Vol.
3. 891-899.
June
1997
Cumulative
Every
Clinical
Pharmacokinetic
Three
Weeks,
Colorectal
Cancer
Erick
Anne
Gamelin,2
R#{233}myDelva,
Combined
Annick
Esteban
Jacques
Robert,
Francis
(+91
Ana#{239}sKrikorian,
Centre
Hospitalier
in
and
Pierre
Allain
Universitaire,
49000
The
patterns
curves
rapidly
mum,
cycle
versus
and its half-life
were
(P < 106)
platinum
22 in the
Angers
22 of the third
0.000018),
=
of RBCs.
cantly
of UC
very
day
there
and
similar
at all sampling
total
and
times.
of the first
22
was equivalent
to
platinum
con-
correlated
The
signifi-
mean
UC:total
ratio was 15% at day 1 and 5% at days 8, 15, and
3-week
treatment
course.
Unlike
cisplatin,
which
accumulates
in plasma
oxaliplatin
accumulate
IA. L. B.. A. T.. A. C.. P. Al: Department
of Medical
Oncology.
Centre
Hospitalier
Universitaire
Paul Brousse,
94800
Villejuif
IE. C.]:
Laboratory
of Biochemistry
and Pharmacology.
Institut
Bergonnie.
33076
Bordeaux
[J. RI: and Debiopharni
France,
94220
Charenton
Le Pont
P
centration
Cvitkovic,
Larra,
% at day
that
Department
of Medical Oncology
and Clinical Pharmacology.
Centre
Paul Papin. Centre Regional de Lutte Contre Ic Cancer, 49033
Angers
Cedex lE. G.. M. B-C.. R. D.. F. LI: Laboratory
of
Pharmacology.
Administered
5-Fluorouracil
cycle,
Turcant,
Cailleux,
Brienza,
with
Boull,
Alain
Silvano
of Oxaliplatin,
891
Research
Patients’
Le
Mich#{232}le Boisdron-Celle,
Study
Cancer
does
in RBCs,
after
recommended
dose
tration
3 weeks).
(every
as both
free
not accumulate
( 130
and
repeated
cycles
mg/rn2)
bound
in plasma,
and
plat-
but it does
at the
schedule
currently
of adminis-
IA. K.. S. B.l. France
INTRODUCTION
Oxaliplatin
ABSTRACT
The cumulative
pharmacokinetic
a new
diamminecyclohexane
ied in patients
with metastatic
was administered
3 weeks,
total
by i.v. infusion
and
5-fluorouracil
tered weekly.
plasma-mass
pattern
platinum
colorectal
(130
and
of oxaliplatin,
derivative,
cancer.
plasma
and ultracentrifugable
(UC)
and
were
adminis-
neurotoxicity.
netics.
tration
other,
3201
ment.
The
We
(161
609
±
Cmax
remained
mean
found
total
for the
mum
platinum
concen-
four
accumulated
levels
throughout
half-life
of total
but we observed
first
cycles
significantly
to an(day
a rapid decrease
(day 8,
total and UC platinum
unchanged
platinum
residual
± 45 rig/liter),
lation
.Lgfliter) and
of both
99 jig/liter).
in plasma
days.
The
curves
were
quite similar
from one course
with a high peak value 2 h after administration
1, Cm,,x
443 ±
levels
courses.
the treat-
in plasma
platinum
no significant
(P
was
on day
accumu-
In contrast,
0.57).
in RBCs
after
9
22
three
courses
(6).
cumulative
tection
of any
therapy,
the
sensitivity
Maine
tion
2/24/97:
accepted
3/5/97.
of this article
were defrayed
in part by the
This article
must thereftre
be hereby
marked
with
I 8 U.S.C.
Section
1734 solely
to
in part by Debiopharm
France.
S.A.. Charenacknowledge
the Coniit#{233}D#{233}parteniental de
et Loire de Ia Ligue
Nationale
Contre
for their
financial
support.
at the 87th
Annual
Meeting
of the AACR,
Washington.
DC.
2
To
(33)41
Langlois
whom
3527(8):
This
Ic Cancer
work
was
held
weeks
Fax:
for
reprints
(33)41
4831
should
90.
be
They
after
after
cisplatin
(5).
The parent
adminisdependent
for the de-
iterative
courses
of
pharmacokinetics
ap-
used.
more
(10-13).
the long-term
total
out regarding
the longafter administration
of
hampered
A
sensitive
cisplatin
of
total
Thus.
with
platin
technique
(7-9).
more
iterative
levels
were
analytical
us to establish
significant
due
UC
administration.
showing
(6).
in
of
atomic
technique.
technique
pharmacokinetics
platinum
lack
was
recent
This
administrations
and
to the
which
We
plasma.
that
has
of plat-
detected
up
to
a progressive
and the Fondapresented
in April
in part
1996 in
The abbreviations
used are: ICPMS.
spectrometry:
UC. ultracentrifugable:
globin:
Cl-C6.
course
I-course
6.
:i
requests
is much
allowed
mum
drugs.
the
and
to patients
interest.
spectrometry
ICPMS.3
oxali
and
pharmacoki-
neurotoxicity
oxaliplatin.
studies
have been carried
of free and bound platinum
of
absorption
Received
8/5/96:
revised
The costs of publication
payment
of page charges.
advertise,neiii
in accordance
indicate
this fact.
