Vol. 4, 783-789, March 1998 Clinical Cancer Research 783

Phenytoin Alters the Disposition of Topotecan and N-Desmethyl

Topotecan in a Patient with Medulloblastoma1

William C. Zamboni, Amar J. Gajjar,

Richard L. Heideman, Jos H. Beijnen,

Hilde Rosing, Peter J. Houghton, and

Clinton F. Stewart2Departments of Pharmaceutical Sciences [W. C. Z.. C. F. S.],Hematology/Oncology [A. I. G., R. L. H.], and MolecularPharmacology [P. J. H.], St. Jude Children’s Research Hospital,Memphis, Tennessee 38105: Department of Pharmacy andPharmacology, Sbotervaart Hospital and Netherlands Cancer Institute,

Amsterdam, the Netherlands [J. H. B., H. R.]: Pharmacology,University of Tennessee, Memphis, Tennessee 38105 [P. J. H.]: andThe Center for Pediatric Pharmacokineties and Therapeutics,University of Tennessee, Memphis, Tennessee 38 105 [P. J. H.,C. F. S.]

ABSTRACT

Topotecan undergoes both renal and hepatic elimina-

tion, with topotecan urinary recovery ranging from 60 to

70%. We evaluated the potential of phenytoin to alter thedisposition of topotecan and its N-desmethyl metabolite. A

5-year-old child with high-risk medulboblastoma received

the first course of topotecan with phenytoin and the second

course without phenytoin. For both courses, topotecan doseswere adjusted to achieve a target topotecan lactone plasma

area under the curve (AUC). Serial plasma samples wereobtained, and lactone and total plasma concentrations of

topotecan, as well as total plasma and cerebrospinal fluidconcentrations of N-desmethyl topotecan, were measured by

high-performance liquid chromatography. Phenytoin coad-

ministration increased lactone and total topotecan clearance

from 43.4 ± 1.9 L/h/m2 to 62.9 ± 6.4 L/h/m2, and 20.8 ± 2.8

L/h/m2 to 30.6 ± 4.1 L/h/m2, respectively (P < 0.05). Con-

comitant phenytoin increased the plasma AUC of total N-

desmethyl topotecan from 7.5 ± 0.68 ng/mlh to 16.3 ± 0.53

ng/mlh (P < 0.05) at plasma AUC of total topotecan of

226.0 ± 5.5 ng/ml-h and 240.9 ± 39.8 ng/mb-h, respectively.

N-Desmethyl topotecan penetrated into the cerebrospinal

fluid (0.12 ± 0.01). The patient experienced no grade 3 or 4toxicity. These are the first data documenting altered topo-

tecan and N-desmethyb topotecan disposition when coadmin-

istered with phenytoin and suggests that topotecan may

Received 10/24/97; revised 12/2/97: accepted 12/3/97.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 toindicate this fact.

I Supported by USPHS Award CA23099, Cancer Center Support GrantCA21765; and the American Lebanese, Syrian Associated Charities.2 To whom requests for reprints should be addressed. at Department ofPharmaceutical Sciences, St. Jude Children’s Research Hospital. 332North Lauderdale, Memphis, TN 38105-2794. Phone: (901 ) 495-3665:Fax: (901) 525-6869.

undergo further hepatic metabolism. Although there is an

increase in exposure to the active N-desmethyl topotecan

metabolite, it is less than the decrease in exposure to topo-

tecan lactone. Therefore, patients concomitantly adminis-

tered phenytoin may require an increase in topotecan dose

to achieve a similar pharmacological effect as a patient not

receiving phenytoin.

