Cremophor pharmacokinetics in patients receiving 3-, 6-, and 24-hour infusions of paclitaxel.

Abstract

Paclitaxel (Taxol) is a new drug with efficacy against a variety of malignant tumors. The clinical formulation of paclitaxel contains 50% Cremophor EL, a polyethoxylated castor oil vehicle (carrier) that can reverse multidrug resistance (MDR) mediated by P-glycoprotein. Three-hour intravenous infusions of paclitaxel can yield end-of-infusion plasma Cremophor concentrations of 1 microL/mL or more, which are sufficient to reverse MDR in vitro by at least 50%. Despite extensive clinical use, the pharmacokinetics of Cremophor have not been described.
We studied the pharmacokinetics of Cremophor in patients with ovarian cancer who were undergoing treatment with paclitaxel to determine whether plasma Cremophor concentrations achieved during and following 3-, 6-, and 24-hour drug infusions were similar to those shown to modulate MDR in vitro.
Eleven patients with previously treated (i.e., with platinum-containing chemotherapy regimens) ovarian cancer were randomly assigned to receive one 3-hour, one 6-hour, and one 24-hour infusion of paclitaxel in varied sequences during their first three cycles of treatment with this drug. Blood samples were collected both during and following the three infusion periods, and Cremophor concentrations in these samples were measured by use of a bioassay based on the ability of Cremophor in plasma samples to reverse cellular resistance to daunorubicin in vitro.
Ten patients were treated with paclitaxel at a dose level of 175 mg/m2, and one patient was treated at a dose level of 135 mg/m2. At the 175-mg/m2 dose level, peak plasma Cremophor concentrations of 1 microL/mL or more were achieved in eight of 10 patients during both the 3-hour and the 6-hour infusions; with the 24-hour infusion, only one patient achieved a peak plasma Cremophor concentration of 1 microL/mL or more. The eight patients who achieved plasma Cremophor concentrations of 1 microL/mL during the 3-hour infusion were above this level 30 minutes into the infusion; the total time that the plasma concentration was greater than 1 microL/mL was 8.9 +/- 5.0 hours (mean +/- standard deviation; range, 4.1-15.6 hours). For the eight patients who achieved plasma Cremophor concentrations of 1 microL/mL during the 6-hour infusion, the total time that the concentration was greater than 1 microL/mL was 10.2 +/- 9.0 hours (range, 0.3-21.9 hours). The patient who received paclitaxel at a dose of 135 mg/m2 achieved a peak plasma Cremophor concentration of 1 microL/mL or more only during the 3-hour infusion.
Paclitaxel infusions of 3 and 6 hours can result in sustained plasma Cremophor concentrations sufficient for substantial reversal of P-glycoprotein-mediated MDR in vitro. These plasma Cremophor concentrations are not achieved during 24-hour infusions of paclitaxel.

Full text

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REPORTS
Cremophor Pharmaeokinetics
in Patients Receiving 3-, 6-, and
24-Hour Infusions of Paclitaxel
Danny Rischin, Lorraine K.
Webster, Michael J. Millward,
Bernadette M. Linahan, Guy C.
Toner, Anne M. Woollett, Carmel
G. Morton, James F. Bishop*
Background: Paclitaxel (Taxol) is a new
drug with efficacy against a variety of
malignant tumors. The clinical for-
mulation of paclitaxel contains 50%
Cremophor EL, a polyethoxylated cas-
tor oil vehicle (carrier) that can reverse
multidrug resistance (MDR) mediated
by P-glycoprotein. Three-hour intra-
venous infusions of paclitaxel can yield
end-of-infusion plasma
concentrations of 1 (iL/mL or more,
which are sufficient to reverse MDR in
vitro by at least 50%. Despite extensive
clinical use, the pharmaeokinetics of
Cremophor have not been described.
