+
7*
153
+13*
103*
8
126
+
18
108
+
10
Cytochrome
P-450
(nmoles/mg
protein)
202±22*
185
+
28*
104±12
191±40*
160+11*
NADPH
cyt
c-reductase
(nmoles/min
mg
prttein)
173
+
9*
142+
5*
118
+
13
N.D.'
N.D.
1
Hydroxylation
of
aniline
(nmoles/min
mg
protein)
106
+
8
81
+
13*
91
+
8
119
+
12
100
+
15*
O-demethylation
of
p-nitroanisole
(nmoles/min
mg
protein)
256
+44*
148
+
17*
91+
5
275+33*
285+51*
Glucuronidation
of
p-nitrophenol
(nmoles/min
mg
protein)
166
+
17*
150+
5*
90±
4
N.D.
1
N.D.'
*Difference
from
control
statistically
significant
(P
<0.05)
1
N.D.:
Not
determined.
the
heme
group
of
cytochrome
P-450,
and
this
interaction
is
much
weaker
than
the
binding
to
yeast
cytochrome
P-450
(19).
The
greater
specificity
of
itraconazole
towards
fungal
enzymes
was
also
illustrated
by
the
absence
of
inducing
properties
when
the
drug
was
given
orally
to
male
rats
for
seven
days,
even
at
the
high
dose
level
of
160
mg/kg/day
(Table
3)
(8).
Besides
cytochrome
P-450
dependent
enzyme
ac-
tivities,
other
components
of
the
hepatic
microsomal
drug
metabolizing
en-
zyme
system,
i.e.,
NADPH-cyt
c-reductase
and
UDP-glucuronyltransferase,
were
not
affected
by
itraconazole.
In
a
comparative
study,
it
was
found
that
miconazole
increased
cytochrome
P-450
and
related
enzyme
activities
at
40
mg/kg,
whereas
ketoconazole
was
only
effective
at
160
mg/kg
(8).
Both
compounds
produced
much
weaker
effects
than
the
classical
inducers
phenobarbital
and
3-methylcholanthrene
(Table
3).
In
vivo,
it
was
also
shown
that
itraconazole
up
to
40
mg/kg
for
5
days,
the
highest
dose
tested,
did
not
influence
the
extent
of
the
methohexital-induced
hypnosis
in
female
rats
(3).
Furthermore,
a
single
dose
of
100
mg/kg
did
not
significantly
af-
fect
the
acenocoumarol-induced
prothrombin
time,
indicating
that
itraconazole
at
this
high
dose
was
devoid
of
inhibitive
properties
in
vivo
(11).
The
results
of
these
animal
studies
correlate
well
with
the
clinical
facts.
Miconazole
has
been
reported
to
interfere
occasionally
with
hepatic
drug
metabolizing
enzymes
in
man
(6).
In
contrast,
ketoconazole
has
no
clear
Parameters
solution,
fasting
capsules,
fasting
capsules,
with
food
T
max
(h)
1.7=0.3
3.3=
1.0
4.0'-1.1
C
max
(ng
/m1)
223=84
38=20
132=67
AUC
0
_
0
,,
(ng.h/ml)
1920=679
722=289
1899=
838
F
re
t
('/.)
100
40=15
102=31
1
1
/2
(h)
19
=
4
24'9
17_3
500
solution
200
•
1007.
R.
4
•1k-
7
---___
50
111
•
\
capsules,
with
food
R
.
-;i
N
N.
20
-.$
t , ,
10
--t
/
,...,
......,
"0-.....
'i
capsules,
fasting
II.--
5
l
i
i
1;
0.2
238
J.
HEYKANTS
ET
AL.
inducing
or
inhibiting
properties
at
clinical
doses
(20)
and,
therefore,
dif-
fers
in
this
respect
from
other
imidazole
antifungals,
e:g.,
clotrimazole
(16,
17).
The
present
data
support
the
conclusion
that
itraconazole
does
not
in-
terfere
with
mammalian
drug
metabolizing
enzymes.
In
this
respect,
itraconazole
is
superior
to
the
commonly
used
antifungals.