INTRODUCTION

Topotecan is a eamptothecin analogue and topoisomerase I

interactive agent ( 1-3). Topotecan undergoes reversible pH-

dependent hydrolysis between the aetive-lactone and inactive-

hydroxy acid forms (2-4). Topotecan undergoes both renal and

hepatie elimination. In children, topotecan total (sum of topo-

tecan laetone and hydroxy acid) urinary recovery ranges from

60 to 70%, suggesting that renal elimination is the primary

clearance pathway (5, 6). We have reported significant intenpa-

tient variability in topotecan laetone pharmacokinetics in chil-

dren with normal renal and hepatie function, with topotecan

lactone clearance ranging from 4.5 to 48.6 L/h/m2 (7). However.

intrapatient variability in topotecan pharmacokineties is reba-

tively small, with a change in topotecan lactone clearance from

cycle one to cycle two of 8.4 ± 5.3% (8, 9). In addition, we

performed a study evaluating topotecan disposition in pediatric

patients with altered renal function, which suggested that topo-

tecan undergoes elimination by processes other than gbomerular

filtration, including hepatie metabolism, biliary secretion. and

renal tubular secretion (10). However, a recent Phase I study of

topotecan in adults with normal and impaired hepatic function

reported no differences in topotecan pharmacokinetics or max-

imum tolerated dose (1 1).

Approximately 30-40% of topotecan undergoes elimina-

tion by nonrenal pathways. Recently, the N-desmethyl metabo-

bite of topotecan was isolated from the urine of patients receiv-

ing topotecan (12). This metabolite has equal antitumor activity

to the parent compound,3 and its formation is consistent with a

hydnoxylation step catalyzed by the CYP� system (Fig. 1 : Ref.

12). However, the CYP isoform responsible for formation of

N-desmethyl topotecan is unknown. The maximum plasma con-

eentration of total (sum of lactone and hydroxy acid) N-des-

methyl topoteean was only 0.5% of total topotecan, and the

average amount of metabolite recovered in the urine was 3-4%

of the administered dose of topotecan. Thus, other nonnenal

routes (e.g. , metabolism) of topoteean elimination are yet to be

identified.

In a previous study, we noted that topotecan clearance was

3 R. Johnson, personal communication.4 The abbreviations used are: CYP. cytochrome P-450: CSF. cerebro-spinal fluid; AUC. area under the plasma concentration-time curve:9-AC, 9-aminocamptothecin.

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CH3

CH3

.� CH3

1�OH

H

CH3

H

784 Phenytoin Increases Topotecan Clearance

CH3

0H

�H�

0H�

H�

Fig. I Metabolic schema fortopoteean. Topotecan under-goes a pH-dependent equilib-rium between the aetive-bactoneand inactive-hydroxy acidforms. In addition, topotecanundergoes oxidative metabo-

lism to form the N-desmethylmetabolite.

greater in patients receiving phenytoin and/or phenobarbital

than those not receiving anticonvulsants ( 13). Phenytoin metab-

olism is mediated by CYP 2C9/l0 isozymes (14-16) and has

been reported to induce CYP 3A, 2B. and 2C9/lO isozymes

( 17-20). Thus, we evaluated the disposition of topotecan and the

N-desmethyl metabolite when administered with and without

phenytoin in the same patient (7, 8, 21).

PATIENT AND METHODSC. S. is a 5-year-old white male diagnosed with medullo-

blastoma, who was enrolled on the high-risk arm of the St. Jude

Children’s Research Hospital risk-adapted medulloblastoma

protocol. Patients were defined as high-risk if there was meta-

static disease or if residual disease after surgery. as documented

on post operative imaging, was > 1 .5 em2. After surgical resee-

tion, high-risk patients received two cycles of topotecan, as

up-front window therapy. followed by eraniospinab irradiation

and high-dose chemotherapy. The study was approved by the

Institutional Review Board at St. Jude Children’s Research

Hospital, and informed, written consent was obtained from the

patient’s parents.

Topotecan was chosen for this protocol because of its

activity in xenograft models of pediatric brain tumors, including

Daoy and Si-Med3 human medulboblastoma xenografts, as well

as the high degree of CSF penetration (30 to 40%) in humans

(22-25). In this protocol. topoteean is administered as a 30-mm

infusion daily for 5 days repeated every 2 1 days for two cycles.

