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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3569-3577
Pharmacokinetics and Pharmacodynamics of Oral Methotrexate and
Mercaptopurine in Children With Lower Risk Acute Lymphoblastic
Leukemia: A Joint Children's Cancer Group and Pediatric Oncology
Branch Study
By
Frank M. Balis,
John S. Holcenberg,
David G. Poplack,
Jeffrey Ge,
Harland N. Sather,
Robert F. Murphy,
Matthew M. Ames,
Mary J. Waskerwitz,
David G. Tubergen,
Solomon Zimm,
Gerald S. Gilchrist, and
W. Archie Bleyer
From the Pediatric Oncology Branch, National Cancer Institute,
Bethesda, MD; and the Children's Cancer Group, Arcadia, CA.
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ABSTRACT |
We prospectively assessed the pharmacokinetics of methotrexate,
mercaptopurine, and erythrocyte thioguanine nucleotide levels in a
homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral
mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drug
concentrations of both agents were highly variable. The area under the
plasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 µmol h/L, and the AUC of mercaptopurine ranged from 0.11 to
8 µmolh/L. Drug dose, patient age, and duration of therapy did
not account for the variability. Methotrexate AUC was significantly higher in girls than boys (P = .007). There was considerable
intrapatient variability for both agents. Erythrocyte thioguanine
nucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb)
and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P = .043) predictor of outcome, but a direct comparison of
mercaptopurine AUC in the remission and relapsed patient groups failed
to show a significant difference. Methotrexate and mercaptopurine
plasma concentrations and erythrocyte thioguanine nucleotide levels
were highly variable, but measurement of these pharmacokinetic
parameters at the start of maintenance will not distinguish patients
who are more likely to relapse.
This is a US government work. There are no restrictions on its use.
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INTRODUCTION |
INTERMITTENT oral methotrexate (MTX) and
daily oral mercaptopurine (MP) are integral components of maintenance
chemotherapy for children with lower risk acute lymphoblastic leukemia
(ALL). Both agents are routinely administered in a standard, fixed
starting dose, and subsequent dose adjustments are based on ensuing
toxicity, primarily myelosuppression or hepatotoxicity. Despite
substantial variability in plasma drug concentrations after oral
dosing,1,2 therapeutic drug monitoring is not routinely
used for individualizing and optimizing dosing of oral MTX and MP.
At standard oral doses of 7.5 to 20 mg/m2, the
bioavailability of MTX is highly variable.1,3-5 Peak plasma
concentrations can occur from 0.5 to 5 hours after oral administration,
and the percentage of the dose that is absorbed ranges from 5% to
97%.1 Absorption from the gastrointestinal tract is also
saturable, such that, if the dose of oral MTX is increased, the
fraction absorbed declines.6-8
The bioavailability of oral MP is limited by extensive first-pass
metabolism of the drug by xanthine oxidase in the liver and intestinal
mucosa and averages less than 20%.2 The resulting plasma
MP concentrations are also highly variable,2,9,10 and only
one third of patients achieve plasma concentrations of MP above the
minimal in vitro cytotoxic concentration of 1 µmol/L.11
This substantial degree of pharmacokinetic variability resulting from
oral administration of MTX and MP has prompted a number of studies that
have attempted to define a relationship between pharmacokinetic
parameters and disease outcome. In a prospective analysis of 127 children with ALL randomized to receive oral or intramuscular MTX,
there was no relationship between MTX pharmacokinetic parameters, such
as peak concentration and area under the plasma concentration-time
curve (AUC), and relapse rate.12 Other
investigators have reported that MP plasma concentration13
and product of the erythrocyte MTX and thioguanine nucleotide levels
(TGN)14 were predictive of disease outcome in children with
ALL.
MP is a prodrug that must be converted to its nucleotide form
intracellularly to exert a cytotoxic effect. Erythrocyte levels of
MP-derived TGN have been monitored as a surrogate of leukemic cell
levels in children receiving oral MP therapy. Erythrocyte TGN are also
highly variable and have been correlated with the degree of
myelosuppression and the risk of relapse.15-17
Study populations from these prior reports have included patients from
all risk groups or combined patients who had received a variety of
treatment regimens. The present study was designed to prospectively
evaluate the relationship between the pharmacokinetics of MTX, MP, and
erythrocyte TGN and disease outcome in children with lower risk ALL who
were treated on the identical standard therapy regimen that included
weekly oral MTX and daily oral MP maintenance therapy.
