Bioavailability of microsize and ultramicrosize griseofulvin products in man


Straughn, A.B.; Meyer, M.C.; Raghow, G.; Rotenberg, K.

Journal of Pharmacokinetics and Biopharmaceutics 8(4): 347-362

1980


The relative bioavailability of ten marketed dosage forms of griseofulvin was evaluated in two separate crossover studies. Each study utilized 12 healthy subjects, with eight of the subjects being common to both studies. Plasma griseofulvin concentrations were determined 1, 2, 3, 4, 6, 8, 10, 25, 34, 49, and 73 hr after dosing, using a high-pressure liquid chromatographic method. The "high-dose" study compared four microsize dosage forms administered as 500-mg doses and two ultramicrosize formulations given as 250-mg doses. The "low-dose" study employed four 250-mg microsize products and two 125-mg ultramicrosize products. The individual plasma level-time profiles for the majority of doses suggested prolonged absorption of microsize griseofulvin. The ultramicrosize dosage forms exhibited peak concentrations which were not significantly different (p > 0.05) from those of the microsize products administered as twice the dose. In the high-dose study, the two 250-mg ultramicrosize dosage forms exhibited areas under the plasma level-time curve (AUC) which were significantly (p < 0.05) less than the AUCs for all but one of the 500-mg microsize products. In the low-dose study the AUCs for the ultramicrosize products were significantly lower than the AUCs for all of the microsize dosage forms. Significant differences were also noted among the AUCs for the microsize products, although the maximum difference was less than 20% in both studies. A comparison of the AUCs observed in the high- and low-dosage studies revealed that the AUCs for two of the 500-mg microsize dosage forms were only approximately 75% the AUC predicted from the 250-mg dose for the eight subjects common to both studies. All other formulations exhibited a dose proportionality for AUC.

Journal
of
Pharmacokinetics
and
Biopharmaceutics,
Vol.
8,
No.
4,
1980
Bioavailability
of
Microsize
and
Ultramicrosize
Griseofulvin
Products
in
Man
Arthur
B.
Straughn,'
Marvin
C.
Meyer,
1,3
Gursharan
Raghow,'
and
Keith
Rotenberg
2
Received
October
15,
1979
—Final
March
20,
1980
The
relative
bioavailability
of
ten
marketed
dosage
forms
of
griseofulvin
was
evaluated
in
two
separate
crossover
studies.
Each
study
utilized
12
healthy
subjects,
with
eight
of
the
subjects
being
common
to
both
studies.
Plasma
griseofulvin
concentrations
were
determined
1,
2,
3,
4,
6,
8,
10,
25,
34,
49,
and
73
hr
after
dosing,
using
a
high-pressure
liquid
chromatographic
method.
The
"high
-dose"
study
compared
four
microsize
dosage
forms
administered
as
500
-mg
doses
and
two
ultramicrosize
formulations
given
as
250
-mg
doses.
The
"low-dose"study
employed
four
250
-mg
microsize
products
and
two
125
-mg
ultramicrosize
products.
The
individual
plasma
level
-time
profiles
for
the
majority
of
doses
suggested
prolonged
absorption
of
microsize
griseofulvin.
The
ultramicrosize
dosage
forms
exhibited
peak
concen-
trations
which
were
not
significantly
different
(p
>
0.05)
from
those
of
the
microsize
products
administered
as
twice
the
dose.
In
the
high
-dose
study,
the
two
250
-mg
ultramicrosize
dosage
forms
exhibited
areas
under
the
plasma
level
-time
curve
(AUC)
which
were
significantly
(p
<0.05)
less
than
the
AUCs
for
all
but
one
of
the
500
-mg
microsize
products.
In
the
low
-dose
study
the
AUCs
for
the
ultramicrosize
products
were
significantly
lower
than
the
AUCs
for
ail
of
the
microsize
dosage
forms.
Significant
differences
were
also
noted
among
the
AUCs
for
the
microsize
products,
although
the
maximum
difference
was
less
than
20%
in
both
studies.
A
comparison
of
the
AUCs
observed
in
the
high-
and
low
-dose
studies
revealed
that
the
AUCs
for
two
of
the
500
-mg
microsize
dosage
forms
were
only
approximately
75%
the
AUC
predicted
from
the
250
-mg
dose
for
the
eight
subjects
common
to
both
studies.
All
other
formulations
exhibited
a
dose
proportionality
for
AUC.
KEY
WORDS:
griseofulvin;
bioavailability;
HPLC
assay;
plasma
levels;
human
study.
This
work
was
supported
in
part
by
a
contract
from
the
Tennessee
Department
of
Public
Health
and
FDA
Contract
No.
223-77-3011.
'Division
of
Biopharmaceutics
and
Pharmacokinetics,
Department
of
Pharmaceutics,
College
of
Pharmacy,
University
of
Tennessee
Center
for
the
Health
Sciences,
Memphis,
Tennessee
38163.
2
Division
of
Biopharmaceutics,
Food
and
Drug
Administration,
Rockville,
Maryland
20852.
3
Address
correspondence
to
M.
C.
M.
