accuracy, feasibility, and clinical impact of prospective ... · received either one or two courses...

Accuracy, Feasibility, and Clinical Impact of Prospective Bayesian

Pharmacokinetically Guided Dosing of Cyclophosphamide,

Thiotepa, and Carboplatin in High-Dose Chemotherapy

Milly E. de Jonge,1 Alwin D.R. Huitema,1

Annemarie C. Tukker,2 Selma M. van Dam,1

Sjoerd Rodenhuis,2 and Jos H. Beijnen1,2

1Department of Pharmacy and Pharmacology, Slotervaart Hospital and2Department of Medical Oncology, the Netherlands Cancer Institute,Amsterdam, the Netherlands

ABSTRACT

Purpose: Relationships between toxicity and pharma-

cokinetics have been shown for cyclophosphamide, thiotepa,

and carboplatin (CTC) in high-dose chemotherapy. We

prospectively evaluated whether variability in exposure to

CTC and their activated metabolites can be decreased with

pharmacokinetically guided dose administration and evalu-

ated its clinical effect.

Experimental Design: Patients received multiple 4-day

courses of cyclophosphamide (1,000–1,500 mg/m2/d), thiote-

pa (80–120mg/m2/d), and carboplatin (area under the plasma

concentration-time curve 3.3–5 mg �min/mL/d). Doses were

adapted on day 3 based on pharmacokinetic analyses of

cyclophosphamide, 4-hydroxycyclophosphamide, thiotepa,

tepa, and carboplatin done on day 1 using a Bayesian

algorithm. Doses were also adjusted before and during second

and third courses. Observed toxicity was compared with that

in patients receiving standard dose CTC (n = 43).

Results: A total of 46 patients (108 courses)were included.

For cyclophosphamide, thiotepa, and carboplatin, a total of 39,

58, and 65 dose adaptations were done within courses and 17,

40, and43beforecourses.Theprecisionwithinwhich the target

exposurewas reached improved comparedwithnoadaptation,

especially after within-course adaptations (precision for

cyclophosphamide, thiotepa, and carboplatin is 19%, 16%,

and13%,respectively); >85%led to an exposurewithinF25%

of the target compared with 60% without dose adjustments.

Toxicity was similar to that in a reference population, although

the incidence of veno-occlusive disease was reduced.

Conclusions: Bayesian pharmacokinetically guided dos-

ing for CTC was feasible and led to a marked reduction in

variability of exposure.

INTRODUCTION

Cyclophosphamide, thiotepa, and carboplatin (CTC) are

alkylating agents widely used in high-dose combination

chemotherapy regimens with bone marrow or peripheral blood

cell transplantation (1). These three compounds are administered

simultaneously in the high-dose CTC regimen, often applied in

the treatment of metastatic breast cancer and relapsing germ cell

cancer (2–6).Cyclophosphamide is a prodrug that requires enzymatic

bioactivation to manifest its cytostatic activity. After administra-tion, cyclophosphamide undergoes a sequence of activating andinactivating pathways, with f75% to 80% being activated to 4-hydroxycyclophosphamide (4OHCP). Various cytochrome P450isoenzymes are involved in the bioactivation of cyclophospha-mide, of which CYP2B6 has the highest activity. 4OHCP is veryunstable and decomposes into phosphoramide mustard, theultimate alkylatingmetabolite. 4OHCP plasma levels are expectedto reflect the intracellular levels of phosphoramide mustard.Circulating phosphoramide mustard in plasma does not contributeto cytotoxicity because it is largely ionized at physiologic pH anddoes not enter cells. The metabolism of cyclophosphamide showsautoinduction, which leads to increased rate of bioactivation ofcyclophosphamide after repeated administrations. Simultaneousadministration of thiotepa has been shown to cause inhibition ofcyclophosphamide bioactivation (7).

Thiotepa is rapidly oxidatively desulfurated to yield its

active metabolite N ,NV,N-triethylenephosphoramide (tepa),

a reaction catalyzed by the cytochrome P450 isoenzyme

subfamilies 3A, 2B, and 2C (8–10). Tepa has pharmacologic

properties similar to parent thiotepa and augments its effect

(10–12). Because tepa has a longer elimination half-life than

thiotepa, it contributes significantly to therapeutic response

and toxicity (8). Cyclophosphamide has been shown to induce

the conversion of thiotepa to tepa (13).

The pharmacokinetics of carboplatin are relatively simple,

with glomerular filtration accounting for almost all drug

elimination (14). In patients with normal renal function, 60%

to 70% of the dose are excreted into urine within the first 24

hours (14). The remainder of the drug binds irreversibly to body

proteins and tissue. The free, ultrafilterable platinum fraction is

considered pharmacologically active.

Substantial differences in pharmacokinetics of CTC between

individuals have been established, resulting in markedly different

exposures, as expressed by the area under the plasma concen-

tration-time curve (AUC), to the individual drugs and their

metabolites in patients treated at the same dose levels (15). In

high-dose chemotherapy protocols, such as the CTC regimen,

doses of the individual compounds are chosen maximal to

maximize the benefit of therapy. Doses are limited by the

occurrence of serious nonhematologic organ toxicities, such as

severe mucositis, ototoxicity, neuropathy, cardiotoxicity, and

hepatotoxicity, as seen in the high-dose CTC regimen (15, 16).

Relationships between exposure to CTC (and their metabolites)

Received 9/29/04; accepted 10/22/04.Grant support: Dutch Cancer Society project NKI 2001-2420.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.Requests for reprints: Milly E. de Jonge, Department of Pharmacy andPharmacology, Slotervaart Hospital, the Netherlands Cancer Institute,Louwesweg 6, 1066 EC, Amsterdam, the Netherlands. Phone: 31-205124657; Fax: 31-205124753; E-mail: [email protected].

