Oncology

Pharmacodynamics of High-Dose Methotrexate

in Pediatric Patients
Irene Aquerreta, Azucena Aldaz, Joaquín Giráldez, and Luis Sierrasesúmaga

OBJECTIVE: To establish a relationship between the pharmacokinetics of high-dose methotrexate (MTX) and toxicity in children of a
pediatric oncology department and to reassess MTX concentrations at which the patients would be at high risk for toxic effects.
METHODS: This study included 37 patients (227 treatment courses) who received a median dose of 4.87 g/m2 of MTX in a 4-hour
infusion. The population pharmacokinetic parameters of MTX were estimated by parametric (IT2B) and nonparametric methods
(NPEM). Gastrointestinal, renal, and hematologic toxicity were evaluated. The relationship between pharmacokinetic parameters
and toxicity was analyzed by logistic regression and multiple linear regression.
RESULTS: Equations to predict hematologic and nonhematologic toxicity were obtained. An increase of 100 µmol/L in the MTX peak
concentration meant a 12% (p = 0.03) higher risk of vomiting; a significant delay in MTX elimination implied a 5.76-fold higher risk of
mucositis (p < 0.001). An increase of 1 µmol/L in the MTX concentration 24 hours after the end of the infusion (Cp24h) led to a 43%
increase in the risk of renal toxicity (p < 0.001). Hematologic toxicity was significantly conditioned by the baseline leukocyte count
and Cp24h (p < 0.001).
CONCLUSIONS: The analysis of high-dose MTX pharmacokinetic/pharmacodynamic relationship to toxicity has led to equations able
to predict toxicity that are easily applicable to daily practice. Cp24h >3.5 µmol/L was confirmed as an indicator of high risk of toxicity.
KEY WORDS: high-dose methotrexate, toxicity.

Ann Pharmacother 2002;36:1344-50.

igh-dose methotrexate (MTX) is useful therapy for a
H diverse range of pediatric tumors such as osteosarco-
1,2 3,4
ma, acute lymphocytic leukemia, and non-Hodgkin’s
5,6
lymphoma. Clinical monitoring, hydration, and urine al-
kalinization have helped to reduce the mortality rate associ-
ated with high-dose MTX therapy from 5–6% to <0.1%.7
Monitoring the serum concentrations of high-dose MTX is
a well-accepted method to identify patients who are at high
risk for severe toxic effects of the drug.8
Criteria for risk assessment vary from one institution to
another. Concentrations of MTX that are likely to produce
a high risk for toxic effects have been defined9,10 at selected
times after the end of the infusion (24, 48, or 72 h). Once a
high-risk concentration has been detected, appropriate
measures, such as leucovorin rescue, must be adopted to
reduce the severity of the toxic effects. Clinical monitoring
is necessary to determine the period over which leucovorin
rescue must be maintained, as it has to be continued until
an MTX serum concentration of 0.05 µmol/L has been
reached.7 To our knowledge, quantitative methods to pre-
dict MTX-induced toxicity based on pharmacokinetic pa-
rameters are limited.11-14 The objective of this study was to
derive predictive equations based on the analysis of phar-
macokinetic/pharmacodynamic relationships in terms of
toxicity to be used in daily clinical practice to help opti-
mize high-dose MTX therapy in pediatric patients.
Methods
PATIENTS

Thirty-seven children (19 boys, 18 girls) who received high-dose

MTX therapy between 1986 and 1993 were studied. The total number of
Author information provided at the end of the text. MTX courses administered was 227 in patients diagnosed with osteosar-