To account for the wide interpatient variability in topotecan

clearance. we adjusted the topotecan dose to attain a single-day

topotecan lactone systemic exposure (as measured by AUC) of

140 ± 20 ng/ml-h (7). A topotecan dose of 2.0 mg/m2 was

administered on day 1. Serial plasma (pre, 0.25, 0.5, 1, 3, and

6 h after administration) and CSF samples (pre, 0.5, 3, and 6 h

after administration) were obtained on days 1, 2, and 5. Based

on the plasma pharmacokinetie results of the preceding day,

topotecan dose was adjusted to attain the target AUC.

Drug Administration and Sample CollectIon. During

cycle 1, the patient received phenytoin oral suspension (5.2

mg/kg/day) as seizure prophybaxis starting 4 weeks prior to

receiving topotecan on cycle 1. On day 1 of topotecan, the total

phenytoin plasma concentration, measured by fluorescence

polarization immunoassay (Tdx; Abbott Laboratories, Abbott

Park, IL), was 3.5 mgIL. Phenytoin was discontinued 17 days

prior to the second cycle of topotecan. The phenytoin plasma

concentration was undetectable on day 1 of the second treatment

cycle.

Plasma samples for topotecan bactone and total (sum of

lactone and hydroxy acid) and plasma and CSF samples for total

N-desmethyl topotecan were processed as described previously

(5, 6, 12, 25). Separate isocratic high-performance liquid chro-

matography assays with fluorescence detection were used to

determine topotecan lactone and total concentrations (6, 25, 26)

and total N-desmethyl concentrations (27).

Pharmacokinetic Analysis A two-compartment model

was fit to topotecan lactone plasma concentration-time data

using Bayesian estimation as implemented in ADAPT II (28,

29) with a prior for the parameter distribution defined by the

independent means and variances from published data for topo-

tecan in children included in the objective function (5, 6, 30).

Individual parameters estimated included volume of central

compartment (Vt), intereompartment rate constants (K12 and

K21), and elimination rate constant (K10). Other parameters

calculated included systemic clearance (CLLAC), volume of

distribution at steady-state (Vd�J, and AUC (A UCLAC) from

zero to infinity (29-31).

To identify total topotecan and total N-desmethyl plasma

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Clinical Cancer Research 785

k43

k12 �LTPT1

4

k21 __________

Fig. 2 Four-compartment model describing topotecan and N-des-

methyl topotecan plasma concentration-time data. The administration oftopotecan is represented by R0. Parameters estimated included the vol-ume of the central compartment for topotecan and N-desmethyl ( Va).

intercompartment rate constants for topotecan (K12 and K21 ), the elim-ination rate constant for topotecan (K50), the rate constant for N-des-methyl formation (K13), the elimination rate constant for N-desmethyl(K30), the rate constant for N-desmethyl CSF penetration (K34). and therate constant for N-desmethyl elimination from the CSF (K43); thevolume of the CSF (V�4) was fixed at 0.14 liter.

pharmacokinetie parameters, a three-compartment model was fit

to total topotecan and total N-desmethyl plasma concentration-

time data using weighted least-squares estimation as imple-

mented in ADAPT II (Fig. 2; Refs. 28 and 29). To achieve

model identifiability, the volume of the central compartment

was assumed to be the same for total topotecan and total

N-desmethyb topotecan. Individual parameters estimated in-

eluded volume of central compartment for total topoteean and

N-desmethyb topotecan (Vu), intereompartment rate constants

for topotecan , and � ),and elimination rate constant for

topotecan (K1 �), rate constant describing N-desmethyl formation

(K13), and elimination rate constant for N-desmethyb (K30).

