Pharmacokinetics of Carboplatin with and without Amifostine in … · Vol. 3, 697-703, May 1997 Clinical Cancer Research 697 Pharmacokinetics of Carboplatin with and without Amifostine

Vol. 3, 697-703, May 1997 Clinical Cancer Research 697

Pharmacokinetics of Carboplatin with and without Amifostine in

Patients with Solid Tumors’

Annelies E. C. Korst,Marianne L. T. van der Sterre,Corien M. Eeltink,

Anne Mane J. Fichtinger-Schepman,Jan B. Vermorken, and Wim J. F. van der Vijgh2University Hospital Vrije Universiteit, Department of MedicalOncology, BR 232, P. 0. Box 7057, 1007 MB Amsterdam[A.E.C.K.,M.L.T.v.d.S.,C.M.E.,J.B.V.,W.J.F.v.d.V.],and

TNO Food and Nutrition Research Institute, P. 0. Box 45, 2280 AARijswijk [A. M. J. F-S.], the Netherlands

ABSTRACT

We showed previously that amifostine (WR 2721;

Ethyol), a protector against carboplatin-induced toxicities,

changed the pharmacokinetics of carboplatin in tumor-

bearing nude mice. In the present study, the influence of

amifostine on the pharmacokinetics of carboplatin was stud-

ied in patients when carboplatin was given in combination

with three doses of amifostine, administered just before the

carboplatin infusion and 2-4 h thereafter. Compared with a

control group of patients who received carboplatin alone,

the patients receiving the combination had a longer final

half-life of ultrafilterable platinum species [5.0 h versus 3.5 h

in patients with a normal creatinine clearance (Clcr > 80

mI/mm); 5.6 h versus 4.2 h in those with an impaired renal

function (50 < Clcr < 80 mI/mm)]. This might be caused by

an influence of amifostine on the renal clearance of carbo-

platin as suggested by a transient increase in serum creati-

nine levels 24 h after treatment in the patients receiving the

combination (mean ± SD: 34.1% ± 17.2% versus -1.8% ±

16.5% in patients treated with carboplatin alone). The im-

pact of these changes on the area under the concentration-

time curves of the ultrafilterable platinum species was

hardly noticeable in patients with a normal renal function

but led to a significant increase in patients with an impaired

renal function (395 ± 59 p.mol/lh versus 280 ± 62 pimol/lh

in patients receiving carboplatin alone). The clinical rele-

vance of this influence is unclear, although theoretically it

may result in an increase in the efficacy of carboplatin, as

has been observed in tumor-bearing nude mice.

Received 6/10/96; revised 12/19/96; accepted 2/4/97.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to

indicate this fact.I This study was supported by Grant IKA 92-104 from the Dutch CancerSociety.2 To whom requests for reprints should be addressed.

INTRODUCTION

Carboplatin [cis-diammine(1,1-cyclobutanedicarboxylato)

platinum(II)] is used in the treatment of several solid tumors. It

has demonstrated less nephrotoxicity, neurotoxicity, and ototox-

icity in comparison to the parent compound cisplatin [cis-diam-

minedichloroplatinum(II)], whereas it appears to have similar

antitumor activity in several tumor types. Its dose-limiting tox-

icity is myelosuppression, especially thrombocytopenia. Modu-

lating agents are under investigation to reduce these Pt3-induced

toxicities and thus to improve their therapeutic efficacy.

Amifostine [S-2-(3-aminopropylamino)ethylphosphoro-thioic acid; WR 2721; Ethyol] was initially developed as a

radioprotector. At present, it is under investigation as an aurac-

tive chemoprotective agent. Preclinical and clinical studies have

shown that amifostine selectively protects against Pt-induced

side effects without reducing the antitumor activity (1-3). This

selective protection is thought to be based on the preferential

formation and uptake of the active metabolite of amifostine, the

aminothiol WR 1065, in nontumor tissues (4, 5).

In some preclinical studies, the combination of amifostine

with a cytostatic agent seemed to be more active than treatment

with the cytostatic agent alone (6-9). We found that amifostine

increased the efficacy of carboplatin in nude mice bearing

OVCAR-3 xenografts. In addition, treatment with amifostine

resulted in higher Pt concentrations in plasma, normal tissues,

and tumor tissue in these mice (9).