347
0090-466X/80/0800-0347$03.00/0
(g)
1980
Plenum
Publishing
Corporation
348
Straughn,
Meyer,
Raghow,
and
Rotenberg
INTRODUCTION
Griseofulvin
is
an
antibiotic,
antifungal
agent
used
in
the
treatment
of
mycotic
diseases
of
the
skin,
hair,
and
nails.
Because
of
its
poor
water
solubility,
oral
administration
of
this
drug
may
be
subject
to
variable
and
incomplete
absorption.
In
order
to
improve
absorption
from
the
gastroin-
testinal
tract,
tablets
and
capsules
are
formulated
to
contain
microsize
crystals
of
griseofulvin.
Erratic
and
incomplete
absorption
with
these
formulations
is
still
possible
as
shown
by
the
sensitivity
of
griseofulvin
bioavailability
to
the
dissolution
rate
of
the
tablets
(1,2).
More
recently,
products
have
been
formulated
with
the
drug
dispersed
in
polyethylene
glycol
6000
(3,4).
The
labeling
of
these
commercially
available
"ultra-
microsize" formulations
indicates
that
the
efficiency
of
absorption
from
the
ultramicrocrystalline
griseofulvin
is
approximately
twice
that
of
the
con-
ventional
microsize
griseofulvin
(5,6).
This
factor,
it
is
claimed,
permits
the
oral
administration
of
half
as
much
griseofulvin
per
tablet.
In
view
of
the
potential
for
microsize
griseofulvin
dosage
forms
to
exhibit
poor
bioavailability
and
the
claims
of
improved
absorption
through
utilization
of
ultramicrosize
dosage
forms,
the
following
studies
were
undertaken
to
evaluate
the
relative
absorption
of
several
commercially
available
griseo-
fulvin
products
administered
at
two
different
dose
levels.
METHODS
Analytical
All
plasma
griseofulvin
samples
were
determined
in
duplicate
within
2
weeks
of
collection
utilizing
a
specific
high-pressure
liquid
chromatographic
assay
(7).
Each
day
subject
samples
were
assayed,
a
standard
curve
was
prepared
using
"spiked"
pooled
plasma.
Product
Selection
The
coding
of
the
products
evaluated
in
this
study
is
given
in
Table
I.
Product
1
was
purchased
locally
and
the
other
nine
were
received
from
FDA
District
Offices
and
passed
required
USP
in
vitro
testing
at
their
facilities.
The
products
in
the
high
-dose
study
were
paired
with
the
product
from
that
same
manufacturer,
administered
as
half
the
dose,
in
the
low
-dose
study.
Only
the
suspension
(product
1)
and
one
of
the
ultramicrosize
tablets
(product
6)
represented
a
pair
of
identical
dosage
forms
from
the
same
lot
in
both
studies.
With
the
other
products,
there
were
distinct
formulation
differences
between
dosage
form
pairs
(i.e.,
500
-mg
tablet
-250
-mg
capsule
or
500
-mg
tablet
-250
-mg
tablet).
Microsize
and
Ultramicrosize
Griseofulvin
Products
in
Man
349
Table
I.
Drug
High
dose
Low
dose
Manufacturer
1"
Grifulvin
V
(suspension)
500
mg
-20
ml
Lot
No.
FB6705
(exp.
6/80)
2"
Fulvicin-U/F
(Tablet)
500
mg
-1
tablet
Lot
No.
7AUG17P58928
(exp.
10/81)
3"
Grifulvin
V
(tablet)
500
mg
-1
tablet
Lot
No,
EM5768
(exp.
1/83)
4"
Grisactin
(tablet)
500
mg
-1
tablet
Lot
No.
1JMQ
(exp.
8/83)
5
b
Fulvicin-P/G
(tablet)
250
mg
-1
tablet
Lot
No.
8RAR7P59358
(exp.
2/80)
Gris-Peg
(tablet)
125
mg
-2
tablets
Lot
No.
B87465
(exp.
4/81)
Grifulvin
V
(suspension)
250
mg
-10
ml
Lot
No.
FB6705
(exp.
6/80)
Fulvicin-U/F
(tablet)
250
mg
-1
tablet
Lot
No.
P589277AUF105
(exp.
11/81)
Grifulvin
V
(tablet)
250
mg
-1
tablet
Lot
No.
FD7166
(exp.
6/83)
Grisactin
(capsule)
250
mg
-1
capsule
Lot
No.
1HZB
(exp.
5/83)
Fulvicin-P/G
(tablet)
125
mg
-1
tablet
Lot
No.
7HHP12
(exp.
10/79)
Gris-Peg
(tablet)
125
mg
-1
tablet
Lot
No.
B87465
(exp.
4/81)
McNeil
Schering
McNeil
Ayerst
Schering
Dorsey
"Microsize
product.
b
Drug
dispersed
in
PEG
-6000
(ultramicrosize
product).
Clinical
Protocol
For
each
study
12
healthy
male
volunteers
were
recruited
from
the
staff
and
students
of
the
University
of
Tennessee
Center
for
the
Health
Sciences.
Eight
of
the
subjects
were
common
to
both
studies.
A
6
-week
period
separated
the
high-
and
low
-dose
studies.