Purpose: We studied the pharmaco-
kinetics of Cremophor in patients with
ovarian cancer who were undergoing
treatment with paclitaxel to determine
whether plasma Cremophor concentra-
tions achieved during and following 3-,
6-, and 24-hour drug infusions were
similar to those shown to modulate
MDR in vitro. Methods: Eleven pa-
tients with previously treated (i.e., with
platinum-containing
regimens) ovarian cancer were ran-
domly assigned to receive one 3-hour,
one 6-hour, and one 24-hour infusion
of paclitaxel in varied sequences during
their first three cycles of treatment
with this drug. Blood samples were col-
lected both during and following the
three infusion periods, and Cremophor
concentrations in these samples were
Cremophor
chemotherapy
measured by use of a bioassay based on
the ability of Cremophor in plasma
samples to reverse cellular resistance to
daunorubicin in vitro. Results: Ten
patients were treated with paclitaxel at
a dose level of 175 mg/m2, and one
patient was treated at a dose level of
135 mg/m2. At the 175-mg/m2 dose
level, peak plasma Cremophor con-
centrations of 1 (iL/mL or more were
achieved in eight of 10 patients during
both the 3-hour and the 6-hour in-
fusions; with the 24-hour infusion, only
one patient achieved a peak plasma
Cremophor concentration of 1 ^L/mL
or more. The eight patients who
achieved plasma Cremophor con-
centrations of 1 (iL/mL during the 3-
hour infusion were above this level 30
minutes into the infusion; the total time
that the plasma concentration was
greater than 1 (iL/mL was 8.9 ± 5.0
hours (mean ± standard deviation;
range, 4.1-15.6 hours). For the eight
patients who achieved plasma Cremo-
phor concentrations of 1 (iL/mL during
the 6-hour infusion, the total time that
the concentration was greater than 1
HL/mL was 10.2 ± 9.0 hours (range,
0.3-21.9 hours). The patient who
received paclitaxel at a dose of 135
mg/m2 achieved a peak plasma Cremo-
phor concentration of 1 (iL/mL or
more only during the 3-hour infusion.
Conclusions: Paclitaxel infusions of 3
and 6 hours can result in sustained
plasma Cremophor concentrations suf-
ficient for substantial reversal of P-
glycoprotein-mediated MDR in vitro.
These plasma Cremophor concentra-
tions are not achieved during 24-hour
infusions of paclitaxel. [J Natl Cancer
Inst 1996;88:1297-1301]
Paclitaxel (Taxol) is a new drug with
significant activity against a number of
different tumors, including breast, ovar-
ian, non-small-cell lung, and head and
neck cancers (/). The infusion duration of
paclitaxel has varied from 1 to 96 hours
in clinical trials (2-4). The optimal sched-
ule has not been established, but 3- and
24-hour infusions are most widely used.
Two mechanisms of paclitaxel resis-
tance have been identified in vitro. One is
associated with overexpression of P-
glycoprotein (Pgp), which confers multi-
drug resistance (MDR) (5), and the other
involves alterations
[Paclitaxel stabilizes microtubules, thus
disrupting vital cellular processes and cell
division (/).] A number of compounds
that are capable of reversing Pgp-asso-
ciated MDR, such as verapamil and
cyclosporin, have been identified, and
early clinical trials with these modulators
have demonstrated responses in patients
who were previously refractory to chemo-
therapy (7,8). Cremophor EL is a poly-
ethoxylated castor oil vehicle that has
been shown to reverse Pgp-associated
MDR in vitro and in vivo (9,10). This
finding is of particular interest because
the clinical formulation of paclitaxel con-
tains 50% Cremophor. We have pre-
viously demonstrated
infusions of paclitaxel result in plasma
Cremophor concentrations at the end of
infusion of 1 (iL/mL or more and that
these concentrations are sufficient to
reverse MDR in vitro by at least 50%
(//). However, our previous study did not
measure Cremophor concentrations dur-
ing the 3-hour infusion period or during
more prolonged periods of infusion. The
time required to achieve plasma Cremo-
phor concentrations sufficient for sub-
stantial reversal of MDR and the duration
in tubulin (6).
that 3-hour
* Affiliations of authors: D. Rischin, M. J.