I This
work was sponsored
ton Le Pont.
France.
We
the early
occurring
of
lower
reversible
of ultrafiltrable
administration
as does
accumulation
organoplatinum
and
intensity.
is consistently
a peripheral
dose,
to be of major
dysesthesia
upper
kinetics
remain
unknown.
in plasma
with repeated
evaluation
Previous
behavior
doses
sensitive
or
the
incidence.
concerned
oxaliplatin
and it induces
on the
in
elimination
platinum
accumulates
of cisplatin
peripheral
and
and
results
that
paresthesia
area
and
a single
but the long-term
drug. cisplatin.
peared
acral
treatments
preliminary
after
acute
increases
repeated
distribution.
trations
induces
by
paresthesia
with
platinum
term
Oxaliplatin
from
at the recommended
laryngo-pharyngeal
Acral
Some
plat-
profile
of nephrotoxicity
characterized
duration
them
toxicity
(2).
the
limbs.
(4).
six or more
schedule
affecting
levels on day 1, at 0, 2, and S h, and on days 8, 15, and 22.
Sixteen
patients
underwent
three or more courses,
and six of
underwent
Its
it is devoid
and
platinum
complex
is different
( 1-3).
2 h every
RBC
platinuni
cers
because
A very sensitive
method,
inductively
coupled
spectrometry,
allowed
for the determination
of
cyclohexane
tumor
types. especially
in some
diseases
such as colorectal
can-
over
mg/m2)
leucovorin
was studOxaliplatin
is a diammine
that is active
in several
solid
cisplatin/carboplatin
refractory
addressed.
Phone:
inductively
coupled
5-FU.
5-fluorouracil:
plasma-mass
Hh. hemo-
Downloaded from clincancerres.aacrjournals.org on June 15, 2017. © 1997 American Association for Cancer
Research.
3
892
Oxaliplatin
in Colorectal
accumulation
iterative
Cancer
of both
total
and
UC
platinums
We
have
applied
pharmacokinetics
little
plasma,
oxaliplatin
metabolized
after
this
after
Actually.
is
technique
several
known
about
oxaloacetate
in dach-platinuni.
Other
derivative
and
the
a good
14). The
response
exist,
publications
activity
have
between
was
proteins.
and
with
by determining
does
not influence
carboplatin.
the
total
Fullerton.
UC
Merck)
concentraoxaliplatin
that
a peristaltic
it is poorly
is completely
The
bound
different
from
that
platinum.
of
between-day
oxaliplatin.
total.
AND
Patients.
metastatic
of the
colorectal
leucovorin
patients
cancer
that
combination.
brain
cardiac
metastasis.
condition
except
.73
no sign of ascitis
Treatment.
eter
was
as
with
venous
or by
of an
infusion.
oxaliplatin
infusion
infusion
in
operated
pump.
I
liter
of
The
for each
patient.
a table
of 5-FU
dose
istered
at 2(X)
5-FU
mg/m2
tional
doses.
required.
were
continued
either
repeated
weekly.
according
iv.
and
device.
5%
was
given
patients
by means
ml of sterile
5-FU
adjustment
All
chamber
3 weeks.
>65
function
of oxaliplatin
acid.
had
of a cathOxaliplatin
glucose
solution
administered
after
by means
of an 8-h
to 5-FU
administered
in association
and
symptomatic
treatments
treatments
at the same
and
8.39
the
spec-
levels
were
containing
Eu-
internal
standard.
centrifuged
was
subsequently
from
was
RBC
with
for 3 h at
Instruments,
diluted
10-
I g/liter
platinum
solution
(Titrisol;
diluted
solutions
in a saline
g/liter
NaCI.
The
chamber
of the
ICPMS,
Gilson.
linear
between
were
0 and
close
5000
jig/liter
to 100C/c. The
of variation
platinum.
were
The
lower
estimated
of
withinthan
limit
and
for
2C/c
of quantifi-
I jig/liter.
the conditions
at
ranged
from
I to
levels
volume
and
of this
study.
1 jig/liter
in RBC
as jig/g
the
limit
in plasma.
5000
The
of
quantifica-
sample
concen-
jig/liter.
were
expressed
both
as jig/liter
of
of Hb.
RESULTS
Patient
eluded
Characteristics.
in the
patient
study
refused
could
plasma
one
patient
3-12).
courses
3-week
two
interval
of
intervals
(85k).
weeks.
Treatment
and
and
64
of
and to
and
reasons
not related
vals
delayed
43
(two
was
for
courses),
two
had 7 courses,
12 courses.
administered.
maintained
were
The
in 58 of 68
no
longer
surgery
to toxicity
4
patients
(six
The
courses),
days
(2
(I course),
(3 courses).
28
108
than
in nine
myelosuppression
(2 courses),
and
number
3 courses,
had
10 courses
were
patients
(mean
underwent
(2 courses).
courses
One
patient
intervals
toxicity
acid was admin(0 h) and at 4 h
course),
68
in-
1995.
Sixteen
were
delayed
convenience
between
one
courses
was
due to gastrointestinal
other
of them
oxaliplatin
between
were
April
treatment
had 6 courses,
I I courses.
patients
and
inclusion.
their
Eight
4 courses.
had
1994
after
throughout
5; range,
two underwent
June
assays
be investigated
of cycles.