D2005 American Association for Cancer Research.

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and toxicity have been established. An inverse correlation

between the cyclophosphamide AUC and both treatment-related

cardiotoxicity and (event-free) survival in women with breast

cancer have been reported (17, 18). In addition, an indication for a

relationship between the AUC of 4OHCP and phosphoramide

mustard and veno-occlusive disease (VOD) of the liver was found

(15). The AUC of both thiotepa and tepa after high-dose therapy

have been associated with response and nonhematologic toxicity

(19, 20), elevation of transaminases (15), and occurrence of

mucositis (15, 21). Toxicities such as nephrotoxicity, ototoxicity,

central nervous system toxicity, and peripheral nervous system

toxicity have been associated with a higher carboplatin exposure

in high-dose regimens (15, 22–26). These relationships form the

rationale to design a strategy to decrease variability in exposure to

decrease morbidity without comprising efficacy.

In this study, we exploited the benefits of therapeutic drug

monitoring (TDM) of CTC in chemotherapy. Population

pharmacokinetic models describing the pharmacokinetics of

cyclophosphamide and 4OHCP (13), thiotepa and tepa (13, 27),

and carboplatin (28), as developed in our institute, formed the

basis for the TDM strategy. The primary aim of the study was to

investigate the ability to obtain target exposures of 4OHCP,

thiotepa and tepa, and ultrafilterable carboplatin based on real-

time pharmacokinetic follow up. In addition, the technical

feasibility of this approach was evaluated. The secondary aim

was to evaluate whether patients receiving pharmacokinetically

guided individualized doses in the CTC regimen had less toxic

events compared with a historical reference population receiving

conventional doses without pharmacokinetically guided dose

(PGD) adaptations.

METHODS

Patients and Treatment. Patients were included in several

clinical studies that employed the CTC high-dose chemotherapy

regimen with peripheral blood progenitor cell transplantation (2–

6). Patients either had high-risk primary breast cancer and received

high-dose chemotherapy as part of their adjuvant treatment or

had advanced breast, germ cell, or ovarian cancer. Two different

high-dose CTC schedules were administered. The full-dose CTC

regimen (2, 3, 5) consisted of 4 days of chemotherapy with

cyclophosphamide (1,500 mg/m2/d) as a 1-hour infusion imme-

diately followed by carboplatin [target AUC 5 mg � min/mL/d as

calculated with the Calvert et al. (29) formula using the Cockcroft-

Gault (30) formula for estimating creatinine clearance] as a daily

1-hour infusion and thiotepa (120 mg/m2/d) divided over two 30-

minute infusions (the second daily dose of thiotepa was ad-

ministered 12 hours after the first dose). The ‘‘tiny’’ CTC regimen

(tCTC) was identical to the CTC regimen, except that it

incorporated two thirds of the dose of each agent (4, 6). Patients

received either one or two courses of CTC or two or three courses

of tCTC, when possible, every 4 weeks.

Mesna (500 mg) was administered six times daily for a total

of 36 doses, beginning 1 hour before the first cyclophosphamide

infusion. All patients received antiemetics both prophylactically

and as indicated, which usually included dexamethasone and

granisetron. Patients received prophylactic antibiotics, including

ciprofloxacin and amphotericin B p.o., starting 4 days before

chemotherapy. Approximately 60 hours after the last thiotepa

infusion, the peripheral blood progenitor cells were reinfused.

The details of the CTC and tCTC regimens have been published

previously (2–6).

All protocols were approved by the Committee of Medical

Ethics of the Netherlands Cancer Institute and written informed

consent was obtained from all patients.

Sampling and Analyses. During the 4-day CTC course,

blood samples were collected from a double lumen i.v. catheter

inserted in a subclavian vein. Samples were collected before the

start of the infusions on all 4 days of chemotherapy. Complete

pharmacokinetic profiles were assessed on two separate days,

always including day 1 and day 3 or 4. On these two days,

samples were taken at 30 minutes after the start of cyclophos-

phamide infusion and at 60 (end of cyclophosphamide infusion

and start of carboplatin infusion), 90, 120 (end of carboplatin

infusion and start of thiotepa infusion), 150 (end of thiotepa

infusion), 165, 180, 210, 285, 390, and 660 minutes. On day 5,

an additional sample was collected f22 hours after the last

cyclophosphamide infusion.

After blood sampling, samples were immediately placed on

ice. Plasma was separated by centrifuging the sample at 3,500� g for 3 minutes at 4jC. A 500 AL volume of plasma was

immediately added to 50 AL of a 2 mol/L semicarbazide solution

and incubated for 2 hours at 35jC for the stabilization of

4OHCP. 4OHCP is an unstable compound and therefore requires

immediate derivatization to a more stable derivative (31). Plasma

ultrafiltrate was prepared immediately by transferring 500 ALplasma in an Amicon micropartition system with a 30-kDa

YMT-14 membrane (Millipore Corp., Bedford, MA) and

centrifuging the system at 2,500 � g for 20 minutes. All

samples were stored at �70jC until analysis.

Analysis of platinum in ultrafiltrate was done using

flameless atomic absorption spectrometry (32). Accuracy and

within-day and between-day precision were <10%. In the first 20

patients, thiotepa and tepa concentrations were quantified with a

validated gas chromatographic assay (33). Accuracy and within-

day and between-day precision were <6% for both compounds.