Millward, B. M. Linahan, G. C. Toner, J. F. Bishop
(Division of Haematology and Medical Oncology),
L. K. Webster (Trescowthick Research Labor-
atories), A. M. Woollett, C. G. Morton (Division of
Nursing), Peter MacCallum Cancer Institute, Mel-
bourne, Australia.
Correspondence to.
Division of Hematology and Medical Oncology,
Peter MacCallum Cancer Institute, Locked Bag No.
I, A'Beckett St., Melbourne 3000, Australia.
See "Notes" section following "References."
Danny Rischin, M.D.,
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of these plasma concentrations during
paclitaxel chemotherapy are likely to be
important factors in the potential modula-
tion of MDR.
Despite extensive use of Cremophor as a
solubilizing agent in clinical formulations
(e.g., with cyclosporin A and teniposide),
its pharmacokinetics in humans have not
previously been studied. The chemical in-
ertness and lack of spectral properties of
Cremophor have precluded the develop-
ment of a specific assay, but the use of a
bioassay circumvents these problems. It is
recognized that
heterogeneous compound and that the
bioassay measures only the MDR-modulat-
ing component(s). However, for the pur-
pose of examining the potential role of
Cremophor in reversing MDR, a bioassay
is preferable to a chemical assay, since the
relevant pharmacologic effect is being as-
sessed more directly, hi this study, we have
used a bioassay to measure plasma
Cremophor concentrations in patients with
ovarian cancer who were randomly as-
signed to receive paclitaxel as 3-, 6-, and
24-hour infusions.
Cremophor is a
Patients and Methods
Study Design
Eligibility criteria for this study included histo-
logically confirmed epithelial ovarian cancer, at
least one prior platinum-containing chemotherapy
regimen but no more than three prior regimens, an
age of 75 years or less, a performance status of 0-2
according to the Eastern Cooperative Oncology
Group criteria, and adequate base-line values of
hematology (an absolute neutrophil count of ^2.0 x
IO9/L and a platelet count of SI00 x 109/L), renal
function (serum creatinine level 50.18 mmol/L [i.e..
SI ,5x the upper limit of normal]), and hepatic func-
tion (serum bilirubin level £21 UJnol/L [i.e., ^l.25x
the upper limit of normal]). Fifteen patients were
eligible for the study. Written, informed consent
was obtained from each individual, and the protocol
was approved by the institutional ethics committee.
The patients were randomly assigned to receive
one 3-hour, one 6-hour, and one 24-hour infusion of
paclitaxel (Taxol: Bristol-Myers Squibb, Mel-
bourne, Australia) in varied sequences during their
first three cycles of treatment. Paclitaxel was sup-
plied as a 6-mg/mL solution in 50% Crcmophor and
50% ethanol and was further diluted in 5% dextrose
for infusion. The starting paclitaxel dose was either
175 or 135 mg/m2, depending on the number of
prior chemotherapy regimens. Treatment cycles
were repeated every 3 weeks. Oral dexamethasone,
intravenous promethazine hydrochloride. and in-
travenous cimetidine were administered prior to all
cycles. Blood samples were collected during the
first three cycles of treatment for the analysis of
Cremophor pharmacokinetics. After three cycles.
patients who had responded or who had stable dis-
ease continued to be treated with 3-hour infusions of
paclitaxel. Eleven of the 15 eligible patients re-
ceived at least three cycles of treatment and had
complete sets of blood samples for analysis.
Blood Sampling Schedule
Blood (20 mL) was sampled from an indwelling
intravenous catheter kept patent with heparinized
saline. The samples were centrifuged immediately
(10 minutes, room temperature) to obtain plasma,
which was stored at -20 'C until assayed. Blood
samples were obtained prior to paclitaxel ad-
ministration and at the following times: for the 3-
hour infusion, at 0.5, 1, and 2 hours during the in-
fusion, at the end of the infusion, and then at 0.5, 1,
2, 3, 6, and 24 hours following the infusion; for the
6-hour infusion, at 1,2, and 3 hours during the in-
fusion, at the end of the infusion, and then at 0.5, 1,
2, 3, 6, and 18 hours following the infusion; for the
24-hour infusion, at 3, 6, and 12 hours during the in-
fusion, at the end of the infusion, and then at 0.5, 1,
and 2 hours following infusion.