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PATIENTS AND METHODS |
Patients.
CCG-105PH accrued patients with lower risk ALL who were treated on the
standard maintenance therapy regimen from the CCG front line leukemia
trials, CCG-104, CCG-105 (regimens 1D and 2D),18 and
CCG-139 (regimen 2).19 Patients eligible for CCG-105PH were 12 months to 21 years old, with a white blood cell count
(WBC) less than 50,000/µL at diagnosis. Patients with
bulky extramedullary disease (lymphoma syndrome) and patients with
greater than 10% lymphoblasts with French-American-British
(FAB) L2 morphology from the initial diagnostic bone
marrow (except for patients who were 2 to 10 years of age with an
initial WBC of <10,000/µL) were excluded. Patients receiving
chronic anticonvulsant therapy were ineligible for CCG-105PH. Patients
who were treated at participating centers were eligible for enrollment
on CCG-105PH if they were in continuous remission at the start of
maintenance therapy.
Treatment regimen.
All patients on CCG-105PH received identical systemic chemotherapy,
which included induction therapy with vincristine at 1.5 mg/m2/wk intravenously (IV) for 4 doses, prednisone at 60 mg/m2/d orally (PO) for 28 days followed by a tapering dose
for 14 days (during consolidation), L-asparaginase at 6,000 IU/m2 intramuscularly (IM) for 3 days per week for 9 doses,
and 2 doses of intrathecal MTX (dosed according to age) on days 1 and
14 of induction; consolidation therapy with vincristine on day 1, MP at
75 mg/m2/d for 28 days, and intrathecal MTX weekly for 4 doses; and maintenance therapy with daily oral MP at 75 mg/m2, weekly oral MTX at 20 mg/m2, and pulses
of vincristine and prednisone at 40 mg/m2/d for 5 days
every 4 weeks. Patients on CCG-105, regimen 1D, received 18 Gy of
cranial radiation in 10 fractions over the first 2 weeks of
consolidation therapy. All other patients received intrathecal MTX on
day 1 of each 84-day maintenance cycle.
The starting doses of oral MTX and MP were based on body surface area,
and the doses were adjusted during maintenance therapy as prescribed by
the primary treatment protocol to maintain the neutrophil count between
1,000 and 2,000/µL and the platelet count above 100,000/µL.
Specially prepared 10 mg tablets of MP (Burroughs Wellcome, Research
Triangle, NC) were provided to patients on CCG-105PH to improve the
accuracy of doses, especially for small children.
Sample collection and processing.
Pharmacokinetic sampling was scheduled to be performed on day 28 of
maintenance cycles 1, 2, 4, and 6 (during months 1, 3, 9, and 15 of
maintenance therapy). Patients were fasted, except for water, for at
least 8 hours before dosing. Patients who were receiving
trimethoprim-sulfamethoxazole as pneumocystis prophylaxis had
this therapy held for at least 3 days before pharmacokinetic testing.
Other chronic medications were allowed but had to be withheld 36 hours
before pharmacokinetic testing. The scheduled doses of vincristine and
prednisone were administered after all of the pharmacokinetic samples
had been drawn.
Patients received their regular oral doses of MP and MTX simultaneously
on the morning of the test. Heparinized blood samples were collected
before and at 0.5, 1, 2, 3, 4, 6, and 8 hours after the oral doses.
Blood samples were kept on ice and centrifuged, and plasma was
separated and frozen. The erythrocyte pellet from the pretreatment
sample was frozen separately for erythrocyte TGN analysis. All samples
were sent on dry ice to the central laboratory at the Pediatric
Oncology Branch (POB; National Cancer Institute, Bethesda,
MD).
Drug assays.