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coma (n = 27), non-Hodgkin’s lymphoma (9), and medulloblastoma (1).
The inclusion criterion was the availability of the relevant data in the pa-
tients’ medical charts.
DATA COLLECTION
The following clinical data were collected by retrospective chart re-
view: age; gender; height; weight; lean body weight; body surface area;
diagnosis; subtype of tumor; location of the tumor; presence of distant
metastases; creatinine clearance (Clcr) estimated by the Schwartz formu-
la15; significant delay in MTX elimination, defined in a previous unpub-
lished work done in our hospital as MTX concentration at 24 hours after
the end of the infusion (Cp24h) >3.5 µmol/L and plasma half-life for the
initial elimination phase (t1/2α) >3.5 hours, or MTX concentration 48
hours after the end of the infusion (Cp48h) ≥0.35 µmol/L and plasma t1/2
for the terminal elimination phase (t1/2β) >12.5 hours; baseline serum cre-
atinine (SCr); maximum SCr; baseline leukocyte count; minimum
leukocyte count; volume of hydration; lowest recorded urine pH; and the
concurrent use of other drugs that could potentially interact with MTX
(trimethoprim/sulfamethoxazole, penicillins, aminoglycosides, nons-
teroidal antiinflammatory drugs [NSAIDs], diuretics, cisplatin, carbo-
platin, vancomycin).
MTX ADMINISTRATION
2
The dose of MTX ranged from 1.2 to 12.3 g/m (median 4.87, and in-
terquartile range [IQR] 2.90). Hydration consisted of 3 L/m2/24 h of dex-
trose 5% in water with 300 mEq of NaHCO3 and 60 mEq of KCl per
liter. Hydration was begun 12 hours before MTX administration and
maintained for 3 days. Urine pH was checked throughout the hydration
period. MTX administration was performed when urine pH was between
7 and 8 in 2 consecutive voids and urine flow was at least 120 mL/min.
If necessary, the NaHCO3 dose was adjusted to obtain a urine pH be-
tween 7 and 8. The MTX dose was diluted in 500 mL of NaCl 0.9% and
infused over a 4-hour period. As this was a retrospective study, it was
not possible to confirm in every MTX course the exact length of the in-
fusion. We assumed that they all were 4-hour infusions, which is the
usual practice in our institution. The standard leucovorin rescue dose was
15 mg/m2 every 6 hours for 3 days, beginning 12 hours after the end of
MTX administration. The chemotherapy regimen in patients with os-
teosarcoma included administration of cisplatin, doxorubicin, bleomycin,
dactinomycin, and ifosfamide. Patients with non-Hodgkin’s lymphoma
received M-BACOD and ICAVP chemotherapy regimens (Appendix I).
PLASMA SAMPLES
MTX concentrations were measured at specific times to determine
adequate leucovorin rescue therapy or supportive care. High-risk con-
centrations of MTX had been determined in our hospital in a preliminary
study in pediatric patients: Cp24h ≥3.5 µmol/L or Cp48h ≥0.35 µmol/L.
Therefore, in most cases, MTX plasma concentrations were determined
at the end of the MTX infusion and at 24 and 48 hours. Crom and
Evans’7 guidelines for modification of leucovorin dosage were followed
in patients with high-risk MTX concentrations ≥42 hours after the begin-
ning of the MTX infusion.
SAMPLE ANALYSIS
MTX plasma concentrations were measured by fluorescence polar-
ization immunoassay (FPIA) with a TDxFLx analyzer.16
PHARMACOKINETIC ANALYSIS
Pharmacokinetic parameters of MTX were estimated by parametric
(IT2B, iterative two-stage Bayesian)17 and nonparametric (NPEM, non-
parametric expectation maximization)18 methods using the software
package USC*PACK 10.7a (University of Southern California, Los An-
geles, CA) and assuming a 2-compartment pharmacokinetic model.
First, pharmacokinetic parameters were estimated by IT2B to obtain a
range of variability of the parameters and estimate the value of σ or in-
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traindividual variability to be applied on NPEM. The assay error pattern
was determined by the Jelliffe and Tahani19 method. The pharmacokinet-
ic parameters obtained by NPEM were chosen for their lower value of
the log-likelihood and their similar predictive performance when com-
pared with that obtained by IT2B. Pharmacokinetic parameters estimat-
ed were elimination rate constant (kel), rate constants for MTX’s move-
ment from the central to peripheral compartment (kcp) and peripheral to
central compartment (kpc), and volume of distribution for the central
compartment (Vc). MTX systemic clearance (Cl) and AUC were esti-
mated according to the following equations1:
Cl = kel × Vc
AUC = dose
Cl
The pharmacokinetic variables analyzed for each MTX course were
dose, peak plasma concentrations, Cp24h and Cp48h after the end of the in-
fusion, Cl, Vc, kel, kcp, kpc, and AUC.
In our previous, unpublished work, patient’s age was found to have a
profound influence on MTX pharmacokinetics. Therefore, relationships
between pharmacokinetics and the incidence of the different toxicities
were analyzed in different age groups (<8, 8–12, >12 y).
TOXICITY ANALYSIS
MTX toxicity was evaluated as gastrointestinal toxicity defined as
vomiting after MTX administration (yes/no) or mucositis scored accord-
ing to the World Health Organization (WHO) scale20 (grade 0 = no reac-
tion; grade 1 = painless ulcers, erythema, or mild soreness; grade 2 =
painful erythema, edema, or ulcers but can eat solids; grade 3 = painful
erythema, edema, or ulcers and cannot eat solids; grade 4 = requires par-
enteral or enteral support for alimentation); renal toxicity was assessed
by the percentage of increase in SCr21 (grade 0 = <25%, grade 1 =
25– 49%, grade 2 = 50 –74%, grade 3 = 75–100%, grade 4 = >100%);
and hematologic toxicity was evaluated by the minimum leukocyte
count per cubic millimeter according to the WHO scale20 (grade 0 =
>4000, grade 1 = 3000 –3900, grade 2 = 2000 –2900, grade 3 =
1000–1900, grade 4 = <1000). When mucositis plus renal and hemato-
logic toxicity were considered as binary variables, they were defined as
absent (grade 0) or present (grade >1).
STATISTICAL ANALYSIS
The relationship between the pharmacokinetic parameters and toxici-
ty was analyzed by logistic regression and by multiple linear regression.
The best logistic regression model was selected by the p value associated
to the Wald χ2. The frequencies of an event such as toxicity were com-
pared using a χ2 test. The criterion used to select the best model by mul-
tiple linear regression was the adjusted R2 (R2adj). The method used in
logistic and multiple linear regression was forward stepwise. The corre-
lations between variables were evaluated using a Pearson or Spearman
correlation coefficient depending on the distribution of the variable. The
program used for statistical analyses was Statistica edition ’99.22 In all
cases, the significance level chosen was p < 0.05.
Results
PATIENTS
Demographic and clinical data on the 37 subjects are
shown in Table 1.
PHARMACOKINETIC ANALYSIS
MTX plasma concentrations expressed as median (IQR)
were peak 450 (320) µmol/L, Cp24h 0.85 (1.09) µmol/L,
and Cp48h 0.14 (0.14) µmol/L. A significant delay in MTX
elimination (Cp24h >3.5 µmol/L and t1/2α >3.5 h, or Cp48h
■ 2002 September, Volume 36 ■ 1345
I Aquerreta et al.