The aim of this study was, therefore, to investigate whether

amifostine also influenced the pharmacokinetics of carboplatin

in patients. To this purpose, the pharmacokinetics of carboplatin

were studied both in patients who received carboplatin plus

amifostine within the context of a Phase I trial and in a control

group of patients receiving carboplatin alone. Total Pt, ultrafil-

terable Pt, and intact carboplatin concentrations were deter-

mined in plasma, and the major carboplatin-DNA adducts G-

Pt-G and Pt-GG (10) were determined in WBCs.

MATERIALS AND METHODS

Patients. This pharmacokinetic study was performed

within the context of a Phase I trial, using escalating doses of

carboplatin with amifostine protection, which was performed

both in our hospital and in the University Hospital in Nijmegen

(1 1). In this study, amifostine was given just before and at 2 and

4 h after the start of the carboplatin infusion in a 4-weekly

interval regimen. This treatment schedule was thought to give a

better protection against carboplatin-induced toxicities than a

single administration of amifostine, because the half-life of WR

1065, the active metabolite of amifostine (t#{189}a, 0.19 h; Ref. 12),

is short in comparison to the half-life of carboplatin.

3 The abbreviations used are: Pt, platinum; Clcr, creatinine clearance;AUC, area under the concentration-time curve.

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698 Effect of Amifostine on Carboplatin Pharmacokinetics

Thirty-four patients were entered in this study and were

either treated with carboplatin alone or with carboplatin in

combination with three doses of amifostine. Five of them re-

ceived both treatment schedules, i.e., carboplatin as a single

agent during the first cycle and carboplatin in combination with

amifostine in the second cycle, four weeks later. This intra-patient comparison was only possible in patients treated at the

starting dose level of carboplatin, i.e., 400 mg/m2. In total, 40

cycles were studied: 27 cycles of carboplatin and amifostine and

13 cycles of carboplatin alone. We were unable to investigate

the complete pharmacokinetic profile (plasma pharmacokinet-

ics, Pt-DNA adducts in WBCs, and the cumulative urinary

excretion) during every cycle. In some patients, only the Pt-

DNA adduct levels or the cumulative urinary excretion was

measured.

Patients were classified according to their creatinine clear-

ance, which was calculated from the serum creatinine level with

the Cockcroft formula (13). Twenty-one patients had a creati-

nine clearance of above 80 ml/min, and 1 1 patients had a

creatinine clearance between 50 and 80 mI/mm. One patient had

a severely impaired kidney function (Clcr, 33 ml/min). Contrary

to the other patients, this patient received a reduced dose of

carboplatin ( I 35 mg/m2).

Drug Administration. Carboplatin (150 mg of lyophi-

lized carboplatin/vial with 150 mg of mannitol; Bristol Myers

Squibb, Woerden, the Netherlands) was reconstituted and di-

luted to a total volume of 165 ml with 5% dextrose. Amifostine

(500 mg lyophilized amifostine/vial with 500 mg of mannitol;

USB Pharma, Nijmegen, the Netherlands) was reconstituted and

diluted to a total volume of 55 ml with 0.9% NaCl. Both drugs

were administered as 15-mm i.v. infusions by using syringe

infusion pumps. Amifostine was administered three times, i.e.,

immediately before carboplatin and at 2 and 4 h after the start of

the carboplatin infusion. Carboplatin was administered at a dose

of 400 or 500 mg/m2, except for the patient with the severe

impaired kidney function, who received 135 mg/m2. In some

patients who participated in the Phase I study, the dose of

carboplatin went up to 720 mg/m2. Amifostine was initially

administered at a dose of 910 mg/m2 (n = 2). However, non-

hematological toxicity forced us to reduce the dose of amifos-

tine to 740 mg/m2 (n = 23; Ref. 1 1).

All patients received at least 1 liter of normal saline before

treatment to reduce the chance of hypotension during the ami-

fostine administration. Blood pressure was recorded every 5 mm

during each amifostine administration to allow an interruption

of the infusion when severe hypotension occurred.

Sampling. For plasma pharmacokinetics, blood samples

of 6 ml were taken in cooled heparinized tubes just before

treatment, at the end of the carboplatin infusion, and at 30 mm

and 1, 2, 4, 8, 1 1, 22, and 24 h after the start of the carboplatin

administration. At 4, 8, 1 1, and 22 h after the start, 18 ml of

blood were collected for the additional analysis of Pt-DNA

adducts in the leukocytes. Urine was collected during the first

24 h after starting the carboplatin treatment.

