Clinical Cancer Research Vol. 6, 1288-1292, April 2000
© 2000 American Association for Cancer Research
Topotecan Lacks Third Space Sequestration
Hans Gelderblom,
Walter J. Loos,
Jaap Verweij,
Maja J. A. de Jonge and
Alex Sparreboom1
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 EA Rotterdam, the Netherlands
 |
ABSTRACT
|
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The objective of
this study was to determine the influence of pleural and ascitic fluid
on the pharmacokinetics of the antitumor camptothecin derivative
topotecan. Four patients with histological proof of malignant solid
tumor received topotecan (0.45 or 1.5 mg/m2) p.o. on
several occasions in both the presence and absence of third space
volumes. Serial plasma and pleural or ascitic fluid samples were
collected during each dosing and analyzed by high-performance liquid
chromatography for both the intact lactone form of topotecan and its
ring-opened carboxylate form. The apparent topotecan clearance
demonstrated substantial interpatient variability but remained
unchanged within the same patient in the presence [110 ± 55.6
liters/h/m2 (mean ± SD of eight courses)] or absence
of pleural and ascitic fluid [118 ± 31.1 liters/h/m2
(mean ± SD of seven courses)]. Similarly, terminal half-lives
and area under the concentration-time curve ratios of lactone:total
drug in plasma were similar between courses within each patient.
Topotecan penetration into pleural and ascitic fluid demonstrated a
mean lag time of 1.61 h (range, 1.37–1.86 h), and ratios with
plasma concentration increased with time after dosing in all patients.
The mean ratio of third space topotecan total drug area under the
concentration-time curve to that in plasma was 0.55 (range,
0.26–0.87). These data indicate that topotecan can be safely
administered to patients with pleural effusions or ascites and that
there is substantial penetration of topotecan into these third spaces,
which may prove beneficial for local antitumor effects.
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INTRODUCTION
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The increased risk of toxicity after chemotherapy in patients with
pleural effusions and massive ascites is widely known and has been well
documented for several compounds including methotrexate (1
, 2)
and fludarabine (3)
. This phenomenon is most
likely related to greater drug accumulation in the peripheral
compartment and a slower transport back to the central compartment,
ultimately resulting in prolonged drug exposure. For this reason, it is
advisable to evacuate large pleural and ascitic effusions before
administration of these agents. On the other hand, penetration of the
delivered chemotherapeutic agent should be sufficient to produce
adequate drug distribution into the pleural or ascitic fluid to induce
relevant local antitumor effects (4)
.
Diffusion of p.o. or systemically administered drugs into the
peritoneum may be diminished by fibrous tissue due to prior surgery or
prior regional i.p. chemotherapy, as reported for mitomycin C
(4)
. In addition, several other factors including
molecular weight, hydrophobicity, blood and lymph flow, and the
capacity of the capillary wall and intervening interstitium have been
shown to affect the peritoneal-blood barrier (5)
. The same
factors may also be applicable for pleural effusions and the pleural
fluid-blood barrier, although few paired plasma/pleural fluid
pharmacokinetic data are available for antineoplastic agents
(5, 6, 7)
.
In the absence of any pharmacokinetic data on third space sequestration
for topotecan, a topoisomerase I inhibitor with substantial antitumor
activity against various malignancies (reviewed in Ref.
8
), we have prospectively evaluated the extent of
penetration of this drug in pleural and ascitic fluid in cancer
patients and assessed the influence of these third spaces on topotecan
plasma pharmacokinetics.
|
MATERIALS AND METHODS
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Patients and Treatment.
Four patients with a histologically confirmed diagnosis of a malignant
solid tumor that was metastatic and progressive after prior therapy
were studied (Table 1)
. All patients had
adequate hematopoietic (absolute neutrophil count 
1.5 x
109/liter and platelet count 100 x
109/liter), hepatic (total serum bilirubin < 1.25 x upper normal limits), and renal (creatinine
clearance 60 ml/min) function (9)
. The study drug
topotecan was supplied as capsules containing either 0.25 or 1.0 mg of
the active compound (SmithKline Beecham Pharmaceuticals Inc., Harlow,
United Kingdom) and administered p.o. once daily, after an overnight
fast, either for 5 consecutive days and repeated every 3 weeks (three
patients) or for 2 consecutive days and repeated every week (one
patient). In all four patients, comedication was uniform and consisted
of cisplatin (50 or 70 mg/m2 administered as a
3-h i.v. infusion immediately before topotecan on day 1 of every
course) and ondansetron (8 mg, i.v.) combined with dexamethasone (10
mg, i.v.) given 30 min before cisplatin. During therapy, the patients
did not use any other medication that might have interfered with
topotecan absorption and disposition. The clinical protocol was
approved by the institutional review board, and patients signed
informed consent forms before entering the study.