All
subjects
underwent
a
urine
analysis,
a
hematological
evaluation
(including
a
reticulocyte
count),
and
SMA
18/90
blood
chemistry
determination
to
ensure
that
they
were
in
good
health.
Urine
and
blood
screenings
were
repeated
at
the
end
of
the
fourth
and
sixth
weeks
of
each
study
in
order
to
identify
any
potential
health
problems
with
the
subjects.
In
the
high
-dose
study,
the
subjects
ranged
in
age
from
21
to
30
years
(mean
24),
in
height
from
174
to
191
cm
(mean
180),
and
in
weight
from
61
to
91
kg
(mean
75).
In
the
low
-dose
study,
they
ranged
in
age
from
21
to
30
years
(mean
24),
in
height
from
175
to
191
cm
(mean
177),
and
in
weight
from
61
to
91
kg
(mean
74).
Each
subject
gave
written
informed
consent.
For
each
of
the
two
studies
the
subjects
received
six
different
griseo-
fulvin
products
over
a
6
-week
period
in
accordance
with
a
crossover
matrix
designed
to
minimize
any
residual
or
cumulative
effects
of
the
preceding
doses
(8).
After
an
overnight
fast,
the
drug
was
administered
to
the
subjects
350
Straughn,
Meyer,
Raghow,
and
Rotenberg
with
8
oz
of
water.
The
griseofulvin
suspension
was
prepared
just
prior
to
administration
by
pipeting
either
10
ml
or
20
ml
of
the
well
-mixed
suspen-
sion
into
a
100-m1
beaker.
The
subjects
took
care
to
completely
ingest
all
of
the
drug
in
the
beaker
by
washing
the
container
four
times
with
approxi-
mately
25-m1
aliquots
of
water.
No
food
was
permitted
until
4
hr
after
administration
of
the
dose,
at
which
time
a
standard
lunch
with
limited
fat
content
was
consumed
by
each
subject.
Subsequent
food
was
not
provided,
but
the
subjects
were
required
to
record
all
food
and
beverage
intake
during
the
study
period.
The
subjects
were
also
required
to
abstain
from
strenuous
physical
exercise
during
the
study
period.
Ten
-milliliter
blood
samples
were
obtained
in
heparinized
containers
prior
to
the
dose
and
at
1,
2,
3,
4,
6,
8,
10,
25,
34,
49,
and
73
hours
after
dosing.
The
blood
samples
were
immediately
centrifuged,
and
the
plasma
fraction
was
stored
frozen
until
assayed.
Data
Analysis
In
both
the
high-
and
low
-dose
studies,
analysis
of
variance
was
used
to
determine
the
presence
of
statistically
significant
differences
(p
<0.05)
at
each
sampling
time
following
administration
of
each
drug
product
to
each
subject
each
week.
In
addition,
the
times
of
peak
plasma
concentration,
peak
plasma
concentration,
and
areas
under
the
plasma
level
—time
curve
(AUC
0-73
hr)
were
subjected
to
the
same
statistical
analysis.
Although
different
doses
were
employed
within
each
study,
parameters
were
not
normalized
for
dose
in
the
statistical
analysis
because
of
the
label
claims
for
the
ultramicrosize
dosage
forms.
In
cases
where
statistically
significant
differences
did
occur,
the
Newman—Keuls
a
posteriori
test
was
used
to
determine
which
products,
subjects,
or
treatment
sequences
(i.e.,
weeks)
were
different
(p
<0.05).
To
evaluate
the
dose
proportionality
of
the
products
from
the
same
manufacturers,
however,
the
normalized
AUC
obtained
only
from
the
subjects
common
to
both
the
high-
and
low
-dose
studies
were
analyzed
using
the
paired
student's
t
test.
During
both
the
high-
and
low
-dose
studies,
there
were
several
instances when
the
dosing
protocol
was
not
followed.
Because
of
a
large
interfering
peak
which
appeared
on
the
chromatogram
of
several
samples
obtained
during
the
high
-dose
study
from
subject
2
during
weeks
3
and
6
and
from
subject
7
during
week
4,
these
subjects
repeated
those
doses
during
the
2
-week
period
following
week
6,
and
the
original
data
were
discarded.
Although
all
subjects
were
cautioned
against
taking
any
other
drugs
during
the
study
period,
it
appeared
that
these
subjects
took
aspirin,
which
has
known
fl
uorescence
properties.
Subject
7
did
not
realize
that
Alka
Seltzer
contained
aspirin,
and
subject
2
inadvertently
took
aspirin
several
days
prior
to
the
study
weeks
3
and
6.
Because
symptoms
usually
ascribed
to
Microsize
and
Ultramicrosize
Griseofulvin
Products
in
Man
351
a
common
cold
were
experienced
by
subject
7
the
night
before
the
adminis-
tration
of
the
dose
for
week
6,
the
fi
nal
week
of
the
low
-dose
study
for
this
subject
was
postponed
for
1
week.
Since
these
breaks
in
the
protocol
represented
three
out
of
a
total
of
72
doses
administered
during
the
high
-dose
study
and
only
a
single
dose
out
of
a
total
of
72
doses
administered
during
the
low
-dose
study,
the
statistical
analysis
of
the
data
was
carried
out
as
though
all
subjects
had
received
their
doses
in
the
prescribed
sequence.