Later, we developed a rapid analysis method based on high-

performance liquid chromatography-mass spectrometry/mass

spectrometry to simultaneously quantify cyclophosphamide,

4OHCP, thiotepa, and tepa in one sample (31). From the time

that this method was operable, cyclophosphamide dose adapta-

tions could be done. Accuracy and within-day and between-day

precision of this method were <15% for all compounds.

Definition of the Target Exposure. For cyclophospha-

mide dose adaptations, a 4OHCP target AUC (AUC4OHCP) was

defined because 4OHCP is the activated component of the

prodrug cyclophosphamide. Because both thiotepa and tepa have

similar alkylating activities, the sum of both thiotepa and tepa

AUC (AUCTT + T) was targeted. For carboplatin, the ultra-

filterable AUCCA was targeted. Because no quantitative relation-

ships have been established between toxicity/efficacy and

exposure to cyclophosphamide, thiotepa, carboplatin, and their

relevant metabolites, the optimal dose of the three compounds in

the CTC regimen is not known. To define a safe and effective

target exposure for 4OHCP, thiotepa and tepa, and carboplatin,

their median values as obtained in complete conventional tCTC

and CTC courses in a reference population were calculated.

This reference population was similar to the population used

Pharmacokinetically Guided Dosing in Chemotheraphy274



for development of the population pharmacokinetic models

used in this study and consisted of 51, 42, and 42 patients for

4OHCP, thiotepa and tepa, and carboplatin, respectively.

Because the ‘‘median’’ patient in this regimen did not experience

extreme toxicities, the median AUC is expected to be a safe

target exposure. Target AUCs for complete tCTC and CTC

courses were 105 and 140 Amol/L � h for AUC4OHCP, 276 and

374 Amol/L � h for AUCTT + T, and 13.3 and 20 mg � min/mL

for AUCCA.

Population Pharmacokinetic Analyses. Bayesian dose

adaptations were done using population pharmacokinetic models

for cyclophosphamide and 4OHCP (13), thiotepa and tepa

(13, 27), and carboplatin (28) as developed with the nonlinear

mixed effect modeling program NONMEM (double precision,

version 1.1; ref. 34).

Carboplatin. Ultrafilterable platinum data were described

with a two-compartment model with first-order elimination

clearance (ClCA), volume of distribution (VCA), and distribution

rate constants k12 and k21 (28). A total of 42 patients receiving

67 courses of tCTC or CTC were used as a reference population

for estimating the population pharmacokinetic variables for this

model. In Fig. 1, the model used for carboplatin is incorporated.

In Table 1, the population pharmacokinetic variables of

carboplatin as used in the model are summarized.

Thiotepa. The population pharmacokinetic model used in

the pharmacokinetic analyses of thiotepa was published recently

(13). In this model, the distribution of both thiotepa and tepa was

described to take place over two compartments with first-order

elimination from the central compartment. The conversion of

thiotepa to its metabolite tepa was induced in the presence of

cyclophosphamide (total thiotepa clearance increased with 10-

25% during a course). The pharmacokinetic variables estimated

for thiotepa were apparent inducible clearance leading to

formation of tepa (ClTTind), apparent noninducible clearance

(ClTTnonind), volume of distribution (VTT), and distribution

microconstants k12 and k21. For tepa, these variables were

elimination rate constant (kT), volume of distribution (VT), and

distribution microconstants k34 and k43. The induction of

thiotepa elimination was modeled using a hypothetical enzyme

compartment (ENZTT) in which the amount of enzyme increased

linearly in the presence of cyclophosphamide with a zero-order

rate constant of kENZTT. ClTTind was directly proportional to the

amount in this hypothetical enzyme compartment. This model

was part of an integrated model (13), describing a mutual drug-

drug interaction of cyclophosphamide and thiotepa, as shown in

Fig. 1 and Table 2, which is described further in the section on

cyclophosphamide.

Because the influence of cyclophosphamide on the phar-

macokinetics of thiotepa was only recognized during this study,

dose adaptations for thiotepa in the first 31 patients of this study

were done using a similar model as described above, only without

the inductive effect of cyclophosphamide (27). This model has

also been published previously. Dose adaptations in the final

patients of our study were done with the improved model (13).

Cyclophosphamide. The pharmacokinetic model devel-

oped for cyclophosphamide (13) also contains thiotepa because

it has been shown that thiotepa inhibits the conversion of

cyclophosphamide to 4OHCP. This model was developed using

plasma concentration-time data of cyclophosphamide, 4OHCP,

thiotepa, and tepa from 49 patients receiving 86 courses of

CTC or tCTC. Pharmacokinetics of cyclophosphamide were

described with a two-compartment model and 4OHCP with a

one-compartment model. Cyclophosphamide was eliminated by

a noninducible route (ClCPnonind) and an inducible route

(ClCPind), the latter leading to formation of 4OHCP. The

apparent clearance of the inducible route leading to 4OHCP

was directly proportional to a hypothetical amount of enzyme

(ENZCPact). Autoinduction led to a zero-order increase (kenzCP)

Fig. 1 Schematic representation of the population pharmacokinetic models of carboplatin (CA), thiotepa (TT), tepa (T), cyclophosphamide (CP), and4OHCP, including the autoinduction process of cyclophosphamide as well as the mutual drug-drug interaction between cyclophosphamide and thiotepa.centr, central compartment; per, peripheral compartment; ENZCPact , active enzyme pool involved in cyclophosphamide metabolism; ENZCPinact ,inactive enzyme pool involved in cyclophosphamide metabolism; ENZTT, enzyme pool involved in thiotepa metabolism.