Parameters calculated included volume of distribution at steady-

state for topotecan and N-desmethyl topotecan (Vd�J, clearance

of topotecan (CL�.oT), clearance of N-desmethyl topotecan

(CLNdm), AUC for topoteean (AUCTOT), and N-desmethyl to-

potecan (A UCNdm) from zero to infinity (29, 3 1). Ratios of

A UCLAC to A UCTOT and A UCNdm tO A UCTOT were calculated.

To identify N-desmethyl CSF pharmacokinetie parameters,

a four-compartment model was fit to total topotecan plasma

concentration-time data and total N-desmethyl topotecan plasma

and CSF concentration-time data using weighted beast-squares

estimation as implemented in ADAPT II (Fig. 2; Refs. 28 and

29). To achieve model identifiability, the volume of the central

compartment was assumed to be the same for total topoteean

and total N-desmethyb, and the volume of CSF (Vc4) was fixed

at 140 ml (25). Individual parameters estimated included those

defined for the three-compartment model, as well as the rate

constant for N-desmethyb penetration into the CSF (K34) and the

elimination rate constant for N-desmethyl from the CSF (K43).

Parameters calculated included those for the three-compartmen-

tab model, as well as clearance of N-desmethyb topotecan from

the CSF (CLNdmCSF) and area under the CSF concentration-time

curve for N-desmethyb topotecan (A UCNdmCSF) from zero to

infinity (29, 31). N-Desmethyl penetration into the CSF was

calculated as the A UCNdmCSF:A UCNdm.

Statistical Analysis. Pharmacokinetie parameters are re-

ported for individual days and as the mean ± SD. The depend-

ent paired t test was used to compare topotecan lactone, total,

and N-desmethyb topotecan clearance and K13 after topotecan

administration alone and in combination with phenytoin. The

Wileoxon paired t test was used to compare the AUCNdm:

A UCTOT ratio after topotecan administration alone and in eom-

bination with phenytoin. A priori level of significance was set at

0.05.

RESULTSPharmacokinetie parameters for topoteean baetone are sum-

manized in Table 1 . Representative concentration-time plots for

total topotecan plasma and total N-desmethyl plasma and CSF

from day two of cycle one are presented in Fig. 3. Because we

adjusted this patient’s topotecan dose to attain a target systemic

exposure, the topotecan dose with and without phenytoin dif-

fered. Thus, to highlight the difference in topoteean disposition

with and without phenytoin, we chose to simulate topotecan

lactone plasma concentration-time plots for a topoteean dose of

2.0 mg/m2 alone and when coadministered with phenytoin (Fig.

4). Topotecan lactone clearances, when coadministered with

(cycle 1) and without (cycle 2) phenytoin, were 62.9 ± 6.4

L/h/m2 and 43.4 ± 1.9 LIh/m2, respectively (P < 0.05). Ac-

eordingly, the dose required to achieve the target topoteean

lactone plasma AUC of 140 ± 20 ng/mlh, when coadministered

with phenytoin, was 45% greater than without phenytoin. The

A UCLAC:A UCTOT ratios after administration of topoteean alone

and in combination with phenytoin were 0.56 ± 0.08 and

0.55 ± 0.09, respectively.

Pharmacokinetic parameters for total topotecan and N-

desmethyl topotecan are summarized in Table 2. For the same

reasons as stated above, we chose to simulate total topotecan

and N-desmethyl plasma concentration-time plots for a topote-

can dose of 2.0 mg/m2 alone and when coadministered with

phenytoin (Fig. 5). After doses that achieved the target bactone

systemic exposure of 140 ± 20 ng/mlh, eoadministration of

phenytoin increased the rate constant describing N-desmethyl

formation (K13), AUCNdm, and the AUCNdmAUCTOT ratio by

2-fold as compared to when topotecan was administered without

phenytoin.

Due to logistical problems, CSF samples were obtained

only on cycle 1 (topotecan coadministered with phenytoin).