MTX and MP assays were performed at the POB. MTX concentration was
measured using the dihydrofolate reductase inhibition
assay.20 MP was measured with a reverse-phase high-pressure
liquid chromatography (HPLC) method.2,21 Dithiothrietol (10 µL of a 1.0 mol/L solution) was added to the thawed plasma samples
before solid phase extraction. Erythrocyte TGN levels were measured at
Children's Hospital of Los Angeles (Los Angeles, CA). The thawed,
lysed erythrocyte pellet was extracted on a mercurial cellulose column
and assayed by HPLC with 4-thiouridine as an internal
standard.22 Thioguanosine triphosphate was the major
intracellular metabolite detected. Because the extraction method
depends on binding of the sulfhydryl group to mercury, this method does
not detect thio-methylated derivatives of the thiopurines. The amount
of TGNs in red blood cells (RBCs) was normalized to the amount of
hemoglobin in the sample, because the erythrocytes were lysed by the
freezing and thawing process.
Pharmacokinetics and statistical analysis.
The AUC was determined by the linear trapezoidal method and the
half-life was derived using regression analysis.23 The
skewed distribution of the MTX and MP AUC and the erythrocyte TGN data could be normalized by log transformation; therefore, the geometric mean is reported. The apparent clearance (Cl/F) was derived from dose/AUC. Gender differences and differences between remission and
relapsed groups were assessed using the nonparametric Mann-Whitney-U test. For these nonparametric analyses, the mean value for plasma MTX
and MP AUCs and erythrocyte TGN from each patient were used. Intrapatient variability was assessed by quantifying the degree of
deviation of the AUC from the prior measurement in patients who were
monitored on  3 maintenance cycles. AUCs were normalized to dose for
this analysis. Deviation was calculated using the equation: % Deviation = (AUC2  AUC1)/AUC1 × 100, where
AUC1 and AUC2 are sequential
normalized AUCs measured in the same patient.
The MTX AUC, MP AUC, and erythrocyte TGN were used as time-dependent
covariates in a Cox regression analysis of event-free survival. The
analyses updated the values each time a patient had a new measurement.
Because not all patients had pharmacokinetic monitoring at the
designated times, the EGRET (Epidemiological Graphics, Estimation, and
Testing) software package (Cytel Software Corp, Cambridge,
MA) was used to allow for the actual serum sampling times of each
patient in a Cox regression. We tested both the most recent values and
the mean of all previous values as predictors of future outcome. Each
pharmacokinetic variable was tested for its ability to predict outcome
as a continuous variable with an assumed linear effect on the
regression and also as a binary variable split into two groups, above
and below the median value.
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RESULTS |
Between January 1984 to January 1991, pharmacokinetic samples were
obtained from 89 patients (37 female and 52 male). The median age of
the patients at study entry was 4.6 years (range, 1.1 to 17.3 years).
Most patients did not have a set of pharmacokinetic samples obtained on
all 4 of the designated maintenance cycles. Twenty patients were
studied on 4 cycles, 18 were studied on 3 cycles, 15 on 2 cycles, and
the remainder on a single cycle. Plasma pharmacokinetics were monitored
after a total of 191 doses of MTX and 190 doses of MP, and 148 erythrocyte samples were obtained for TGN. The median dose of MTX was
18.5 mg/m2 (range, 2.1 to 36 mg/m2), and the
median dose of MP was 66 mg/m2 (range, 17.5 to 99 mg/m2).
Pharmacokinetic parameters for MTX and MP are summarized in
Tables 1 and 2,
respectively. There was marked interpatient variability in the AUCs of
MTX and MP (Fig 1). The AUC of MTX varied
by 20-fold (range, 0.63 to 12 µmolh/L), and the AUC of MP varied
by 70-fold (range, 0.11 to 8.0 µmolh/L). The dose of MTX and MP
varied in these patients, because of adjustments made for toxicities;
but there was a poor correlation between AUC and dose for both drugs
(Fig 2). There was also no apparent
increase or decrease in dose or AUC of MTX and MP over the course of
maintenance therapy (Table 3).
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| Fig 1.