CLINICAL
PHARMACOKINETICS
Single
Dose
Pharmacokinetics
in
Healthy
Volunteers
ORAL
BIOAVAILABILITY
AND
INFLUENCE
OF
FOOD
This
was
studied
in
six
healthy
volunteers
randomly
assigned
to
three
treatments.
After
an
over-
night
fast,
subjects
were
administered
100
mg
doses
either
as
20
ml
of
a
5
mg/ml
oral
solution
of
itraconazole
in
dimethyl-g-cyclodextrin
(reference
solution),
or
as
two
50
mg
capsules
containing
itraconazole
in
a
polyethylene
glycol
matrix.
A
standard
breakfast
was
served
2
hr
after
dosing.
In
addi-
tion,
the
two
50
mg
capsules
were
also
studied
when
administered
immediate-
ly
after
a
breakfast.
Itraconazole
was
rapidly
absorbed
from
the
solution,
with
T
max
values
between
1.5
and
2
hr
(Fig.
12).
Absorption
from
the
cap-
PL
ASM
A
ITRACONAZ
OLE
CO
NCENTR
ATI
ON
(ng
/m
I
0.1
12
24
'
1
1
36
48
60 72
84
96
HOURS
Figure
12
Mean
itraconazole
plasma
concentrations
and
pharmacokinetic
parameters
(mean
±
S.D.)
after
a
single
100
mg
dose
in
solution
or
capsules
to
six
healthy
volunteers.
PHARMACOKINETICS
OF
ITRACONAZOLE
239
soles
was
slower,
with
peak
concentrations
reached
within
1.5
to
4
hr.
After
the
peak,
plasma
concentrations
declined
biexponentially
with
a
terminal
half
life
in
the
order
of
20
hr.
The
relative
bioavailability
of
the
capsules
taken
in
the
fasting
state
averaged
40%.
Intake
of
the
capsules
after
a
meal
enhanced
the
bioavailability,
as
demonstrated
by
a
mean
C
max
of
132
ng/ml
and
a
bioavailability
of
102%
relative
to
the
reference
solution
(Fig.
12).
Therefore,
it
is
recommended
to
administer
itraconazole
capsules
immediate-
ly
after
a
meal
to
ensure
an
optimal
oral
bioavailability.
DOSE
DEPENDENCY
The
oral
absorption
and
bioavailability
of
itraconazole
was
also
studied
as
a
function
of
the
dose.
After
oral
doses
of
50,
100
and
200
mg
given
as
capsules
after
a
meal,
increases
in
AUC
were
more
than
proportional
(Table
4).
This
augmented
oral
bioavailability
with
increas-
ing
dose
is
likely
to
be
explained
by
a
transient
saturation
of
the
metabolic
processes
in
the
liver.
Table
4
Pharmacokinetic
parameters
(mean+SD)
of
a
single
50,
100
and
200
mg
dose
of
itraconazole
as
capsules
to
six
healthy
volunteers
Parameter
50
mg
100
mg
200
mg
T.
(h)
3.2+
1.3
4.0
+
1.1
.
4.7+
1.4
C
max
(ng/ml)
44.5+
16.4
132
+
67
289
±
100
t
1
/
2
(h)
13
+
2
17
±
3
18
±
4
AUC._.(ng.h/m1)
567
+264
1899
+838
5211
+2116
Repeated
Dose
Pharmacokinetics
in
Healthy
Volunteers
In
healthy
volunteers,
three
studies
determined
itraconazole
phar-
macokinetics
during
and
after
repetitive
oral
dosing
of
100
mg
once
daily
for
two
to
four
weeks
(Tables
5
and
6).
The
itraconazole
plasma
concen-
trations
of
the
1-month
study
are
shown
in
Figure
13.
Table
5
Pharmacokinetic
parameters
(mean+SD)
following
repeated
oral
doses
of
100
mg
itraconazole
once
daily
to
10
healthy
male
volunteers
Parameter
Initial
dose
After
two
weeks
After
four
weeks
Crain
(ng/ml)
—
240+
126
196+
170
C,
(ng/ml)
19.9+
13.4
244+
140
190+
169
C
max
(ng/ml)
122
±
67
672+
212
621+
337
AUC
0
_,
(ng.h/m1)
1361
+721
9416
±
3805
8166+5228
t1
(h)
—
—
28±
8
'I
V
.
