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Vol. 4, 2321-2329, October 1998 Clinical Cancer Research 2321
Phase I Trial of Cremophor EL with Bolus Doxorubicin
Michael J. Millward,’ Lorraine K. Webster,
Danny Rischin, Kerrie H. Stokes, Guy C. Toner,
James F. Bishop, Ian N. Olver,
Bernadette M. Linahan, Martha E. Linsenmeyer,
and David M. WoodcockDivision of Hematology and Medical Oncology [M. J. M., D. R.,G. C. T.. J. F. B., I. N. 0.], Pharmacology and DevelopmentalTherapeutics Unit [M. J. M., L. K. W., K. S., B. M. L.], Molecular
Genetics Laboratory [M. E. L., D. M. W.], Peter MacCallum Cancer
Institute, Melbourne 3000, Australia
ABSTRACT
Cremophor EL (cremophor), a component of the pacli-
taxel formulation, can potentially reverse P-glycoprotein-associated multidrug resistance. A Phase I trial of cremo-phor as a 6-h infusion every 3 weeks was performed withbolus doxorubicin (50 mg/m2). The cremophor dose wasescalated from 1 to 60 mI/rn2. A standard paclitaxel premed-ication was given before cremophor. Using a bioassay, p0-
tentially active cremophor levels (�1 �il/ml) were measured
in plasma from patients receiving cremophor doses of 30, 45,and 60 mum2. A cross-over design was used to assess the
influence of cremophor 30 mI/rn2 on the pharmacokinetics of
doxorubicin and doxorubicinol. The plasma area under the
concentration versus time curve (AUC) of doxorubicin in-
creased from 1448 ± 350 to 1786 ± 264 nglmlh (P = 0.02)
in the presence of cremophor, whereas the AUC of doxoru-
bicinol increased from 252 ± 104 to 486 ± 107 ng/mlh (P =
0.02). This pharmacokinetic interaction was associated with
significantly increased neutropenia. With reduction of the
doxorubicin dose to 35 mg/rn2, the cremophor dose was
increased to 60 ml/m2. Dose-limiting toxicities occurred in
two of six patients after 45 mum2 and two of four patients
after 60 mI/rn2, which included febrile neutropenia andgrade HI cremophor-related toxicities of rash, pruritus,headache, and hypotension. All patients who received 45
mUm2 cremophor reached plasma levels �1.5 �ilJml, but at60 mI/rn2, only two of four reached this level, and the cal-culated plasma clearance of cremophor was significantly
faster at this dose. One patient with hepatoma resistant to
epirubicin achieved a near-complete response. Cremophor
45 mI/rn2 over 6 h with 35 mg/rn2 doxorubicin is recom-mended for further studies. The pharmacokinetic interac-
Received 1/23/98; revised 7/9/98; accepted 7/10/98.
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.
I To whom requests for reprints should be addressed, at Sydney Cancer
Centre. Royal Prince Alfred Hospital, Sydney 2050, Australia. Phone:
61-2-95 157680: Fax: 61 -2-95 191 546; E-mail: michaelm@canc.rpa.cs.
nsw.gov.au.
tion between cremophor and doxorubicin is quantitativelysimilar to that described in trials of paclitaxel with doxoru-
bicin and suggests that the cremophor in the paclitaxel
formulation is responsible.
INTRODUCTIONThe development of resistance to anticancer chemotherapy
is a major reason for the occurrence of treatment failure in the
management of patients with malignant disease. Although a
number of potential mechanisms of such drug resistance have
been described, the most widely studied is that of MDR2 related
to the overexpression of a surface glycoprotein termed P-gp (1,
2). P-gp-associated MDR confers resistance in vitro to several
important classes of anticancer drugs including anthracyclines,
Vinca alkaloids, epipodophyllotoxins, and taxoids (3, 4). Anal-
ysis of human tumor samples for the presence of P-gp-associ-
ated MDR with a variety of techniques have shown its occur-
rence in both previously untreated and chemotherapy-refractory
patients and its relationship between failure to respond to chem-
otherapy and poor prognosis (5- 8).
Reversal of P-gp-associated MDR in vitro can be achieved
with a variety of compounds. Initial clinical trials of these
modulators were performed with drugs developed for other
clinical uses, for example verapamil, tamoxifen, and cyclosporin
A (9-14). Although some promising results were achieved,
suggesting the ability of such modulators to enhance the re-
sponse of tumors to coadministered chemotherapy, toxicity to
normal tissues generally prevented the administration of doses
necessary for MDR reversal in vitro. Current interest has fo-
cused on the development of analogues having potentially less
toxicity and the investigation of novel compounds as MDR
modulators (15-18).