RESULTS
AND
DISCUSSION
Plasma
Levels
at
Each
Sampling
Time
Tables
II
and
III
summarize
the
mean
plasma
griseofulvin
levels
at
each
sampling
time,
for
the
high-
and
low
-dose
studies,
respectively.
These
values
are
graphically
illustrated
in
Figs.
1
and
2.
The
ranking
of
the
products
according
to
the
plasma
level
achieved
at
each
sampling
time,
as
well
as
the
significant
differences
(p
<0.05)
evaluated
by
the
Newman—Keuls
a
posteriori
test,
are
shown
in
Tables
IV
and
V.
The
difference
between
the
products
with
the
highest
and
lowest
mean
at
each
sampling
time
was
always
greater
than
20%
for
both
studies.
Both
the
analysis
of
variance
and
the
Newman—Keuls
a
posteriori
test
showed
that
this
difference
was
significant
(p
<0.05)
at
the
majority
of
the
sampling
times.
An
obvious
trend
in
the
ranking
of
the
products
indicates
that
the
two
ultramicrosize
products
(products
5
and
6)
in
each
of
the
studies
were
significantly
lower
in
concentration
at
the
later
sampling
times
than
several
of
the
other
products.
Also,
in
the
high
-dose
study
product
2
had
the
highest
concentration
at
all
the
sampling
times
except
49
hr
while
in
the
low
-dose
study
it
had
the
highest
concentration
at
the
majority
of
the
sampling
times
after
4
hr.
The
suspension
(product
1)
was
initially
included
in
the
studies
as
a
reference
dosage
form.
However,
the
results
of
both
the
high-
and
the
low
-dose
studies
indicated
that
the
bioavailability
of
several
of
the
solid
dosage
forms
was
at
least
equivalent,
if
not
superior,
to
that
of
the
suspension.
Peak
Plasma
Concentration
Tables
VI
and
VII
summarize
the
model
-independent
parameters
determined
in
both
studies.
The
statistical
analysis
of
these
values
is
given
in
Tables
IV
and
V.
In
the
high
-dose
study,
the
peak
plasma
concentration
ranged
from
0.70
µg/ml
(products
3
and
4)
to
0.92
µg/ml
(product
2).
The
low
-dose
study
peak
concentrations
ranged
from
0.44
µg/ml
(product
1)
to
0.58
µg/ml
(products
2
and
4).
In
both
studies
the
difference
between
the
Table
II.
Plasma
Levels
at
Each
Sampling
Time:
High
-Dose
Study'
Product
No."
1
hr
2
hr
3
hr
4
hr
6
hr
8
hr
10
hr
25
hr
34
hr
49
hr
73
hr
1
0.43
0.69
0.82
0.82
0.74
0.68
0.64
0.42 0.31
0.17
0.03
(53.8) (56.2) (51.6)
(49.7)
(42.1)
(39.5) (39.5)
(30.2)
(36.3)
(70.8)
(144.3)
2
0.47
0.75
0.82
0.85
0.83
0.77
0.73
0.45
0.34
0.17
0.05
(60.3)
(42.3) (39.1)
(31.0) (24.1)
(20.9)
(25.8)
(31.0)
(43.4)
(65.1)
(142.1)
3
0.30
0.52
0.64
0.65
0.62 0.62
0.58
0.36
0.27
0.13
0.03
(57.5)
(38.1)
(36.5)
(40.2) (51.5)
(49.5)
(46.8) (32.4)
(48.1)
(69.7)
(130.3)
4
0.22
0.44
0.60
0.64
0.63
0.58
0.54
0.39
0.32
0.19
0.04
(82.9) (54.6) (41.0) (37.4)
(43.3)
(41.5)
(36.9)
(36.1)
(40.0)
(67.7)
(110.5)
5
0.38
0.62
0.76
0.75 0.65
0.60
0.54
0.28
0.19
0.07
0.01
(82.4)
(58.2)
(51.0)
(47.3) (39.3)
(36.6) (33.9) (35.1)
(56.4)
(95.8)
(206.0)
6
0.41
0.66
0.80
0.79
0.69
0.63
0.57
0.28
0.19
0.06
<0.01
(50.6)
(41.0) (41.5)
(31.7)
(25.3)
(27.2)
(29.0)
(35.0) (55.1)
(79.5)
(239.1)
'Each
value
(µg/m1)
represents
the
mean
of
the
12
subjects.
The
relative
standard
deviation,
standard
deviation
x
100/mean,
is
given
in
parentheses.
"See
Table
I
for
product
code
numbers.
Straughn,
Meyer,
Raghow,
and
Rotenberg
Table
III.