1,
3
SIN
VN
AgH
I
OVZ
Table
6
Peak
plasma
concentrations
(mean*SD,
ng/ml)
of
itraconazole
after
repeated
oral
dosing
Subjects
Dosage
Duration
of
treatment
in
weeks
1
2
3
4
5
6
18
healthy
volunteers
100
mg
o.d.
411+
43
459+
55
6
healthy
volunteers
100
mg
o.d.
361+
38
426+
18
10
healthy
volunteers
100
mg
o.d.
380+
54
645+
68
573+
70
602+108
neutropenic
children
50
mg
o.d.
75+
29
120+
44
49+
20
—
151+
49
—
(age
3-15
years)
(n
=
7)
(n
=
7)
(n
=12)
(n
=
8)
non-neutropenic
200
mg
o.d.
388+123
290
+
128
416+100
211+
62
372+178
337
+
141
patients
(n=7)
(n
=6)
(n=5)
(n
=5)
(n
=4)
(n
=3)
neutropenic
patients
200
mg
b.i.d.
335+
43
457*
65
537+
84
599
+102
639
+
153
526
+
113
(n=34)
(n=
31)
(n=
24)
(n=14)
(n=12)
(n=21)
1000
500
I
TRACO
NAZ
OLE,
ng
fm
l
p
lasma
200
100
50
20
10
5
PHARMACOKINETICS
OF
ITRACONAZOLE
241
0
0
0
0
a
0
0
100
mg
itraconazole
once
daily
2
0
7
14
1
28
35
DAYS
Figure
13
Mean
itraconazole
plasma
concentrations
after
repetitive
oral
doses
of
100
mg
once
daily
for
I
month
in
10
healthy
volunteers.,
Steady
state
was
attained
within
10
to
14
days.
At
steady
state,
mean
trough
and
peak
concentrations
fluctuated
between
200
and
600
ng/ml
and
were
higher
than
predicted
from
a
single
dose.
This
is
consistent
with
the
earlier
observed
dose-dependent
kinetics
after
single
dose
administration.
At
steady
state,
AUC
values
over
a
24
hr
interval
were
in
the
order
of
8000-9000
ng.h/ml
(Table
5),
about
fourfold
the
AUC,_
co
of
a
single
dose.
After
cessation
of
the
repetitive
dosing,
the
terminal
half-lives
of
20-30
hr
were
similar
to
those
after
single
dosing.
Repeated
Dose
Pharmacokinetics
in
Patients
Steady-state
plasma
concentrations
have
been
measured
in
neutropenic
children
and
adults,
as
well
as
in
other
patients,
for
dosages
of
50
to
200
mg
once
or
twice
daily
(Table
6).
Steady
state
was,
in
general,
reached
within
2
weeks
of
dosing.
Plasma
concentrations
were
lower
than
in
healthy
volunteers.
Sudden
decreases
in
concentrations
were
clearly
related
to
itraconazole
intake
in
the
fasting
state
or
vomiting
due
to
the
cytostatic
comedication.
The
latter
is
illustrated
in
Figure
14,
where
the
itraconazole
plasma
concentrations
are
shown
in
patients
treated
for
10
days
before
and
for
1
month
after
a
bone
marrow
transplantation
(10).
Before
the
transplan-
tation,
the
oral
bioavailability
of
itraconazole
decreased
but
rapidly
ameliorated
afterwards.
In
these
cases,
antiemetics
can
be
coadministered,
and
itraconazole
should
be
given
with
meals.
242
J.
HEYKANTS
ET
AL.
BONE
MARROW
TRANSPL
ANT
,
I
/
I
•
•
/
•
/
I
•
cf
200
mg/day
200
or
300
mg/day
5
10
15
20
25
30
35
'
40
DAYS
Figure
14
Mean
peak
and
trough
plasma
concentrations
of
itraconazole
after
repetitive
oral
doses
of
200
mg
once
daily
to
9
patients,
10
days
before
and
1
month
after
bone
marrow
transplantation.