Cremophor (polyoxyethylenglyceroltriricinoleat 35; BASF) is
a nonionic solubilizer and emulsifier that is made by reacting
ethylene oxide with castor oil (19). Castor oil is primarily a ti-i-
glyceride of 12-hydroxy-oleic acid, and in cremophor, 35 moles of
ethylene oxide are reacted per mole of triglyceride. Cremophor is a
pale yellow, oily liquid consisting of a mixture of components,
primarily polyethylene glycol conjugates of this triglyceride. Fatty
acid esters of polyethyleneglycol are also present, as well as hy-
drophilic polyethylene glycols and ethoxylated glycerol. Cremo-
phor is used as an emulsifying agent and aqueous solubilizer for
hydrophobic products including certain drugs, fat-soluble vitamins,
animal feed, and cosmetics. It is present in the iv. formulations of
the anticancer drugs teniposide and paclitaxel. The paclitaxel for-
mulation (Taxol; Bristol Myers Squibb Co. Wallingford, CT) con-
sists of 6 mg/mi in 50% ethanol and 50% cremophor. Thus, a
patient receiving paclitaxel at a widely used dose of 175 mg/m2
will also receive -� 14 mI/rn2 of cremophor.
2 The abbreviations used are: MDR, multidrug resistance; P-gp, P-
glycoprotein; cremophor, Cremophor EL; AUC, area under the concen-
tration versus time curve: CV, coefficient of variation.
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2322 Cremophor with Doxorubicin
While examining the MDR-reversing potential of corn-
pounds dissolved with cremophor, we observed that cremophor
itself was able to reverse MDR in tumor cells in vitro (20, 21).
Other groups have reported similar results (22, 23). The effect of
cremophor on increasing the sensitivity of MDR cells is rapid
and reversible and may be either due to a direct interaction with
P-gp (22, 24) or the result of a general membrane perturbation
affecting the function of this protein pump (25, 26). Cremophor
concentrations �0. 1 �i.lJml produce some increase in the sensi-
tivity of MDR cells, with --50% reversal at 1 .0 p1/mi and
complete reversal to wild-type sensitivity occurring at concen-
trations of 1 .5-2.0 �i.lJml (27, 28).
In patients receiving paclitaxel formulated with cremophor,
we have measured the resulting plasma cremophor concentra-
tions using a bioassay. This assay depends on the ability of
cremophor to alter the intracellular daunorubicin fluorescence in
the MDR-expressing human T-cell leukemia cell line CEM/
VLB(5). The cremophor levels in patients after short infusions
of 175 mg/rn2 paclitaxel (0.8-1.8 p.l/ml) are in the range in
which MDR modulation occurs in vitro (27, 29).
Cremophor can cause histamine release in dogs (30) and
has been implicated in the hypersensitivity reactions observed in
patients receiving paclitaxel (31). Such reactions can be suc-
cessfully prevented in nearly all patients by the use of a pro-
longed infusion of paclitaxel and the administration of prophy-
lactic antiallergy prernedication (3 1 ). Other than hyper-
sensitivity reactions, no clear toxicity to humans has been de-
scribed from cremophor. It is therefore suitable for clinical
investigation as a potential MDR modulator.
The aim of this clinical trial was to investigate the use of
cremophor as a potential MDR modulator by determining: (a)
the feasibility of administering 6-h infusions of cremophor with
bolus doxorubicin; (b) whether plasma levels of cremophor
sufficient to modulate MDR in vitro could be obtained without
limiting toxicity; (c) the pharmacokinetics of cremophor at
different doses after a 6-h infusion; and (d) the effect of crerno-
phor on the pharmacokinetics of doxorubicin and its principal
metabolite, doxorubicinol.
PATIENTS AND METHODS
Eligibility. Patients were required to have histologically
proven advanced cancer resistant to conventional chemotherapy
or for which no satisfactory chemotherapy exists. Other eligi-
bility criteria were: performance status 0-2 by the criteria of the
Eastern Cooperative Oncology Group and life expectancy >8
weeks, absolute neutrophil count �2.0 X lO9Iliter, platelet
count � 150 X l09/liter, serum bilirubin < 1.5 times upper limit
of normal for the institution, serum creatinine � 1 20 �i.mol/liter,
and cardiac ejection fraction �50% determined by radionuclide
angiocardiography imaging. Patients with serious concurrent
medical illnesses or requiring concurrent treatment with calcium
channel blocking agents (for example veraparnil, nifedipine, and
diltiazem) were excluded. Written informed consent was ob-
tamed from all patients, and the protocol was approved by the
Institutional Ethics Committee of the Peter MacCallum Cancer
Institute. Separate written informed consent was obtained for
participation in the pharmacokinetic studies.
Table I Dose levels
Level Cremophor dose Doxorubicin dose Patients entered
1 1 mum2 so mg/m2 3
2 7.5 mI/rn2 50 mg/m2 43 15 mUm2 50 mg/m2 64 3Oml/m2 50mg/rn2 74A 30m11m2 50mg/rn2 II
5 45 mUm2 35 mg/m2 66 60 mllm2 35 mg/m2 4
Trial Design. This trial was performed in three stages. In
the first stage (dose levels 1-4, Table 1) all patients received 50
mg/m2 doxorubicin as a bolus, and the dose of cremophor was
escalated in cohorts of three to seven patients. When end-
infusion cremophor concentrations were measured to be � 1.0
p.1/mI, a cross-over design was used to investigate the influence
of this dose of cremophor on doxorubicin pharmacokinetics.