Total N-desmethyl CSF samples were below the lower limit of

quantification on day 1. The average ±SD of N-desmethyl CSF

penetration, A UCNdmCSF, and CLNdmCSF were 0. 12 ± 0.01,

1 .9 ± 0.24 ng/mlh, and 0.47 ± 0. 18 L/h/m2, respectively.

The patient tolerated therapy with topoteean very well

during cycles 1 and 2. No grade 3 or 4 hematological or

nonhematological toxicity (National Cancer Institute, Common

Toxicity Criteria) was observed.

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‘I000

100

10

0.1

Fig. 3 Concentration-time plots for total topote-can plasma and N-desmethyl topotecan plasmaand CSF from day 2 of cycle 1. Individual datapoints and best fit line of the data are representedfor total topotecan plasma (#{149},-), total N-des-methyl topotecan plasma (0. ---). and total N-desmethyl topotecan CSF (A, ---).

0 2 4 6 8 10 12 14 16

Time (hr)

786 Phenytoin Increases Topotecan Clearance

Table I Topotecan lactone pharmacokinetic parameters are presented for each day and summarized as the average ± SD for cycle 1(coadministration of topotecan and phenytoin) and cycle 2 (administration of topotecan alone)

Cycle 1 Cycle 2

Day 1 Day 2 Day S Average ± SD Day 1 Day 2 Day 5 Average ± SD

Dose (mg/m2)AUCLAC (ng/ml . h)i/c (Urn2)

K10 (h’)

CLLAC (L/h/m2)Vd�� (Um2)

2.030.1

25.0

2.9

71.2

56.2

8.0135.1

18.5

3.3

60.163.7

8.0142.6

51.5

1.1

56.9177.0

31.7 ± 14.3

2.4 ± 0.9

62.9 ± 6.4”

99.0 ± 52.0

3.074.6

30.0

1.4

41.6

69.5

5.5

136.6

20.1

2.1

42.6

58.6

5.5

127.1

20.0

2.3

46.0

51.6

23.3 ± 4.7

1.9 ± 0.4

43.4 ± 1.9”59.9 ± 7.4

�1 p < 0.05.

E-�)

C

C0

(0

Ca)C’)C0

0

DISCUSSION -

This is the first report documenting altered disposition of

topoteean when coadministered with phenytoin compared with

the administration of topotecan alone. In a previous clinical trial,

we noted high clearance rates of topotecan in patients receiving

phenytoin but were unable to study patients off phenytoin or to

measure metabolite formation (6). In the present study, we also

note for the first time altered disposition of the N-desmethyl

metabobite when topotecan is coadministered with phenytoin.

Moreover, we show that this metabolite penetrates into the CSF.

As indicated earlier, this metabolite has pharmacological aetiv-

ity equivalent to that of the parent compound.3 Our data also

suggest that topoteean undergoes hepatie metabolism with for-

mation of other presently unidentified metabobites, in addition to

the active N-desmethyb metabolite (5, 6, 12). The possible

clinical importance of altered topoteean disposition by other

drugs is underscored by the steep relationship we have reported

between topoteean exposure and response (i.e., toxicity or an-

titumor), such that a small reduction in topoteean systemic

exposure may lead to a loss of activity (5, 6, 30). Furthermore,

topotecan is presently under evaluation for the treatment of

primary central nervous system tumors and central nervous

system metastatie disease, both situations in which patients may

receive phenytoin as seizure prophybaxis or treatment. In addi-

tion, other drugs that induce or inhibit CYP isoforms, such as

phenobarbitab, fluconazobe, and dexamethasone, may also alter

topotecan disposition (14, 32).