Itraconazole
Distribution
in
Tissues
and
Body
Fluids
PROTEIN
BINDING
The
plasma
protein
binding
of
itraconazole
as
well
as
its
distribution
in
blood
were
studied
in
vitro
using
equilibrium
dialysis
(13).
In
human
whole
blood,
99.8
0
70
of
itraconazole
is
bound,
with
less
than
0.2%
free
in
plasma
water
and
94.9
0
1a
and
4.9%
bound
to
plasma
proteins
and
blood
cells,
respectively.
The
blood
to
plasma
concentration
ratio
was
0.58.
In
plasma,
the
binding
averaged
99.8
0
70.
At
concentrations
of
100
to
500
ng/ml,
the
plasma
protein
binding
was
independent
of
the
drug
concentra-
tion
and
the
pH
(range
6.7-8.1).
Albumin
was
the
main
binding
protein
in
plasma.
BODY
FLUIDS
AND
TISSUES
Tissue
distribution
in
humans
has
been
deter-
mined
after
single
or
repeated
oral
administration
of
100
or
200
mg
itraconazole.
In
most
body
fluids,
concentrations
of
itraconazole
were
below
1-2
ng/ml
(Table
7).
This
finding
can
be
explained
by
the
low
free
fraction
of
itraconazole
in
blood
available
for
distribution
over
the
total
body
water.
In
excreta
such
as
vaginal
fluid,
sputum
and
bronchial
exudates,
concen-
trations
were
up
to
400
ng/ml.
High
itraconazole
concentrations
of
3
µg/m1
have
been
measured
in
pus.
Urine
concentrations
were
below
5
ng/ml;
this
is
because
of
the
negligible
renal
elimination
of
itraconazole.
In
spite
I
TRA
CONA
Z
OL
E
PLA
SM
A
L
EV
EL.
ng
/m
l
1000-
500
-
200
100-
50
20
-
10
—
5
2
-
0
PHARMACOKINETICS
OF
ITRACONAZOLE
243
Table
7
Distribution
of
itraconazole
in
human
body
fluids
and
tissues
Dosage
Fluids
Number
of
patients
Itraconazole
concentration
ng/ml
(range)
Fluid/plasma
ratio
(range)
200
mg
single
vaginal
fluid
20
33-
379
0.12-
0.48
100
mg
o.d.
saliva
1
5
2
50.002
200
mg
o.d.
cerebrospinal
fluid
8
lc
2
50.002
eye
fluid
1
550
5.0.007
bronchial
exudate
3
5.5-35
—
sputum
7
15-
442
0.07-0.38
pus
4
1060-3170
1.3
-3.4
Dosage
Tissues
Number
of
patients
Itraconazole
concentration
ng/g
(range)
Tissue/plasma
ratio
(range)
200
mg
single
vaginal
tissue
20
151-
376
2.9-
7.5
cervical
mucus
18
29-
547
3.2-11.4
endometrium
6
270-1329
5.8-13.9
uterus
2
606-
802
6.2-
6.4
tuba
3
190-
365
3.9-
7.3
portio
5
151-
317
1.6-11.2
ovarium
1
695
19.9
100
mg
o.d.
skin
9
75-1366
0.5-
2.0
200
mg
o.d.
lung
5
156-1090
0.9-
2.4
or
b.i.d.
kidney
1
479
1.5
liver
1
1070
3.5
bone
1
1470
4.7
skin
3
569-15700
3.1-10.5
stomach
1
703
3.8
omentum
1
4710
26
fat
(adipose)
1
4160
23
spleen
1
569
3.1
muscle
1
440
2.4
of
the
high
plasma
protein
binding,
tissue
concentrations
of
itraconazole
are
much
higher,
indicating
that
the
drug
is
distributed
extensively
to
the
tissues.
So,
itraconazole
concentrations
in
lung,
kidney,
liver,
bone,
stomach,
spleen
and
muscle
were
two
to
three
times
higher
than
the
cor-
responding
plasma
concentrations
(Table
7).
