Download Clinical pharmacology of filgrastim following high-dose chemotherapy and autologous bone marrow transplantation.

Vol. 3, 705-711,
May
Clinical
1997
Clinical
Pharmacology
of Filgrastim
following
Chemotherapy
and Autologous
Bone
Marrow
Transplantation’
William
and
P. Petros,2
William
Bone
Rabinowitz,
Ann
ited
Stuart,
Transplant
Medical
Department
Program,
Center,
Durham,
North
of Medicine,
Carolina
Duke
27710
tial
ABSTRACT
namics
following
evaluated
the
of filgrastim
high-dose
marrow
pharmacokinetics
transplantation.
and
were
developed
Serum
10 patients
of
(tm)
volume
of distribution
counts
fusion,
the 4-h
receiving
study
periods
Clearance
4-32
4-h
systemic
infusion
group
was
volume.
by
in all
during
WBC
14
of severe
patients
recovery.
The
by a differential
a static
component
WBC concentration.
and one component
These
data suggest
dosing
strategies
transplantation
may
effect
equation
following
that
marrow
the
of
in
of
doses
of WBCs
included
autologous
bone
Clinical
the therapeutic
following
multiple
remain
therapeutic
these
(5625
-3),
proteins
and
regarding
their
the
pharmacological
optimal
characteristics.
myeloaquestions
use
of
A lim-
characteristics
of
these
to pharmacody-
variables
All
as part
in
Review
regimen
bone
previously
marrow
II-IV
approved
and
was
breast
G-CSF
that
derived
following
and
outlined
the extinction
from
coefficient
should
product.
continuous
starting
Escherichia
3 h after
bone
immediately
receiving
lected
daily
5, 10,
1 (6).
the
Autolend
of
Amgen,
Inc.).
Amgen
revised
the doses
reported
to the currently
was administered
by either
or daily 4-h infusions
for 21
marrow
Sampling.
Single
daily
during
the continuous
infusion
to day
of 4, 8, 16, 32,
recombinant,
trial,
thus,
in
(165
-6
after
by 1.2 to be equivalent
The cytokine
iv. infusion
or
Duke
cisplatin
coli;
of this
for filgrastim;
be multiplied
the
(day
in Fig.
4 days
the completion
cancer
by
of 4 days
reinfused
trial
bone
for Clinical
Trials
of cyclophosphamide
mg/m2),
the course
clinical
autologous
was
(600
over
and
Board
consisted
filgrastim
I/il
of stage
study
carmustine
as described
received
of a Phase
chemotherapy
This
administered
patients
chemotherapy
(day + I). Patients
received
doses
or 64 pUg/kg/day of filgrastim
(nonglycosylated,
here
to
cell
and ABMT,
consent
for the treatment
mg/m2),
mg/m2)
mar-
of
link
seems
granulocytic
METHODS
Institutional
The ablative
Note
benefits
which
blood
or
substan-
chemotherapy
Therapy.
to high-dose
marketed
14-day
administering
hematopoietic
growth
factors
blative chemotherapy
and ABMT;3
however,
unanswered
AND
and
University
Humans.
days
trials have demonstrated
that
support
human
INTRODUCTION
disposition,
or
ABMT
data suggest
the pharmacokinetic
to evaluations
melanoma.
with
used
be suboptimal.
in
for
volunteers
following
These
in peripheral
high-dose
metastatic
ogous
of
(1-5).
describes
is available
to healthy
the cytokine
following
informed
and
that varied
that currently
report
following
subsequent
neutropenia.
receiving
patterns
PATIENTS
plasma
WBC
received
variability
to
Patients
immediately
postinin the disappearance
of
on Cls was described
row
197 mm,
plasma
then rebounded
with a delay
(CIs)
705
effects.
Models
Mean
theory.
on the presence
increased
fflgrastim
infusions.
clearance
approximated
based
sag/kg/day
namic
colony-stimu-
had
interpatient
related
addition
information
its administration
chemotherapy
filgrastim
cytokine
bone
colony-stimulating
factor.