Seventeen
between
personal
assays
an
(Beckman
nebulization
courses),
plasma
(15.
Folinic
bolus just before
platinum
was
performed
recoveries
Eighty-five
serum
through
a battery1300 mg/m2
was adjusted
ondansetron,
Sampling.
2.
a
patients
clearance,
hepatic
folinic
0.9%
saline
initial dose of
Previous
infusion.
I, 0.
and
in 250
by
was
Other
Blood
day
normal
and
All
(creatinine
had
criteria
months.
The
(one
inter-
36
(one
course,
for
surgery).
antiemetics.
ever
platin
treatment.
old.
as
performed
Corp.).
100.2
diluted
pump
Platinum
cell
was
estimated
trations
and
infusion.
Oxaliplatin
lactic
5-FU
implantable
and
weekly
after
of <3
was
informed
Noninclusion
established
every
5-FU
written
survival
function
5-FU
at I 30 mg/m2
a 2-h
function.
them
access,
means
given
of
to the
gave
or pleural
effusion.
Chemotherapy
consisted
in combination
long-term
renal
All
refractory
tion
proven.
18 and less than 70 years
WHO
criteria)
was required.
contraindicating
m2).
histologically
patients
expected
two had normal
ml/min/l
had
was
All
consent
and were more than
Perfcrmance
status
<
III (by
well as normal
bone
marrow
were
was
two
prep-
solution.
into
and
Under
METHODS
All
supernatant
coefficients
UC.
RBC
100
TLA
(Sigma).
The
cation
PATIENTS
The
method
to
and
the plasma
rotor
contained
using
(Perkin-Elmer
g/liter).
calibration
introduced
5000
was
( 10).
Co.:
solution
were
previously
Cheniical
CA).
The
standard
described
in a solution
assay.
into
further
assay.
dilution
using
tubes.
at 4#{176}C.
split
quantification
in plasma
fold in the Europium
the
was
without
a 20-fold
platinum
rpm
plasma
assay.
platinum
an Elan
platinum
UC
(3,
and
was
after
100,000
and
Platinum
method
used
in heparinized
by centrifugation
platinum
for the UC
ICPMS
collected
separated
stored,
Assay.
(Sigma
the pharmacokinet-
Moreover,
its metabolism
For
drugs
cancer
one
Total
shown
to characterize
were
were
for the total
and
measured
that
plus
both
colorectal
study
of oxaliplatin.
and
aration,
trometer
but they
colorectal
cancer
with oxaliplatin
in 5-FU-resistant
It also
of cisplatin
2 h
They
pellets
one
Platinum
platinum
and other
platinuni
levels,
as well as RBC platinum
We can assume
that 5-FU does not modify
pharmacokinetics.
ics
In
is quickly
used measure
of oxaliplatin
some
of the present
retention
was immediately
ropium
clinical
rate
infusion.
The plasma
aliquots.
is detectable
probably
currently
study
because
synergistic
objective
long-term
plasma
tions.
and
oxaliplatin
Globular
mnetabolites.
oxaliplatin
nietabolites
of platinum
metabolites.
leucovorin,
previously
and
upon
of oxaliplatin.
residue
The patients
presented
with advanced
resistant
to 5-FU. They were treated
5-FU
study
oxaliplatin
No
are not known.
The techniques
and do not permit
the separate
platinum
to the
administrations
loosens
administration.
was
occurred
infusions.
were
for
allowed
concomitant
each
collection
times
5 h:
8,
when-
seven
cases
cycles):
cycle.
on the basis
and
day
blood
22,
of oxali-
samples
befare
were:
the
next
and
after
drug-related
(b)
a quite
and
(d)
3 cycles
toxicity
tract
()
cycles);
was stopped
(three
gastrointestinal
conditions
icity);
of 5-ml
15.
The treatment
prophy-
at conven-
dose.
For
days
with
corticosteroids
toxicity.
stable
patient
disease
due
to: (a) tumor
and
four
in four
after
cases
treatment
refusal
in
12
(cardiac
myelosuppression,
in two
progression
4. 6. 7. and
and
cases
in two
(after
cases.
toxicity.
skin
tox-
8 and
after
4 courses.
All
oxaliplatin
treatments
were
administered
at the recom-
Downloaded from clincancerres.aacrjournals.org on June 15, 2017. © 1997 American Association for Cancer
Research.
11
3
Clinical
Table
I
Incidence
of toxic
events
in the
First
population
3 months
of patients
treatment.
neuropathy
first
three
courses
and
Whole
III
5
4
5
5
7
1
6
9
I0
I
6
3
Leukopenia
5
1
Thrombopenia
0
3
throughout
grade
II
Toxicity
Mucositis
Diarrhea
Peripheral
Anemia
WHO
for the
0
the
Cancer
whole
treatment.
Research
893
treatment
WHO
grade
II
Ill
8
7
1
1
0
6
4
4500
1475±933
(n
4)
4000
3526113117
3500
3349±796
(n
3201±60
3000
r
3095+542
(n=l6)9
(n-
(n
0
2619±805
2500
(n
t’187
2)
(ii
6)
2664i365
2503/625
8)
2316i343
2316±463
2267±276
3276
2914±571
l6)
C
C
a)
-
3287±424
6)
(ii
16)
=
C)
C
8
2000
C
1500
.