Several factors are important to consider when evaluating the

ability of phenytoin to increase topotecan laetone clearance. Topo-

tecan is 30-40% nonrenally eliminated; thus, an increase of -50%

in total systemic clearance through this pathway may be clinically

relevant. The total phenytoin plasma concentration in our patient

(3.5 mg/b) was below the therapeutic range of 10 to 20 mg/b,

whereas a phenytoin concentration within the therapeutic range

may have resulted in an even greater increase in topoteean clear-

ance (18, 20, 33). Phenytoin altered topotecan disposition through

increased conversion to the active N-desmethyl metabolite, in ad-

dition to a 30% increase in topotecan clearance through other

metabolic pathways (12). We have previously reported relatively

low intrapatient variability in topotecan clearance (9). Thus, the

increase in topoteean clearance in this patient is associated with

eoadmimstration ofphenytoin and is not likely to be due to inherent

intrapatient variability in topotecan clearance. We attempted to

collect urine on this patient, but because of logistical problems. we

were unable to quantitate the urinary recovery of topotecan. Thus,

we were unable to evaluate topotecan renal clearance.

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Fig. 4 Simulation of topotecan lactone concentra-tion-time plots after a dose of 2.0 mg/m2 adminis-tered alone and in combination with phenytoin. -.

topotecan alone: - - -. topotecan in combinationwith phenytoin. The plasma AUC of topotecanlactone after administration of topotecan alone andin combination with phenytoin was 46.2 and 30.1ng/ml�h. respectively.

100

10

1

0.10 1 2 3 4 5 6 7 8 9 10

Time (hr)

Clinical Cancer Research 787

-J

E

C

C0

(0

Ca)C’)C0C’)a)C0C’)

(0CCaC’)

00.0

F-

Table 2 Pharmacokinetic parameters for total topotecan and total N-desmethyl topotecan are presented for each day and summarized as theaverage ± SD for cycle 1 (coadministration of topotecan and phenytoin) and cycle 2 (administration of topotecan alone)

Cycle 1 Cycle 2

Day I Day 2 Day 5 Average ± SD Day I Day 2 Day S Average ± SD

Dose (mg/m2) Topotecan 2.0 8.0 8.0 3.0 5.5 5.5

AUC�0�(ng/mlh) 67.9 260.7 211.0 145.7 220.5 231.5

V� (Um2) 48.5 47.2 62.7 52.8 ± 7.0 37.6 40.7 31.0 36.4 ± 4.1K,0 (h�) 0.57 0.54 0.53 0.55 ± 0.02 0.53 0.58 0.76 0.62 ± 0.10CL.�OT (L/h/m2) 28.5 27.1 36.3 30.6 ± 4.1” 20.7 24.3 17.5 20.8 ± 2.8”Vd�� (Um2) N-Desmethyl 42.6 94.7 127.4 88.2 ± 34.9 57.0 78.8 94.4 76.8 ± 15.3AUCN4fl, (ng/ml . h) 3.0 17.6 15.2 7.1 8.3 6.7K13 (h ‘) 0.021 0.033 0.049 0.034 ± 0.01 1” 0.019 0.018 0.013 0.017 ± 0.003kK35, (h I) 0.46 0.53 0.64 0.54 ± 0.07 0.40 0.47 0.45 0.44 ± 0.03CLNdfl, (L/h/m2) 22.3 25.0 40.1 29.2 ± 7.8’ 15.1 19.1 13.9 16.0 ± 2.2’

AUCNdm:AUCT0T 0.044 0.068 0.072 0.061 ± 0.01 1d 0.049 0.038 0.029 0.039 ± 0.010”

�1 /3 < 0.05.

“P < 0.05.

‘. P < 0.05.

“P < 0.05.