The effect
on filgrastim
Cls was determined
continuous
infusions
by segregation
granulocyte
concentrations
patients
daily
filgrastim
transiently
fell,
which
correlated
serum
WBC
granulocyte
receptor-binding
half-life
in
I study of this
and
autologous
pharmacokinetic
who
recovery.
This
pharmacody-
were determined
by ELISA
in
continuous
i.v. filgrastim
infu-
receiving
for
incorporation
and
during
a Phase
chemotherapy
lating
factor
concentrations
21 patients
receiving
14-day
sions
of
standard-dose
Research
High-Dose
following
to patients
be
We
amount
filgrastim
P. Peters
Marrow
University
Josh
Cancer
administration
(day
+1).
serum
samples
were
obtained
regimen.
Samples
before
and
after
infusion
were
collected
4-h infusions.
In addition,
15, 20, 30, 45, 60,
120,
240,
from
the patients
samples
were coland
360
mm
after
the
completion
of the 4-h infusions
on day + 15. Urine
was collected for 24 h after drug administration
in a subset
of patients
receiving
Received
7/8/96; revised 2/7/97; accepted
2/10/97.
The costs of publication
of this article were defrayed
in part by the
payment of page charges. This article must therefore be hereby marked
advertisement
in accordance
with
18 U.S.C.
Section
1734 solely
to
indicate
this
fact.
This work was supported
by NIH Grant 1PO1CA47741-01A3.
2 To whom
requests for reprints should be addressed,
at Duke University
Medical
Center,
Box 3961 (DUMC),
Durham,
NC 27710. Phone:
(919) 684-6707;
Fax: (919) 684-5177;
E-mail: [email protected].
3 The
abbreviations
used are: ABMT, autologous
bone marrow transplantation;
CSF, colony-stimulating
factor; G-CSF, granulocyte
CSF;
sCr, serum creatinine.
I
the 4-h
infusion
regimen
on day
+ 1 and
day
+ 15.
Analytic
Procedure.
Immunoreactive
G-CSF was measured in our laboratory
using a double-antibody
sandwich
technique
(Amgen
Diagnostics,
Thousand
Oaks,
CA).
Microtiter
plates
for
were
precoated
G-CSF.
incubated
One
with
hundred
polyclonal
for 4 h at 37#{176}C.
Serum
anti-G-CSF
jugate
was
rabbit
p.1 of test
was
samples
2-h incubation
tetramethylbenzidine
at 37#{176}C.
After
was
further
added
and
were
removed
monoclonal
antibody-horseradish
added and bound
to the G-CSF
antibody
and
specific
added
and
100 pA of
peroxidase
conon the well during
a
washing,
oxidized
100 p.1 of dilute
by
enzyme
to
706
Filgrastim
Clinical
Pharmacology
Day
-6
-8
Cyclophosphamide
(1875 mg/rn ‘/day)
Cisplatin
(55/mg/rn
-4
Marrow
2
6
4
Infusion
8
10
12
14
16
18
20
‘U.
#{176}/day)
U
Fig. 1
Marrow
Infusion
Filgrastim
14-day
Treatment
administration
scheme.
*
Infusions
continuous
- 64
(4
0
-2
Carrnustine
(600 mg/rn)
Bone
from
IV
pg/kg/day)
or
21-day
four hour
(4 - 64
pg/kg/day)
yield
a blue
QD
complex
IV
during
a 30-mn
room
temperature
incu-
years,
and
89%
of the
females
bation.