Plasma
Levels
at
Each
Sampling
Time:
Low
-Dose
Study
Product
No.
b
1
hr
2
hr
3
hr
4
hr
6
hr
8
hr
10
hr
25
hr
34
hr
49
hr
73
hr
1
0.16
0.30
0.39
0.40
0.39
0.36
0.33
0.24
0.17
0.08
0.01
(50.0)
(44.6)
(50.3) (37.0) (30.3)
(30.2)
(32.1) (24.8)
(37.6) (49.7)
(190.3)
2
0.16
0.32
0.43
0.49
0.56
0.49
0.45
0.31
0.23
0.09
0.01
(76.8)
(59.6)
(29.4)
(26.6)
(23.8)
(20.9)
(26.5)
(36.5) (45.4)
(57.7)
(127.0)
3
0.18
0.40
0.47
0.49
0.43
0.38
0.34
0.26
0.19 0.09
0.02
(68.0)
(55.9)
(53.7) (46.8) (35.1)
(27.6) (22.5)
(32.8)
(39.4)
(74.6)
(135.9)
4
0.27
0.48
0.54
0.53
0.48
0.43
0.39
0.28
0.21
0.09
0.02
(79.0)
(44.6)
(26.6)
(20.7)
(24.0)
(23.6)
(23.7)
(30.9) (34.5)
(50.3)
(105.9)
5
0.29
0.44
0.46
0.44
0.39
0.33
0.29
0.12
0.06
0.02
0.00
(41.6)
(30.5)
(22.1)
(21.2)
(21.0)
(22.0)
(25.7)
(42.8)
(53.2) (91.2)
(000.0)
6
0.23
0.42
0.45
0.43
0.38
0.32
0.27
0.13
0.07
0.02
<0.01
(60.1)
(47.6) (29.0) (22.1)
(18.6)
(18.7) (18.2)
(40.3)
(50.8)
(107.2)
(346.4)
"Each
value
(14/m1)
represents
the
mean
of
the
12
subjects.
The
relative
standard
deviation,
standard
deviation
x
100/mean,
is
given
in
parentheses.
b
See
Table
I
for
product
code
numbers.
Microsize
and
Ultramicrosize
Griseofulvin
Products
in
Man
354
Straughn,
Meyer,
Raghow,
and
Rotenberg
.s
A
.7
J
V
V
Z
H
J
I0
mm
30
Ho
Elm
SO
70
BO
TIME
<HRS>
Fig.
1.
Griseofulvin
plasma
levels
in
the
high
-dose
study.
Each
point
represents
the
mean
of
12
subjects.
See
Table
I
for
identification
of
product
code
numbers.
Key:
0,
product
1;
A,
product
2;
■,
product
3;
♦,
product
4;
•,
product
5;
❑,
product
6.
highest
and
lowest
peak
plasma
levels
was
approximately
25%,
but
this
difference
was
not
significant
(p
>
0.05).
Time
of
Peak
Plasma
Concentration
The
estimation
of
time
of
peak,
uncorrected
for
any
lag,
may
be
subject
to
error
since
the
actual
time
of
peak
plasma
level
may
be
in
between
the
times
plasma
samples
were
obtained.
The
mean
time
of
peak
plasma
concentration
varied
from
3.3
hr
(product
5)
to
6.9
hr
(product
3)
in
the
high
-dose
study
and
from
3.4
hr
(products
5
and
6)
to
9.2
hr
(product
3)
in
the
low
-dose
study.
The
analysis
of
variance
indicated
that
the
difference
in
time
of
peak
concentration
was
significant
in
the
low
-dose
study
(p
<0.05)
but
not
in
the
high
-dose
study.
However,
the
Newman—Keuls
a
posteriori
test
did
not
detect
differences
among
the
products
for
this
parameter
in
either
study.
The
large
relative
standard
deviations
(greater
than
100%),
Microsize
and
Ultramicrosize
Griseofulvin
Products
in
Man
355
0
V
V
z
V
z
In
a
10
20
30
HO
SO
50
70
60
T1ME<HR5>
Fig.
2.
Griseofulvin
plasma
levels
in
the
low
-dose
study.
Each
point
represents
the
mean
of
12
subjects.
See
Table
I
for
identification
of
product
code
numbers.
Key:
0,
product
1;
0,
product
2;
0,
product
3;
product
4;
A,
product
5;
A,
product
6.
which
occurred
with
two
products
in
each
study,
were
due
to
several
peak
times
of
greater
than
24
hr
which
occurred
randomly
throughout
the
studies.
Examination
of
the
individual
plasma
level
-time
curves
for
these
dose
administrations
showed
that
an
earlier,
but
somewhat
lower,
peak
occurred
during
the
fi
rst
10
hr.
If
these
initial
peak
times
were
utilized
in
the
determination
of
the
mean
time
of
peak
plasma
concentration,
the
longest
mean
peak
time
would
be
5.1
hr
and
the
relative
standard
deviations
would
be
reduced
to
less
than
40%.
However,
the
ranking
of
the
products
did
not
change
and
the
observed
differences
were
still
not
statistically
significant
(p
>
0.05).
Visual
examination
of
each
of
the
individual
plasma
level
-time
profiles
for
each
dose
administered
to
each
subject
indicated
that
74
of
the
144
curves
obtained
in
both
studies
exhibited
the
type
of
plasma
level
-time
profile
represented
by
subject
1
in
Fig.
3.
In
contrast,
the
data
for
subject
3
illustrate
the
type
of
profile
obtained
for
the
remaining
70
individual
data
sets.
Data
such
as
those
shown
in
Fig.