Sample Pretreatment. Blood samples were immediately

placed on ice and centrifuged at 2000 X g for 5 mm at 4#{176}C.

Plasma was ultrafiltrated (1500 X g for 30 mm at 15#{176}C)using

MPS-l systems provided with YMT filters (Amicon, Capelle

a/d Ijssel, the Netherlands). The plasma ultrafiltrate was chro-

matographed in duplicate (2 X 100 p.1) on a reversed phase

column [microspher C18 3p., 100 X 4.6-mm; mobile phase, I

mM phosphate buffer (pH = 7.0)], and the fractions containing

intact carboplatin were collected. The RBCs were washed once

with PBS. Plasma, plasma ultrafiltrate, carboplatin fractions,

and RBCs were stored at -20#{176}C until Pt analysis. For the

analysis of Pt-DNA adducts, 27 ml of whole blood was stored at

- 80#{176}Cuntil analysis. The urine fractions were pooled and after

measuring of the total volume, an aliquot was stored at -20#{176}C

for Pt determination.

Analytical Methods. Plasma samples were diluted 10 or

30 times with 0.38 M NaC1 in 0.5 M HC1 and 0. 1 % Triton

X/Antifoam B. Plasma ultrafiltrate samples were diluted 2.5 or

25 times with 0.15 M NaCI in 0.2 M HC1. The intact carboplatin-

containing column fractions were evaporated and reconstituted

in water. The urine samples were diluted 10 times with 0.15 M

NaC1 in 0.2 M HC1. RBCs were destroyed overnight with 0.5 ml

benzethoniumhydroxide (Sigma Chemical Co., Zwijndrecht, the

Netherlands; at 55#{176}C)and diluted with 4.25 ml 0.2 M hydro-

chloric acid. Calibration standards and quality control samples

were prepared by spiking blank plasma, plasma ultrafiltrate,

urine, and RBCs and were treated the same way as the patient

samples. The Pt concentrations were measured with flameless

atomic absorption spectrophotometry (Spectra AA-300 Zeeman

AAS; Varian, Houtem, the Netherlands).

For the analysis of the carboplatin-DNA adducts, the DNA

was isolated from the leukocytes followed by immunochemical

detection of the Pt-DNA adducts (ELISA; Refs. 14 and 15).

Pharmacokinetic Analysis. The pharmacokinetic pa-

rameters were calculated by the pharmacokinetic data analysis

program Topfit 2.0 (Gustav Fischer, Stuttgart, Germany). For

total Pt and ultrafilterable Pt, a three-compartmental analysis

resulted in the best curve fit, whereas for intact carboplatin, a

two-compartment model was most suitable. This was estab-

lished by inspection and Akaike Information Criterion. A weight

factor of l/y was applied. The results of the two- or three-

compartmental analysis, especially the AUC value (calculated

by using the macro rate constants) and the final half-life, were

compared with the results obtained with the noncompartmental

data analysis to check the quality of the compartmental curve fit.

For the calculation of the final half-life in the noncompartmental

data analysis, the three final data points were used, i.e., for total

Pt and ultrafilterable Pt, t = 1 1, 22, and 24 h, and for intact

carboplatin, t = 4, 8, and 1 1 h. For approximately six plasma

concentration-time curves, the three-compartmental curve fit-

ting of total or ultrafilterable Pt resulted in an unrealistic long

final half-life, when compared to the results from the noncom-

partmental analysis. In that case, the curve was fitted again with

the three-compartmental analysis after fixation of the elimina-

tion rate constant to the value obtained from the noncompart-

mental analysis. Because there were no indications to assume

that the carboplatin pharmacokinetics were not linear with in-

creasing doses, the AUC values were normalized to 400 mg/m2

to compare the pharmacokinetic data of patients treated at

different dose levels of carboplatin.

The pharmacokinetics of carboplatin was investigated dur-

ing 12 courses after treatment with carboplatin alone and during

16 courses of patients treated with carboplatin in combinationwith amifostine. The pharmacokinetic data of one of the patients



Fig. 1 Plasma concentration-timecurves of total Pt (S, 0), ultrafilterable

Pt (A, L�1), and intact carboplatin (U,El) in a patient after treatment withcarboplatin alone (open symbols) andcarboplatin in combination with ami-fostine (closed synthols). Intact carbo-platin after treatment with carboplatinalone (�) was undetectable at 1320rain.