Addition
of 100 p.1 of 0.5 N sulfuric
acid stopped
the
reaction
and yielded
a yellow
color. Absorbance
was determined
by an ELISA
plate reader
with a 450-nm
interface
filter, using
eration
of WBC
related,
with
650
con-
of
con-
Patients
nm
as the
centrations
taming
trations
>25
were
calculated.
range
G-CSF
sample
to minimize
coefficients
wavelength.
in the
ng/ml
using
the standards
were
reference
were
were
diluent.
always
patient
receiving
ping
a 4-h
(RSTRIP
sequent
V.4.03;
evaluations
nonlinear
tical
model
determined
i.v.
infusion
the
following
using
unknown
conducted
with
values
standards
infusion
was
performed
MicroMath,
Salt
data
regression
Systemic
receiving
City,
clearance
=
UT).
Sub-
conducted
using
V.3.0.;
Statis-
drug
clearance
filgrastim
noncompartmental
equation:
Lake
sets were
as
described
infusion
rate/serum
by
con-
centration.
Statistical
Analysis.
paired
analyses,
nonpaired
group
during
ory.
Wilcoxon
and the Mann-Whitney
comparisons.
Modeling
continuous
infusion
A differential
equation
concentration-time
approximated
The
data
by a linear
was
based
relating
was
was
used
U test was
of clearance
on pharmacokinetic
This
to expedite
for
used for
changes
pharmacokinetic
developed.
equation
test
thetheory
relationship
ported
to
was
analysis.
able
for pharmacokinetic
Twenty-eight
purposes.
The
patients
mean
patient
were
WBC
evalu-
age was 40
those
clearly
found
dose
at doses
previously
(7,
discernably
of 64
throughout
infusions
less
pjg/kg/day
therapy.
climbed
steadily
concentrations
also
Three
To investigate
(Fig.
the acute
counts
effects
fell
4-5
precipi-
infusion
the 4-h filgrastim
the next
of G-CSF
WBC
2).
following
over
following
who had day
h. Interestingly,
did not decay
significantly
during
ing
0.001
between
G-CSF
and
WBC
concentra-
inverse
and
relation-
G-CSF
con-
collected
included
due
and
WBC
parameters
for 10 individuals
i.v. infusion
are shown
in Table
at 0,
to high
counts
1, 2, 4,
variability
elimination
approximating
and
n =
following
model
process
with
best
plasma
volume.
G-CSF
Mean
were
concentration
infusion,
zero-order
described
parameters
included
volume
of distribution
receiv1. Only
6 h postinfusion
in serum
immediately
A one-compartment
cases. Calculated
of 198 mm and
0.84,
for each).
The pharmacokinetic
filgrastim
by 4-h
samples
the
(Fig. 2). We selected
the three
+ 15 WBC counts
of >4 X 106 cells/mi
to
centration
postinfusion
was noted in each patient
(r
=
0.92, and 0.93 for patients
231, 233, and 234, respectively;
<
and
serum
infusion
the relationship
P
pa-
(patients
of 64 pUg/kg/day
tions with linear regression
analysis.
A linear
ship between
WBC concentration
postinfusion
8 and
8).
hema-
taken off the study drug prematurely
Other clinical
results
have been re-
Infusions.
samples
evaluate
had
at a dose
counts
not
up
accel-
administration
on the WBC count,
seven patients
counted
at the same time points
as the postinfusion
hour
hour
reported
made
(i.e.,
(7, 8).
in the first
first
as
continuous
tously
above.
RESULTS
Population
and
lower
pharmacokinetic
then
was
response
4 pjg/kg/day
response,
cancer
response
to filgrastim
pig/kg/day,
only
previously
of breast
therapeutic
hematopoietic
231, 233, and 234) were
due to suspected
toxicity.
first-order
Patient
32
receiving
patients
was
by continuous
methods
recovery)
and
of filgrastim
had WBCs
strip-
The
maximum
receiving
manifested
the diagnosis
group.
Intermittent
for each
by curve
(PCNONLIN
KY).
patients
estimation
16,
tients
of the appropriate
parameter
8,
topoietic
to
the inter- and intraday
for both high and low
Selection
and initial
Lexington,
in those
concen-
corresponding
All samples
obtained
during continuous
in the same run for individual
patients
of individual
least-squares
Consultants,
appropriate
and
however,
< 10%
to eliminate
any potential
bias.