This cohort of patients (dose level 4A, Table 1) were random-
ized to receive either 50 mg/rn2 doxorubicin with cremophor or
the same dose of doxorubicin alone in the first cycle and the
alternative treatment in the second cycle. In the third stage (dose
levels 5 and 6, Table 1), the dose of cremophor was further
escalated, and patients were randomized to receive either doxo-
rubicin with cremophor or 50 mg/m2 doxorubicin in the first
cycle and the alternative treatment in the second cycle. The dose
of doxorubicin given with cremophor to these cohorts was
calculated to produce the same doxorubicin plasma AUC as 50
mg/rn2 doxorubicin when given alone.
The initial dose level was selected as a minimum cremo-
phor exposure because of the possible risk of hypersensitivity.
Subsequent dose escalation was based on the calculated expo-
sure of patients receiving paclitaxel to cremophor and the levels
obtained (27, 29) and the results obtained from lower dose levels
in this trial.
At all dose levels, cycles were repeated every 3 weeks. The
cremophor dose was not escalated for any individual patient. No
maximum number of cycles was specified. Patients participating
in the cross-over stages of the trial received additional treatment
with doxorubicin and cremophor after the second cycle. Pro-
phylactic use of recombinant colony-stimulating factors to pre-
vent rnyelosuppression was not permitted.
While on study, complete blood count including differen-
tial, electrolytes, and liver function tests were performed three
times a week. Patients were reviewed weekly for symptoms and
signs of toxicity for at least the first two cycles. Tumor imaging
was repeated after every two cycles. Toxicity and response to
treatment were graded by the standard criteria of the WHO (32).
Limiting toxicity was defined as febrile neutropenia, grade IV
thrombocytopenia or anemia, or grade III or IV nonhematologi-
cal toxicity (excluding nausea, vomiting, and alopecia). Uncom-
plicated grade IV neutropenia was not considered a limiting
toxicity.
Drug Administration. Cremophor was obtained from
BASF Chemicals and formulated for this trial as a sterile l00-ml
solution containing 25% v/v cremophor by F. H. Faulding
Pharmaceuticals (Mulgrave, Australia). This was further dis-
solved in I liter normal saline solution and infused as a 6-h i.v.
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Clinical Cancer Research 2323
infusion. Patients received a standard prernedication consisting
of 8 mg dexamethasone, 50 mg ranitidine, and 25 mg prometh-
azine, all given iv. 30 mm before the commencement of crc-
mophor. As a further precaution, in the first stage of the trial,
patients received the first 50 ml of the cremophor infusion over
30 mm with the remainder over 5.5 h. Because no hypersensi-
tivity reactions were observed, this precaution was dropped for
subsequent patients.
All patients received doxorubicin as an iv. bolus. Doxo-
rubicin was given 1 h after the commencement of the cremophor
infusion. For the cross-over pharmacokinetic part of the trial, on
the doxorubicin-alone cycle, patients also received a control
infusion of 1 liter of normal saline commencing 1 h before the
administration of doxorubicin. Additionally, the same premed-
ication was given 30 mm before the control infusion to eliminate
the effect of any pharmacokinetic interaction between doxoru-
bicin and these drugs.
Pharmacokinetics. Cremophor was measured in plasma
during and after the patient’s first infusion of cremophor. Ini-
tially, cremophor levels were measured in patients at dose levels
3 and 4 at three time points, mid-infusion, end-infusion, and 1 h
after infusion. At subsequent dose levels, more detailed sam-
pling was performed to define the pharmacokinetics of cremo-
phor. Samples were collected at the following times: prior to the
administration of premedication; immediately after the admin-
istration of doxorubicin; 2, 3, and 5 h after the start of the
cremophor infusion; end-infusion; and 1, 3, 7, 19, 31, and 43 h
after the completion of the cremophor infusion. Blood (10 ml)
was collected into heparinized tubes and centrifuged immedi-
ately, and the plasma was stored at -70#{176}.
Cremophor was measured using a bioassay as described
previously (27, 29). Briefly, this assay depends on the ability of
cremophor in the plasma sample to modulate the equilibrium
intracellular fluorescence of daunorubicin assessed by flow cy-
tometry in the MDR-expressing cell line CEM/VLB �. The
patient’s pretreatment plasma was used to derive a six-point
standard curve for that patient against which the subsequent
samples were compared. All measurements were done in trip-
licate. The within-day CV was < 10%, the interassay CV was
14%, and the lower limit ofdetection was 0.05 pJ/ml. The assay
could not reliably quantify cremophor levels of >2.0 �i.l/ml,
even with dilution; consequently, samples measured to be >2.0
p.l/ml were analyzed as being equal to 2.0 �i.l/ml.