Frequency distribution of the AUCs of MTX (A) monitored
after 191 oral doses ranging from 2.1 to 36 mg/m2 (median,
18.5 mg/m2), and the AUCs of MP (B) monitored after 190 oral doses ranging from 17.5 to 99 mg/m2 (median, 66 mg/m2).
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| Fig 2.
Scattergram relating dose to AUC for all monitored doses
of oral MTX (A) and MP (B). The correlation coefficients (r)
for a linear regression forced through the origin were .23 and .22 for
MTX and MP, respectively.
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We assessed the influence of age on the degree of interpatient
variability by correlating age with apparent clearance, which is a
parameter that is dose-independent and incorporates both bioavailability and elimination (Fig 3).
Although the patient population encompassed a broad age range, age
accounted for only less than 2% of the variability in Cl/F for both
MTX (r2 = .014) and MP (r2 = .0025).
Gender comparisons for the AUCs of MTX and MP are shown in
Table 4. MTX AUCs were significantly higher
in girls than in boys, but there were no gender differences for MP. The
higher AUC of MTX in girls could not be accounted for by a higher dose
of oral MTX.
Intrapatient variability of MTX and MP was evaluated in the 38 patients
who were monitored on 3 cycles of maintenance therapy. The plasma
concentration-time profile of MP appeared to be more variable within
patients than that of MTX (Fig 4). The
coefficient of variation (CV) for the AUCs was derived for each of the
38 patients, and these individual CVs were then averaged for each agent. The average of the individual CVs for MTX and MP were 34% and
45%, respectively. The degree to which AUCs deviated from the
previously measured value was also assessed in each patient, as
described in Materials and Methods. Subsequent AUC determinations deviated by more than 25% from the previous value in 70% of the subsequent AUC measurements with MTX and in 68% of the subsequent AUC
measurements with MP, indicating that a single measurement of the AUC
was poorly predictive of subsequent measurements. Regression analysis
also showed a poor correlation between baseline and subsequent normalized AUC measurements for MTX (r = .27) and MP (r = .21).
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| Fig 4.
Plasma drug concentration profile for MTX (A) and MP (B)
monitored after 4 doses on maintenance cycles 1 ( ), 2 ( ), 4 ( ), and 6 ( ) in a single patient who was on a stable dose of 20 mg/m2 of MTX and 75 mg/m2 MP. The plots
illustrate the greater intrapatient variability with MP.
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Erythrocyte TGN levels were also highly variable in this patient
population (Fig 5). The median erythrocyte
TGN from the 148 erythrocyte samples was 1.6 pmol/g hemoglobin (range,
0 to 10 pmol/g hemoglobin). There was no correlation between
erythrocyte TGN and MP dose or AUC (Fig 6).
When analyzed by maintenance cycle, there was no apparent increase or
decrease in the erythrocyte TGN (data not shown). Age (data not shown)
and gender (Table 4) did not appear to influence the erythrocyte TGN.
Erythrocyte TGN levels were also variable within individual patients
over the course of maintenance therapy. Subsequent erythrocyte TGN
determinations in patients studied on multiple maintenance cycles
deviated by more than 25% from the previous (baseline) value in 75%
of the subsequent erythrocyte TGN measurements.
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| Fig 5.
Frequency distribution of the erythrocyte TGN levels in
148 erythrocyte samples obtained during maintenance therapy.
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Disease outcome was available in 82 patients. Six patients who were
treated according to standard treatment regimen, but not officially
enrolled on the CCG trial, and one patient who was enrolled on CCG-105
regimen 1D, but later taken off study and treated with the BFM
intensification regimen, were not included in the outcome analysis. The
potential duration of follow-up exceeded 60 months. Disease outcome in
the patients entered on the CCG-105PH was not significantly different
than the outcome of other patients treated on the standard therapy arms
of CCG-104, CCG-105, and CCG-139 (P = .82). Fifty-four patients
remain in complete remission and 28 have experienced a relapse,
including 17 bone marrow relapses, 8 meningeal relapses, and 3 testicular relapses. Twenty-one of the 28 relapses occurred during
therapy or within 6 months of the end of maintenance therapy and are
considered on-therapy relapses. The MTX and MP AUCs and erythrocyte TGN
according to disease status are shown in
Fig 7. In all cases, the range of values in
the patients who experienced a relapse fell within the range of values
for the patients who have remained in complete remission, but median erythrocyte TGN in the relapsed groups was approximately 20% lower than the median from the remission group. There were no statistically significant differences in plasma MTX and MP AUCs and erythrocyte TGN
between the relapsed groups (all relapses, bone marrow relapses, extramedullary relapses, on-therapy relapses, and on-therapy bone marrow relapses) and the remission group.