Pharmacokinetic
Analysis.
pharmacokinetic
to
curve
Unknowns
densities
regression,
were
samples.
analyzed
standard
ng/ml.
diluted
intemin
variation;
of variation
were
quality
control
infusions
were
1-25
Optical
fit by linear
Assays
The
of
with
study
these
as described
input
data
and
a
in all
an average
half-life
(t1,)
(Vd) of 0.06 liter/kg,
systemic
exposure,
as
Clinical
Cancer
Research
707
300
-J
w
E
C)
-I
C
C)
ID
Fig. 2 Mean serum G-CSF
(-)
and WBC
(- - - -) concentrations
from
seven patients
following
the 4-h fligrastim
infusions.
Concentrations
were
normalized
to a dose of 16 pg/kg for comparison.
U.
(I)
ID
0
0
5
4
30
100
0
200
Time
Table
Patient
no.
Dose
Pharmacokinetic
1
AUC
(.Lg/kg/day)
param eters
(p.g/mL
mm)
-
for patients
C,,.
post
receiving
4 hour
infusion
filgr astim
Vd (liter/kg)
(ng/mI)
300
by 4-h
(minutes)
v infusion
(mm)
t1,
400
Cls (mi/h/kg)
WBCs#{176}
(X l0/ml)
311
4
30.3
81.3
0.061
160.3
15.8
1.0
287
247
8
16
37.7
285.0
1 16.0
0.038
123.4
12.7
4.3
499.7
255
256
261
268
269
16
16
16
32
32
119.0
25.8
121.5
343.2
413.3
273.4
84.9
330.4
734.2
469.1
0.025
0.040
0.095
0.030
0.031
0.058
3.4
8.1
37.2
7.9
5.6
4.6
3.0
6.3
3.4
1.3
1.2
1.5
281
280
32
64
18.0
487.6
68.6
1635.1
303.3
206.6
105.9
156.7
229.8
521.1
66.4
101.4
197.5
106.9
7.9
21.0
15.3
0.5
133.5
31.7
0.171
0.019
0.057
Mean
SD
0.046
a
Measured
on the day of pharm acokinetic
measured
dose;
by area under
however,
interpatient
(coefficient
sidered
of variation,
apparent
tinguish
the
between
evaluation.
curve
(AUC)
or C,,,,
variability
in clearance
151%).
because
These
current
endogenously
values
Continuous
infusions
also
ance.
continuous
estimates
infusion
should
be con-
methods
cannot
produced
G-CSF
and
concentrations
with
large
disexog-
+ 1 and day
G-CSF
was
added
to urine
Patients
receiving
continuous
i.v.
large interpatient
variability
in clear-
and
laboratory
i.v. infusion
data
are shown
for
individuals
in Table
re-
2. Clearance
are divided
into values obtained
at an early point in the
regimen
(day +4 to day +8) when the WBC count was
cells/mm3
few days
recovery
in all patients
of infusion
(day
was in progress.
an equilibration
patients
G-CSF
Infusions.
manifested
Pharmacokinetic
ceiving
<250
Known
rose
was
analytical
enously
administered
drug.
Twenty-four-h
urine samples
collected
on day
+ 15 from
five patients
showed
that no detectable
present
in urine.
were detectable.
receiving
point
<64
and
those
+ 13 to day
Serum
((20%
daily
p.g/kg/day.
G-CSF
F-
obtained
on the final
when hematopoietic
concentrations
reached
+ 15)
fluctuation)
However,
by day
patients
64 p.g/kg/day
continued
recovery.
hematopoietic
tion
from
ng/ml
day
+4
in these
increased
to day
patients.
slightly
+3
The
was over
+8
Conversely,
over
tients who had therapy
ifested
rapidly
increasing
of infusion.
to accumulate
Median
increase
third
this
p.gfkg/day
crease
20%
to early
by
106 cells/mI.
dysfunction
time
period.