Clinical Cancer Research 275



in amount of this enzyme during treatment in the presence of

cyclophosphamide. The influence of thiotepa on the bioactiva-

tion of cyclophosphamide was modeled as a thiotepa

concentration-dependent reversible deactivation of the enzyme

resulting in the formation of an inactive enzyme (ENZCPinact).

Mass transport between both activated and inactivated enzyme

pools was modeled using an association and dissociation rate

constant (kass and kdiss), corresponding to deactivation by

association of the active enzyme with thiotepa and reactivation

by the dissociation of inactive enzyme and thiotepa.

For more details on the model, we refer to ref. 13. The

model is schematically represented in Fig. 1 with the involved

pharmacokinetic variables summarized in Table 2.

PGD Strategy. Prospective dose interventions took place

both during and between courses. During days 1 and 2 of the

first course, patients received the standard CTC dose. Blood

samples were collected on day 1. Plasma concentrations of

cyclophosphamide, 4OHCP, thiotepa, tepa, and carboplatin

were determined immediately after collection in the sample

collected until 285 minutes after the start of the course. The

concentrations in these samples were available the next day.

Based on these data, Bayesian estimates were generated for the

individual pharmacokinetic variables of cyclophosphamide,

4OHCP, thiotepa, tepa, and carboplatin. These estimates were

obtained with the POSTHOC option of NONMEM taking both

population pharmacokinetic variables and individual data into

Table 2 Population pharmacokinetic variables of cyclophosphamide, 4OHCP, thiotepa, and tepa in the model used for Bayesian dose adaptations

Variable Notation Estimate(% relative SE)

% Interindividualvariability

% Interoccasionvariability

Noninducible clearance of thiotepa (L � h�1) ClTTnonind 17.0 (13)* 46 24Initial inducible clearance of thiotepa (L � h�1) ClTTind 12.4 (14)* 31 19Volume of distribution of thiotepa (L) VTT 44.5 (5.7) 25 15Rate constant distribution thiotepa from centralto peripheral compartment (h�1)

k12 0.314 (13) 45

Rate constant distribution thiotepa from peripheralto central compartment (h�1)

k21 0.493 (12)

First-order elimination rate constant of tepa (h�1) kT 0.555 (8.5) 22Rate constant distribution tepa from central toperipheral compartment (h�1)

k34 3.49 (12) 35

Rate constant distribution tepa from peripheralto central compartment (h�1)

k43 1.01 (6.5)

First-order formation and zero-order eliminationrate constant of the enzyme involved in thiotepametabolism (h�1)

kENZTT 0.0343 (12) 200

Maximal value of enzyme induction Emax 0.361 (10)Volume of distribution of tepa (L) VT 14.2 (12)Noninducible clearance of cyclophosphamide (L � h�1) ClCPnonind 1.76 (16) 54 32Initial inducible clearance of cyclophosphamide (L � h�1) ClCPind 2.91 (8.5) 2Volume of distribution of cyclophosphamide (L) VCP 31.9 (6.6) 16 17Zero-order formation rate constant of the enzyme involvedin cyclophosphamide metabolism (h�1)

kENZCP 0.0220 (7.6) 36

First-order elimination rate constant of 4OHCP (h�1) k4OHCP 169 (8.1) 2Rate constant of reversible enzyme inactivation (h�1 � Amol/L�1) kass 0.169 (9.4) 35Rate constant of reversible enzyme activation (h�1) kdiss 0.405 (6.8)Rate constant distribution cyclophosphamide fromcentral to peripheral compartment (h�1)

k56 0.105 (28) 37 30

Rate constant distribution cyclophosphamide fromperipheral to central compartment (h�1)

k65 0.280 (24)

Proportional error of thiotepa (%) 21.7Additive error of thiotepa (Amol/L) 0.0645Proportional error of tepa (%) 16.7Additive error of cyclophosphamide (Amol/L) 0.242Additive error of 4OHCP (Amol/L) 0.270

*Estimated correlation (q) of noninducible and inducible clearance of thiotepa (% relative SE) = �0.66 (45.0).

Table 1 Population pharmacokinetic variables of carboplatin in the model used for Bayesian dose adaptations

Variable Estimate (% relative SE) % Interindividualvariability

% Interoccasionvariability

Clearance (L � h�1) 7.44 (5.4) 20 15Volume of distribution (L) 10.4 (6.7) 13 16Rate constant distribution from centralto peripheral compartment k12 (h�1)

0.672 (13)

Rate constant distribution from peripheralto central compartment k21 (h�1)

0.491 (9.3) 19

Additive residual error (Amol/L) 0.300Proportional residual error (%) 18




account (34). Based on the estimated individual pharmacoki-

netic variables, an appropriate dose for days 3 and 4, to

approach the defined target values, was calculated.

For dose adjustment during a course, the defined target values

were used without correction for the exposure already obtained

during days 1 and 2 of the course to prevent the administration of

excessive high or low doses after adjustment to compensate for very

low or very high exposures on the first 2 days of the course.

Before second and third courses, Bayesian estimates were

generated based on all results of the previous course(s). The

doses for days 1 and 2 of these courses were again based on

approaching the defined target exposures. During second and

third courses, doses were again adjusted on days 3 and 4 based

on the concentrations in samples collected at day 1 of that course

and data of previous course(s), which is similar to the procedure

employed during course 1. In case it was proven impossible to

adjust the dose during the course, the dose of days 1 and 2 was

maintained for the other days of the course.