0.
1000
7311± 125
2142±229
2108±227
500
242±64
.
0
0
Fig. I
a slow
Mean
total platinum
of residual
dose
median
of
to WHO
occurred
1104i31
concentrations
dose
was
and
60
in plasma.
observed
given
from
as a 2-h
of oxaliplatin
was
events,
evaluated
criteria,
during
before
are displayed
this
had a toxidermia.
and the toxic
Total
Platinum
els of total
characterized
trial.
S h were
70%
and those
measured
of the peak
course)
plasma
were
value,
levels
still
after
seventh
The
(range,
The
a rapid
decrease.
of platinum
It should
after
. No
toxic
with
5-FU
the treatment
was
mean
1ev-
days
100
course
12(1
plasma
courses
are
the end of
plasma
measured
levels
after
were
I 5. 7, and
be noticed
that
2 h,
3%
signif-
after
the first
significantly
(range.
administration.
The
mean terminal
half-life
of total platinum
in plasma
determined
from three points,
measured
on days 8, 15, and 22, was 9 ± 0.7
l(l)
throughout
8.42-9.66;
reproducibility
eight
and
long
ISO
courses.
Only
22,
a trend
toward
illustrate
the
and
the
significantly
a trend
toward
the
residual
first
levels
the difference
sampling
compared
times
half-life
between
courses
increase
of
not
were
curve
third
jig/liter).
52
illustrate
In
these
the
cases.
a
was observed
on
15 days.
sampling
times
(Fig.
I and Table
residual
and
0.13)
did
levels
(+SOC/d.
(P
<
in-
observed
slope
10
of the
However,
).
when
when
not
3). Only
was
The
significant
together
(P
29
slope
was 0.71
statistically
taken
the
course
28 (six
and 108 (one
jig/liter
(range.
results
plasma.
was
at early
regression
with
in
levels
a slow
on days
94-I
These
concentration
to the seventh
was
performed
(range.
platinum
terminal
platinum
administrations.
(one patient).
levels:
183
jig/liter
of
results
iterative
respectively.
of the platinum
Total
These
samplings
109
13 jig/liter.
retention
breakdown
from
late
jig/liter).
I I 1-272
crease
2).
after
36 (four
patients).
58
showed
residual
platinum
jig/liter.
very
Table
of the kinetics
12 patients.
patients).
patient)
was
141)
( + 50’4).
days
day
( 16 1 ± 45 jig/liter
22 days
cycle
after a treatment.
came.
Another
The
of the levels
new
I
presented
8, 1 5, and 22 days
respectively.
measured
each
presented
in Fig. I . All
peak value
at 2 h after
by
after
icant
Characteristics.
followed
measured
225±22
did not increase
to the
mg/m2
in Table
A patient
In these two cases,
event disappeared.
platinum
are
by a high
administration,
first
infusion.
520
related acute angina pectoris
at home, the night
It spontaneously
resolved
before
the physician
patient
stopped.
80
Concentrations
the
364±61
302t31l
2011±13
For
260-1560
mg/m2).
Toxicity.
Toxic
death
302±46
187±31
40
levels
I 30 mg/m2
cumulative
according
310±43
161±45
20
increase
mended
266±34
all of the
the
first
or the fourth
(P
course
0.57)
course.
Pharmacokinetics
UC
platinum
plasma
of UC
concentration
Platinum.
curves
The
pattern
is similar
to
of
the
that
of
Downloaded from clincancerres.aacrjournals.org on June 15, 2017. © 1997 American Association for Cancer
Research.
894
Oxaliplatin
in Colorectal
Table
2
throughout
Cancer
platinum
Mean
the treatment.
half-lives
Mean
in plasma
platinum
(total
half-life
and
in RBCs
UC
platinum)
was almost
and
in RBCs
equivalent
Course
I
Total
platinum
8.4
± 1.1
6.8 ± 2
UC platinum
RBC platinum
Table
50
Comparison
accumulate
3
8.4
6.4
10
±
46.6
of platinum
in plasma.
3
± 1.31
± I
8.7
7.2
concentrations
and neither
9.7
9.3
9.5
6.8
6.5
RBC
NS”
NS
-5%
NS
very
stable
might
be covalent.
P
7
9.4
± 0.5
± 0.8
8
± 0.7
8.5
± 0.5
8.5
vs. the first course.
and rapidly
increased
Total platinum
in RBCs.
vs. Cl
C6
UP
were
6
0.94
±
RBCs
at the third and sixth courses
In contrast.
platinum
significantly
TP
did
not
C6 vs. C3
TP
UP
+73%
<0.01
+I2/c
NS
NS
-24%
NS
+57%
<0.01
+17%
<0.05
+18%
<0.05
20%
NS
+ 107%
+27%
<0.01
+40%
+96%
<0.01
+16C/
+21%
time
Half-lives
that the binding
5
± 0.47
C3 vs. Cl
Sampling
courses.
suggesting
(days)
8
in plasma
and
UC platinutii.
did
successive
4
± 0.78
± 0.7
± 14
45.5
II
±
for
to that of RBCs.