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| Fig 7.
Box plots of MTX AUC (A), MP AUC (B), and erythrocyte TGN
level (C) in remission and relapse. AUCs and erythrocyte TGN level are
the mean value for each patient. The box represents the 1st to 3rd
quartile (the middle 50% of the data), the horizontal line is the
median value, the bars represent the range, and the individual points
are statistical outliers. On Rx, on therapy (see text for definition);
BM, bone marrow.
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Plasma MTX and MP AUCs and erythrocyte TGN were analyzed as
time-dependent covariates with event-free survival in a Cox regression analysis. Either the most recent measured value or the mean of all
previous values for each patient was used, and these variables were
assessed as continuous variables and split into two groups (above and
below the median value). The results of the Cox regression analysis are
presented in Table 5. MTX AUC was not a
statistically significant predictor of event-free survival. The
predictive value of MP AUC was of borderline significance (P = .043) only for the mean value as a continuous variable. The regression
coefficient was .43, suggesting that there was a better outcome
for children with higher MP AUCs. The most recent MP AUC was not
predictive. The most recent value for erythrocyte TGN also showed a
trend toward significance as a continuous variable (P = .07).
The regression coefficient of .0068 suggests that children with
the highest values had the best outcome. There were no significant
correlations when the pharmacokinetic variables were split into two
groups.
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Table 5.
Cox Proportional Hazards Survival Analysis for MTX AUC,
MP AUC, and Erythrocyte TGN Level as Continuous Variables and Split
Into Two Groups (above and below the median)
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DISCUSSION |
Current empirical dosing methods for oral MTX and MP result in highly
variable plasma drug concentrations and erythrocyte TGN levels, as
demonstrated by the present study and by other investigators.1-5,9,10 The variability presumably arises
primarily from individual differences in bioavailability. Other factors that could contribute to this variability were evaluated in this homogeneous group of patients who were treated on the identical standard therapy regimen. We studied children over a wide age range,
but age did not account for the variability. Patients were also
monitored throughout maintenance therapy, but there was no apparent
relationship between maintenance cycle and MTX or MP AUC. The doses of
MTX and MP varied in our patient population because of dose adjustments
made in patients experiencing toxicity. However, dose was a poor
predictor of AUC for both drugs.
Gender did appear to have some impact on the bioavailability or
elimination of MTX. The AUC of MTX was 30% higher in girls compared
with boys receiving the same dose. The mechanism for this difference is
unclear, but may be related to differences in the carrier-mediated
absorption mechanism. In a study of 297 children with ALL, Schmiegelow
et al14 reported higher erythrocyte MTX levels in boys than
girls, but plasma pharmacokinetics of MTX were not determined in these
patients. Plasma drug exposure (AUC) is determined by bioavailability
and the rate of drug elimination, whereas intracellular MTX levels are
determined by drug uptake into the cell and polyglutamation; therefore,
the results from these two studies may not be contradictory. Although
girls tend to have a better outcome than boys in most ALL trials, we
cannot conclude that this improved outcome is related to a greater
exposure to MTX, because we were unable to identify a relationship
between MTX AUC and disease outcome.
In the initial subset of 14 patients on the CCG-105PH study, we
evaluated MP pharmacokinetics on 2 consecutive days, with and without
MTX, and demonstrated that MTX, which is an inhibitor of xanthine
oxidase, resulted in a 30% increase in the mean AUC of
MP.24 The role of this pharmacokinetic drug interaction in the variability of MP plasma concentrations is probably not significant in this study, because, after the initial measurements on the first 14 patients, all other subjects always received the drugs together for
pharmacokinetic monitoring.