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Clinical Cancer Research 699

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who was treated with carboplatin alone and 4 weeks later with

carboplatin and amifostine could not be integrated in the results

of the two treatment groups, because of the severely impaired

kidney function of the patient (Clcr, 33 mI/mn). The data of this

patient were only used for a within-patient comparison.

Statistics. Student’s t test was used for the statistical

evaluation of the results.

RESULTS

The pharmacokinetic analyses were based on three differ-

ent Pt species: total Pt, ultrafilterable (not protein-bound) Pt, and

intact carboplatin. In Fig. 1, the plasma concentration-time

curves of these three components are shown for a patient, who

was first treated with carboplatin alone and 4 weeks later with

carboplatin and amifostine. An increase in the ultrafilterable Pt

and intact carboplatin concentrations was observed after treat-

ment with carboplatin in combination with amifostine. This was

observed only in the final part of the plasma concentration-time

curves, suggesting a change in the final half-lives. The means of

the pharmacokinetic parameters of the total group of patients

after treatment with carboplatin with and without amifostine are

shown in Tables 1 and 2. Because carboplatin is predominantly

excreted via the kidneys, the pharmacokinetic parameters are

highly dependent on the renal function of a patient. Therefore,

the results of the patients were split up according to their

creatinine clearance. Table 1 shows the results in patients with

a normal kidney function (Clcr > 80 mI/mn), whereas in Table

2, the results are summarized in patients with an impaired

kidney function (50 < Clcr < 80 mI/mn). The AUC values

were normalized to a dose of 400 mg/m2. The individual data of

the AUC values and the final half-lives are shown in Figs. 2

and 3.

The pharmacokinetic parameters after treatment with car-

boplatin alone were comparable to results reported previously

(16). When comparing these data with those after treatment with

carboplatin in combination with amifostine, no influence of

amifostine on the AUC value of total Pt was observed both in

patients with a normal renal function and in patients with an

impaired kidney function (Tables 1 and 2, Fig. 2). However, the

AUC values of ultrafilterable Pt and intact carboplatin, which

are thought to be more related to cytotoxicity than total Pt,

seemed to increase under the influence of the amifostine treat-

ment. This increase was more pronounced in patients with an

impaired renal function (P < 0.05 for ultrafilterable Pt). The

AUC value for total Pt in the erythrocytes of the patients with a

normal renal function was not influenced by amifostine. In the

patients with an impaired kidney function, an increase in AUC

value was observed, but this included only a small number of

patients (Tables 1 and 2). The half-lives of the triphasic decrease

of total Pt in plasma were not influenced by amifostine, although

in both groups (with normal and impaired kidney function) there

was a trend for a decreased final half-life after administration of

amifostine (Tables 1 and 2; Fig. 3). For ultrafilterable Pt, an

increase of t#{189}�5 and t#{189}-� was observed, but this was only signif-

icant for t#{189}-y. In the case of intact carboplatin, a significant

increase in final half-life (t#{189}�) was observed only in the patients

with an impaired kidney function. The mean residence time

showed a tendency to decrease for total Pt and to increase for

ultrafilterable Pt and intact carboplatin after treatment with

amifostine. This was only significant in the case of ultrafilter-

able Pt in patients with a normal renal function. The total body

clearance and the distribution volume were not significantly

influenced by amifostine. No difference in the cumulative uri-

nary excretion was observed between patients treated with car-

boplatin alone and patients treated with carboplatin and amifos-

tine (Tables 1 and 2).

In the patient with the severely impaired kidney function

(Clcr = 33 mI/mn), the same trends were observed when

comparing the pharmacokinetic parameters after treatment with

carboplatin alone during the first course with those after treat-



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ment with carboplatin and amifostine during the second course.

After treatment with amifostine, the AUC values in this patient

increased, from 121 1 to 1465, from 778 to 847, and from 640 to

687 p.Mh for total Pt, ultrafilterable Pt, and intact carboplatin,

respectively. These data related to increases in final half-lives

from 15.4 to 17.3, 5.5 to 7.7, and 3.6 to 4.8 h for total Pt,

ultrafilterable Pt, and intact carboplatin, respectively.

When comparing the results of Table 1 with those in Table

2, the influence of the creatimne clearance on the pharmacoki-

netics of carboplatin is clear. In general, final half-lives and

AUC values were increased, whereas total body clearance and

cumulative urinary excretion decreased in patients with an im-

paired kidney function. Surprisingly, the final half-life of total

Pt decreased in patients with a lower Clcr.