TP
UP
+13%
-1%
NS
NS
-6%
+24%
+27%
-
<0.01
-
+50%
+20%
+17%
<0.01
NS
2h
(7( change
P
5h
change
(/(
P
8 days
(4 change
P
15 days
C/
change
P
22 days
%change
-
‘,
total
not
‘
(Fig. 2). Early
administration
mum
the treatment
did
not
until
levels
22 days
after
pling
Table
3). although
in plasma
(Table
platinum
(10
every
course
(Fig.
different
statistically
± 0.7 days;
UC
of
at 2 and 5 h
by a rapid
elimination
half-lives
were someplatinum
ones and did not change
(7.15
accumulate
significant
+91%
<0.01
NS
high peaks appeared
and were followed
decrease.
The UC platinum
what shorter
than the total
throughout
between
the
jig/liter)
plat-
small
but
were
2). The
courses.
2). UC
values
were
whatever
not
the
plasma
with
total
versus
total
platinum
was
r
courses
and
two
and
5 h).
coefficient
less
(days
than
in RBCs
(Fig.
4).
bOo
was
infusion
and
reached
sam-
levels
r
0.69
=
>
platinum
(P <
levels
in
a maximal
declined
slowly
(Fig.
after
the
course.
the
r
RBCs
value
4). Compared
levels
each
at the
was
I 5%.
l06;
Fig.
increased
at 2 and
samthe
platinum
with
the
for
platinum
platinum
RBCs.
day
Thus,
Hb,
15 than
from
was
and
platinum
meas-
observed
a progressive
treatment
course:
5 h; afterward,
to the values
third
obtained
cycles
.Lg/g
day
(values
were
Hb;
Hb; on day
22,
3.92
±
In
three
the
platinum
with
the
It did
instances,
variations
it
of
RBC
for three
patients,
from day 8 to day
RBC
ratios
in
always
lower
day
15: 4.82
C2,
±
6.2
jig/g
and
C3,
Hb,
day
±
1.23,
7.02,
1.43,
on
accumulation
Thus,
and
and
I 5 than
from
±
in
lower
we calculated
on
1.51,
±
always
a progressive
I, 2 h, 7.4
8, 4.91
concentrations
were
course.
accumulation
0.77,
are for Cl,
The
calculated
Hb because,
unexpectedly
treatment
on day
on
2).
8. We observed
was
jig/g
between
concentrations
ratios
14.28
a link
to the third
numlHb
during
(Table
platinum/Mb
3).
rapidly
course
calculated
on day
RBC
in RBCs,
those
of
increased
these
the first
of the
rise of Hb level occurred
at the same time.
the trapping
and the increase
of platinum
in
Fig.
of treatment
and
we
and
one-half
in this compartment.
8, 15, and 22, was 48 ± 10.5 days.
levels
and
RBC levels
15. A spontaneous
which could explain
reaching
22, the residual
represented
storage
half-life
on days
afterward,
22. On day
in RBCs
terminal
change
higher
on day
a long
reached
70 days.
We looked
3).
strikingly
levels
indicating
concentrations
jig/g
the
were
concentrations
platinum
plasma
5%,
they
of plasma
values,
mean
and the
For
but
8 10 ± 40%
platinum
courses
second
the
course,
For early
1,000 jig/liter,
0.65 (P < l06;
in RBCs.
Platinum
three
of UC
of correla-
=
over
cor-
throughout
the percentage
patients
they
first
ratio
within
be observed.
total
jig/liter,
for eight
Platinum
mean
8. 15, and 22) and for total
coefficient
of correlation
was
Platinum
Accumulation
ured
time
platinum
versus
of correlation
strongly
the coefficient
sampling
could
with
The
and
It did not change
the
of UC
late samplings
and
l06).
<
with
closely
levels.
7.7%,
patterns
percentage
levels
(P
changed
were
plasma
was
different
(2
mean
levels
platinum
0.94
=
but
plings
tively),
not
platinum
related
tion
were significantly
higher
(Fig. 4 and Table
3). For the first
cycle, platinum
levels in RBCs were close to the total platinum
values
on day 1, 2 and S h (83 ± 12 and 130 ± 9%. respec-
peak
measured
time.
UC
NS
-
significant.
platinum
oxaliplatin
after
NS
NS
P
<0.01
the first
1.67,
8.43
and
7.14
on
10.4
±
these
plati-
day
8. We
to the third
± 2.11,
1.98,
8.8
jig/g
±
and
Hb:
0.64
respectively).
Downloaded from clincancerres.aacrjournals.org on June 15, 2017. © 1997 American Association for Cancer
Research.
and
10.78
and
jig/g
on
Hb
Clinical
Cancer
Research
895
700
600
500
.
C
0
Mean
UC platinum
concentrations
in plasma
throughout
seven
courses.
UC platinum
did
not accumulate,
although
small
but significant
levels of UC platinuni were measured
until 22 days
after every course.
Fig.
2
400
C
C)
C)
C
I
.
300
200
100
0
0
20
40
60
80
00
20
4(1
days
900
I 0(1
800
01)
81)
700
71)
600
C
0
a
60
500
C
C)
C)
C)
C
0
C)
‘iou
50
0
U
.
300
40
E
C
a
.
30
0
200
L)
20
I 00
I0
0
3800
3300
total
2800
platinum
2300
concentration
0
1800
800
6(1(1
( .tgft.)
total
400
I)latinLita
20))
concentration
( (tgi’I.)