≥0.35 µmol/L and t1/2β >12.5 h) was observed in 37 cours- an increase of 1 µmol/L increased the risk of vomiting by
es (16.30%). The dose of leucovorin administered was 0.11%. When considering an increase of 100 µmol/L, the
177.20 (71.14) mg/m2. Urine pH <7 was detected in only 4 OR increases to 1.12 (95% CI 1.01 to 1.24). Thus, an in-
MTX courses. In 3 of these cases, the acid urine pH crease of 100 µmol/L in peak concentration means a 12%
(5–6.5) resulted in a significant delay in MTX elimination. greater risk of vomiting after MTX administration. The fol-
Pharmacokinetic parameters estimated by NPEM present- lowing equation can be used to determine the risk of devel-
ed an optimal predictive performance (determination coef- oping vomiting that is associated with an increase in the
ficient between observed and predicted plasma concentra- peak (Table 2):
tions R2 = 0.98). MTX Cl was 6.25 (2.80) L/h and AUC
OR = e(0.00112 × ∆peak)
was 2392.64 (1777.74) µmol/L/h.
The only variable significantly related to mucositis (p <
TOXICITY
0.05) was the delay in MTX elimination (Wald p < 0.001;
Table 2). The OR obtained shows that patients who experi-
Different types of toxicity were observed: emesis 24 enced significant delay in MTX elimination had a 5.76-
hours after MTX administration was reported in 55 treat-
ment courses, mucositis 1 week after administration of
MTX in 8 courses, renal toxicity between grades 1 and 4 Table 1. Anthropometric and Clinical Variablesa
in 65 courses, and hematologic toxicity between grades 1
Variable Mean SD CV (%) Range
and 4 in 52 courses. Not all the clinical charts included an-
alytical data of renal and hematologic information after ad- BSA (m2) 1.40 0.33 23.48 0.67–2.28
ministration of MTX. Indeed, only 180 and 81 MTX Weight (kg) 46.67 15.99 34.38 15.32–96.43
courses presented renal and hematologic information to as- LBW (kg) 38.32 12.34 32.30 13.87–75.79
sess toxicity, respectively. WBC (x 103/mm3)
baseline 5.17 2.29 44.24 1.24–16.0
minimum 3.64 1.61 44.29 8.0–9.1
RELATIONSHIP BETWEEN MTX PHARMACOKINETICS AND Clcr (mL/min) 120.8 46.23 38.27 46.23–216.69
TOXICITY Median IQR