2).
ducted
Two
discontinued
early due
G-CSF
concentrations
patient
had
her
continuous
700
and three
Only
infusion
for all patients
infusion
of seven
one patient
(total bilirubin,
Three
(Table
of these
with
2).
had
WBC
272)
mg/dl)
developed
baseline
patients
final
(patient
>5.0
and did not demonstrate
to 1500
of the
patients
three
stopped
on day
recov-
receiving
The
<64
median
counts
in-
increased
of > 1 X
of < 1 X
experienced
during
pa-
to toxicity
manbefore
the end
was drawn.
during
hematopoietic
in therapy
sion, whereas
six patients
creatinine,
more than twice
+4 in all
from
in clearance
was 27% (P = 0.001).
Clearance
for six of seven patients
with final WBC counts
106 cells/nil
receiving
100%,
the Cls for the other
before
a G-CSF
serum sample
Systemic
clearance
increased
ery compared
serum
G-CSF
before
in G-CSF
concentra-
hepatic
filgrastim
infu-
renal dysfunction
(serum
value during therapy; Table
pharmacokinetic
altered
disposition
studies
compared
conto
708
Filgrastim
Clinical
Pharmacology
Table 2
Pharmacoki
netic and clinical
laboratory
d ata for patients
receivi ng filgrastim
by con tinuous
iv.
infusion
Cls (mi/h/kg)
Patient
Dose
(p.g/kg/day)
no.
Change
Late’
Early’
5.95
in Cisc
(%)
WBC
(X
count”
l06/ml)
sCr, day 6
(mg/dl)
sCr, maxe
(mg/dl)
267
285
283
4
4
8
4.07
7.58
7.72
32.05
8.07
30
688
7
0.6
2.1
0.8
0.6
0.7
0.7
0.6
1.3
0.9
272
314
8
8
5.13
4.50
5.67
6.51
11
45
2.7
0.5
0.6
0.8
2.3
0.6
218
224
207
215
238
16
16
16
16
16
4.87
4.87
3.32
3.16
6.17
4.98
5.38
214
32
3.65
4.99
21 1
213
4.54
2.18
1.58
3.92
4.70
0.9
0.7
1.6
2.4
0.6
3.1
0.8
0.6
0.7
0.8
0.7
0.5
0.7
0.7
0.7
1.8
1.0
1.2
0.7
0.9
0.7
1.1
0.8
0.7
254
32
32
32
64
2
10
20
40
23
37
4
1.0
0.8
1.2
0.7
265
64
3.81
0.8
0.9
234
233
232
23 1
229
64
64
64
64
64
N/A1
3.37
4.54
3.81
1.02
0.7
0.7
1.4
1.6
246
a
b
C
d
e
3.99
4.42
7.58
56
3.40
156.86
2.56
9841
-35
9.26
70.4
0.8
143
1.4
N/A
N/A
N/A
N/A
4.32
N/A
1.14
N/A
N/A
-5
N/A
12
0.7
0.8
1.4
N/A
0.8
0.9
0.6
2.4
1.7
Average values for days 4-8 of continuous
infusion.
Average
values for days I 3-15 of continuous
infusion.
[Cls Late - Cls Early]/Cls
Early.
Final day of continuous
infusion.
During infusion.
1N/A,
not available.
4 mcg/kg/day
-1-
8 mcglkglday
-*-
16 mcg/kg/day
-9--
32
mcg/kg/day
-*--
64
mcg/kg/day
.0
-J
Fig. 3 Median
clearance
of filgrastim
during
continuous
infusion grouped by dose level. Studies were conducted
before (Day 4-8) and during
(Day 13-15) hematopoietic
recovery (n
18).
E
0
C
to
to
04
0
3
2
others
Day4-8
with
to be related
cry,
scribe
similar
WBC
to dose
both
as shown
in Fig. 3.