Sample Collection.
Material for pharmacokinetic analysis was collected during the first
treatment course on days 1, 2, and 5 from patients on the 5-day
schedule and during courses 1, 2, and 3 on days 1 and 2 from the
patient on the 2-day schedule. Blood samples were collected in 4.5-ml
glass tubes containing lithium heparin as an anticoagulant (Becton
Dickinson, Meylan, France) and were obtained before dosing and 0.5, 1,
1.5, 2, 3, 4, 6, 8, and 12 h after topotecan administration. The
blood samples were placed immediately in an ice bath and centrifuged
within 10 min at 3000 x g for 5 min at 4°C to
separate the plasma. Subsequently, a volume of 250 µl of the plasma
sample was added to 750 µl of ice-cold (-20°C) methanol in 2.0-ml
polypropylene vials (Eppendorf, Hamburg, Germany). After vortex mixing
for 10 s, the samples were stored at -80°C until the day of
analysis. Pleural and ascitic samples were obtained at the same time
points as blood samples using a Medicut 16GA cannula (45 x 1.7
mm, internal diameter; Sherwood Medical, Tullamore, Ireland) and
collected in 4.5-ml polypropylene tubes after discarding the first 10
ml of fluid. These samples were processed as described above for
plasma. To assess the extent of drainage of all fluid, ultrasonography
or chest X-ray was performed after drainage.
Topotecan Assay.
The samples, plasma as well as pleural liquid and ascites, were
analyzed using reverse-phase high-performance liquid chromatography
with fluorescence detection as described previously (10)
,
with minor modifications. In brief, samples were centrifuged for 5 min
at 23,000 x g at 4°C, followed by a 5-fold dilution
in PBS before the injection of 200-µl aliquots into the
high-performance liquid chromatography system. Chromatographic
separations of topotecan carboxylate and lactone forms and endogenous
compounds were achieved on a Hypersil BDS column (100 x 3 mm,
internal diameter; 3-µm particle size; Shandon, Cheshire,
United Kingdom) that was maintained at 35°C. The mobile phase,
composed of 10 mM potassium
dihydrogenphosphate-methanol-triethylamine (1750:500:4, v/v/v) with the
pH adjusted to 6.0 (orthophosphoric acid), was delivered at a flow rate
of 0.70 ml/min. The excitation and emission wavelengths of the Jasco
FP920 fluorescence detector (Tokyo, Japan) were set at 381 and 525 nm,
respectively, with an emission bandwidth of 40 nm. Chromatographic data
analysis was performed based on peak height measurements relative to
injected standards using the ChromCard system of Fisons (Milan, Italy).
Pharmacokinetic Analysis.
Individual plasma concentrations of topotecan lactone and carboxylate
forms were fit to a linear two-exponential equation using the Siphar
version 4 software package (SIMED, Creteil, France), based on a variety
of considerations including Akaike’s and Schwarz’ information
criterion. The concentration-time profiles were obtained after
zero-order input, with a weighted least-squares algorithm applying a
weighting factor of 1/y. The
AUC2
values were
determined for both the lactone (AUCL) and
carboxylate forms (AUCC) on the basis of the best
fitted curves. The apparent plasma CL/f was calculated by dividing the
dose administered by the observed AUC. The apparent terminal
disposition half-life (T1/2) was
calculated as ln2/kel, where
kel is the observed elimination rate
constant of the terminal phase. The peak plasma concentrations
(Cmax) were determined graphically
from the observed experimental values. The L:T ratio was defined as
AUCL/(AUCL +
AUCC). The fraction of drug penetrating into
pleural or ascitic fluid was derived from the ratio of the topotecan
total drug AUCs in the third space and plasma.