Doxorubicin and doxorubicinol were measured in plasma
from patients at dose levels 4A, 5, and 6 after doxorubicin alone
and the first course of doxorubicin given with crernophor. Sam-
ples were collected at the following times: prior to the admin-
istration of doxorubicin; immediately after the administration of
doxorubicin; and 10, 20, and 40 mm and 1, 2, 4, 6, 8, 12, 24, 36,
and 48 h after doxorubicin. Blood (10 ml) was collected into
heparinized tubes and centrifuged immediately, and the plasma
was stored at -70#{176}.When the sample times for cremophor and
doxorubicin coincided, a 20-ml blood sample was divided and
prepared and stored separately for the assays.
Doxorubicin and doxorubicinol were measured in plasma
by an HPLC method modified from Maessen et a!. (33) using
daunorubicin as the internal standard. Samples were prepared by
solid phase extraction of 1.0 ml of plasma using C18 Sep-Pak
Vac 1-ml cartridges (Waters, Milford, CT) with the solvent
volumes reduced to match the amount of sorbent. Separation
was on a 8 Nova-Pak Radial-Pak cartridge (8 mm X 10 cm)
with a Nova-Pak C18 Guard-Pak (both Waters) using a gradient
mobile phase (A: 20% acetonitrile, 0.02 M NaH,P04, pH 4; B:
45% acetonitrile, 0.02 M NaH2PO4, pH 4). Samples were quan-
tified by fluorescence detection (excitation wavelength, 480 nm;
emission wavelength; 580 nrn) against a log-weighted linear
standard curve in human plasma from 0.5 to 3 125 ng/ml for both
doxorubicin and doxorubicinol. The minimum quantifiable con-
centration (lowest concentration with a CV <20%) was 0.5
ng/ml.
Pharmacokinetic parameters were calculated using the
SIPHAR program (SIMED, Creteil, France). For cremophor,
model-independent analyses were performed. The terminal
elimination half-life was determined by linear regression of the
final four points on the log-linear concentration-time profile.
The AUC for cremophor was calculated using the trapezoidal
method and extrapolated to infinity (AUC1�f). Total clearance of
cremophor was calculated as dose/A UC10f normalized to body
surface area. Because the bioassay measures a pharmacological
effect of cremophor rather than a defined chemical compound,
the terms “apparent AUC” and “apparent clearance” are used for
cremophor.
For doxorubicin, pharmacokinetic parameters were esti-
mated by nonlinear weighted least-squares analysis using the
Powell minimization algorithm. Individual models were chosen
on the basis of Akaike’s Information Criterion and visual in-
spection of the observed versus fitted concentration-time points.
The parameters computed from the model were: half-lives,
AUC10f, volume at steady-state (V�5), mean residence time
(MRT), and clearance (CL). Additionally, a model-independent
analysis calculated the doxorubicin AUC to the last measured
time point (AUCT) by the trapezoidal method. The doxorubici-
nol AUCT was calculated by the same method as the doxorubi-
cm A UCT, and the metabolite ratio was used to describe the
exposure to the metabolite relative to the parent drug.
Statistics. Pharmacokinetic parameters for doxorubicin
and doxorubicinol and neutropenia in the presence and absence
of cremophor were compared using the Wilcoxon signed rank
test. Cremophor pharmacokinetics at different doses were corn-
pared using the Mann Whitney test. All Ps are two-sided, and
those <0.05 were considered significant.
RESULTS
Forty-one patients were enrolled on this trial (Table 2).
Most patients had received prior chemotherapy with 20 of 41
(50%) having had at least one chemotherapy drug capable of
inducing P-gp-associated MDR. Of these patients, 12 had pre-
viously received an anthracycline (doxorubicin or epirubicin), 8
had received etoposide, 7 had received a Vinca alkaloid, and 3
had received paclitaxel. The number of patients enrolled at each
dose level is given in Table 1 . One patient entered at dose level
4A received doxorubicin alone in the first cycle but developed
rapid symptomatic deterioration and was removed from the
study, having never received doxorubicin with cremophor. Two
patients entered at dose level 4A, two patients at dose level 5,
and one patient at dose level 6 received only doxorubicin plus
cremophor because they went off study after the first cycle or
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Table 2 Patient details (n = 41)
4.0
3.5Age
Mean
RangeSex
Male
Female
Performance status0
2
Tumor typesColorectal
Renal
Melanoma
Sarcoma
Breast
Unknown primaryNon-small cell lungHepatorna
GastricOvary
Non-Hodgkin’s lymphoma
Small round cell/Ewing’sOthers
Prior chemotherapyNoYes, non-MDR drugs
Yes, MDR drugs
52 years24 -75 years
24
17
7
1915
10
4
4
3
3
2
2
2
2
2
2
2
3
61520
a
-J
0
x
0
z
b4.0
3.5
3.0-I
�2.5
.�- 2.00� 1.5
1.0
0.5.
rCA
Dox Dox/cremophor
2324 Cremophor with Doxorubicin
because of unwillingness to participate in the pharmacokinetic
studies.
Toxicity. Hernatological toxicity was evaluated with the
combination of doxorubicin and cremophor following 74 cycles
in 39 patients. One patient at level 4A could not be evaluated
because of a lack of nadir counts. Another eight cycles were not
evaluated because the doxorubicin dose was reduced after he-
matological toxicity in previous cycles.