Age (y) 14 7 37.88 4–21

The dose of MTX, its peak concentration, and concur-
Height (cm) 158 30 14.38 105–192
rent administration of penicillins were identified by logistic
SCr (mg/dL)
regression as significant related to delay in MTX elimina- baseline 0.6 0.2 25.25 0.3–1.50
tion (p < 0.05). These variables were included in multivari- maximum 0.7 0.3 32.47 0.3–3.0
ate analysis; the best model selected was the one that in- BSA = body surface area; Clcr = creatinine clearance estimated by the
cluded the MTX peak concentration considering the value Schwartz formula; IQR = interquartile range; LBW = lean body weight;
of p associated to Wald χ2 (p < 0.001) (Table 2). The odds SCr = serum creatinine; WBC = white blood cell.
a
37 patients; 227 courses of high-dose methotrexate.
ratio (OR) associated with the peak concentra-
tion was 1.0041, implying that an increase of 1
µmol/L increases the risk of presenting signifi-
cant delay (0.41%) in MTX elimination. An in- Table 2. Logistic Regression Models for Significant Delay in MTX
crease of 100 µmol/L in the peak MTX con- Elimination, Vomiting, Mucositis, and Renal Toxicity
centration raises the OR to 1.50 (95% CI 1.31
Parameter β SE Wald p OR OR 95% CI
to 1.72), implying a 50% higher risk of devel-
oping significant delay in MTX elimination. Delay in MTX
elimination
The following equation can be used to deter- intercept –4.21 0.53 <0.001 0.015 0.0052 to 0.043
mine the risk of developing significant delay in peak concen- 0.0041 0.00070 <0.001 1.0041 1.0027 to 1.0055
tration
MTX elimination that is associated with an in-
Vomiting
crease in peak concentration (∆peak) (Table 2): intercept –1.76 0.34 <0.001 0.17 0.089 to 0.33
OR = e(0.00406 × ∆peak) peak concen- 0.0011 0.00051 0.030 1.0011 1.00011 to 1.0021
tration
Logistic regression led to the identification Mucositis
of 3 variables as significant determinants of the intercept –3.83 0.51 <0.001 0.022 0.00803 to 0.059
risk of developing vomiting (p < 0.05). They delay in MTX 1.72 0.73 0.020 5.76 1.32 to 23.59
elimination
were concomitant administration of NSAIDs,
Renal toxicity
total leucovorin dose (mg/m2), and peak con- intercept 1.17 0.77 0.13 3.23 0.70 to 14.92
centration of MTX. By multiple logistic regres- Cp24h (µmol/L) 0.36 0.13 0.0075 1.43 1.10 to 1.86
sion, the best model selected was the one that SCr (mg/dL) –3.71 1.31 0.0055 0.025 0.0018 to 0.33
included MTX peak concentration (Wald p = Cp24h = MTX plasma concentration at 24 hours after the end of the infusion; MTX =
0.030; Table 2). The OR associated with the methotrexate; peak concentration = MTX plasma concentration at the end of the
infusion; SCr = baseline serum creatinine.
peak concentration was 1.0011, meaning that