Cremophor Assay
The multidrug resistant CEM/VLBIOO human T-
cell leukemia cell line was maintained at 37 "C in
Eagle's minimum essential medium (a-modifica-
tion; Gibco, Melbourne, Australia) supplemented
with 10% fetal calf serum and 100 ng/mL vinblas-
tine (F. H. Faulding Pharmaceuticals, Adelaide.
Australia). Cremophor EL was purchased from
BASF Fine Chemicals (Melbourne). The assay was
performed as described previously with minor
modifications (9,11). Briefly, this assay measures
the ability of plasma samples to modulate MDR in
vitro. Our initial experiments (9,//) had indicated
that a Cremophor concentration of 1 uL/mL or more
was sufficient for maximum (100%) MDR reversal
in vitro. However, repeat experiments have shown
that a concentration of 1 uL/mL is sufficient for
50% reversal of MDR and that concentrations of
1.5-2.0 u.L/mL are required for maximum reversal
(unpublished observations). Inhibition of the Pgp
drug-efflux pump by Cremophor results in increased
intracellular daunorubicin accumulation. To mea-
sure Cremophor in the plasma from patients.
CEM/VLBIQQ ceils (5 x 105) were incubated at
37 "C for 1 hour with 0.5 mL plasma and 0.5 mL
growth medium containing 2 ng/mL daunorubicin.
Intracellular daunorubicin fluorescence was mea-
sured by means of flow cytometry (FACStar Plus
cell sorter Becton Dickinson. NJ. or Coulter Epics-
Profile II; Coulter Electronics, Miami, FL). All
measurements were done in triplicate. The within-
day coefficient of variation was less than 10%, the
interassay coefficient of variation was 14%, and the
lower limit of detection was 0.05 u.L/mL. Pretreat-
ment plasma was used to derive a 6-point standard
curve for the effect of Cremophor on intracellular
daunorubicin fluorescence. The increase in equi-
librium intracellular daunorubicin fluorescence in
assays containing post-treatment plasma gave a
measure of the Cremophor concentration.
Pharmacokinetics
Pharmacokinetic parameters for Cremophor in
plasma were calculated with standard model-inde-
pendent equations, using the SIPHAR/W1N com-
puter package (SIMED; Creteil, France). The area
under the plasma concentration versus time curve
(AUC) was estimated with the trapezoidal rule and
was extrapolated to infinity (AUC,nf) for the 3- and
the 6-hour infusions only. Since the bioassay used in
this study measures the pharmacologic effect of
Cremophor rather than a defined chemical species,
the term "apparent AUC" is applied to this
parameter. The terminal elimination half-life was
calculated by linear regression of the final three to
four points on the log-linear concentration-time
profile. Total clearance was calculated as dose/
AUCmf and was normalized to body surface area.
Statistical Methods
A comparison of the peak Cremophor concentra-
tions for the three infusion groups was made by use
of analysis of variance for crossover trials (12). The
Glim statistical package (13) was used to carry out
the analysis. Two-tailed significance levels have
been reported, with no correction for multiple com-
parisons. Results were deemed to be significant if
the P value was less than .05.
Results
Patient Characteristics
Eleven women with epithelial ovarian
cancer had plasma Cremophor concentra-
tions assayed after 3-, 6-, and 24-hour in-
fusions of paclitaxel. The median patient
age was 59 years (range, 35-67 years).
Ten patients received paclitaxel at a dose
of 175 mg/m2, and one received the drug
at a dose of 135 mg/m2.