Two
pharmacodynamic
the
relationship
(model
0) assumes
Systemic
and
after
models
between
during
continuous
infusion.
eliminated
by a first-order
first
counts.
before
Dayl3-15
Both
process
WBC
were
and
clearance
hematopoietic
considered
G-CSF
models
assume
in the absence
that WBC-mediated
appeared
recov-
order.
Applying
the
steady-state
assumption
in this
case
yields
the equation:
to de-
C1s1*[GJ,
= Dose
= C1s1*[G]1
(A)
+ K0*WBCf,
elimination
that G-CSF
is
of WBCs.
The
elimination
is zero-
where
[G] represents
sents
the
time
when
refers
to the clearance
the concentration
WBC
counts
of filgrastim
of G-CSF
were
<250
in the absence
and
cells/mm3.
i repreCls1
of significant
Clinical
Model
Cancer
Research
709
0
-J
E
C
CD
CD
Fig. 4
Comparison
oftwo proposed models of
disposition.
Model
0, plot of the
change in G-CSF concentrations
from beginsting to the end of infusion
versus
the final
WBC count divided by the initial Cls as described
by Eqs. A and B (r = 0.63; P <
0.001). Model 1, plot of the change in filgrastim CIs from end to beginning
infusion versus
the end of infusion WBC count as described in
Eqs. C and D (r = 0.51; P = 0.004).
-,
regressions
of all data,
, regressions
cxcluding the patient with a WBC count of 70 X
106 cells/mi (patient 246).
filgrastim
0.05
Model
0.5
WBC1/C11
50
5
(ceIIs105/hr/kg)
1
2
.0
-J
E
0)
0
ID
0
100
WBC1
WBC
counts
and is assumed
to be constant.
the absolute
amount
of G-CSF eliminated
time (zero-order)
in units
of ng/kg/h
(cells’lO#{176}/mL)
The term K0 reflects
by each WBC per unit
per (cells
X 106/ml).
Parameters
followed
by f are those observed
etic recovery.
Rearranging
terms yields:
[G]1 The
ination
tion
alternative
of G-CSF
in this
case
[G]f
model
by WBC.
yields
=
during
Applying
1) assumes
WBC
(B)
first-order
the steady-state
dimassump-
of G-CSF
X 106/ml).
(Cls1 + K1*WBCf)*[G]f,
WBC
by each
The clearance
(first-order)
in the presence
of
is:
Comparison
(C)
K*WBC1.
= Cls1 +
of the two models
4. Regression
excluding
patient
infusion
analysis
246
(highest
was
patient
performed
final
(D)
was determined
log(Clsf
Cls1) versus
log(WBCf),
i.e.,
and log([G]1
- [G])
versus log(WBC/Cls1),
Eq. B) for all continuous
the equation:
= Dose
per (cells
(Cls)
Fig.
C1s1*[G]1
K1 is the clearance
in mi/h/kg
hematopoi-
K0*WBCCls1.
(model
where
WBC
model
by plotting
1 (from
i.e., model
data
sets,
both
count
Eq. D);
0 (from
as shown
including
and clearance)
in
and
710
Filgrastim
due
Clinical
Pharmacology
to the large
model
influence
of this
1 did not accurately
describe
0.4);
in contrast,
0.41,
P
model
0.02).
<
however,
model
0 was
0.001
versus
WBC
elimination
yielded
a value
if WBC
r
=
still
0.51,
In the latter
set (r
a significant
246
superior
P
0.004).
These
(r
both
=
1 (r
= 0.63,
data
suggest
P
<
X l06/ml).
Data
from
lack
0
or 1 .3 pg/kg/day.