3
could
be
attributed
to
prolonged
or
erratic
absorption,
as
suggested
by
previous
workers
who
observed
that
356
Straughn,
Meyer,
Raghow,
and
Rotenberg
Table
IV.
Newman—Keuls
a
Posteriori
Test
for
Significant
Product
Differences
in
Parameters
Studied:
High
-Dose
Study
Parameter
Product
ranking
(lowest
to
highest)''
b
1
hr
4
3
5
6
1
2
2
hr
4
3
5
6
1
2
3
hr
4
3
5
6
1
2
4
hr
4
3
5
6
1
2
6
hr
3
4
5
6
1
2
8
hr
4
5
3
6
1
2
10
hr
4
5
6
3
1
2
25
hr
5
6
3
1
4
2
34
hr
5
6
3
4
1
2
49
hr
6
5
3
2
1
4
73
hr
6
5
3
1
4
2
Cpmax
3
4
5
6
1
2
T
max
5
6
1
2
4
3
AUC
(0-73
hr)
5
6
3
4
1
2
'Products
underlined
by
a
common
line
not
found
to
differ
significantly
(p
>
0.05).
b
See
Table
I
for
product
code
numbers.
orally
administered
griseofulvin
may
continue
to
be
absorbed
over
a
30
-hr
(9)
to
3
-day
(3)
period.
The
peak
times
seen
in
the
present
study
are
in
agreement
with
the
results
of
earlier
studies
(4).
On
the
basis
of
the
peak
concentration
and
the
peak
time
values,
it
would
appear
that
the
ultramicrosize
dosage
forms
included
in
both
studies
were
more
rapidly
absorbed,
although
the
observed
differences
were
not
statistically
significant.
Further,
the
ultramicrosize
products
generally
pro-
vided
for
plasma
level
—time
profiles
represented
in
Fig.
3
by
subject
3,
while
the
microsize
products
were
more
typically
represented
by
subject
1.
It
also
appeared
that
some
subjects
were
less
prone
to
exhibit
the
prolonged
absorption
curves,
although
there
were
no
obvious
subject
characteristics
which
could
explain
this
observation.
Table
V.
Newman-Keuls
a
Posteriori
Test
for
Significant
Product
Differences
in
Parameters
Studied:
Low
-Dose
Study
Parameter
Product
ranking
(lowest
to
highest)
°
'
b
1
hr
1
2
3
6
4
5
2
hr
1
2
3
6
5
4
3
hr
1
2
6
5
3
4
4
hr
1
6
5
3
2
4
6
hr
6
1
5
3
4
2
8
hr
6
5
1
3
4
2
10
hr
6
5
1
3
4
2
25
hr
5
6
1
3
4
2
34
hr
5
6
1
3
4
2
49
hr
5
6
1
3
2
4
73
hr
5
6
1
2
4
3
Cpmax
1
5
6
3
4
2
T
ma
.
6
5
4
1
2
3
AUC
(0-73
hr)
5
6
1
3
4
2
'Products
underlined
by
a
common
line
not
found
to
differ
significantly
(p
>
0.05).
b
See
Table
I
for
product
code
numbers.
Table
VI.
Model
-Independent
Pharmacokinetic
Parameters:
High
-Dose
Study'
Product
No.
b
Peak
plasma
concentration
(µg/ml)
Time
to
peak
plasma
concentration
(hr)
AUC
(0-73
hr)
(p,g/m1
hr)
1
0.90
4.4
24.00
(45.4) (44.3) (23.7)
2
0.92
4.6
26.03
(26.7)
(57.0) (22.0)
3
0.70
6.9
20.25
(43.4)
(126.6)
(25.9)
4
0.70
6.2
21.01
(37.7)
(100.4)
(29.8)
5
0.79
3.3
17.06
(46.4)
(32.1)
(28.2)
6
0.86
3.8
17.51
(36.8)
(36.6)
(24.4)
°
Each
value
represents
the
mean
of
the
12
subjects.
The
relative
standard
deviation
is
given
in
parentheses.
b
See
Table
I
for
product
code
numbers.
358
Straughn,
Meyer,
Raghow,
and
Rotenberg
Table
VII.
Model
-Independent
Pharmacokinetic
Parameters:
Low
-Dose
Study'
Product
No."
Peak
plasma
concentration
(µg/m1)
Time
to
peak
plasma
concentration
(hr)
AUC
(0-73
hr)
(µg/ml-hr)
1
0.44
4.9
12.16
(40.0)
(54.5)
(25.2)
2
0.58
9.1
15.85
(21.0)
(108.0)
(24.3)
3
0.52
9.2
13.67
(46.6)
(107.9)
(14.4)
4
0.58
3.6
15.08
(26.8)
(38.4)
(18.4)
5
0.49
3.4
8.17
(21.3) (33.8)
(25.8)
6
0.50
3.4
8.38
(31.5) (49.4) (19.5)
'Each
value
represents
the
mean
of
the
12
subjects.
The
relative
standard
deviation
is
given
in
parentheses.
b
See
Table
I
for
product
code
numbers.
Area
Under
the
Plasma
Level
-Time
Curve
The
AUC
(0-73
hr)
ranged
from
17.1
µg/ml-hr
(product
5)
to
26.0
µg/ml-hr
(product
2)
in
the
high
-dose
study.