The principal hematological toxicity was neutropenia. The
incidence of grade IV neutropenia increased with increasing
cremophor doses. Grade IV neutropenia occurred in 0 of 3
patients at level 1, 1 of 4 patients at level 2, 4 of 6 patients at
level 3, and 1 1 of 16 patients at levels 4 and 4A. With the
reduction of doxorubicin dose, grade IV neutropenia occurred in
I of 6 patients at level 5 and 2 of 4 patients at level 6. Febrile
neutropenia occurred in one patient at level 3, three patients at
levels 4 and 4A, one patient at level 5, and one patient at level
6. There was one death at level 4 from neutropenic sepsis.
Thrombocytopenia was rare, with two patients having grade IV
thrombocytopenia (one at level 4A and one at level 6), both in
the setting of febrile neutropenia. One patient at level 4A had
grade IV anemia.
In six patients at level 4A, neutropenia could be evaluated
in the first two cycles in the presence and absence of cremophor.
All these patients received 50 mg/rn2 doxorubicin. The mean
neutrophil nadir was 1.9 X 109/liter after doxorubicin alone and
0.58 X l09fliter after doxorubicin with cremophor (P = 0.03;
Fig. la). Three patients at level 5 and three patients at level 6
had neutropenia evaluated in the first two cycles. These patients
received 50 mg/rn2 doxorubicin alone and 35 mg/rn2 with crc-
mophor. The mean neutrophil nadir was 1.7 X lO9Iliter after
Fig. I Nadir absolute neutrophil count (ANC) in patients receivingeither doxorubicin (Dox) alone or doxorubicin with cremophor. Eachpair of points represents an individual patient. a, patients receiving 50
mg/m2 doxorubicin alone or the same dose with 30 mUm2 cremophor. b,
patients receiving 50 mg/m2 doxorubicin alone or 35 mg/rn2 doxorubi-
cm with cremophor 45 mI/rn2 (-) or 60 mI/rn2 (----).
doxorubicin alone and 1.4 X 109/Iiter after doxorubicin with
cremophor (P = 0. 16; Fig. lb).
Other doxorubicin-related toxicity was infrequent. Stoma-
titis was recorded in 12 patients, but only 2 reached grade III
(one patient at level 4A and one at level 5). Only three patients
received five or more cycles of doxorubicin with cremophor.
One patient at level 4 developed angina after eight cycles. This
patient had previously documented ischemic heart disease and
had undergone a coronary angioplasty. His prestudy left yen-
tricular ejection fraction was 6 1%; after six cycles of doxoru-
bicin and 30 ml/m2 crernophor, it was 56%, and after eight
cycles, it had fallen to 43% with global dysfunction, indicating
anthracycline cardiotoxicity. After an additional angioplasty, the
angina resolved, but the ejection fraction did not improve. One
patient at dose level 1 received nine cycles of doxorubicin and
cremophor and one patient at level 5 received five cycles of
doxorubicin and cremophor plus one cycle of doxorubicin alone.
Neither of these patients had any fall in their ejection fraction.
No major hypersensitivity reactions to cremophor were
observed, and no patients had their infusion discontinued or
modified. Toxicities considered potentially related to crernophor
were cutaneous (pruritus, flushing, or rashes), hypotension or
dizziness, and headache. Because of the subjective nature of
some of these symptoms, they were graded as grade I (mild and
not requiring treatment or interfering with function), grade II
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Clinical Cancer Research 2325
Table 3 Crc mophor pharmacokinetics
Crernophor Total dose (ml) CMAX” (p.1/mI) CDOX (p.l/ml)Apparent AUC1�1
(�i.l/ml . h)Apparent Cl
(mLfhJm2) Half-life (h)Level dose Patients Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD
4A 30 ml/m2 9 54.7 ± 6.8 1.33 ± 0.17 0.87 ± 0.18 28.0 ± 5.8 1 124 ± 303 15.1 ± 5.4
5 45 ml/m2 6 80.6 ± 9.3 1.85 ± 0.17 1.34 ± 0.42 33.4 ± 13.4 1543 ± 610 1 1.5 ± 6.3
6 60 rnl/m2 4 106.9 ± 4.3 1.63 ± 0.32 1.41 ± 0.46 31.9 ± 15.6 2205 ± 944 16.2 ± 8.9
(a CMAX, maximum measured cremophor concentration; C00�, cremophor concentration at time of bolus doxorubicin administration; Cl.
clearance.
(moderate causing some impairment of function but not requir-
ing hospitalization), or grade III (severe requiring hospitaliza-
tion or causing significant interference with function). No grade
II or III crernophor toxicity was recorded at the first three dose
levels. One patient at level 4A had grade II dizziness, one
patient at level 5 had grade II rash, one patient at level 5 had
grade III headache and grade III pruritus, and one patient at level
6 had grade III hypotension and grade III rash. In none of these
patients did these symptoms occur when the patient received
doxorubicin alone, confirming their relationship to cremophor.
These symptoms commenced several hours to days after crc-
mophor and persisted for 1-2 weeks with the exception of the
patient at level 5, whose pruritus gradually resolved over 3
months after discontinuing cremophor.