Fig. 3
Close
early sampling
platinum
platinum
curve
was
correlation
between UC and total platinum concentrations
in plasma (346 samples.
Two different
patterns
could he observed.
A. 6r
times (2 and 5 h) and high total platinum levels (>1000 ig/1iter), the coefficient
of correlation
r was 0.69, P < 10 “. the ratio UC:total
in plasma
was 15%. and the coefficient
of the linear regression
curve was 0. 1 1 . B. for late sampling
times (days 8. I 5. and 22) and low
levels (< 1000 jig/liter).
the coefficient
of correlation
r was 0.65, P < l06.
the ratio was 5%. and the coefficient
of the linear regression
0.048.
At late sampling
levels
lated
were higher
significantly
on day 8, r
0.67
10
6;
platinum.
Fig.
5).
This
=
The
times
(days
8, 15 and
22),
RBC
platinum
Likewise,
total plasma
platinum
levels but correthem (coefficients
of correlation:
r =
were
either
these
two
0.75
on day
separate
same
relationship
15, and r
observation
was
could
not
found
0.55
on day 22,
be made
for
the
P <
with
early
UC
mI/mm).
platinum
above,
two patients
had a renal
by a low creatinine
clearance
At all of the sampling
levels
were 20-40%
their
sam-
plings.
As mentioned
baseline
characterized
UC
than
with
function
(26 and
at
32
times,
their total and RBC
higher
than the whole
group.
platinum
higher
patients
had
statistical
exclusion
We looked
levels
or very
in these
close
a different
analysis
patients
to those
compared
pharmacokinetic
the different
and showed
no difference
(data
for a link between
accumulation
RBCs and anemia
incidence.
RBC levels
who experienced
subsequent
anemia
(ii
the mean levels between
the two groups
8 (P
after
=
0.015),
the first
on day
day
15 (P
administration
=
0.05),
on day
I . 5 h.
1 . 2 h. Because
behavior,
courses
a
after
not shown).
of platinum
in
were higher in patients
4). The differences
of
were significant
at day
and day 22. 2 h (P
=
0.014).
of oxaliplatin.
Downloaded from clincancerres.aacrjournals.org on June 15, 2017. © 1997 American Association for Cancer
Research.
896
Oxaliplatin
in Colorectal
Cancer
5000
4500
4000
;0.
3500
C
0
3000
.
Fig.
C
C)
Mean platinum
throughout
three
4
RBCs
2500
U
E
2000
.
concentration
in
courses.
Platinum
levels
increased
rapidly
after infusion
and
reached
a niaximal
value
at 2 and 5 h:
afterward,
they declined
slowly.
and, thus.
a progressive
accumulation
could
be ob-
ca
0.
served.
Ld
1500
1000
500
0
0
10
20
30
40
days
A
50
60
70
B
21)00
I600
1800
.
1400
1600
.
C
.
.
#{149}.
.
.
1200
C
I 400
0
0
a
1000
1200
C
C)
C
C)
.
C
U
..
.
.
...
.
1000
.
C
0
800
0
U
E
U
E
800
.
600
C
.
.
C
ca
600
.
0.
0.
.
400
400
200
200
0
4300
3800
total
Fig.
was
5 Correlation
high for late
3300
platinum
between
sampling
2800
2300
concentration
RBCs
times:
r
1800
800
total
(iWI)
and total
0.65.
platinum
P <
10
in plasma
(120 samples).
A. there
.
and the linear
regression
curve
DISCUSSION
Some
preliminary
oxaliplatin
ever.
have
no
ICPMS
data
been
were
allowed
concentrations
been
five
ously
per
have
to
study
administered,
Toxicity
with
total.
this
its
UC,
of
drugs
with
was
type
consistent
of
pharmacokinetics
a single
courses
organoplatinum
been
patient.
reported
after
early
regarding
successive
for other
cycles
cycles
us
on
reported
available
for
done
results
600
association
course
(5).
long-term
and
of
RBC
(6,
as
10-13).
a median
with
(I.
had
Eighty-
number
of 5
remained
whereas
neurotoxicity
The
the
data
2).
Myelosup-
previ-
was
unchanged.
sisted
until
mucositis
residual
the beginning
terminal
and
related
of total
Significant
increasing
a significant
sampling
and
The
courses.
at early
concentration
treatment,
half-life
These
of total
accumulation
times.
resulted
curves
the
B. the
correlation
from
5-FU,
to oxaliplatin.
were
terminal
levels
results,
platinum,
if the
very
half-lives
platinum
of the following
trend.
platinum
0
(.tg/L)
moderate,
the
eight
longed
concentration
platinum
slightly
200
was no correlation
was 1(8)9.
throughout
platinum
chemotherapy,
platinum
pression
How-
retention.
400
of
similar
remained
were
constant
over
total
platinum
per-
course
and
combined
may
interval
showed
with
cause
us to fear
between
Downloaded from clincancerres.aacrjournals.org on June 15, 2017. © 1997 American Association for Cancer
Research.
a
a pro-
two
Clinical
courses
is reduced
the incidence
If we
cisplatin
the
of
after
clear
shown
and
significant
courses
(6).
cance.