Concentrations
in
adipose
tissue
and
omentum
were
twenty
times
the
plasma
concentration.
In
twen-
ty
patients
undergoing
hysterectomy,
itraconazole
concentrations
in
various
parts
of
the
genital
tract
were
three
to
ten
times
higher
than
the
plasma
concentrations
(7).
Itraconazole
is
a
highly
keratinophylic
substance.
After
repetitive
100
mg
oral
doses,
important
uptake
in
the
stratum
corneum
was
found
(Fig.
15).
After
the
first
dose
there
was
already
a
rapid
accumulation
of
itraconazole
244
J.
HEYKANTS
ET
AL.
2000
r
1000—
'6
500
200
0
.
ce
100—
50
2
-
O
w
o
20
-
10
ce
5
2
.....
.......
.
beard
..
.•.
..
•
...........
..
■
▪
back
•
•
t
1
/
2
=
3.2
d.
-
-o--
h
and
'‘
's
\ •
0
t
1
/
2
=
1.4
d.
100
mg
/day
plasma
12
16
20
24
28
32
36
20
44
48
52
56
DAY
S
4
8
Figure
/5
Itraconazole
concentrations
in
plasma,
beard
shavings
and
in
skin
scrapings
of
the
hand(palm)
and
the
back
after
repetitive
oral
administration
of
100
mg/day
in
a
healthy
subject.
in
the
skin
of
the
hand
and
the
back.
At
steady
state,
concentrations
in
scrapings
of
the
palm
of
the
hand
were
comparable
to
the
plasma
concen-
trations,
but
concentrations
in
scrapings
of
the
back
were
about
five-
to
tenfold
those
in
plasma.
After
cessation
of
dosing,
there
was
a
delay
of
1
to
2
weeks
before
itraconazole
concentrations
in
these
keratinous
tissues
started
to
decline.
In
beard
shavings,
concentrations
gradually
increased
up
to
a
steady
state
and
declined
only
1
week
after
the
end
of
the
itraconazole
therapy.
Itraconazole
elimination
in
these
keratinous
tissues
occurred
with
a
half-life
of
3
days.
This
is
slower
than
the
20-30
hr
estimated
elimination
half-life
from
plasma.
This
finding
clearly
indicates
that
these
keratinous
tissues
can
be
considered
as
a
separate
compartment
with
very
rapid
and
extensive
uptake
of
itraconazole
but
from
which
redistribution
into
plasma
no
longer
occurs.
It
is
evident
that
the
renewal
of
the
stratum
corneum
and
the
growth
of
the
hair
are
the
rate-determining
steps
in
the
itraconazole
elimination
from
these
tissues.
As
with
ketoconazole,
secretion
of
itraconazole
in
sweat
and
sebum
might
be
the
underlying
mechanism
for
the
high
concentrations
in
these
keratinous
tissues.
Pharmacokinetics
in
Patients
with
Renal
or
Liver
Insufficiency
In
five
uremic
patients
(mean
age
69
years)
with
a
creatinine
clearance
of
12
ml/min/1.73
m
2
,
not
yet
on
maintenance
hemodialysis,
a
single
200
mg
dose
of
itraconazole
was
given
together
with
a
meal
(4).
Comparison
PHARMACOKINETICS
OF
ITRACONAZOLE
245
Table
8
Pharmacokinetic
parameters
(mean
+SD)
after
single
100
or
200
mg
doses
of
itraconazole
to
pa-
tients
with
renal
or
liver
insufficiency
Parameter
Renal
insufficiency
n
=
5
Liver
insufficiency
n
=
3
Dose
(mg)
200
100
T
max
(h)
3.6
+
0.9
3.0
±
1.0
C
maz
(ng/ml)
231
+
206
81
+
41
t
i
1
/
2
(h)
25.6
+
4.7
29.5
±
2.3
AUC
0
_
0
,
(ng.h/ml)
3750
+3690
1240
+510
of
the
pharmacokinetic
parameters
in
this
group
of
elderly
patients
(Table
8)
with
those
in
young
healthy
volunteers
(Table
4)
permits
the
conclusion
that
the
pharmacokinetics
of
itraconazole
are
not
significantly
affected
by
renal
dysfunction
or
by
age.