Transient increases in bilirubin were recorded in two pa-
tients at level 3, one patient at level 4, and one patient at level
4A. All of these were grade II. One patient at level 4 had grade
III hyperbilirubinemia in the setting of severe sepsis. One pa-
tient at level 6 had grade III hyperbilirubinemia after both
doxorubicin with cremophor and doxorubicin alone. Another
patient at level 6 developed jaundice 3 weeks after doxorubicin
and cremophor, but investigations showed progressive hepatic
metastases.
Limiting toxicity did not occur at the first two levels. At
level 3, limiting toxicity occurred in I of 6 patients ( 17%), at
level 4 in 5 of 17 (29%), at level 5 in 2 of 6 (33%), and at level
6 in 2 of 4(50%).
Response. Responses were observed in two patients. One
patient at dose level 4 with hepatoma that had not responded to
previous epirubicin had multifocal hepatic lesions on computed
tomography scan with a serum a-fetoprotein of 15,700 units/
liter at baseline. Over eight cycles of doxorubicin with cremo-
phor, the a-fetoprotein fell to 23 units/liter (normal, <20 units/
liter) with minor residual abnormalities on computed
tomography. Treatment was discontinued because of potential
cardiac toxicity, and the response duration was 56 weeks. One
patient at level 4A with a small round cell tumor who had
received two prior chemotherapy regimens including doxorubi-
cm had a 48% reduction in the size of intraabdominal lymph
nodes lasting 16 weeks.
Cremophor Pharmacokinetics. Plasma cremophor con-
centrations were measured in three patients at level 3 and four
patients at level 4. None of the patients at level 3 reached a
cremophor concentration of 1 .0 p.l/ml, with mid-infusion con-
centrations ranging from 0.30-0.76 p.l/ml and end-infusion
concentrations ranging from 0.36-0.92 p.l/ml. With 30 mi/rn2
crernophor (level 4), all four patients tested had a plasma crc-
mophor concentration > 1 .0 p.l/ml, with mid-infusion concen-
trations ranging from 1.06-1 .48 �iA/ml and end-infusion con-
centrations ranging from 0.96-1.16 p.1/mI. Two patients had
concentrations � 1 .0 �ilJml at I -h after infusion. Because 1.0
�xl/ml cremophor produces some reversal of MDR in vitro (27,
28), a more detailed study of cremophor levels was done at
subsequent dose levels.
Crernophor pharmacokinetics at these dose levels are pre-
sented in Table 3. There were less than proportionate increases
in maximal concentration and apparent A UC�f with increasing
doses. The apparent clearance of cremophor was significantly
faster after 60 ml/m2 than after 30 mi/rn2 (P = 0.02). All
patients at level 4A achieved a plasma cremophor concentration
> 1 .0 pi/mI, but only two reached 1 .5 p.l/ml. All patients at level
5 achieved 1.5 p.l/ml, with 2 reaching �2.0 p.1/mI. At level 6,
only two patients achieved 1 .5 pJ/ml, with one reaching �2.0
�i.l/ml.
Pharmacokinetics of Doxorubicin and Doxorubicinol.
Pharmacokinetics of doxorubicin and doxorubicinol in the pres-
ence and absence of 30 ml/m2 cremophor were evaluated in
eight patients in the cross-over design at level 4A. The pharma-
cokinetic parameters are listed in Table 4, and representative
patients are shown in Fig. 2. The doxorubicin clearance and
A UC1flf were significantly altered in the presence of cremophor
(P = 0.02). The increase in doxorubicin AUC1�1 was 28% ±
27% (mean ± SD) with a range of -2% to 79%. The doxoru-
bicinol AUCT was also significantly increased in the presence of
crernophor (P = 0.02), and the magnitude of the increase was
greater at 105% ± 61% (mean ± SD). This resulted in the
metabolite ratio being significantly higher in the presence of
cremophor (P 0.008).
At dose levels 5 and 6, the doxorubicin dose was reduced
by 30% to balance the increase in A UC11,1 that occurred in the
presence of 30 ml/m2 cremophor. Three patients at level 5 and
three patients at level 6 had doxorubicin and doxorubicinol
pharmacokinetics studied in the cross-over design. Results from
these six patients were combined because there were no statis-
tically significant differences between the two groups. The
doxorubicin AUC1�f (mean ± SD) was 1655 ± 439 ng/mlh after
50 mg/m2 doxorubicin and 1666 ± 280 ng/mlh after 35 mg/m2
doxorubicin with cremophor (P = 0.6). As expected, the doxo-
rubicin clearance was slower in the presence of cremophor,
being 530 ± 1 10 ml/min/m2 (mean ± SD) for doxorubicin
without crernophor and 364 ± 64 ml/min/m2 (mean ± SD) for
doxorubicin in the presence of cremophor (P = 0.03). Despite
the lower doxorubicin dose, the AUC’T for doxorubicinol was
higher after 35 mg/rn2 doxorubicin with cremophor than after 50
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Table 4 Pharmacokinetics (mean ± SD) of doxorubicin anddoxorubicinol
A
E
C
0C0
C)0)
0)C
0C0
C)0)
2ci
1000
100
10
I
1000
100
10
I
0 10 20 30 40 50
B
(1 p = 0.02.