Pharmacokinetic Validation. To evaluate the obtained

AUCs after dose adaptations, individual pharmacokinetic varia-

bles of cyclophosphamide, 4OHCP, thiotepa, tepa, and carbopla-

tin in a specific course were calculated by individual fits of the

data using the developed models. With this method, we obtained

independent values of the pharmacokinetic variables, unbiased

toward the population model. Based on these individual

pharmacokinetic variables, the AUCs of 4OHCP, thiotepa and

tepa, and carboplatin were calculated for that specific course.

Subsequently, the total course AUC the patient obtained by dose

adjustment (AUCadapted) was compared with the AUC the patient

would have obtained in case the standard dose was administered

during the whole course (AUCstandard). Both AUCadapted and

AUCstandard were compared with the defined target AUC.

Toxicity. When the dose of at least one compound was

adapted in a course, the toxicity data of this patient were included

in the analysis. Toxicity was scored during CTC chemotherapy

and after each course and was graded according to the National

Cancer Institute Common Toxicity Criteria version 2.0 (35).

Because some toxicity were infrequent, they were registered in a

dichotomous (e.g., no toxicity or toxicity of any grade) or de-

scriptive way. Toxicity data were compared with toxicity data

reported in a reference population of 43 patients who received

75 courses of high-dose CTC with standard doses as published

previously (15). Patient characteristics of this population were

similar as the population in our study.

Significance of the difference in toxic outcome between the

two groups was compared using the v2 test.

RESULTS

A total of 46 patients have been included in the study,

who received a total of 108 CTC or tCTC courses. Because the

infrastructure for cyclophosphamide dose adaptations only be-

came available during the studies, dose adaptations for

cyclophosphamide were only done in the last 26 patients (56

courses). In Table 3, baseline patient characteristics are

summarized. These characteristics were comparable with those

in the populations used for development of the pharmacokinetic

models of CTC.

The proposed dosing strategy for CTC seemed to be

technically feasible in clinical practice. Of all patients, full

pharmacokinetic profiles could be obtained of day 1 and day 3 or

4 of the course, which could be used for the adjustment of the

dose and the evaluation of the dose adjustment. In six patients,

the planned overnight analyses of thiotepa and tepa in the

samples obtained at day 1 was not possible due to technical

problems with the method of analysis (33), preventing a dose

adjustment during the course. This problem did not occur with

the rapid high-performance liquid chromatography-mass spec-

trometry/mass spectrometry (31).

Carboplatin. Dose adaptations for carboplatin were done

in 46 patients. A total of 65 adaptations were done during the

CTC courses and 43 adaptations before the start of a new course.

In Fig. 2A , the results of the dose adaptations of carboplatin are

graphically shown. The individualized doses approach the target

with a greater precision compared with the situation in which a

conventional dose was administered. In Table 4, the accuracy and

precision of the PGD adaptations are presented. Overall, after

Bayesian dose adaptations during a course, target AUCCA levels

were approached with a mean precision of 13% versus 30% for

standard creatinine clearance–based dosing. Adaptations be-

tween courses resulted in target AUCCA levels with a mean

precision of 19% versus 31%, respectively. Highly deviating

exposures from the target AUC were effectively prevented by

dose adaptation, which can be concluded from Table 5. A total of

95% of the doses adapted during a course resulted in exposures

within F25% of the target compared with 69% without

adaptations. Doses of six patients, who would have received

exposures with >50% deviation from the target (range, 51-127%),

were successfully adjusted during the course to reach exposures

<30% of the target (range, 6-29%). With dose adaptations before

the second and third courses, doses of six patients who would

have obtained deviations >50% (range, 51-82%) were adapted to

obtain exposures in the range 9% to 51%. Median percentage

carboplatin dose change during courses was 6.8% (range, �54%

to 28%). Between courses, the median change in dose was �11%

(�37% to 18%).

Thiotepa. The results of the thiotepa dose adaptations can

be divided into two parts. In the first 31 patients (78 courses), the

dose adaptations were based on a pharmacokinetic model

without recognition of induction of thiotepa metabolism by

cyclophosphamide (27). In the following 13 patients (22

courses), the full model as shown in Fig. 1 and Table 2 was

Table 3 Baseline patient characteristics

n Median (range)

Patients 46Male 19Female 27

Site of disease (protocol)Breast cancer stage III (1 CTC) 6Breast cancer stage IV

(3� tCTC)21

Germ cell cancer(2� CTC or 3� tCTC)

19 (16/3)

Age (y) 36 (17–54)Body surface area (m2) 1.91 (1.54–2.94)Weight (kg) 77 (52–170)Height (cm) 171 (158–210)




used (13). Because of the different models applied, the obtained

results are presented separately.

Using the first model, a total of 34 thiotepa dose adaptations

were done before start of a second or third course and 41

adaptations were done during a course. From Fig. 2A , it is clear

that the dose adaptations of thiotepa resulted in a better

approximation of the target compared with conventional dosing.

In Table 6A , the accuracy and precision of the PGD adaptations

are presented. Overall, after Bayesian dose adaptations during a

course, target AUCTT + T levels were approached with a mean

precision of 16% versus 40% for standard dosing. Adaptations

between courses resulted in target AUCTT + T levels with a mean

Fig. 2 A, deviations from the target exposureof carboplatin after dose adaptations betweenand within courses (.) compared with thesituation in which no adaptation would havebeen done (o). B, deviations from the targetexposure of thiotepa and tepa after doseadaptations between and within courses usingthe primary model (27) (.) compared withthe situation in which no adaptation wouldhave been done (o). C, deviations from thetarget exposure of 4OHCP after dose adapta-tions between and within courses (.) com-pared with the situation in which no adaptationwould have been done (o).




precision of 35% versus 61%. Median percentage dose change

during courses was �9% (range, �51% to 42%). Between

courses, the median change in dose was �4.4% (�47% to 46%).