This
difference
a difference
used
an ultracentrifugation
concentrations
platinum
was
after
does
not
account
the binding
or peptides,
(21).
the
involve
this
technique
assessment
ological
study
was
and
22 plasma
closely
did
although
oxaliplatin
administration
of four
method
fourth
in plasma
had
for the detection
of small
tions
mechanisms
(16).
Two
cumulation
of free
ultrafiltrable
following
These
results
could
oxaliplatin
mulative
nephrotoxicity
tion,
in deep
cokinetics
( I 2,
is
linked
chronic
absence
with
limit
in free
that
the
and
free
in part,
cisplatin,
27).
long-standing
(12,
of
storage
and
26-30).
in plasma
did
not
and
with
ours
binds
and
5%
has
first
protein
as
sulfliy-
(30,
39,
molecular
after
with
2 h after
such
globulins,
affinity
suggest
first
to several
glutathione
hand,
high
the
to high
albumin,
only
for
thiols
and
other
had
bind
proteins
long-term
rapid.
and
low
transferrin
weight
that,
oxaliplatin
after
with
both
high
later
with
high
admin-
molecular
molecular
40).
weight
carboplatin
weight
proteins
and
(40).
adminis-
low
molecular
molecular
than
than
the plasma
weight
22
might
plasma
levels
levels
and
decreased
markedly
The
difference
57-107%)
was
a
uptake
much
became
more
higher
Consequently,
from
between
highly
underwent
platinum
subsequently
in the late samplings.
increased
on days
one
cycle
RBC
course
I and
significant
for
arguments
binds with
an increase
were
higher
three
ondary
to
cycle
all
the
3 (an
sampling
uptake
total
22, RBC
and
suggest
UC
that
RBC platinum
beplasma
platinum.
platinum
levels
platinum
Hb,
than
on
because
day
15.
The
the terminal
the
major
binding
it reached
70 days,
after
a first
which
a
protein
may
in
in its storage.
levels on day
of platinum
half-life
to that of RBCs, as determined
techniques,
which is about
by RBCs
show
in plasma.
platinum
and plays a major role
of Hb occurred,
RBC platinum
be covalent
instances,
at early times,
UC and bound
8, 15, and
with
RBCs was similar
phosphate
labeling
the
RBC
platinum
in
correlation
Some
pharma-
explain
platinum
The
Our results
show that
independently
from
strong
distribu-
months
that
in RBCs.
times.
However,
cu-
RBC
those
of
we showed
process
The
slowly
species
(6).
study,
retention
haved
irreversible
could
only
platinum
platinum
In contrast,
was
No study
I to day 22 (6, 33.
bind
weight
affinity
as
the
weight
RBC,
When
several
On
tration,
a close
long-term
cisplatin
such
40).
results
increase
ac-
one
A quick
for
and
These
to clear
long-term
neurotoxicity
13, 17, 23,
accumulation
concentra-
free
to
sampling
and
day
that
molecular
a high
kDa)
38,
platinum
thiols
of toxicity
the
33,
one.
total
according
at early
patients,
could
methionine,
with
(>25
9,
previously
cysteine,
following
the
the
characterize
(6,
or
varied
from
platinum
low
it binds
did not allow
ability
(23-25).
slow
groups,
levels
the differences
especially
and a very
This
including
platinum
(22)
levels
of UC platinum
administration.
period,
shown
species,
determination
progressive
platinum,
accumulation
been
administration,
In the present
after
reported
platinum
(9, 3 1,
proteins.
administered
platinum
courses
compartments
of oxaliplatin
was
the
It has
persisted
22 days
the sampling
cisplatin
was
explain
of cisplatin
nephrotoxicity
until
a reduced
1 3, 26,
remained
administration
detection
accumulation,
retention
and
either
and
a progressive
levels
repeated
explain,
iterative
of UC platinum
cisplatin
could
total
after
than
of free
significant
15%
some
the
lower
half-life
proportion
in
each
than
not sensi-
38).
istration,
0.994).
=
as residual
variations
progressive
between
r
with
between
the
test,
25-30%
other
the
administration
these
influences
were
detect
approximately
22 after
that
the
of a few hours
could
(6). The
It was
even
that
a maximum
we
cycle
8 to day
6% throughout
(8,
were
platinum:
platinum
correlation
comparing
in plasma
study,
a high
laboratory
with
ICPMS,
the
was
to stress
so that
modifications
concluded
cis-
that
administration
or they
level
after
reported
compartments
eliminated
platishowed
this phenomenon
with cisplatin,
for which
the ratio
UC and total platinum
was constant
at approximately
proteins
3 and 4).
after
discrepant
adapted
A method-
techniques
of cisplatin
accumulation
In the
particularly
reaching
reported
between
different
total
platinum
cisplatin
out ex viva,
oxaliplatin
time.
total
It is important
short,
with
after
897
upon
studies
authors
33).
platinum
the whole
day
Later,
platinum.
very
whereas
and
carried
studies
with
Two
most
after
were
detect
These
plasma
dryl
of the two
period
(Figs.
proteins
lipoproteins
4104)
amounts
studies
weight
into
model
accumulate
treatment
con-
(Amicon,
correlation
not
whole
platinum
7, 22).
results
significant
the
Three
be
in our
Cnaax as well
throughout
free
The
of oxaliplatin.