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fold higher risk of presenting mucositis than those who able to develop equations that may predict toxicity. Some
eliminated MTX at a normal rate. of the limitations of our study were the relatively low num-
By simple logistic regression, the variables significantly ber of patients included, the retrospective design, and the
related to renal toxicity were Cp24h, baseline SCr, Clcr, kcp, relatively large number of correlative factors analyzed.
kpc, AUC, and MTX Cl (p < 0.05). The model selected by Different authors have described the mechanism by
multiple logistic regression included the variable Cp24h and which renal toxicity and consequent delay in MTX elimina-
baseline SCr (Wald p = 0.00064; Table 2). The Cp24h OR tion is produced. MTX and its metabolite, 7-hydroxy-
obtained shows that an increase of 1 µmol/L in Cp24h was methotrexate (7-OH-MTX), precipitate in distal tubules, in-
reflected in an increase of 43% in the risk of renal toxicity ducing renal dysfunction as well as having a direct nephro-
(95% CI 10% to 86%). The equation to predict the risk of toxic action on distal tubule cells.23 This leads to a decrease
nephrotoxicity that is associated with an increase in Cp24h in the renal elimination of MTX, causing an increase in the
(∆Cp24h) is: concentration of MTX and, consequently, a higher inci-
OR = e(0.359 × ∆Cp24h) dence of adverse events such as hematologic and gastroin-
testinal toxicity. Thus, renal toxicity induced by MTX in-
(Table 2). When renal toxicity was analyzed as percentage
hibits its own renal excretion.11,24 Indeed, high-dose MTX
of the increase in SCr by multiple linear regression, the
therapy has been shown23 to produce a decrease in glom-
variables that explain renal toxicity were Cp24h and base-
erular filtration even in otherwise nontoxic courses.
line SCr. Both variables were able to explain a 44.39%
Logistic regression analysis shows that an increase of
variability in the percentage increase of SCr (R2adj = 0.44;
100 µmol/L in the peak concentration of MTX increases
p < 0.001). The regression equation obtained was:
the risk of developing significant delay in the elimination
increase of SCr (%) = 38.91– 45.82 × baseline SCr of MTX by 50%. The strong correlation observed between
(mg/dL) + 7.15 × Cp24h (µmol/L) the peak concentration and the dose of MTX (Spearman R
The Cp24h at which significant differences in renal toxicity = 0.83; p < 0.001; Figure 1) indicates that the main factor
were detected was evaluated. Significant differences were responsible for delay of MTX elimination is its dose.
detected by the χ2 test at Cp24h 3.5 µmol/L (p = 0.018), with a Many other factors have been described that increase
sensitivity of 20% and specificity of 94.19%. The OR ob- the risk of MTX toxicity including inadequate hydration,25
tained was 2.09, which means that patients whose Cp24h ex- acidic urine pH,11 presence of extravascular third spaces,7
ceeded 3.5 µmol/L presented a double risk of nephrotoxicity. concomitant administration of other drugs (e.g., NSAIDs,26
The only significant variable associated with hemato- nephrotoxic agents27), low concentration of plasma pro-
logic toxicity by logistic regression was the baseline leuko- teins,28 emesis,11 or poor nutritional status.7 Nevertheless, in
cyte count (p < 0.001). A decrease of 1000 leukocytes per many cases, delayed MTX elimination cannot be related to
cubic millimeter in baseline leukocyte count leads to a four any of these risk factors. Given the high incidence of un-
fold increase in the risk of developing hematologic toxici- predictable delays in MTX elimination, it is useful to mon-
ty. When the minimum leukocyte count was
considered the dependent variable in multiple
linear regression, the explanatory variables
were the baseline leukocyte count and Cp24h (p
< 0.001; R2adj = 0.64). The regression equa-
tion obtained was:
minimum leukocyte count/mm3 = 735.36 +
0.65 × baseline leukocyte count – 80.92 ×
Cp24h (µmol/L)
Significant differences were obtained in the in-
cidence of hematologic toxicity at Cp24h above
or below 3.5 µmol/L by the Mann–Whitney
U-test (p = 0.034).
It seems that hematologic toxicity increases
with age; however, no significant differences
were detected in hematologic or renal toxicity
between the different age groups analyzed. No
significant influence of age was identified for
gastrointestinal toxicity.