Analysis
of
variance
indicated
that the
34.5%
difference
between
these
two
products
was
highly
significant
(p
<
0.001).
The
Newman-Keuls
a
posteriori
test
revealed
both
ultramicro-
size
dosage
forms
(products
5
and
6)
had
significantly
lower
AUCs
than
products
1,
2,
and
4,
but not
product
3.
In
the
low
-dose
study,
product
2
had
the
highest
mean
AUC
(15.9
1.1,g/ml-hr)
while
an
ultramicrosize
dosage
form
(product
5)
had
the
lowest
mean
AUC
(8.2
µg/ml-hr).
This
48.5%
difference
was
also
highly
significant
(p
<
0.001),
and
the
Newman-Keuls
a
posteriori
test
revealed
that
both
ultramicrosize
dosage
forms
were
significantly
lower
in
AUC
than
the
four
microsize
products.
The
microsize
dosage
form
with
the
lowest
AUC
(product
1)
was
significantly
lower
than
the
microsize
tablet
with
the
highest
AUC
(product
2),
but
this
difference
was
less
than
15%.
In
contrast
to
these
fi
ndings,
earlier
studies
utilizing
both
single-
and
multiple
-dose
protocols
concluded
that
there
were
no
differences
in
the
AUC
obtained
after
administration
of
500
-mg
microsize
tablets
and
one-
half
the
dose
given
as
ultramicrosize
tablets
(4,
10).
These
apparently
conflicting
data
may
be
due
to
differences
in
subject
populations,
study
protocols,
or
assay
methodology.
For
example,
the
high-pressure
liquid
chromatographic
method
employed
in
the
present
study
has
been
reported
Microsize
and
Ultramicrosize
Griseofulvin
Products
in
Man
359
I
.0
-
.0
t
-
J
E
.7
a
V
Z
V
Z
J
.3
.2
ll
.
I
I0
20
30
40
50
60
70
80
T
I
ME<
HOS
>
Fig.
3.
Griseofulvin
plasma
levels
in
the
low
-dose
study
for
subject
1
after
receiving
a
250
-mg
microsize
tablet
(0)
and
in
subject
3
after
receiving
a
125
-mg
ultra-
microsize
tablet
(•).
to
be
specific
for
griseofulvin
(7).
It
is
also
possible
that
the
500
-mg
microsize
reference
product
employed
in
the
earlier
studies
may
have
been
less
bioavailable
than
some
of
the
500
-mg
microsize
dosage
forms
utilized
in
the
present
investigation.
Because
most
of
the
73
-hr
samples
contained
no
detectable
griseofulvin
and
the
drug
levels
in
all
of
these
samples
were
below
10%
of
the
peak
level,
no
attempt
was
made
to
determine
the
AUC
to
time
infinity.
Further,
the
apparent
prolonged
absorption
evident
in
the
majority
of
the
plasma
level
profiles
precluded
an
accurate
estimation
of
half-life.
For
those
data
sets
where
a
half-life
could
be
estimated,
the
values
ranged
from
8
to
20
hr,
in
agreement
with
earlier
studies
utilizing
intravenous
dosing
(9).
Dose
Proportionality
These
results
are
based
on
the
assumption
that
the
absorption
and
elimination
of
griseofulvin
is
fi
rst
order,
so
the
AUC
for
the
low
dose
could
360
Straughn,
Meyer,
Raghow,
and
Rotenberg
be
normalized
to
the
larger
dose
using
a
multiplication
factor
of
two.
It
should
be
noted
that
only
the
AUC
data
obtained
from
the
eight
subjects
common
to
both
studies
were
used
for
the
analysis,
the
results
of
which
are
presented
in
Table
VIII.
Both
of
the
ultramicrosize
dosage
forms
(products
5
and
6),
the
suspension
(product
1),
and
the
microsize
tablets
exhibiting
the
largest
AUC
in
both
the
high-
and
low
-dose
studies
(product
2)
showed
dose
proportionality
in
terms
of
AUC.
The
tablet
—capsule
pair
(product
4)
results
indicated
that
absorption
efficiency
from
the
capsule
was
significantly
enhanced
from
this
dosage
form.
The
tablet
pair
(product
3)
also
indicated
better
absorption
from
the
250
-mg
microsize
tablet
compared
to
the
500
-
mg
microsize
tablet.
An
earlier
study
(4)
found
only
a
35%
increase
in
AUC
with
data
from
subjects
receiving
either
four
125
-mg
or
two
125
-mg
ultramicrosize
tablets.
This
study,
however,
employed
two
different
groups
of
subjects
for
the
comparison.
Differences
Among
Subjects
and
Weeks
With
the
exception
of
the
34-
and
49
-hr
samples
for
the
low
-dose
study,
there
were
no
significant
(p
>
0.05)
differences
found
among
study
weeks.
However,
with
the
exception
of
the
4
-hr
sample
for
the
low
-dose
study,
and
the
maximum
time
values
for
both
studies,
significant
(p
<
0.05)
differences
were
observed
among
subjects
for
all
parameters.