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RESULTS
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Plasma Pharmacokinetics.
Peak plasma concentrations and AUCs of topotecan lactone after
administration of a p.o. dose of 1.50 mg/m2 to
patients 1 and 2 were similar before and after pleural fluid was
drained (fluid volumes, 3.1 liters and 1.1 liter, respectively; Table 2
). Complete drainage of all fluid was
confirmed by ultrasonography or chest X-ray after drainage. Data from
patient 3, who had recurrent ascites during all topotecan
administrations with volumes of 8.4 and 9.4 liters drained on days 2
and 6, respectively, indicated no difference in pharmacokinetic
parameters between treatment days. Similarly, ascites (estimated to be
4.0 liters, 1.0 liter, and 1.0 liter on three occasions by
ultrasonography and percutaneous drainage) had no measurable effect on
topotecan plasma pharmacokinetics in patient 4 (Table 2)
. Overall, the
CL/f demonstrated substantial interpatient variability but remained
unchanged within the same patient in the presence [110 ± 55.6
liters/h/m2 (mean ± SD; eight courses)] or
absence of pleural or ascitic fluid [118 ± 31.1
liters/h/m2 (mean ± SD; seven courses)].
Topotecan L:T ratios in plasma were very similar between courses within
each patient and averaged 40.0 ± 3.89% (drained) and 40.0 ± 6.11% (not drained), respectively.
Pleural and Ascitic Fluid Penetration.
Given the low plasma protein binding of topotecan (
35%; Ref.
11
) and the relatively high total protein content in
pleural fluid and ascites of the patients (range, 38–45 mg/ml), no
correction for protein binding was performed. Topotecan concentrations
in pleural fluid and ascites peaked at 6 h after oral dosing,
demonstrating a mean lag time of 1.61 h (range, 1.37–1.86 h;
overall mean ± SD in plasma, 0.63 ± 0.28 h), and rose
slowly to equal that in plasma by 8 h (Fig. 1, A–C)
. Topotecan
disappearance from pleural fluid [apparent
T1/2, 12.0 h (n =
1)] and ascites [apparent T1/2,
8.0 h (n = 1)] appeared to be slower than that
from plasma. As a result, third space penetration, expressed as the
ratio of concomitant pleural fluid or ascites:plasma concentration of
total topotecan, depended greatly on the sampling time point and
increased significantly with time in all patients (Fig. 1, D–F)
. Overall, the mean ratio of third space topotecan
total drug AUC to that in plasma was 0.55 (range, 0.26–0.87). The
hydrolysis of topotecan to the ring-opened form was rapid, and L:T AUC
ratios were 18.1% and 23.5% in pleural fluid and 29.2% in ascites.
Measurement of topotecan in ascites from patient 3 indicated that less
than 1% of the administered dose was present in ascites at 6–8 h
after dosing, indicating the lack of a sink effect.
Toxicity.
Overall, treatment was very well tolerated in the four patients. No
severe hematological toxicity or other organ toxicity was observed
after p.o. topotecan administration at these doses. The third patient
experienced fatigue (grade 2 on a 4-point scale, National Cancer
Institute Common Toxicity Criteria), whereas the fourth patient had
mild nausea and vomiting.
|
DISCUSSION
|
|---|
This study was performed to explore the influence of
pleural and ascitic fluid on the pharmacokinetic behavior of topotecan
in cancer patients. Although the topotecan administration was preceded
by cisplatin infusion in this study in all patients, important
pharmacokinetic interactions that may have influenced the generated
data are not very likely: (a) comparison of the kinetics of
topotecan in clinical combination therapy regimens with cisplatin with
the kinetics of single-agent therapy did not reveal an apparent
interaction (12)
; and (b) using a randomized
cross-over design for the administration order, no statistically
significant differences in clinical pharmacokinetics were observed
between sequences of p.o. topotecan and i.v. cisplatin
(9)
.
Topotecan concentrations in pleural fluid and ascites were initially
less than those in plasma, and several hours were required for
equilibrium to be attained between these fluids and plasma. The limited
surface area for topotecan diffusion relative to the volumes of fluid
and the fact that pleural fluid and ascites are not well stirred, in
addition to the hydrophilic nature of the drug, likely contributed to
the slow equilibrium kinetics. Overall, both pleural fluid and ascites
represented only a small additional compartment for topotecan
distribution, particularly in view of the already large topotecan
steady-state volume of distribution of 73-133 liters (13)
.