constant,
out
(Pearson
platinum
courses
to
is
for
take
to
throughout
in
32,
either
between
was
34-37),
from
physical
not
low-density
ultrafiltration
samples.
correlated
UC
molecular
with
appeared
carried
does
jig/liter.
times,
was
drug
a
enough
100
9, 29,
system
the sampling
plati-
which
free
as
and
to low
We
superior
low
of non-protein-bound
ultracentrifugation
with
dialysis,
measuring
case
to
and
It appeared
a membrane
be the
be
for studying
techniques
to equilibrium
of drugs
may
and/or
free
tive
platinum
(6). Ultracentrifuga-
other
18-21).
when
binding
drugs.
measuring
ultracentrifugation,
as can
Thus,
for
for
with
(8,
Moreover,
method,
of the two
as we did previously
for reliability
especially
centrations.
cisplatin
(8,
were
reversible
correlated
UC
3 1), but
to proteins
irreversible
constants
in-
(6,
two studies
often
administration.
between
binding
protein
signifi-
proteins
administration
of reference
reproducibility,
and
correlation
platinum
most
are closely
oxaliplatin
administration
of rate
(50%
statistical
platin
UC
residual
is
Research
(4).
levels
after
three
and
lower
of
to plasma
technique
a
been
after
platinum
is much
limit
of distribution
previously
comparable
the technique
levels
platinum
values
a similar
total
has
of total
Cmin
oxaliplatin
cisplatin
and
whereas
num
neurotoxicity
discontinuation
UC
is
(6, 16, 17). We
of total
binding
in plasma,
compared
oxaliplatin
and
was a progressive
of these
the
between
platinum
num
found
at
in the volume
tion
and
Criax
the increase
courses),
UC
in plasma
that there
administration
seven
plasma
administration
in both
oxaliplatin
free
why
difference
of oxaliplatin,
a doubling
In contrast,
main
of platinum
cisplatin
with
due to a different
of
for cisplatin
increase
platinum,
after
increase
of oxaliplatin
the
administrations
repeated
plasma
after
could
pharmacokinetics
accumulation
previously
levels
accumulation
treatment
accumulation
after
have
crease
This
administrations,
iterative
significant
described
the
repeated
absence
quite
15 days.
compare
after
platinum
to
of neurotoxicity.
Cancer
to
of platinum
Hb
in
by radioactive
60 days (41). In
suggest
a see-
release.
Downloaded from clincancerres.aacrjournals.org on June 15, 2017. © 1997 American Association for Cancer
Research.
898
Oxaliplatin
in Colorectal
As
been
for
oxaliplatin,
previously
Carboplatin
very
Cancer
a particular
reported
distribution
fast
so
that
in RBCs
its
concentration-time
those
curves
platinum
reached
high
icantly.
A few
(8.
peaks
9.
45).
binding
release
ination
(45).
of
and
Some
rapid,
Vermorken
RBCs
half-life
of
about
30
days.
terminal
half-life
involved
an
increased
resulting
from
the long-term
ministrations
This
RBCs
kinetics
of platinum
cisplatin
important
might
probable
study
cytotoxicity
of
and
play
understanding
of
the
To
that
this
knowledge.
after
repeated
studied
thus
retention
of
toxic
elim-
of RBCs
our
ad-
far.
platinum
in
manifestations.
be of major
platinum
The
interest
adduct
a
a second
concluded
9).
been
Hb could
that
with
in RBCs
not
found
breakdown
(8,
in some
with
found
They
prolonged
a role
interaction
and
has
9)
for the
formation
and
Although
the
a prospective
goal
platinum
of the
plasma
pharmacodynamic
present
levels
study,
with
cisplatin
(17.
reported
values
with
was
we did
28).
Total
cisplatin
perhaps
has
platinum
small
38).
in our
299-303,
reported
for
as has
been
the number
cohort,
and
of
we could
not elicit
any clear
relationship
between
platinum
levels
plasma
and the neurotoxicity
pattern.
Moreover.
neurotoxicity
occurs
after
a 700
whereas,
in the
oxaliplatin
was
520
Likewise.
incidence
mg/m2
experienced
looked
for
individual
at days
of oxaliplatin,
but
In the present
study,
in plasma
half-life
after
mended
dose
once
accumulates
Ci,,ax5
of total
and
oxaliplatin
throughout
levels
on
dose
day
neurotoxicity
between
again.
after
the
we showed
the
groups
of
that
at
as
UC
platinum
the
treatment,
22.
These
both
free
levels
despite
differences
is consistently
higher
first
F., Bensmaine,
M. A.,
Levi.
F., Misset,
II clinical
using
an
893-900,
J. L., Brienza,
trial
ambulatory
1992.
5. Bastian,
with normal
I 994.
with
5-fluorouracil.
multichannel
the
and
299,
not
long
recom-
cisplatin,
bound
platinum,
remain
might
total
explain
Metzger.
folinic
acid.
programmable
I., Russel,
platinum
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platinum
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S., and
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Cumulative pharmacokinetic study of oxaliplatin, administered
every three weeks, combined with 5-fluorouracil in colorectal
cancer patients.
E Gamelin, A L Bouil, M Boisdron-Celle, et al.
Clin Cancer Res 1997;3:891-899.
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