Results obtained with this model were slightly positively biased.

Using the full model, a total of 17 dose adaptations were

done during courses and 6 between courses. Results are

presented in Table 6B . Overall, after Bayesian dose adaptations

during a course, target AUCTT + T levels were approached with

a mean precision of 16% versus 26% for standard dosing.

Adaptations between courses resulted in target AUCTT + T levels

with mean precision of 14% versus 24%. Median percentage

dose change during the course was 6.2% (range, �39% to 34%).

Between courses, the median change in dose was 0% (�24% to

17%). Results obtained with this model were slightly negatively

biased (obtained exposures were lower than the target expo-

sures), although the number of patients was low.

With both models, highly deviating exposures from the

target AUC were effectively prevented by dose adaptation, as

can be seen in Table 5. Only 10% of the doses adapted during a

course resulted in exposures not within F25% of the target

compared with 40% in case of no dose adaptation. Exposures

>50% above the target were successfully prevented with during-

course dose adjustments because all 9 patients who would have

had these exposure (range, 50–149%) were within 35% of

the target after the adjusted doses (range, �5% to 35%). With

adaptations before courses 2 and 3, exposures >50% were

prevented in 11 patients (range, 52–203%) to result in exposures

within the �11% to 103% range.

Cyclophosphamide. A total of 39 cyclophosphamide

dose adaptations were done during courses and 17 adaptations

before start of a new course. In Fig. 2C , the results of the dose

adaptation of cyclophosphamide are graphically shown, and in

Table 7, the results are summarized. Overall, after Bayesian dose

adaptations during a course, target AUC4OHCP levels were

approached with a mean precision of 19% versus 29% for

standard dosing. Adaptations between courses resulted in target

AUC4OHCP levels with mean precision of 19% versus 23% for

standard dosing. Median percentage dose change during the

course was 0% (range, �47% to 55%). Between courses, the

median change in dose was �3% (�23% to 24%). Also for

cyclophosphamide, extremely high deviations from the target

exposure were prevented (Table 5) because 85% of the adapted

doses resulted in exposures within F25% of the target AUC

compared with 67% in case of no adaptations. Doses in four

patients who were to receive exposures with deviations from the

target >50% (range, �55% to 89%) were successfully adjusted

during the course to receive exposures withinF31% of the target

value (range, �30% to 24%).

Toxicity. In general, there were few toxic events in the

individualized patient population and no toxic deaths were

encountered. In comparing the toxicities of our population with

those of the reference population (15), we focused on the

occurrence of serious toxicities with a possible relationship with

exposures to cyclophosphamide, thiotepa, carboplatin, or their

metabolites. In Table 8, the toxicities in the population with

adapted doses are summarized and compared with those

obtained in the reference population receiving fixed doses.

VOD occurred in three patients after their second CTC

course, with ascites and grades 3 to 4 toxicity of alanine

aminotransferase, aspartate aminotransferase, and bilirubin.

Because the occurrence of VOD has been correlated with

4OHCP exposure (15), it is important to notice that cyclophos-

phamide doses were not adapted in these three patients. In the 26

patients of our study population in which cyclophosphamide

doses were adapted, not a single case of VOD occurred. In the

reference population, VOD occurred in two patients after a

second and third course of tCTC. It therefore seemed that the

Table 4 Bias and precision with which the target AUC was approached after pharmacokinetic dosing of carboplatin both during and betweenCTC courses compared with conventional dosing

Moment of adaptation(amount of adaptations)

Precision (95% CI) Bias (95% CI)

Pharmacokinetic dosing Conventional dosing Pharmacokinetic dosing Conventional dosing

During course 1 (n = 34) 13 (9–16) 33 (9–45) 6 (2–10) 16 (6–26)Before course 2 (n = 31) 21 (15–25) 33 (22–41) �1 (�9 to 6) 17 (6–27)During course 2 (n = 21) 11 (0–17) 25 (12–33) �2 (�6 to 2) 11 (1–21)Before course 3 (n = 12) 15 (4–20) 26 (12–35) 3 (�6 to 13) 15 (1–29)During course 3 (n = 10) 13 (5–18) 28 (13–38) 8 (0–16) 20 (5–35)During courses (n = 65) 13 (10–15) 30 (19–38) 4 (1–7) 15 (9–21)Before courses (n = 43) 19 (14–23) 31 (23–38) 0 (�6 to 6) 16 (8–25)

NOTE: Abbreviation: 95% CI, 95% confidence interval.Bias: (percentage mean prediction error, MPE%); Precision: (percentage root mean squared prediction error, RMSE%).

Table 5 No. dose adaptations (pharmacokinetic dosing) resulting inexposures within F25% of the target AUC compared with those

after conventional dosing

Adaptations Exposures within F25% of the target, n (%)

Pharmacokinetic dosing Conventional dosing

CarboplatinDuring courses

(n = 65)62 (95) 45 (69)

Before courses(n = 43)

35 (81) 27 (63)

ThiotepaDuring courses

(n = 58)52 (90) 35 (60)


28 (70) 25 (62)

CyclophosphamideDuring courses

(n = 39)33 (85) 26 (67)


13 (76) 13 (76)




occurrence of VOD was decreased in patients receiving adapted

doses of cyclophosphamide.

All other serious events were of similar frequency and

severity in the adapted dose group compared with the

conventional dosed group. Three patients (also receiving adapted

cyclophosphamide doses) developed hemorrhagic cystitis after a

first CTC course, a second CTC course, and a third tCTC course.