Nevertheless, concentrations equivalent to that in plasma were achieved
after 8 h, and topotecan appeared to be more slowly eliminated
from the pleural and peritoneal cavity than from plasma. This is in
keeping with earlier findings indicating slow peritoneal clearance of
topotecan and high peritoneal:plasma concentration ratios of >10 after
i.p. drug administration (14
, 15)
.
Topotecan has been detected previously in ascites of two patients
treated with a combination of i.v. topotecan and p.o. etoposide
(16)
. However, the reported ascitic fluid:plasma
concentration ratios were established by single-point measurements at
different times after administration. Because these concentration
ratios were shown in our patients to be by no means constant parameters
during the dosing interval (Fig. 1, D–F)
, single-point data
are clearly inappropriate to directly compare the extent of penetration
by topotecan. Hence, the approach of using paired AUC values in third
space fluids and plasma, as performed in the present study, should be
considered the gold standard to report these ratios. Although the
described data on topotecan accumulation are limited to only four
patients, our results suggest that oral administration of topotecan can
produce adequate drug distribution in pleural fluid and ascites at
concentrations associated with significant antitumor activity in
experimental models (17
, 18)
. In this context, it is of
particular interest that topoisomerase I inhibitors were previously
shown to be highly S-phase specific and that cytotoxicity is a function
of the time to drug exposure above a certain threshold concentration
(19)
. The topotecan penetration and subsequent
accumulation in the third spaces thus might offer a potential
therapeutic advantage in that tumor cells in the thoracic and
peritoneal cavity are exposed to high local drug levels for prolonged
time periods. This concept has also been described recently for
systemic therapy with the structurally related camptothecin derivative
irinotecan, although in contrast to topotecan, concentrations appeared
to decline in parallel with those in plasma (20)
. The
reason for this discrepant behavior is unknown, but it is likely to
reflect intrinsic differences in physicochemical and/or pharmacokinetic
properties of both compounds, including differential binding to
(plasma) proteins.
The plasma pharmacokinetics of topotecan revealed a substantial degree
of interindividual variability, in line with previous observations
(9)
.3
By comparing topotecan plasma levels in the same patient before and
after drainage of pleural or ascitic fluid, no differences in rate of
absorption and elimination became apparent. The lack of increased
systemic exposure to topotecan in patients with massive third space
volumes was further substantiated by the lack of excess toxicity.
Hence, in contrast to clinical information on irinotecan treatment that
suggested an increased risk of severe toxicity in patients with large
pleural effusions or ascites (20)
, there was no evidence
that the severity of toxicity differed between study courses with and
without third space volumes in our patients treated with topotecan.
In conclusion, we have shown that: (a) topotecan plasma
pharmacokinetics are unaltered in patients with third space volumes;
(b) topotecan can be safely administered to patients with
large pleural effusions or massive ascites; and (c) there
appears to be a substantial penetration of topotecan into these third
spaces, which may prove beneficial for local antitumor effects.
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FOOTNOTES
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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.
1 To whom requests for reprints should be
addressed, at Department of Medical Oncology, Rotterdam Cancer
Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam,
Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands. Phone:
31-10-4391112; Fax: 31-10-4391053; E-mail: sparreboom{at}onch.azr.nl 
2 The abbreviations used are: AUC, area under the
concentration-time curve; CL/f, topotecan clearance; L:T, the ratio of
the systemic exposure of topotecan lactone to total drug.
3 W. J. Loos, H. Gelderblom, J. Verweij,
M. J. A. de Jonge, and A. Sparreboom. Inter- and intrapatient
variability in oral topotecan pharmacokinetics: implications for body
surface area dosage regimens, submitted for publication.
Received 9/24/99;
revised 12/23/99;
accepted 12/29/99.
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Top
ABSTRACT
INTRODUCTION
) and ascites (patients 1 and 2) or pleural fluid (patient
4; •) and corresponding topotecan third-space fluid:plasma
concentration ratios (
) in patients 1 (A and
D), 2 (B and E), and 4
(C and F).