Memorandum
Division
of
Clinical
Pharmacology
4
Office
of
Clinical
Pharmacology
Center
for
Drug
Evaluation
and
Research
(
301)
796­
2170
Date:
May
19,
2006
From:
John
A.
Lazor,
Pharm.
D.
Director
Division
Clinical
Pharmacology
4
Subject:
EPA
1,2,4
Triazole
Consult
Response
To:
Debra
Edwards,
Ph.
D.
Director
Special
Review
and
Reregistration
Division
Office
of
Pesticide
Programs
Environmental
Protection
Agency
Through:
Shiew­
Mei
Huang,
Ph.
D.
Deputy
Director
for
Science
Office
of
Clinical
Pharmacology
Center
for
Drug
Evaluation
and
Research
Food
and
Drug
Administration
Through:
Thushi
Amini,
Ph.
D.
Science
Policy
Analyst
Office
of
Executive
Programs
Center
for
Drug
Evaluation
and
Research
Food
and
Drug
Administration
This
memorandum
serves
as
a
response
to
a
consult
received
from
the
United
States
Environmental
Protection
Agency
(
EPA).
The
EPA
is
currently
reviewing
the
registration
of
three
fungicide
pesticides,
propiconazole,
triadimefon,
and
triadimenol.
The
metabolism
of
these
pesticides
results
in
the
formation
of
the
1,2,4
triazole
compound.
The
EPA
is
conducting
aggregate
human
health
risk
assessments
for
the
1,2,4
triazole
and
the
triazole
conjugates
(
triazole
alanine
and
triazole
acetic
acid).
In
their
risk
assessment
of
these
pesticides,
the
EPA
would
like
to
also
consider
potential
exposures
of
the
1,2,4
triazole
and
its
conjugates
after
the
administration
of
"
azole"
antifungal
drug
products.
DEPARTMENT
OF
HEALTH
&
HUMAN
SERVICES
Food
and
Drug
Administration
Page
2
The
chemical
structures
for
the
three
compounds
of
interest
are:

The
Division
of
Clinical
Pharmacology
4
evaluated
the
metabolism
of
the
approved
"
azole"
antifungal
drug
products
in
response
to
this
consult.
The
drug
products
that
were
assessed
are
Ketoconazole,
Fluconazole,
Itraconazole,
and
Voriconazole.
Posaconazole
was
also
identified
by
the
EPA
as
a
pharmaceutical
of
interest,
however
since
posaconazole
is
not
an
approved
drug
product,
it
is
not
included
in
this
response.

There
was
no
evidence
in
the
information
submitted
in
these
New
Drug
Applications
that
identified
specifically
the
1,2,4
triazole
metabolite,
triazole
alanine,
and
triazole
acetic
acid
as
metabolites
to
any
of
these
drug
products.
However,
these
drug
products
do
contain
the
1,2,4
triazole
moiety,
except
for
ketoconazole.
Metabolites
also
are
formed
that
contain
the
1,2,4
triazole
structure.
Ketoconazole
is
an
imidazole
coumpound
and
not
a
triazole
antifungal
agent
so
the
1,2,4
triazole
moiety
would
not
be
a
constituent
of
ketoconazole
itself
or
any
of
its
metabolites.

In
a
telephone
conversation
on
May
11,
2006
with
Michael
Doherty
and
Kelly
Sherman
of
the
EPA,
I
suggested
that
EPA
may
want
to
assess
the
exposure
of
1,2,4
triazole
after
the
administration
of
anastrozole.
Anastrozole
is
a
nonsteroidal
aromatase
inhibitor
indicated
in
the
treatment
of
breast
cancer.
Anastrozole
is
administered
at
a
dose
of
1
mg
per
day.
Anastrozole
is
extensively
metabolized
with
about
10%
of
the
dose
excreted
in
the
urine
as
unchanged
drug.
Three
metabolites
of
anastrozole
(
triazole,
a
glucuronide
conjugate
of
hydroxy­
anastrozole,
and
a
glucuronide
conjugate
of
anastrozole
itself)
have
been
identified
in
human
plasma
or
urine.
Several
minor
(
less
than
5%
of
the
radioactive
dose)
metabolites
excreted
in
the
urine
have
not
been
identified.
The
major
metabolite
of
anastrozole
in
the
circulation
is
triazole,
but
it
lacks
pharmacologic
activity.

The
following
sections
describe
what
is
known
of
the
metabolism
of
the
approved
triazole
antifungal
agents.
Information
was
obtained
from
the
NDAs,
drug
product
Page
3
labeling,
and
the
literature.
There
is
insufficient
information
to
derive
exposure
estimates
of
the
metabolites
of
these
compounds.

Fluconazole
Fluconazole
has
two
1,2,4
triazole
groups
flanking
a
biflourinated
aromatic
ring.
Following
a
single
50mg
oral
dose
of
the
radiolabeled
drug
in
3
male
volunteers,
about
80%
of
the
administered
dose
was
excreted
in
the
urine
as
the
unchanged
parent
drug
and
about
11%
was
excreted
as
unidentified
metabolites.
Significant
concentrations
of
these
metabolites
were
not
detected
in
the
systemic
circulation.
The
very
low
amounts
of
these
metabolites
in
the
urine
precluded
the
accurate
quantitation
of
the
individual
metabolites.

The
average
maximal
concentration
of
fluconazole
following
a
single
oral
dose
of
Diflucan
400
mg
is
6.7mcg/
mL.