The increase in fmal half-life of ultrafilterable Pt by ami-

fostine suggested an influence of this agent on the renal clear-

ance of carboplatin, which was, however, not confirmed by a

decrease in the cumulative urinary excretion. However, we

investigated whether the addition of amifostine to carboplatin

had an impact on the serum creatinine levels. Indeed, the serum

creatinine concentration (mean ± SD) significantly changed

(P < 0.0001) between 24 and 0 h after the start oftreatment with

carboplatin in combination with amifostine (34.1 ± 17.2%, n

15) in comparison to carboplatin alone (- 1.8 ± 16.5%, n 9).

In Table 3, the values of the major carboplatin-DNA ad-

ducts Pt-GG and G-Pt-G (mean ± SD) are given for blood

samples taken at different time points after the start of the

treatment. Because the adduct levels were very low (the detec-

tion limit is about 0.15 fmol/p.g DNA), the variation was rather

high. However, there was no indication for any influence of

amifostine on the formation or repair of the carboplatin-DNA

adduct levels. No correlation could be found between the DNA

adduct levels and the AUC of ultrafilterable Pt (r� = 0.1-0.7).

DISCUSSIONOur results indicate that treatment with amifostine influ-

ences the pharmacokinetics of carboplatin in patients. The final


Fig. 2 AUC values of total Pt (TPt), ul-trafilterable Pt (UFPt), and intact carbo-platin (carbo) in patients with a normal

renal function (Clcr > 80 mI/mm; #{149},0) oran impaired renal function (50 < Clcr <

80 ml/min; A, A) after treatment with car-boplatin alone (closed symbols) and carbo-platin in combination with amifostine(open symbols).

Fig. 3 Final half-lives of total Pt (TP:), ultra-filterable Pt (UFPt), and intact carboplatin (car-

bo) in patients with a normal renal function(Clcr > 80 mI/rain; #{149},0) or an impaired renal

function (50 < Clcr < 80 mI/mn; A, A) after

treatment with carboplatin alone (closed sym-

bols) and carboplatin in combination with ami-fostine (open symbols).




4 Unpublished results.

Table 3 Pt-DNA adduct levels (mean ± SD) in leukocytes of patients treated with carboplatin alone (CA)or in combination with amifostine (CAWR)

Clcr > 80 mI/mm 50 < Clcr < 80 mI/mm

Pt-GG G-Pt-G Pt-GG G-Pt-G

lime (h) Treatment n (fmol/p.g DNA) (fmol4�g DNA) n (fmol/p.g DNA) (fmol4i.g DNA)

4 CACAWR

27

0.16 ± 0.040.22 ± 0.23

0.18 ± 0.040.33 ± 0.50

2

30.24 ± 0.09

0.15 ± 0.050.30 ± 0.02

0.1 1 ± 0.038 CA

CAWR5

150.22 ± 0.15

0.17 ± 0.080.36 ± 0.31

0.24 ± 0.142

50.24 ± 0.03

0.38 ± 0.290.21 ± 0.01

0.39 ± 0.3211 CA

CAWR5

150.25 ± 0.100.20 ± 0.09

0.32 ± 0.1 10.19 ± 0.10

46

0.43 ± 0.050.36 ± 0.38

0.34 ± 0.240.38 ± 0.24

22 CA

CAWR3

80.21 ± 0.100. 19 ± 0. 10

0.19 ± 0.050. 16 ± 0.06

02 0.16 ± 0.15 0.16 ± 0.08

half-lives of ultrafilterable Pt and intact carboplatin were in-

creased (Table 1; Fig. 3). This may be explained by an influence

of amifostine on the distribution of carboplatin. However, an

influence of amifostine on the renal clearance of carboplatin is

a more plausible explanation because an increase in serum

creatinine concentration was observed in patients treated with

carboplatin in combination with amifostine. This increase was

only transient and completely reversible, because within 1 week,

serum creatinine levels returned to normal in all cases. As a

result, the AUCs of the Pt species increased, but only to a small

extent, because only the relatively low concentrations at the end

of the curve were enhanced.

The influence of amifostine on the renal clearance of

carboplatin, however, was not accompanied by a decrease in the

cumulative urinary excretion. This suggested that the reduction

of the kidney function was not an immediate effect of amifostine

but mainly manifested itself after 6 h when most of the free

carboplatin was already excreted in the urine (17).