Also,
the
plasma
protein
binding
(99.8
±
0.02
0
70)
was
identical
to
that
in
healthy
subjects.
Preliminary
results
in
three
cirrhotic
cpatients
indicate
that
the
phar-
macokinetics
of
itraconazole
after
a
single
100
mg
dose
(Table
8)
are
com-
parable
to
those
in
healthy
subjects
after
administration
of
the
same
dose
(Table
4).
Both
studies
suggest
that
the
itraconazole
dose
regimen
requires
no
adjustment
in
either
group
of
patients.
Drug
Interactions
INTERACTIONS
ON
PLASMA
PROTEIN
BINDING
The
plasma
protein
binding
of
itraconazole
was
not
influenced
by
high
therapeutic
concentrations
of
imipramine,
propranolol,
diazepam,
cimetidine,
indomethacin,
tolbutamide,
sulfamethazine
and
warfarin.
High
diphenylhydantoin
concentrations
caus-
ed
a
17
0
70,
but
clinically
insignificant,
increase
in
the
unbound
itraconazole
fraction
in
plasma.
High
itraconazole
concentrations
of
2µg/ml
did
not
alter
the
plasma
protein
binding
of
imipramine,
propranolol,
diphenyihydantoin,
diazepam
or
warfarin
(13).
METABOLIC
INTERACTIONS
Antipyrine
is
extensively
metabolized
by
the
cytochrome
P-450
oxidizing
system
in
the
liver.
It
is
generally
accepted
as
a
sensitive
probe
of
hepatic
oxidation
in
man.
Therefore,
the
effects
of
chronically
administered
itraconazole,
100
mg
once
daily,
on
the
disposi-
tion
of
antipyrine
were
determined
in
10
healthy
volunteers.
There
were
no
differences
in
volume
of
distribution,
clearance
or
elimination
half-life
of
antipyrine
in
the
control
state
or
after
a
2
or
4-week
itraconazole
dosing
(Table
9).
Antipyrine
kinetics
were
also
not
altered
1
week
after
cessation
of
the
itraconazole
treatment.
Hence,
there
is
no
indication
that
therapeutic
doses
of
itraconazole
for
1
month
have
either
inducing
or
inhibitory
ef-
246
J.
HEYKANTS
ET
AL.
Table
9
Antipyrine
kinetics
(mean
+SD)
on
itraconazole
coadministration
(100
mg/day)
in
10
volunteers
Pretreatment
2
weeks
itraconazole
4
weeks
itraconazole
1
week
after
the
last
itraconazole
dose
clearance
(ml/min)
54
+6
52
+7
52
+6
50
+9
'
are
,
(1)
54
+5
52
+8
52
+5
51
+7
t
1
/
2
(h)
11.5+1.3
11.8+1.9
11.6+1.7
12.0
+
2.2
fects
on
the
hepatic
microsomal
enzymes.
The
absence
of
any
effect
on
the
metabolizing
system
has
been
confirmed
in
the
rat
after
a
7-day
treatment
with
160
mg/kg
itraconazole
once
daily
(8).
In
this
perspective,
no
interac-
tions
thus
far
have
been
reported
between
itraconazole
and
therapeutically
important
drugs
such
as
insulin,
anticoagulants
and
cyclosporine
A.
The
lack
of
an
interaction
with
cyclosporine
A
was
also
demonstrated
in
the
rat
(D.
White,
personal
communication).
The
interaction
with
the
antituberculous
agent
rifampicin
was
investigated
in
six
healthy
volunteers
and
in
one
patient.
Rifampicin
is
a
very
powerful
inducing
agent
of
hepatic
drug
metabolizing
enzymes
and
may
reduce
the
bioavailability
of
concomitantly
given
drugs
(1).