The
approved
dosing
regimen
of
fluconazole
varies
depending
on
indication.
The
usual
dose
is
200
mg
on
day
one,
followed
by
100
mg
per
day.
Doses
up
to
400
mg
per
day
can
be
given.
Duration
of
treatment
also
varies
depending
on
the
indication.
The
usual
duration
of
therapy
is
2
to
3
weeks.
Treatment
for
cyptocococcal
meningitis
lasts
10­
12
weeks
after
cerebrospinal
fluid
cultures
become
negative.

Itraconazole
Ten
of
eleven
identified
metabolites
of
itraconazole
have
the
1,2,4
triazole
ring
structure
and/
or
the
1,2,4
triazolone
moiety.
(
See
Figure
1.)
Following
the
administration
of
Sporanox
200
mg
twice
daily
with
full
meals
for
15
days,
the
mean
±
sd
Cmax
of
itraconazole
was
2282
±
514ng/
mL.
Following
a
single
100
mg
oral
dose
of
radiolabeled
itraconazole,
the
peak
radioactivity
was
1000ng/
mL­
equivalents.
The
peak
plasma
concentration
of
itraconazole
at
2
hours
post
dose
was
200ng/
mL.
Based
on
the
maximal
concentration,
the
parent
compound
is
about
20%
of
the
radioactivity.
Based
on
the
area
under
the
concentration
 
time
curve
(
AUC),
the
parent
compound
represents
about
10%
of
the
total
radioactivity.
After
the
administration
of
a
single
oral
dose
of
3H­
itraconazole,
54%
of
the
radioactivity
was
recovered
in
the
feces
and
35%
was
recovered
in
the
urine
within
7
days
of
administration.
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.
No
single
excreted
metabolite
represents
more
than
5%
of
the
dose.

When
200
mg
intravenously
was
given
daily
for
7
days,
the
itraconazole
peak
concentration
was
2.9mcg/
mL
with
an
average
concentration
(
Css)
of
1.3mcg/
mL.
The
hydroxyitraconazole
metabolite
(
the
major
metabolite)
maximum
concentration
was
1.9mcg/
mL.
Page
4
The
itraconazole
dose
ranges
from
200
mg
daily
to
400
mg
daily.
For
life
threatening
infections,
itraconazole
can
be
dosed
as
200
mg
3
times
daily
for
3
days
as
a
loading
dose.

Voriconazole
The
1,2,4
triazole
ring
is
part
of
the
parent
compound
and
all
known
metabolites
of
voriconazole.
Following
the
intravenous
administration
of
3
mg/
kg
radiolabeled
voriconazole
to
3
healthy
male
subjects,
the
mean
±
sd
concentration
of
parent
compound
was
3.5
±
1.2
mcg/
mL.
The
N­
oxide
metabolite
concentration
was
2.8
±
0.2
mcg/
mL.

Following
the
oral
administration
of
170
mg
radiolabeled
voriconazole
after
the
oral
administration
of
200
mg
voriconazole
to
steady
state,
the
mean
±
sd
Cmax
of
parent
compound
was
1.8
±
1.1
mcg/
mL
and
the
N­
oxide
metabolite
was
2.7
±
0.1
mcg/
mL.
The
N­
oxide
metabolite
accounts
for
approximately
72%
of
the
circulating
metabolites.
Voriconazole
is
eliminated
via
hepatic
metabolism,
with
less
than
2%
of
the
dose
excreted
unchanged
in
the
urine.
After
administration
of
a
single
radiolabeled
dose
of
oral
or
intravenous
voriconazole,
preceded
by
multiple
oral
or
intravenous
dosing,
approximately
80%
to
83%
of
the
radioactivity
is
recovered
in
the
urine.

The
Vfend
product
labeling
states
that
following
the
administration
of
200
mg
Vfend
orally
to
patients
with
aspergillosis
for
14
days,
the
mean
Cmax
concentration
was
3.0
mcg/
mL
(
CV
51%).
Following
the
administration
of
300
mg
orally
for
14
days
to
patients
with
aspergillosis,
the
mean
Cmax
concentration
was
4.7
(
CV
35%).
When
Vfend
was
administered
to
healthy
volunteers
at
a
dose
of
200
mg
every12
hours
for
10
days,
the
mean
Cmax
was
2.1
mcg/
mL
(
CV
62%)
and
following
the
intravenous
administration
of
3
mg/
kg
for
10
days,
the
mean
Cmax
was
3.1
mcg/
mL
(
CV
31%).

Cytochrome
CYP2C19
is
significantly
involved
in
the
metabolism
of
voriconazole.
This
enzyme
exhibits
genetic
polymorphism.
The
prevalence
of
poor
metabolizers
in
Caucasians
and
Blacks
is
3­
5%
and
15­
20%
for
the
Asian
population.
Poor
metabolizers
have
about
a
4­
fold
higher
exposure
than
extensive
metabolizers.
Patients
who
are
heterozygous
have
about
a
2­
fold
higher
exposure
of
voriconazole
than
extensive
metabolizers.

The
metabolic
profile
of
voriconazole
is
outlined
in
Figure
2.

The
dose
of
voriconazole
is
200
mg
orally
every
12
hours
following
a
loading
dose
of
6
mg/
kg
every
12
hours
for
24
hours.
The
intravenous
maintenance
dose
is
3
mg/
kg
to
4
mg/
kg
every
12
hours.
Page
5
Figure
1:
Metabolic
Pathway
of
Itraconazole
in
Humans
Page
6
Figure
2:
Metabolic
Pathways
of
Voriconazole
in
Humans