The results of the present study suggest that phenytoin

alters topotecan disposition. at least partly. by inducing hepatic

oxidative metabolism of topotecan, which is consistent with our

prior reports of increased topotecan clearance in patients reeeiv-

ing anticonvulsants, including phenytoin (13, 32). Phenytoin has

been shown to increase the clearance of tolbutamide and war-

farm, in addition to chemotherapeutie agents such as etoposide,

teniposide, and paclitaxel (32, 34-36). Recently, a study of

another camptothecin analogue, 9-AC, in patients with newly

diagnosed and recurrent high-grade astroeytomas reported a

2-fold lower steady-state concentration of 9-AC in patients

receiving phenytoin, carbamazepine, and/or phenobarbitab com-

pared with patients administered 9-AC alone (37). In the present

study, phenytoin resulted in a doubling of the AUCNdm, but this

accounted for only a small proportion of the A UCTOT (6. 1 ±

0.01 %).

Phenytoin undergoes hepatie oxidative metabolism by CYP

2C9/lO isozymes (14-16). Phenytoin has been reported to alter the

disposition ofdrugs through induction ofCYP 2B, 2C9/l0, and 3A

isozymes, in addition to other possible Phases I and II metabolic

enzymes (14, 17-20). However, topotecan does not alter paclitaxel

metabolism, which is mediated by CYP 3A4 and 2C8 (38). This

suggests that topotecan hepatic metabolism may not be mediated

by these isozymes. The increased exposure of the N-desmethyl

metabolite when coadministered with phenytoin is consistent with

formation of the N-desmethyl metabolite by hepatic oxidative me-

tabobism (12). In addition, the 2-fold increase in N-desmethyl

clearance when coadministration with phenytoin suggests the in-

duction of Phase II metabolic enzymes (i.e., glucuronidase). Thus,

the mechanism by which phenytoin alters topotecan and N-des-

methyl topotecan disposition may be through induction ofCYP 2B,

2C9/lO, 3A isozymes other than 3A4, and other Phases I and II

metabolic enzymes.

Based on the results of this study, further investigation of

topotecan metabolism and elimination are required. Coadmin-

istration of phenytoin with topotecan increased topotecan lac-

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100

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Fig. 5 Simulation of total topotecan and total N-

desmethyl topotecan concentration-time plots after

a dose of 2.0 mg/m2 administered alone and in

combination with phenytoin. Lines represent total

topotecan (A, -) and total N-desmethyl topotecan

(a, -) alone. and total topoteean (B, ---) and total

N-desmethyl topotecan (b, ---) in combination with

phenytoin. The plasma AUC of total topotecan

after administration of topotecan alone and in com-

bination with phenytoin was 81.3 and 52.4 ng/mlh, respectively. The plasma AUC of total N-

desmethyl topotecan after administration of

topotecan alone and in combination with phenytoin

was 2.9 and 4.0 ng/mbth, respectively.

0 2 4 6 8 10 12 14 16 18

Time (hr)

788 Phenytoin Increases Topotecan Clearance

_1

E-�)

CC0Ca

Ca)C’)C00

Ca

0I-

tone and total systemic clearance by 45 and 47%, respectively.

In addition, we observed a 2-fold increase in the N-desmethyl

oxidative metabobite of topotecan when coadministered with

phenytoin. The ability of phenytoin to alter the disposition of

topotecan and the N-desmethyl metabolite suggests that hepatie

metabolism may be clinically important in the overall ebimina-

tion of topoteean in humans. Although there is an increase in

exposure to the active N-desmethyb topotecan metabolite after

phenytoin treatment, it is less than the decrease in exposure to

topoteean lactone. Therefore, patients concomitantly adminis-

tened phenytoin may require an increase in topotecan dose to

achieve a similar pharmacological effect as a patient not reeeiv-

ing phenytoin.

ACKNOWLEDGMENTSWe thank Suzan Hanna, Audrey Smith, and Yuri Yanishevski for

technical support. We also thank Margaret Edwards, Lisa Walters, Sheri

Ring, and Terry Kuehner for assistance in obtaining plasma samples.

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1998;4:783-789. Clin Cancer Res   W C Zamboni, A J Gajjar, R L Heideman, et al.   topotecan in a patient with medulloblastoma.Phenytoin alters the disposition of topotecan and N-desmethyl

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