Plasma Cremophor Pharmacokinetics
With 175 mg/m2 paclitaxel, the total
amount of Cremophor delivered was 23.5
± 2.4 mL (mean ± standard deviation
[SD]; n = 10). The mean peak Cremophor.
concentrations for the 3-, 6-, and 24-hour
infusions were 1.47, 1.24, and 0.65
|iL/mL, respectively (Fig. 1). There was a
significant difference between the three
groups (P-cOOOl). In particular, both the
3- and the 6-hour results were significant-
ly higher than the 24-hour results (P<
.0001), and the 3-hour results were higher
than the 6-hour results (P = .04). The
peak plasma Cremophor concentration
was 1 u.L/mL or more in eight of 10
patients during both the 3- and the 6-hour
infusions. Only one patient achieved a
peak level of 1 [iL/mL or more during the
24-hour infusion. The patient who re-
ceived paclitaxel at a dose of 135 mg/m2
achieved a plasma Cremophor concentra-
tion of 1 jiL/mL or more only with the 3-
hour infusion. No patient attained a
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E
ion (
rat
Concent
Peak Cremophor
2.0 -i
1.8 -
1.6 -
1.4 -
1.2 -
1.0 -
0.8 -
06 -
0.4 -
02 -
00 -
#
#
•
3
•
• •
:
•
i i
6 24
Paclitaxel Infusion (hr)
Fig. 1. Individual peak plasma
Cremophor concentrations in 10
patients who each received 175
mg/rn' paclitaxel as 3-, 6-, and
24-hour infusions. The line at 1
uL/mL indicates the concentra-
tion of Cremophor that results in
50% reversal of multidrug resis-
tance in vitro.
plasma Cremophor concentration of 2 |iL
or more, although six patients achieved a
concentration of 1.5 nL or more during
the 3-hour infusion.
The mean plasma Cremophor con-
centrations in 10 patients receiving 175
mg/m2 paclitaxel for each infusion dura-
tion are shown in Fig. 2. By 30 minutes
into the 3-hour infusion, the eight patients
at this dose who achieved at least 1
|iL/mL Cremophor were already above
this level, suggesting that high Cremo-
phor concentrations are reached rapidly
with 3-hour paclitaxel infusions. Further-
more, the concentration-time profile for
the 3-hour infusion was unusual in that
the mean plasma Cremophor concentra-
tions decreased during the infusion
period. For the 6-hour infusion, the mean
plasma Cremophor concentration was
above 1 (aL/mL by 2 hours into the in-
fusion. In the eight patients who reached
plasma concentrations of 1 ^L/mL during
the 3-hour infusion, the total time that
Cremophor concentrations were greater
than 1 nL/mL was 8.9 ± 5.0 hours (mean
± SD; range, 4.1-15.6 hours). For the 6-
hour infusion, the total time above 1
UL/mL was 10.2 ± 9.0 hours (range, 0.3-
21.9 hours; n = 8). Thus, interpatient
variability in the duration of plasma
Cremophor concentrations
is high. The Cremophor concen-
above 1
Fig. 2. Semilogarithmic plot of mean ±
standard error (only upper or lower
error limits shown) plasma Cremophor
concentrations versus time after the
start of 175 mg/m paclitaxel infusions
in 10 patients receiving the drug over 3
(•).6(»), and 24 (A) hours.
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trations during the 24-hour infusion
period remained below the level required
for at least 50% reversal of MDR in vitro.
Table 1 summarizes the pharmaco-
kinetic parameters for Cremophor in nine
patients who received 175 mg/m2 pacli-
taxel. One patient was excluded from the
pharmacokinetic analysis because of in-
sufficient data on the terminal-elimina-
tion phase during the 6-hour infusion.
The reported terminal-elimination half-
lives must be considered as estimates
only, since the durations of sampling
were not three times the calculated half-
life values. The pharmacokinetics were
nearly identical for both the 3- and the 6-
hour infusions, and, despite the long es-
timated half-lives, the peak plasma
concentration for each infusion time was
reached prior to the end of the infusion.
In contrast, Cremophor concentrations
during the 24-hour infusion period were
highest at the end of the infusion.