Infusion
of filgrastim
ABMT
can
toxicities
and
is widely
used
been
following
reduce
in such
recovery,
settings.
differences
transplant
patient,
to the most
marrow
due
and peripheral
of this study demonstrated
yond
16 pjg/kg/day
did
efficacy
of therapy,
actually
slow
of this
ablation.
data
dosage
cytokine
higher
of 64 pg/kg/day
cases
in the
of
portion
based
on both
in vitro
of an endogenous
bethe
seemed
(7, 8). One
to
possible
and the receptor
of only a small
to be internalized
(1 1). Occupancy
receptors
on a particular
biological
response
to provide
activity,
rethe
a clearance
to be sufficient
receptor
mechanism,
to the cell
of available
beyond
binding
suspected
immediate
as was
is thought
noted
to
margmnation
be
(15).
coincided
with
persisted
in this
have
a transient
for approximately
time
1-h time
yielded
point
trial
accounted
We
concentration,
in WBC
reduction
data
(13,
for
by
alterations
that
this
delay
in drug
a re-
Use
at the end of infusion
clearances
this
neutrophil
in WBC
elimination,
1 h postinfusion.
apparent
in
which
of multiple-
and following
that were
on linear
WBC
counts
reach
sets.
regression
below
be
exceed
the
in the same
WBCs
have
the
In particular,
cytokine
to
than
saturate
all
per (cells X 106/ml;
that in patients
with
hematopoietic
elimination
pig/kg/day,
regardless
of dose.
is presumably
first-order;
there-
1.3
of G-CSF
this theoretical
optimum
the G-CSF-receptor
of
to be a zero-
of the
sufficient
1 X 106 cells/mI,
not
and
cells
appears
doses
K = 54 ng/kg/h
of Eq. B) implies
Using
(e.g.,
interaction
13 igfkg/day
and
a filgrastim
pg/kg/day
would be reasonable.
of the clearance
relationships
when
One
filgrastim
would
was
2 gig/kg/day)
can
minimizing
the
while
dose
in the range
It is important
described
above
administered
anticipate
by s.c. injection;
doses than those
similar
by continuous
effects
i.v.
is given
however,
these effects
found here because
the
may occur
bioavailability
at higher
of the
These
of therapy
The data
chemotherapy
data
imply
that
an optimal
following
ilar to that
investigational
(regramostim)
of patients
by others,
(1, 3, 4). Our
of filgrastim
to increase
of the
(2).
We have
Alternatively,
an earlier
dis-
following
which
have
high-dose
identified
between
the apparent
clearance
of filgrastim
in patients
with chronic
neutropenia
(2) or
chemotherapy
the disposition
would
continue
schedule
of therapy
at low
occurs,
quite
the
altogether.
from this study
confirm
reports
a direct correlation
and WBC
counts
infusion.
the cytokine
of what
is typically
practiced
today.
more consideration
could
be made
for
continuation
of 15-20
to realize
that all
were determined
when
is incomplete.
opposite
perhaps
uct
data
would
periods
amount
of drug eliminated
by alternate
mechanisms.
Higher
doses may be of use when the desired
WBC count is >1 X 106
cells/mI.
For example,
if a WBC count of 1 X i0 cells/ml
is
desired,
then hematopoietic
elimination
could
be expected
to
as described
infusion
doses
maximize
others
the continuous
receptors.
based
range of values
noted in both adult (5) and pediatric
(3) patients
following
nonablative
chemotherapy;
however,
this methodology will not allow for detailed
investigation
of nonlinear
effects,
with
report
lower
latter
by
reduction
available
in this
during
of G-CSF.
of G-CSF
that
(7, 8).
igIkg/day)
clearance
quantities
clearance
suggests
patients
hematopoietic
of G-CSF
administration
may entail initiation
doses
and titration
upward
as reconstitution
14). Mechanistically,
noted
used
G-CSF
to
the course
(>20
for patients
set.
lead
64 p.g/kg/day.
to be detri-
in three
of fligrastim
developing
is likely
patient
may
receiving
appeared
that
dependent
during
toxicities
doses
limited
in this
maximum
for full
protease
followed
those
severe
suspect
dose
clearance
appears
acute
effects
following
a filgrastim
infusion
on the
WBC concentration
have been described
previously
include
bound,
In addition,
types of
complex
for filgrastim.