Discussion
Figure 1. Correlation between MTX dose and peak concentration. The regression equa-
In analyzing the relationship between high- tion obtained was as follows: peak concentration (µmol/L) = –61.75 + 107.06 × dose (g/m2);
dose MTX and toxicity in children, we were Spearman rank order correlation (p < 0.001). MTX = methotrexate.

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I Aquerreta et al.
itor its concentrations in all high-dose courses10,29 and to
define high-risk MTX concentrations at specific times. Re-
nal dysfunction as the result of the MTX administration
appears to be the main factor involved in significant delay
of elimination.
Vomiting was related to the peak concentration of MTX
by logistic regression analysis (p < 0.001). An increase in
the peak concentration of 100 µmol/L increases the risk of
vomiting by 12%, which can be considered slightly rele-
vant. As was the case for delayed MTX elimination, the
close correlation observed between peak concentration and
dose (R = 0.83) indicates that the main factor involved in
vomiting was the dose.
The incidence of mucositis was related to the delay in
MTX elimination, with the risk being 5.76 times higher in
patients who experienced significant delay in elimination.
Rask et al12,14 also found a significant correlation between
mucositis and low systemic clearance of MTX and high
plasma concentration 28 hours after starting the infusion.14
The incidence of mucositis that we observed was lower
(3.52%) than that reported10,12,20 by other authors (33–
52%). This difference can be explained by the delayed ap-
pearance of mucositis, an effect that appears ≥1 week after
MTX administration. Within that time, if the drug has been
adequately eliminated, the patient has been discharged; in
addition, mucositis is not always recorded in the medical
records. Other authors have probably performed a closer
monitoring over a longer period of time after MTX admin-
istration and so were able to detect late toxic events. Mean
length of stay of our patients was 3 days, and no clinical
data were collected after they were discharged.
The variables related to renal toxicity were baseline SCr
and Cp24h. Baseline SCr was included in the model as a
corrective factor of how renal toxicity was evaluated (per-
centage increase in SCr related to baseline value). At a
Cp24h >3.5 µmol/L, the incidence of renal toxicity was
twofold greater than normal. This group of patients exhib-
ited a mean t1/2α >3.5 hours. These results corroborate the
high-risk MTX concentration and t1/2 obtained in a prelimi-
nary study conducted in our department and show that the
Cp24h is important in detecting patients with a high risk of
developing toxic effects.
The only variable significantly related by logistic re-
gression to hematologic toxicity was the baseline leuko-
cyte count; however, multiple linear regression showed
that Cp24h also has a significant influence. Other authors14
have found a significant correlation between hematologic
toxicity and long exposure to MTX measured as AUC.
The Cp24h seems to be an indicator of the risk of develop-
ing both renal and hematologic toxicity.
No significant influence of other chemotherapy agents
was detected in the incidence of toxic effects. Despite the
different MTX doses administered, no significant differ-
ences were detected in the incidence of toxic effects be-
tween the patients diagnosed with osteosarcoma and non-
Hodgkin’s lymphoma, although it tended to be higher in
patients with osteosarcoma. The percentage of MTX treat-
ment courses that were associated with vomiting was 25%
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in osteosarcoma patients and 20% in those with non-
Hodgkin’s lymphoma. Similarly, nephrotoxicity was 30%
versus 28%, respectively. Mucositis was detected only in
patients with osteosarcoma.
Hematologic toxicity appears to increase with age. How-