Power
Analysis
Power
analysis
is
employed
to
evaluate
the
minimum
difference
between
dosage
forms
which
would
be
statistically
significant
(a
=
0.05,
=
0.2),
or
the
number
of
subjects
required
for
a
20%
difference
to
be
significant.
The
results
of
this
analysis
are
given
in
Tables
IX
and
X
and
indicate
that
the
number
of
subjects
employed
in
both
studies
was
adequate
for
a
19-22%
difference
in
AUC
to
be
statistically
significant.
Because
of
the
Table
VIII.
Paired
Student's
t
-Test
for
Dose
Proportionality
Drug
Pairs"
(AUC)
high
b
(p..g/ml.hr)
2(AU0,0,/,
(jig/ml.hr)
t
value
1
25.8
(15)
24.6
(28)
+0.675
N.S.
2
28.0
(16)
30.3
(24)
—0.959
N.S.
3
20.1
(21)
28.4
(13)
—6.825
p<0.001
4
23.0
(31)
30.1
(20)
—3.083
p<0.05
5
18.8
(26)
16.5
(24)
+1.845
N.S.
6
19.0
(23)
17.0
(18)
+1.114
N.S.
"See
Table
I
for
product
code
numbers.
b
Mean
AUC
of
the
product
administered
to
the
eight
subjects
common
to
both
studies.
Relative
standard
deviation
in
%
is
given
in
parentheses.
Microsize
and
Ultramicrosize
Griseofulvin
Products
in
Man
Table
IX.
Power
Analysis
Table:
High
-Dose
Study'
361
Parameter
Number
of
subjects
for
20%
difference
Minimum
detectable
difference
(%)
Actual
difference
(%)
1
hr
>30
67
55.5
2
hr
>30
48
41.3
3
hr
>30
46
26.8
4
hr
>30
42
24.7
6
hr
>30
42
25.3
8
hr
>30
41
24.7
10
hr
>30
38
26.0
25
hr
26
28
37.8
34
hr
>30
35
44.1
49
hr
>30
53
68.4
73
hr
>30
115
100.0
Tmax
>30
101
51.2
C'
f
,
max
>30
43
23.9
AUC
(0-73
hr)
14
22
34.5
'a
=0.05,13=0.2.
b
[(Mean
highest
value
—mean
lowest
value)/
mean
highest
value]x100.
variability
in
the
other
parameters,
between
15
and
greater
than
30
subjects
would
have
been
required
for
a
20%
difference
in
other
values
to
be
significant.
However,
because
the
actual
differences
observed
for
the
various
parameters
were
generally
in
excess
of
25%,
many
of
the
differences
were
statistically
significant.
Table
X.
Power
Analysis
Table:
Low
-Dose
Study'
Parameter
Number
of
subjects
for
20%
difference
Minimum
detectable
difference
(%)
Actual
difference
b
(%)
1
hr
>30
62
44.8
2
hr
>30
52
37.5
3
hr
>30
44
27.8
4
hr
>30
40
24.5
6
hr
23
29
32.1
8
hr
18
25
34.7
10
hr
17
25
40.0
25
hr
15
23
61.3
34
hr
25
30
73.9
49
hr
>30
54
77.8
73
hr
>30
113
100.0
CP
Max
>30
39
24.1
T.
>30
95
63.0
AUC
(0-73
hr)
11
19
48.5
"a=
0.05,
=
0.2.
b
[(Mean
highest
value
—mean
lowest
value)/mean
highest
value]
x
100.
362
Straughn,
Meyer,
Raghow,
and
Rotenberg
CONCLUSION
On
the
basis
of
the
maximum
plasma
concentration
and
the
time
of
maximum
concentration,
the
two
ultramicrosize
dosage
forms
(products
5
and
6)
appeared
to
be
somewhat
more
rapidly
absorbed.
They
also
were
more
uniformly
absorbed,
as
determined
from
the
variability
in
time
of
maximum
plasma
concentration
among
the
various
formulations.
The
ultramicrosize
dosage
forms,
administered
as
one-half
the
dose
of
the
microsize
products,
resulted
in
significantly
less
drug
being
absorbed
than
for
all
but
one
of
the
microsize
products.
The
ultramicrosize
products,
as
well
as
products
1
and
2,
exhibited
dose
proportionality
for
the
comparison
of
the
AUCs
determined
in
the
high-
and
low
-dose
studies.
However,
the
high
-dose
AUCs
for
products
3
and
4
were
only
71%
and
77%
,
respectively,
of
the
values
predicted
from
the
low
-dose
study.
It
was
concluded
that the
ultramicrosize
dosage
forms
were
more
rapidly,
completely,
and
uniformly
absorbed
than
the
microsize
formulations.
However,
claims
indicating
that
absorption
efficiency
for
the
ultramicrosize
formulations
is
approximately
twice
that
of
the
microsize
products
were
not
substantiated
by
this
study.
ACKNOWLEDGMENTS
The
authors
thank
Ms.
Cathie
Grady,
Ms.
Laura
Lucius,
and
Ms.
Vicki
Proefrock
for
their
technical
assistance
and
Philip
Lieberman,
M.D.,
for
serving
as
the
medical
monitor
for
this
study.
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