The
study
in
volunteers
showed
that
simultaneous
oral
administration
of
a
single
100
mg
oral
dose
of
itraconazole
and
600
mg
rifampicin
increased
the
AUC
0
_
8
,,
of
itraconazole
by
8070,
but
three
days
later,
the
AUC
was
reduced
to
20%
of
the
value
in
the
control
state.
A
single
dose
of
rifampicin
apparently
inhibited
itraconazole
metabolism
when
given
together
but
strongly
increased
the
clearance
of
itraconazole
for
at
least
three
days
after
rifampicin
administra-
tion.
In
one
aspergilloma
patient,
an
almost
complete
disappearance
of
itraconazole
from
plasma
was
noted
when
rifampicin
was
given
con-
comitantly.
When
rifampicin
was
discontinued,
itraconazole
levels
return-
ed
to
normal
after
about
one
week.
DISCUSSION
AND
CONCLUSIONS
Itraconazole
is
an
extremely
weak
base,
lipophilic
and
only
soluble
in
a
few
solvent
systems
(e.g.,
acidified
polyethylene
glycols).
Studies
in
dogs
revealed
a
different
pharmacokinetic
profile
for
itraconazole
as
compared
with
ketoconazole:
itraconazole
has
a
20
times
higher
volume
of
distribu-
tion
and
a
35
times
longer
elimination
half-life,
whereas
its
clearance is
twice
lower.
Important
consequences
of
this
different
profile
are
the
high
tissue
to
plasma
concentration
ratios
and
the
relatively
small
oscillations
between
peak
and
trough
steady-state
levels
for
itraconazole.
This
may
result
in
an
almost
continuous
and
better
exposure
(bioavailability)
of
itraconazole
PHARMACOKINETICS
OF
ITRACONAZOLE
247
to
the
fungal
infection
sites,
which
are
located
in
the
tissues
and
not
in
the
body
fluids.
In
animals
and
man,
itraconazole
(in
solution)
is
almost
completely
ab-
sorbed
from
the
gastrointestinal
tract,
extensively
distributed
to
the
tissues
and
metabolized
into
a
large
number
of
metabolites,
which
are
predominant-
ly
excreted
with
the
bile.
Itraconazole
is
not
excreted
as
unchanged
drug
in
the
urine.
Metabolites
in
urine
and
bile
are
virtually
devoid
of
antifungal
activity
suggesting
that
the
parent
drug
is
the
active
substance.
The
binding
to
mammalian
cytochrome
P-450
is
much
weaker
for
itraconazole
than
for
other
azole
antimycotics;
this
explains
the
greater
specificity
towards
fungal
enzymes.
Even
at
high
dose
levels,
itraconazole
does
not
interfere
with
mammalian
drug
metabolizing
enzymes,
minimiz-
ing
the
risk
of
interaction
with
other
drugs
or
of
disturbance
of
the
cytochrome
P-450
dependent
pathways
of
endogenous
compounds
(e.g.,
steroid
hormones)
(R.
de
Coster
et
al.,
this
Telesymposium).
Absorption
studies
in
healthy
subjects
and
clinical
experience
in
neutropenic
patients
indicated
that
itraconazole
(PEG
capsules)
is
better
absorbed
when
taken
with
a
meal.
As
with
ketoconazole
(20),
plasma
levels
of
itraconazole
increase
more
than
proportionally
at
increasing
doses.
Steady
state
in
volunteers
and
patients
is
attained
within
10
to
14
days
and
the
half-life
(20-30
hr)
is
similar
after
single
and
repeated
dosing.
This
relative-
ly
long
half-life
allows
patients
to
be
treated
on
a
once
daily
dosing
regimen.
Itraconazole
is
strongly
bound
to
plasma
proteins
(99.8
0
7o),
mainly
to
albumin.
As
the
free
fraction
in
blood
determines
the
drug
concentration
in
body
water,
itraconazole
levels
in
most
body
fluids
(e.g.,
urine,
saliva,
cerebrospinal
fluid)
are
low.
In
contrast,
tissue
concentrations
are
much
higher
than
total
plasma
concentrations
pointing
to
a
stronger
binding
of
itraconazole
to
tissues
and,
presumably,
also
to
the
microorganisms.