ever, no significant differences were detected between the
different age groups. Some investigators30,31 have found that
toxicity caused by high-dose MTX is milder and more tol-
erable in younger patients, probably because of the higher
values of MTX Cl and Vc in that population that determine
lower MTX exposure.32 Wang and Fujimoto33 found that
the incidence of moderate or severe toxicity was signifi-
cantly lower in patients <15 years old,33 and Rask et al.14
observed a significant increase in liver toxicity with age.
Summary
We have been able to obtain predictive equations of gas-
trointestinal and renal toxicity by high-dose MTX in a
population of pediatric patients. The MTX peak concentra-
tion is the main factor that affects the significant delay in
elimination and emesis. This delay is unpredictable; conse-
quently, all high-dose MTX courses should be closely
monitored. Cp24h >3.5 µmol/L is an MTX concentration
associated with a high-risk toxicity. MTX concentrations
and supportive measures should be adopted if this level of
exposure is reached. We found no significant correlation
between Cp48h and toxicity, and the Cp48h toxicity criteria
obtained in our preliminary study could not be confirmed.
The predictive equations derived from our observations
could be useful in the evaluation of MTX toxicity in pa-
tients whose clinical data were above the toxicity level in
order to adopt the adequate supportive and treatment mea-
sures.
Irene Aquerreta PharmD PhD, Staff Pharmacist, Pharmacy De-
partment, University Hospital of Navarra, Pamplona, Spain
Azucena Aldaz PharmD PhD, Staff Pharmacist, Pharmacy De-
partment, University Hospital of Navarra
Joaquín Giráldez PharmD PhD, Director, Pharmacy Department,
University Hospital of Navarra
Luis Sierrasesúmaga MD PhD, Director, Pediatrics Department,
University Hospital of Navarra
Reprints: Irene Aquerreta PharmD PhD, Pharmacy Department,
University Hospital of Navarra, Avda. Pío XII 36, 31008 Pamplona,
Spain, FAX 34 948 175278, E-mail iaquerreta@unav.es
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EXTRACTO
OBJETIVO: El objetivo de este estudio retrospectivo consistió en
establecer una relación entre la farmacocinética de altas dosis de
methotrexate (MTX) y la toxicidad en niños del departamento de
Oncología Pediátrica y establecer las concentraciones de MTX a las que
los pacientes presentaban riesgo de sufrir toxicidad.
MÉTODOS: Este estudio incluyó 37 pacientes (227 ciclos de tratamiento)
que recibieron una mediana de dosis de 4.87 g/m2 de MTX en una
infusión de 4 horas. Los parámetros farmacocinéticos de MTX fueron
estimados mediante métodos paramétricos (IT2B) y no paramétricos
(NPEM). Se evaluó la toxicidad gastrointestinal, renal, y hematológica.
La relación entre los parámetros farmacocinéticos y la toxicidad se
analizó mediante regresión logística y regresión lineal múltiple.
Appendix I. Chemotherapy Regimens
Osteosarcoma
Before surgery
cisplatin 40 mg/m2/d ia, days 1, 2, 3, 21, 22, and 23
doxorubicin 30 mg/m2/d iv, days 1, 2, 22, 23
MTX 6 g/m2 iv, days 7, 14, 29, 36
cisplatin 40 mg/m2/d ia, days 43, 44, 45
2 wk after surgery
(A) MTX 6 g/m2 iv
(B) cisplatin 40 mg/m2/d iv for 3 d
doxorubicin 25 mg/m2/d iv for 3 d
(C) bleomycin 10 mg/m2/d iv for 3 d
dactinomycin 0.5 mg/m2/d iv for 3 d
ifosfamide 1.5 g/m2/d iv for 3 d, with Mesna 300 mg/m2 adminis-
tered before and 4 and 8 h after ifosfamide
cycles B and C repeated every 21 d; cycle A administered be-
tween cycles B and C, days 7 and 14
NHL
M-BACOD
bleomycin 4 mg/m2 im, day 1
doxorubicin 45 mg/m2 im, day 1
cyclophosphamide 600 mg/m2 iv, day 1
vincristine 1 mg/m2 iv, day 1
dexamethasone 6 mg/m2 po, days 1–5
methotrexate 3 g/m2 iv, day 14
ICAVP
ifosfamide 3 g/m2 iv, day 21
cisplatin 50 mg/m2 iv, day 21
etoposide 60 mg/m2 iv, days 21–23
cytarabine 20 mg/m2 iv for 12 doses, days 21–23
prednisone 60 mg/m2/d po, days 21–25
MTX = methotrexate.

