phase i trial of cremophor el with bolus doxorubicin · mum2 cremophor reached plasma levels 1.5...

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: [email protected].

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.



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



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


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




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



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.


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”



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-




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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