Discussion
In this study, we have confirmed our
previous finding that 3-hour infusions of
paclitaxel produce plasma Cremophor
concentrations at the end of infusion that
are sufficient for substantial reversal of
MDR in vitro (//). Moreover, Cremophor
concentrations are maintained at levels
that could potentially reverse MDR for
prolonged periods of time both during
and following 3- and 6-hour infusions in
most patients. However,
variability was found to be high, and no
patient achieved a plasma Cremophor
concentration of 2 [lL/mL or more (i.e., a
concentration sufficient for maximum
MDR reversal in vitro). Since Cremophor
is a known inhibitor of Pgp and since
paclitaxel is transported by this efflux
pump, sustained Cremophor concentra-
interpatient
tions achieved with paclitaxel infusions
of up to 6 hours in duration may poten-
tially reverse MDR in tumors that overex-
press Pgp. The Cremophor concentrations
achieved during 24-hour infusions of
paclitaxel were not adequate for ample
MDR reversal in vitro. However, it is not
known whether Cremophor concentra-
tions capable of reversing MDR in vitro
are capable of reversing MDR in patients.
Furthermore, the relative importance of
Pgp-associated MDR in the development
of intrinsic or acquired clinical resistance
to paclitaxel is not known. A preliminary
report (14) has suggested that there is an
association between the response to 24-
hour infusions of paclitaxel and low to
nonexistent levels of Pgp expression in
patients with metastatic breast cancer.
The optimum infusion duration for
paclitaxel is controversial. Significant
antitumor activity has been reported in
clinical trials with infusion durations
ranging from 1 to 96 hours (2-4). A ran-
domized trial that compared 3- and 24-
hour infusions in patients with relapsed
ovarian cancer found no difference in
response rates or survival (2). Experimen-
tal data do suggest that a more prolonged
exposure may be more efficacious against
some cell lines (15). More prolonged ex-
posure can also decrease the degree of
resistance in MDR cell lines exposed to
paclitaxel in vitro (15). However, com-
plete reversal does not occur, unlike the
situation with Cremophor, where com-
plete reversal of paclitaxel resistance in
Pgp-expressing human breast cancer cell
lines has been demonstrated (16). It is
noteworthy that responses have been seen
with 96-hour infusions in patients with
breast cancer who were refractory to 3-
hour infusions (17). The relationship be-
tween Pgp expression and response in
that study is not known. It is possible that
more prolonged infusions may be more
efficacious for tumors that do not overex-
press Pgp, whereas short infusions that at-
tain high concentrations of Cremophor
may be better in treating tumors that
overexpress this protein. Randomized tri-
als that include an analysis of Pgp expres-
sion will be required to resolve this issue.
Our finding of sustained high Cremo-
phor concentrations with short infusions
of paclitaxel also has implications for the
interpretation of clinical trials of other
MDR modulators that have been used
with paclitaxel [e.g., 3-hour infusions of
paclitaxel in combination
verapamil or the cyclosporin SDZ PSC
833 (18,19)]. In such studies, the effect of
two potential modulators is being ex-
amined. Additional benefit would be ex-
pected only if more complete inhibition
of Pgp than can be achieved with Cremo-
phor alone translates into improved rever-
sal of MDR.
The pharmacokinetic parameters deter-
mined for Cremophor in the present study
are effectively those of the MDR-active
component only. This may explain the
apparent nonlinear pharmacokinetics sug-
gested by the unusual shape of the plasma
concentration versus time curve during
the 3- and the 6-hour infusions, whereby
the maximum Cremophor concentration
was reached prior to the end of the in-
fusion, despite the estimated elimination
half-life of 26 hours. The maximum con-
centration and the AUC achieved with the
24-hour infusion were approximately half
the values determined with the shorter in-
fusions. Although the metabolism and ex-
cretion of Cremophor are unknown, the
pharmacokinetics suggest that the MDR-
active component is a relatively low
clearance compound.
Cremophor pharmacokinetics follow-
ing paclitaxel administration are of inter-
with R-
Table 1. Plasma Cremophor pharmacokinetics (mean ± standard deviation, n = 9) in patients receiving infusions of paclitaxel at 175 mg/m^,t
Infusion
duration, h
3.1 ±0.1
6.1 ±0.1
24.9 ± 1.8
Tmo.1, h
1.3 ± 0.6
4.6 ± 1.8
24.9 ± 1.8
Cma*. JlL/mL
l-5±0.3
1.3 ±0.3
0.7 ±0.2
t ^ , h
26.1 ±8.8
26.4 ± 8.0
n.c.