In the reference population, two patients developed this toxicity.

During our study, four patients developed sinus-tachycardia

grade 1 after a first (n = 3) or second (n = 1) tCTC course. In two

of these patients, cyclophosphamide dose adaptations were done.

In the reference population, grade 1 cardiotoxicity was seen in

three patients. One patient, not receiving cyclophosphamide dose

adaptations, developed pneumonia, a side effect ascribed to

cyclophosphamide treatment. Two patients receiving CTC

without cyclophosphamide dose adaptations had dyspnea grade

2 after a first and second course, whereas three patients receiving

tCTC with adapted cyclophosphamide doses had dyspnea grade

2 after their first tCTC course. In the reference population,

pulmonary toxicity grades 1 and 2 was reported in six courses.

One patient developed mucositis grade 4 after a first tCTC

course; therefore, treatment was discontinued. Mucositis grade 3

occurred after a first CTC course (n = 2), a first tCTC course

(n = 1), and after a second tCTC course (n = 1). In the

reference population, grade 3 mucositis was observed after

single courses of CTC in six patients. Grade 3 neuropathy was

observed in four patients (seven courses) after first, second, and

third courses. In the reference population, grade 3 neurotoxicity

was never observed. Exposures to carboplatin in the patients

with grade 3 neuropathy were not extremely deviating from the

target exposures. A relatively high incidence of ototoxicity was

observed. Grade 2 ototoxicity after first, second, and third

courses was reported in 11 patients (12 courses). Similar results

were obtained in the reference population.

DISCUSSION

Toxicity in high-dose CTC chemotherapy may be severe

and sometimes life threatening. Individualized dosing may be

applied to minimize interpatient variability in drug exposure to

maximize the benefit of therapy while keeping the risk of serious

adverse effects at an acceptable level. Especially for anticancer

agents like cyclophosphamide and thiotepa that display a high

interpatient pharmacokinetic and pharmacodynamic variability,

and for which clear exposure-response relationships have been

identified, it may be beneficial to monitor plasma drug

concentrations to improve treatment outcome. However, patients

may only benefit from an adapted dose when the adaptation is

done in an early stage of treatment. Real-time TDM therefore

requires rapid sample analysis with results available the next

morning and accurate and reliable assays for the determination of

all analytes. These techniques are available in our laboratory for

Table 6 Bias and precision with which the target AUC was approached after pharmacokinetic dosing of thiotepa both during and between CTC coursescompared with conventional dosing in the first 31 patients (A) and in the final 13 patients (B)




ADuring course 1 (n = 20) 15 (10–18) 44 (0–65) 7 (1–13) 17 (�2 to 37)Before course 2 (n = 20) 34 (15–45) 61 (29–81) 23 (12–35) 40 (18–62)During course 2 (n = 11) 13 (0–21) 35 (6–49) 4 (�5 to 13) 23 (4–41)Before course 3 (n = 14) 36 (0–54) 62 (0–100) 25 (9–40) 31 (0–63)During course 3 (n = 10) 21 (9–29) 34 (0–49) 13 (1–26) 21 (1–40)During courses (n = 41) 16 (12–20) 40 (21–52) 8 (3–12) 20 (9–31)Before courses (n = 34) 35 (20–45) 61 (29–81) 24 (15–33) 36 (19–54)

BDuring courses (n = 17) 16 (13–19) 26 (21–30) �15 (�18 to �11) �15 (�26 to �3)Before courses (n = 6) 14 (0–20) 24 (10–32) �8 (�20 to 5) �4 (�29 to 22)

Bias: (percentage mean prediction error, MPE%); Precision: (percentage root mean squared prediction error, RMSE%).

Table 7 Bias and precision with which the target AUC was approached after pharmacokinetic dosing of cyclophosphamide both during and betweenCTC courses compared with conventional dosing




During course 1 (n = 23) 19 (15–23) 33 (16–44) �13 (�19 to �7) �4 (�18 to 10)Before course 2 (n = 11) 20 (0–29) 22 (0–32) �2 (�16 to 11) �3 (�19 to 12)During course 2 (n = 10) 20 (11–25) 20 (0–30) 1 (�13 to 16) 1 (�13 to 16)Before course 3 (n = 6) 17 (6–23) 25 (5–33) �5 (�22 to 12) �1 (�27 to 25)During course 3 (n = 6) 13 (1–18) 24 (5–33) �1 (�15 to 13) �1 (�27 to 25)During courses (n = 39) 19 (15–21) 29 (18–37) �8 (�13 to �2) �2 (�11 to 7)Before courses (n = 17) 19 (9–25) 23 (13–9) �3 (�13 to 6) �3 (�14 to 7)

Bias: (percentage mean prediction error, MPE%); Precision: (percentage root mean squared prediction error, RMSE%)




CTC, allowing fast dose adaptations already from the third day

of the course on.

The primary objective of this study was to prospectively

validate the performance of the applied Bayesian dose adaptation

strategy for CTC in approaching desired plasma levels. This

study showed that adaptation of the CTC doses resulted in less

variability in exposure between patients compared with conven-

tional dosing. Moreover, patients with a highly deviating

pharmacokinetic profile were effectively recognized and their

dose was adjusted to approach the target exposure. Dose

adaptations during a course generally led to a better approxima-

tion of the target exposure compared with adaptations between

courses, which may be explained by substantial intrapatient

course-to-course variability.