The
peripheral
and
cell is thought
(12).
returned
fraction
WBC
that
process
near
G-CSF.
appears
surface
fact
order
clearance
setting
is not
of available
receptors
on several
the G-CSF-receptor
the
fore,
receptors
and/or
responsive
hematopoietic
cells.
The
question
in dose selection
appears
to be the number
of
and their precursors
present,
as well as the capacity
of
surface
binding,
to use only
Metabolic
as
G-CSF
critical
WBCs
to use
potential
be
by
on systemic
would
not
concentrations
between
that
of dose
however,
prescribed
relationship
evidence
in vivo
of filgrastim
therapy
in the posttransplant
by the dose infused
but rather by the number
cells
The
provides
such
a, which
may down-regulate
G-CSF
10). Overall,
these results
suggest
that
G-CSF
binds to cell
WBCs
in vitro. Following
neutropema.
will
efficacy
limited
these
not be routinely
absolute
a similar
shown
are complicated
One
in patients
concentrations
high
have
as seen
drug
with
that
of G-CSF
and
cytokine
coinciding
suggests
(3).
elimination
serum
should
of
degree
The clinical
in some
effects,
factor
(9,
cytokine
sparse
appropriate
to the typically
a dose
is the stimulation
necrosis
expression
mental,
that increasing
filgrastim
dose
not seem to significantly
improve
whereas
for these
evidence,
the
increasing
This
ABMT.
Pharmacokinetic
in the present
study, alludes
blood
hematopoiesis
explanation
this
relatively
in disposition
perhaps
thus
However,
in regard
chemotherapy
of chemotherapy-induced
or other
CSFs
following
such as that provided
to potential
tumor
ceptor
high-dose
the severity
hematopoietic
speed
published
filgrastim
information,
bone
than
both bein Fig. 3.
data
should
concentrations,
of therapy,
as demonstrated
These
escalating
G-CSF
DISCUSSION
have
delivery
of the ligand;
at high
greater
(1)
was evident
as shown
influence
of fllgrastim
concentrations
to decrease
humans
of the latter
of the potential
clearance
Doses
and
some
due to s.c. drug
metabolic
at low
Thus,
of G-CSF
of filgrastim
reconstitution,
(16)
however,
of knowledge
steadily
with
animals
absorption
that
Model
elimination
Dose-related
clearance
and after hematopoietic
fore
relationship;
models;
process.
per (cells
WBC
then
P =
relationship
is a zero-order
cells/mI,
case,
= 0.05,
improved
to model
of K0 = 54 ng/h/kg
106
point.
the data
patient
of G-CSF
1 X
ng/kg/h
is 54
0 yielded
Including
data
sigmoidal
evaluated
approach
(Eq. C) proposes
with WBC count
relationship
previously
recombinant
in patients
that
to describing
that the clearance
and thus is dissimwas
postulated
the pharmacokinetics
granulocyte
treated
macrophage
with
exactly
by
of an
CSF
prod-
the
same
Clinical
high-dose
namic
noted
chemotherapy
regimen
effect between
on that trial;
WBCs
however,
(17).
A similar
dysfunction
during
cytokine
administration
fusion
displayed
reduced
drug clearance.
We
apparent
treated
study
lack
with
of such
receptor
or
concentrations
patients
who
Further
of
studies
secondary
cytokine
should
renal
of
higher
regramostim.
of the cytokines
In
to detect
contrast,
relationship
between
to optimize
and toxicity
dosage
while
Sensitive
results
release
also
dysfunction
is possignificant
granulocyte
between
and specific
obtained
by
filgrastim
regimens
maximizing
and toxic
Clinical
clearance
of fllgrastim
therapeutic
con-
WBCs,
and
bioassays
should
ELISA.
The role
in the therapeutic
be considered.
should
clearance,
effects
utilization
and
WBCs
be
of
of
of the
may
by minimizing
response.
help
cost
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