For total Pt, no increase in final half-life was observed, but

instead a trend for a decrease in final half-life was seen when

amifostine was administered. In combination with the observed

increase in the final half-life of ultrafilterable Pt, this suggests a

possible change in the binding of carboplatin to proteins. How-

ever, in vitro, amifostine nor its active metabolite WR 1065 has

an influence on the protein binding of carboplatin.4 Surpris-

ingly, when the final half-life of total Pt in patients with an

impaired renal function was compared to the final half-life in

patients with a normal kidney function, a decrease instead of an

increase in final half-life of total Pt was observed (Table 1versus 2). This suggests that the final half-life of total Pt is not

primarily dependent on the kidney function. As reported earlier

for cisplatin, it is largely dependent on the turnover rate of the

proteins to which the Pt compound binds irreversibly (18). In

contrast, t#{189}f3 of total Pt was slightly increased under the influ-

ence of amifostine treatment, which might be explained by the

predominant presence of free Pt species during the first part of

the elimination phase.

The influence of amifostine on the Pt-DNA adduct levels in

leukocytes is still unclear. Because the protective effect of

amifostine is thought to be based on the prevention of the

formation of Pt-DNA adducts in normal tissues, a decrease in

Pt-DNA adduct levels would have been expected. However, the

observed influence of amifostine on the pharmacokinetics of

carboplatin resulting in higher ultrafilterable Pt concentrations

in plasma would possibly result in the opposite effect. Because

of the low Pt-DNA adduct levels and the large variation, no

conclusion can be drawn.

Our results regarding the influence of amifostine on the

AUC and final half-life of, especially, ultrafilterable Pt do not

correspond to data reported previously. Budd et a!. (19) reported

that no pharmacokinetic interaction between carboplatin and

amifostine was observed in patients treated with carboplatin in

combination with two doses of amifostine. However, this was

investigated in only four patients, and no control group was

included in this study.

In nude mice studies, treatment with carboplatin in com-

bination with amifostine not only resulted in an increase of Pt

concentrations in plasma ultrafiltrate but also in tumor and

normal tissues. This was probably the explanation for the ob-

served increase in antitumor activity of carboplatin when com-

bined with amifostine (9). Whether this effect also occurs in

patients is still unclear. The influence of amifostine on the

plasma pharmacokinetics of carboplatin was less pronounced in

patients than in nude mice, and the influence on the Pt concen-

trations in tissues, especially tumor tissue, in patients is still

unknown. In patients, the influence of amifostine on the phar-

macokinetics of carboplatin was observed in the last part of the

Pt concentration-time curve. Thus, the effect of amifostine was

only observed on relatively low Pt concentrations. Therefore,

the clinical relevance of this pharmacokinetic interaction is

uncertain, and whether amifostine has an impact on the efficacy

of carboplatin in patients still needs to be established. There is

no reason to assume that the pharmacokinetic interaction be-

tween carboplatin and amifostine will have a negative effect on

the reduction of the carboplatin-induced toxicities by amifos-

tine. The maximum tolerated dose of carboplatin, given in

combination with three doses of amifostine, was increased to

500 mg/m2 in patients treated previously and 720 mg/m2 in

chemo-naive patients (20). Dose-limiting toxicity on both occa-sions consisted of myelosuppression, with two of five patients

showing grade 4 neutropenia and three of five showing grade 4

thrombocytopema at the highest dose level in the chemo-naive




patients. Additional details about the toxicities observed during

the Phase I trial will be part of a separate report.

In conclusion, the treatment of patients with carboplatin in

combination with three doses of amifostine resulted in an in-

crease of the final half-life of ultrafilterable Pt and a small

increase in the AUC value. This pharmacokinetic effect could be

due to a direct influence of amifostine on kidney function,

because also an increase in serum creatinine levels was ob-

served. The clinical relevance of this influence is still unclear.However, theoretically it might result in an increase in the

efficacy of carboplatin, as has been observed in tumor-bearing

nude mice.

ACKNOWLEDGMENTS

H. Gall is acknowledged for excellent assistance.

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1997;3:697-703. Clin Cancer Res A E Korst, M L van der Sterre, C M Eeltink, et al. patients with solid tumors.Pharmacokinetics of carboplatin with and without amifostine in

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Pharmacokinetics of Carboplatin with and without Amifostine in … · Vol. 3, 697-703, May 1997 Clinical Cancer Research 697 Pharmacokinetics of Carboplatin with and without Amifostine