1� p = 0.008.
‘ P = 0.03.
2326 Cremophor with Doxorubicin
50 mg/rn2doxorubicin
50 mg/rn2doxorubicin
with crernophor
Dose level 4Doxorubicin
AUC�� (ng/rnl . h)Cl (ml/min/rn2)
1448 ± 350612 ± 179
1786 ± 264”477 ± 70”
MRT(h)
V5� (L/m2)T112� (h)Tipn (h)� (h)
Doxorubicinol
17.0±8.0618 ± 311
0.08 ± 0.021.7 ± 1.3
22.5 ± 8.4
21.0 ±5.1567 ± 116
0.10 ± 0.022.9 ± 1.3
25.7 ± 5.9
AUCT (ng/rnl . h)Metabolite ratio
252 ± 1040.23 ± 0.07
486 ± 107”
0.37 ± 0.11”
50 mg/rn2doxorubicin
35 mg/rn2doxorubicin
with crernophor
Dose levels 5 and 6Doxorubicin
AUC1flf (ng/rnl . h)
Cl(ml/min/rn2)1655 ± 439
530± 1101666 ± 280
364±64’Doxorubicinol
AUCT (ng/ml . h)
Metabolite ratio453 ± 272
0.3 1 ± 0. 1 1860 ± 428C
0.60 ± 0.22c
mg/rn2 doxorubicin alone (860 ± 428 ng/mlh versus 453 ± 272
ng/mlth; P = 0.03). The metabolite ratio was 0.31 ± 0. 1 1 after
50 mg/m2 doxorubicin and 0.60 ± 0.22 after 35 mg/rn2 doxo-
rubicin with cremophor (P = 0.03).
DISCUSSION
In the initial clinical evaluation of compounds as potential
modulators of MDR, it is important to establish that adequate
amounts of the drug can be administered without producing
excessive normal tissue toxicity. The type of assay used in this
trial allows a more direct measurement of the desired biological
effect of the modulator than measurement of total or free plasma
drug levels and has been used by several groups investigating
new modulators such as PSC 833, S9788, and dexveraparnil (15,
34, 35). Although issues, including the standardization of such
assays, and the relationship between plasma and tumor bioassay
results require further investigation, a bioassay was particularly
appropriate for evaluating cremophor, because when this trial
was performed, the specific component of crernophor that pro-
duces MDR reversal had not been identified, and consequently
no specific assay for it was possible.
When given as a 6-h infusion, 45 mi/rn2 cremophor re-
sulted in plasma levels sufficient to potentially reverse P-gp-
mediated MDR in all patients. Although the limitations of the
bioassay do not allow definitive conclusions about the possible
nonlinear pharmacokinetics of the MDR-modulating compo-
nent(s) of cremophor to be drawn, the 45 mi/rn2 dose appears
most suitable for testing cremophor as a potential MDR modu-
lator in Phase II trials.
0 10 20 30 40 50
Time (hours)
Fig. 2 Plasma concentration-time curves for doxorubicin (circles) ordoxorubicinol (squares) in two representative patients receiving doxo-rubicin alone (open symbols) or with crernophor (closed symbols). A,
patient on dose level 4A, receiving 50 mg/rn2 doxorubicin alone or with30 mI/rn2 cremophor; B. patient on dose level 5, receiving 50 mg/rn2doxorubicin alone or 35 mg/m2 doxorubicin with 45 mI/rn2 cremophor.
Using the same assay, we have reported previously that in
the same patient population after 175 mg/rn2 paclitaxel over 3 or
6 h, the apparent half-life of crernophor was 26.1 ± 8.8 h and
26.4 ± 8.0 h, respectively (29). This is longer than found in this
Phase I study. It is possible that at the lower doses correspond-
ing to this paclitaxel dose, cremophor has a different pharma-
cokinetic behavior. It may also reflect that in the previous study
(29), cremophor levels were only measured up to a maximum of
24 h after completion of the paclitaxel infusion, whereas in this
study, more protracted sampling was undertaken. The present
study is therefore likely to have more accurate calculations of
the apparent half-life. It is also possible that when given corn-
bined with paclitaxel and ethanol, crernophor pharmacokinetics
are different than when cremophor is given alone.
In this trial, all patients were given a standard premedica-
tion schedule. No acute hypersensitivity reactions were ob-
served during cremophor infusions, but toxicities such as rash,
pruritus, and hypotension seen at the higher crernophor doses
are likely to be drug related. The cross-over design allows the
elimination of doxorubicin or the premedications themselves as
causative factors. It is possible that a more protracted regimen of
corticosteroids and/or antihistamines could reduce or prevent
these symptoms. One patient had persistent pruritus after crc-
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Clinical Cancer Research 2327
mophor, a toxicity reported recently in 5 of 14 patients who
received high doses of paclitaxel (250-265 mg/rn2 over 3 h;
Ref. 36).