We also observed substantial intrapatient and interpatient variability
in erythrocyte TGN levels, and the variability was not related to
variation in the dose or AUC of MP. Patient age and gender and the
maintenance cycle on which the erythrocyte TGNs were measured did not
account for the variability. Because erythrocyte TGN levels reflect
accumulation over multiple doses, patient compliance could contribute
to variability.25 Several patients on our study had
undetectable erythrocyte TGN levels on a single measurement, which
could be a reflection of poor compliance.
The present study was designed to determine if the substantial
variability in pharmacokinetic parameters after standard doses of MTX
and MP had an impact on disease outcome in a homogeneous population of
patients treated on an identical standard therapy regimen. The
hypothesis being tested was that some relapses occur because of
subtherapeutic drug concentrations. If a relationship could be
identified between pharmacokinetic parameters and disease outcome, then
therapeutic levels could be defined and dose adjustments could be based
on plasma drug concentrations (therapeutic drug monitoring). An
underlying assumption of therapeutic drug monitoring is that plasma
concentrations measured after a single dose are representative of drug
disposition for subsequent doses. Therefore, intrapatient variability
is an impediment to therapeutic drug monitoring. Basing dose
adjustments on the plasma concentrations measured after a single dose
is not likely to be a successful strategy if the same dose on a
different day yields a substantially different result. In patients who
were monitored on multiple maintenance cycles, we observed substantial
intrapatient variability with both agents; as a result, measuring an
AUC of MTX or MP early in maintenance therapy may not be predictive of
drug exposure over the entire course of maintenance therapy.
We observed a trend in Cox regression analysis suggesting that higher
MP AUC (P = .04) and erythrocyte TGN (P = .07) values were predictive of better disease outcome. The association with MP AUC
was marginally significant only for the mean value as a continuous
variable. The most recent MP AUC was not predictive, presumably because
the intrapatient variability resulted in the single measurements being
less predictive of drug exposure over the course of maintenance
therapy. The fewer number of monitored doses in this analysis also may
have reduced the power of the statistical analysis. In the direct
comparison of MTX and MP AUC and erythrocyte TGN level (Fig 7),
remission and relapse groups failed to show a significant difference
for any of the pharmacokinetic parameters. The range of values in the
relapse group overlapped completely with the remission group,
indicating that these pharmacokinetic parameters could not
prospectively identify patients who are at higher risk of relapse. In
addition, without a clear difference between the relapse and remission
groups, therapeutic concentrations cannot be defined for these
parameters. Because of the substantial degree of intrapatient
variability and the inability to define a therapeutic level for any of
the pharmacokinetic parameters, this study does not support a role for
therapeutic drug monitoring as a dosing strategy for oral MTX and MP.
Prior studies have found a significant relationship between MP
pharmacokinetic parameters or a combination of MTX and MP parameters and disease outcome.13-15 Lennard and
Lilleyman15 reported that children with ALL whose
erythrocyte TGN level was below the median value of 275 pmol/8 × 108 erythrocytes had a significantly higher relapse rate
than patients with values above the median. However, the erythrocyte
TGN levels in the 19 patients in the relapse group (median, 228 pmol/8 × 108 RBCs; range, 156 to 742 pmol/8 × 108 RBCs) overlapped with values for the total study group
of 120 patients (median, 275 pmol/8 × 108 RBCs;
range, 126 to 832 pmol/8 × 108 RBCs). The median
erythrocyte TGN level was 17% lower in the relapse group, which is
similar to the 19% lower levels in our relapsed group, but we did not
find a significant difference when patients were split into two groups
based on the median erythrocyte TGN level.
Koren et al13 reported that systemic exposure to MP was
predictive of outcome in 23 children with low or average risk ALL. However, the MP AUCs in their study were normalized to a dose of 1 mg/m2 (AUC/dose), which is actually the reciprocal of
apparent clearance (dose/AUC) rather than a true measure of drug
exposure (AUC). The intrapatient variability that we observed would
suggest that a single measurement of MP AUC would not be predictive of
MP exposure over the course of maintenance therapy.