Ex-
amples
of
the
preferential
tissue
uptake
are
the
high
concentrations
in
fat,
keratinous
tissues
such
as
skin
and
hair
and
in
the
various
tissues
of
the
female
genital
tract.
Preliminary
studies
suggested
that
no
dose
adjustments
of
itraconazole
are
required
in
patients
with
renal
or
liver
insufficiency.
Itraconazole
does
not
displace
other
drugs
from
their
protein
binding
sites.
Thus
far,
no
ef-
fect
on
the
clearance
of
concomitantly
administered
drugs
(e.g.
antipyrine,
insulin,
anticoagulants
and
cyclosporine
A)
has
been
reported.
However,
when
given
together
with
rifampicin
or
other
inducing
agents,
the
bioavailability
of
itraconazole
may
be
reduced.
For
most
therapeutic
indications,
monitoring
of
the
itraconazole
plasma
levels
seems
unnecessary.
In
some
clinical
situations,
especially
in
patients
with
impaired
absorption,
regular
monitoring
of
the
plasma
levels
may
op-
248
J.
HEYKANTS
ET
AL.
timize
the
therapy.
Although
both
HPLC
and
bioassay
are
useful
for
this
purpose,
a
more
rapid
assay
would
be
more
practical.
ACKNOWLEDGEMENTS
The
authors
wish
to
thank
the
investigators
who
participated
in
the
clinical
pharmacokinetic
studies
on
itraconazole
and
Mrs.
Ann
Siegers
and
Mr.
L.
Leijsen
for
the
preparation
of
the
manuscript.
References
1.
Acocella,
G.,
Conti,
R.
Interaction
of
rifam-
picin
with
other
drugs.
Tubercle
1980;
61:
171-177.
2.
Alton,
K.
Determination
of
the
antifungal
agent,
ketoconazole,
in
human
plasma
by
high-performance
liquid
chromatography.
J
Chromatogr
1980;
221:
337-344.
3.
Awouters,
F.H.L.,
Niemegeers,
C.J.F.
In
vivo
study
of
the
possible
inhibition
and
induction
of
microsomal
enzymes
by
the
antimycotic
R
51211.
Janssen
Pharmaceutica
Preclinical
Research
Report
R
51211/4,
1983.
4.
Boelaert,
J.,
Sas,
S.,
Van
Peer,
A.,
De
Don-
cker,
P.
Pharrnacokinetics
of
itraconazole
in
renal
dysfunction.
26th
lntersci
Conf
An-
timicrob
Agents
Chemother
(Sept
28-Oct
1,
New
Orleans
1986;
Abst
801,
p.
242).
5.
Gascoigne,
E.,
Barton,
G.,
Michiels,
M.,
Meuldermans,
W.,
Heykants,
J.
The
kinetics
of
ketoconazole
in
animals
and
man.
Clin
Res
Rev
1981;
1:
177-187.
6.
Heel,
R.C.,
Brogden,
R.N.,
Pakes,
G.F.,
Speight,
T.M.,
Avery,
G.S.
Miconazole:
A
preliminary
review
of
its
therapeutic
efficacy
in
systemic
fungal
infections.
Drpgs
1980;
19:
7-30.
7.
Larosa,
E.,
Cauwenbergh,
G.,
Cilli,
P.,
Woestenborghs,
R.,
Heykants,
J.
Itraconazole
pharmacokinetics
in
the
female
genital
tract:
Plasma
and
tissue
levels
in
patients
undergo-
ing
hysterectomy
after
a
single
dose
of
200
mg
itraconazole.
Eur
J
Obst
Gyn
1986;
23:
85-89.
8.
Lavrijsen,
K.,
Van
Houdt,
J.,
Thijs,
D.,
Meuldermans,
W.,
Heykants,
J.
Induction
potential
of
antifungals
containing
an
im-
idazole
or
triazole
moiety.
Miconazole
and
ketoconazole,
but
not
itraconazole
are
able
to
induce
hepatic
drug
metabolizing
enzymes
of
male
rats
at
high
doses.
Biochem
Pharmac
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