Initial carboplatin doses are usually already individualized

based on renal function of a patient. Appropriate a priori doses

can be based on the Calvert formula using an individuals

glomerular filtration rate, as determined using the 51Cr EDTA

clearance, as input (29). Due to imprecise estimations of

glomerular filtration rate, using creatinine clearance estimated

by the Cockcroft-Gault (30) formula as in our study, this dosing

method may still result in large individual differences in

carboplatin exposure (28). Retrospective studies showed that

TDM of carboplatin is a possibility for a better approximation

of a desired carboplatin exposure (28, 36). In our study, we

confirmed this prospectively. Highly precise Bayesian estima-

tions of carboplatin pharmacokinetic variables can be obtained

using only a few blood samples (28, 36).

The dose adaptations for thiotepa using the primary

developed model resulted in more precise but slightly positively

biased results. The recognized interaction between cyclophos-

phamide and thiotepa, with cyclophosphamide inducing thiotepa

metabolism (13), seemed to be responsible for a significantly

increased clearance of thiotepa during a CTC course (10–15%),

resulting in more tepa formation in time. Because tepa has a

longer half-life than thiotepa, AUCTT + Twas therefore increased.

Not taking this interaction into account resulted in an underes-

timation of AUCTT + T at the end of a CTC course with

concomitant dose adaptations that were too low. Adaptation of

thiotepa doses with the newly developed model, taking into

account the induction of metabolism by cyclophosphamide,

however, resulted in slightly negatively biased results due to

overestimation of the tepa concentrations. More patients should

be included to prospectively validate the accuracy of this model.

TDM of cyclophosphamide faces the challenge of a prodrug

undergoing a complex metabolism, producing both active and

inactive products (7). Because the kinetics of cyclophosphamide

itself may not be predictive for the activation of this drug (37–40),

we based dose adjustments of cyclophosphamide on the

pharmacokinetic profile of 4OHCP. A complicating factor in the

individualization of cyclophosphamide dose is the nonpredictable

variation in enzyme activity during a course. This enzyme activity

is influenced by both autoinduction and thiotepa and becomes

apparent only until after the second day of treatment and cannot be

fully predicted from data of day 1. Estimating the extent with

which cyclophosphamide induces the conversion of thiotepa to

tepa during a course is similarly complicated when only day 1 data

are available.

It should be clear that approximation of desired target

exposures is a surrogate end point because we are mainly

interested in the clinical results of the dose individualization.

Therefore, the secondary objective of the study was to evaluate

the incidence and severity of toxicity obtained in the individu-

alized dosing group compared with patients receiving conven-

tional doses. The previously established pharmacokinetic-

pharmacodynamic relationships of CTC only accounted for

exposures to individual compounds and not their combined

effects. Nevertheless, the compounds have overlapping toxicities;

therefore, adapting the doses of all three agents simultaneously

was done. In our study, no clear difference in toxic outcome was

detected in patients receiving adapted doses compared with

patients receiving conventional doses. Only the incidence of

VOD seemed to be reduced in patients who received an adapted

cyclophosphamide dose. A factor highly contributing to these

findings is the heterogeneity of response in patients. Observed

relationships between CTC pharmacokinetics and toxicity, as

outlined in INTRODUCTION, were not very strong but

significant. Therefore, large number of patients will be necessary

to establish significant differences in pharmacodynamic outcome

between individualized and reference populations. Moreover, the

relatively low number of severe toxic events in both our

population and the reference population necessitates large patient

populations to show a beneficial effect of TDM.

In this prospective study, we also showed the feasibility of

the proposed dosing strategy in clinical practice. In this study, all

planned dose adaptations were done, with the exception of a few

adaptations for thiotepa due to bioanalytic problems. In general,

for fast and routine dose adaptations, trained personnel and short

lines among doctors, technicians, and clinical pharmacists are

a prerequisite. A trained technician for the bioanalysis as well as

a clinical pharmacologist able to perform and interpret the

mathematically complex pharmacokinetic calculations have

proven to be indispensable for rapid dose individualizations.

In conclusion, Bayesian PGD of CTC has proven to be

technically and logistically feasible in the short interval of a 4-

day course. The dosing strategy led to a marked reduction in

the variability of exposures to 4OHCP, thiotepa and tepa, and

carboplatin, especially when dose adaptations were done during

a course. Our study did not show a clear benefit for

individualized dosing in the CTC high-dose chemotherapy

Table 8 Comparison of toxicities encountered in patients receivingadapted doses compared with those receiving conventional doses (15),with focus on those toxicities expected to be correlated to exposureto cyclophosphamide, thiotepa, carboplatin, or their metabolites

Toxic event No. patients (%) P

Referencepatients(n = 43)

Patientsreceiving

adapted doses(n = 46)

VOD 2 (5) 3 (7)* NSHemorrhagic cystitis 2 (5) 3 (7) NSCardiotoxicity z grade 1 3 (7) 4 (9) NSPulmonary toxicity z grade 1 6 (14) 6 (13) NSMucositis z grade 3 6 (14) 5 (11) NSNeuropathy z grade 3 0 (0) 4 (9) NSOtotoxicity z grade 2 9 (21) 11 (24) NS

*None of these patients received an adjusted dose ofcyclophosphamide.




regimen compared with standard dosing in terms of reduced

toxicity, although an indication for reduction of the occurrence

of VOD was found.

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2005;11:273-282. Clin Cancer Res Milly E. de Jonge, Alwin D.R. Huitema, Annemarie C. Tukker, et al. ChemotherapyCyclophosphamide, Thiotepa, and Carboplatin in High-DoseBayesian Pharmacokinetically Guided Dosing of Accuracy, Feasibility, and Clinical Impact of Prospective

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