MTX AUC was not predictive of outcome in this study and a prior
trial.12 Schmiegelow et al14 monitored
erythrocyte MTX and TGN concentrations over multiple maintenance cycles
in children with ALL and found that the product of the erythrocyte MTX
and TGN levels, but not the erythrocyte MTX and TGN alone, was
predictive of outcome (a higher erythrocyte-MTX erythrocyte-TGN
was associated with a better outcome). However, these investigators
used a mean value for these parameters across multiple maintenance
cycles that does not account for the influence of intrapatient
variability.
Demonstrating a relationship between pharmacokinetic parameters of
individual agents and disease outcome is complicated for a disease that
is treated with combination chemotherapy. Based on the experience with
single-agent therapy in ALL, it is unlikely that an individual agent in
the combination regimen accounts for the success or failure of the
regimen, and the contribution of each agent may vary from patient to
patient based on the underlying sensitivity or resistance to the agents
included in the combination regimen.
Despite the high degree of interpatient variability in the
pharmacokinetic parameters measured in the present study, we were unable to define a relationship between the plasma pharmacokinetics of
MTX and MP or the erythrocyte TGN levels and disease outcome. A
relationship between erythrocyte TGN levels and outcome has been
observed in prior trials, but the lack of relationship between MP dose
and erythrocyte TGN level suggests that modifications of MP dose may
not have a predictable or proportional effect on erythrocyte TGN
levels. Thus, the current dosing method of increasing or decreasing MTX
and MP dose based on each patient's blood counts may still be the most
rational dosing method.
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APPENDIX |
Participating Principal Investigators Children's Cancer Group
(Institution, Investigators, Grant No.): Group Operations Center, Arcadia, CA, W. Archie Bleyer, MD, Anita Khayat, PhD, Harland Sather,
PhD, Mark Krailo, PhD, Jonathan Buckley, MBBS, PhD, Daniel Stram, PhD,
Richard Sposto, PhD, CA 13539; University of Michigan Medical Center,
Ann Arbor, MI, Raymond Hutchinson, MD, CA 02971; University of
California Medical Center, San Francisco, CA, Katherine Matthay, MD, CA
17829; Children's Hospital & Medical Center, Seattle, WA, Ronald
Chard, MD, CA 10382; Children's Hospital of Los Angeles Los Angeles,
Los Angeles, CA, Jorge Ortega, MD, CA 02649; Vanderbilt University
School of Medicine, Nashville, TN, John Lukens, MD, CA 26270;
Doernbecher Memorial Hospital for Children, Portland, OR, Lawrence
Wolff, MD, CA 26044; University of Minnesota Health Science Center,
Minneapolis, MN, William Woods, MD, CA 07306; University of Texas
Health Sciences Center, San Antonio, TX, Thomas Williams, MD, CA 36004;
Memorial Sloan Kettering Cancer Center, New York, NY, Peter Steinherz,
MD, CA 42764; James Whitcomb Riley Hospital for Children, Indianapolis,
IN, Philip Breitfeld, MD, CA 13809; Children's Hospital Medical
Center, Cincinnati, OH, Robert Wells, MD, CA 26126; Harbor/UCLA & Miller Children's Medical Center, Torrance/Long Beach, CA, Jerry
Finklestein, MD, CA 14560; Children's Hospital of Denver, Denver, CO,
Lorrie Odom, MD, CA 28851; Izaak Walton Killam Hospital for Children,
Halifax, Canada, Dorothy Barnard, MD; University of North Carolina
Chapel Hill, Chapel Hill, NC, Joseph Wiley, MD.
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FOOTNOTES |
Submitted March 18, 1998;
accepted July 8, 1998.
For research support, see Appendix.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Frank M. Balis, MD, Pediatric Oncology
Branch, NCI, Bldg 10, Room 13N240, 10 Center Dr, MSC 1928, National
Institutes of Health, Bethesda, MD 20892-1928; e-mail:
balisf{at}.nih.gov.
| |
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Pharmacokinetics of oral methotrexate in children.
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Zimm S, Collins JM, Riccardi R, O'Neill D, Narang PK, Chabner B, Poplack DG:
Variable bioavailability of oral mercaptopurine.
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Abstract
Introduction