Although antitumor activity was not an end point of this
Phase I trial, two responses were observed in pretreated patients,
including an almost complete response in a patient with hepa-
torna previously resistant to anthracycline. Tumor biopsy for
P-gp expression was not required in this trial, but hepatomas are
known to express high levels of P-gp (37). This impressive
response demonstrates that additional studies of potential MDR
modulators such as cremophor in patients with hepatoma are
indicated.
A significant pharmacokinetic interaction between cremophor
and doxorubicin was demonstrated in this trial. When administered
with cremophor, the doxorubicin AUC increased by -30%. There
was an even greater increase in the AUC of doxorubicinol. We
have shown previously that in mice, cremophor produced a similar
pharmacokinetic interaction with doxorubicin and doxorubicinol
(38). This successful prediction shows the potential of such pre-
clinical studies to help design clinical trials with potential MDR
modulators. The pharmacodynamic end point of neutropenia was
measured and found to be significantly greater when doxorubicin
was given with cremophor.
The reason for this pharmacokinetic interaction could not
be determined from this trial. Doxorubicin is metabolized to
doxorubicinol by cytoplasmic aldoketoreductase enzymes, and
doxorubicinol is further metabolized to noncytotoxic aglycones
by microsornal P450 reductase. A similar effect to that observed
in this trial with cremophor has been reported when the MDR
modulator cyclosporin A was combined with doxorubicin (13).
Thus with cyclosporin A the doxorubicin AUC increased by
55%, and the doxorubicinol AUC increased by 350% with
increased neutropenia (1 3). In contrast, another trial showed
increased doxorubicin AUC but a lower then expected metab-
olite ratio (14) when doxorubicin and cyclosporin A were corn-
bined; however, patients were not evaluated after doxorubicin
alone (14). Pharmacokinetic interactions have also been re-
ported when doxorubicin has been combined with other MDR
modulators (39, 40), as well as when other drugs primarily
metabolized in the liver such as etoposide and paclitaxel are
combined with MDR modulators (15, 41, 42). Generally, such
interactions are characterized by slower clearance of the cyto-
toxic agent and increased normal tissue toxicity. Direct inhibi-
tion of P-gp in liver, biliary tract, and kidney, inhibition of
metabolizing enzymes such as hepatic cytochrorne P450 sys-
tems, and alterations of protein binding of the cytotoxic agent
may occur as a result of combining the agent with an MDR
modulator. It is likely that the observed pharrnacokinetic inter-
actions reflect a combination of these effects and may be de-
pendent on the modulator and cytotoxic used and perhaps on the
dose and schedule of the cytotoxic agent.
The pharmacokinetic results found in this trial are of rel-
evance for the observed pharmacokinetic interaction between
paclitaxel and doxorubicin. When paclitaxel was given as a 24-h
infusion immediately before a 48-h infusion of doxorubicin, the
doxorubicin clearance was reduced by 30% (43). Gianni et a!.
(44) recently reported a series of pharmacokinetic studies of the
paclitaxel/doxorubicin doublet. When a 3-h infusion of pacli-
taxel was given immediately after bolus doxorubicin, the doxo-
rubicin AUC increased by up to 30%, and the doxorubicinol
AUC increased by up to 100% compared to when paclitaxel was
commenced 24 h after doxorubicin. At least for doxorubicinol,
the effect was more pronounced when the paclitaxel dose was
increased from 150 to 200 mg/rn2. Concurrent 3-h administra-
tion of doxorubicin and paclitaxel led to lower doxorubicin and
doxorubicinol AUCs than bolus doxorubicin followed by a 3-h
pacitaxel infusion (44). In another study where both drugs were
given by 72-h infusion, concurrent paclitaxel increased the
steady-state concentration of doxorubicin and doxorubicinol,
although only the latter was statistically significant (45). Over-
all, despite the different schedules of both drugs used, admin-
istration of paclitaxel reduces the clearance of doxorubicin and
to a greater extent doxorubicinol. Our results indicate this is at
least in part due to the crernophor in the paclitaxel formulation.
Because cremophor is not a pure substance, it is difficult to
develop as a pharmaceutical. Studies to identify the specific
component or components responsible for in vitro MDR rever-
sal (46, 47) and develop potentially more active analogues (48)
have shown some success. Additional clinical studies with crc-
mophor and subsequently with these agents are indicated to
develop this novel class of compounds. Other observed preclin-
ical effects of cremophor may also translate into worthwhile
clinical outcome (49).
ACKNOWLEDGMENTS
We thank the members of the nursing and pharmacy staff at thePeter MacCallum Cancer Institute for their contribution to this study, in
particular Carmel Morton, Ann Fennessy, Ann Woollett, Karen Tin-
nelly, Lisa Sheeran, Rosetta Maisano, Jill Davis, and Judy Bingham. We
also appreciate the thoughtful comments of Professor John Zalcberg on
the manuscript.
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1998;4:2321-2329. Clin Cancer Res M J Millward, L K Webster, D Rischin, et al. Phase I trial of cremophor EL with bolus doxorubicin.
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