AUC
O-t.±uL h/mL
23.9 ±5.3
20.9 ±7.1
11.7 ±3.4
(apparent)
0-~. uL h/mL
47.3 ± 16.1
44.9±2l.l
n.c.
Cl (apparent).
mL/h/m2
361 ±183
402±2IO
n.c.
•Total amount of Cremophor delivered to an individual patient was the same for each infusion duration (23.9 ± 2.3 mL).
tT,,^ = time to achieve maximum plasma concentration: C,^ = maximum plasma concentration: t'/i = terminal elimination phase half-life; AUC = area under
the plasma concentration versus time curve: Cl = clearance: t = time: n.c. = not calculated.
±The final sample collection time depended on the infusion duration, and was 27. 24. and 27 hours for the 3-. 6-. and 24-hour infusions, respectively.
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est for several reasons in addition to the
potential for MDR reversal. We have
recently reported that Cremophor, when
given as an MDR modulator with
doxorubicin, results in an increase in the
AUC of doxorubicin and doxorubicinol
{2021). Cremophor may also alter the
pharmacokinetics of etoposide (22). The
altered pharmacokinetics of other drugs
by Cremophor has significant implica-
tions for combination chemotherapy with
paclitaxel. For example, Cremophor has
been implicated in the high doxorubicin
and doxorubicinol concentrations seen
when 3-hour infusions of paclitaxel were
combined with doxorubicin (23), and this
may have contributed to the 21% in-
cidence of cardiac failure in that trial
(24). It is also possible that Cremophor
may affect the pharmacokinetics of
paclitaxel and may contribute to the non-
linear pharmacokinetics seen with short
infusions (25). Cremophor has also been
demonstrated to antagonize the cyto-
toxicity of paclitaxel in cell lines that do
not overexpress Pgp (26). It will now be
possible to determine the effect of the
clinically relevant Cremophor concentra-
tions achieved with short and prolonged
infusions on paclitaxel cytotoxicity in
vitro. Cremophor also alters human plas-
ma lipoproteins, and these effects are
more marked with 3-hour infusions than
with 24-hour infusions of paclitaxel (27).
The effect on lipoproteins is due to a
component of Cremophor that is different
from the one that modulates MDR.
The efficacy of paclitaxel against can-
cers resistant to other chemotherapeutic
agents cannot be explained solely by
reversal of MDR by Cremophor, since,
prolonged infusions also have activity in
this setting despite low Cremophor con-
centrations. Clinical drug resistance may
be caused by several mechanisms, with
the predominant mechanism depending
on a number of factors, including tumor
type and previous chemotherapy. Never-
theless, we have demonstrated in this
study that short infusions of paclitaxel
result in sustained plasma Cremophor
concentrations that are sufficient
modulate MDR, thus having the potential
to contribute to the efficacy of paclitaxel
when Pgp-associated MDR is the limiting
mechanism for response. The ultimate
significance of our findings awaits further
studies that are required to define the role
to
of Pgp-associated MDR in clinical pacli-
taxel resistance.
References
(/) Rowinsky EK. Donehower RC. Paclitaxel
(Taxol) [published erratum appears in N Engl
J Med 1995:333:75]. N Engl J Med 1995:332:
1004-14.
(2) Eisenhauer EA. ten Bokkel Huinink WW.
Swenerton KD. Gianni L. Myles J. van der
Burg ME. et al. European-Candian ran-
domized trial of paclitaxel in relapsed ovarian
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Notes
Supported in pan by Bristol-Myers Squibb and by
a grant from the Anti-Cancer Council of Victoria.
We thank Kerrie Stokes for her help with sample
collections, assay development, and data analysis;
Ralph Rossi for his technical assistance; Kally Yuen
for her statistical advice: and Margaret Arumets for
her secretarial assistance.
Manuscript received February 9. 1996; revised
May 8. 1996; accepted June 24. 1996.
Journal of the National Cancer Institute, Vol. 88, No. 18, September 18, 1996
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