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I Aquerreta et al.

RESULTADOS: Se obtuvieron ecuaciones para predecir la toxicidad
hematológica y no hematológica. Un incremento de 100 µmol/L en la
concentración de MTX al final de la infusión supuso un aumento del
12% (p = 0.03) en el riesgo de presentar vómitos, mientras que los
pacientes con retraso en la eliminación de MTX presentaron un riesgo
de desarrollar mucositis 5.76 veces superior (p < 0.001). Un aumento en
1 µmol/L en la concentración de MTX 24 horas tras el fin de la infusión
(Cp24h) supuso un aumento del 43% en el riesgo de presentar toxicidad
renal (p < 0.001). La toxicidad hematológica estaba relacionada
significativamente con el recuento basal de leucocitos y con la Cp24h (p
< 0.001).
CONCLUSIONES: Mediante el análisis de la relación entre farmacocinética
y farmacodinamica de altas dosis de MTX en términos de toxicidad
permitió obtener ecuaciones para predecir la toxicidad que son
fácilmente aplicables a la práctica clínica. La Cp24h > 3.5 µmol/L se
confirmó como un indicador de riesgo elevado de presentar toxicidad.
Irene Aquerreta
RÉSUMÉ
OBJECTIF: Le but de cette étude rétrospective consistait à établir une
relation entre la pharmacocinétique du méthotrexate (MTX) et la
toxicité chez les enfants d’un département d’oncologie pédiatrique et à
déterminer à quelles concentrations de MTX les malades présenteraient
plus de risques au niveau des effets toxiques.
MÉTHODOLOGIE: Cette étude comprenait 37 patients (227 cycles) ayant
reçu 1 dose médiane de 4.87 g/m2 de MTX en perfusion de 4 heures. Les
paramètres pharmacocinétiques du MTX pour cette population ont été
estimés par des tests paramétriques et non-paramétriques. Les toxicités
gastro-intestinale, rénale, et hématologique ont été évaluées. Les
relations entre les paramètres pharmacocinétiques et la toxicité ont été
analysées par régression logistique et par régression multiple linéaire.
RESULTATS: Pour prédire la toxicité hématologique et non-
hématologique, les cliniciens ont développé des équations. Ainsi, une
augmentation de 100 µmol/L du pic plasmatique de MTX signifiait un
risque de 12% (p = 0.03) plus élevé de développer des vomissements
tandis qu’un délai significatif dans l’élimination du MTX impliquait un
risque 5.76 fois plus élevé de développer des mucosites (p inf. à 0.001).
Une hausse de 1 µmol/L de la concentration de MTX 24 heures après la
fin de la perfusion (Cp24h) a occasionné une augmentation de 43% du
risque de développer de la néphrotoxicité (p inf. à 0.001). La toxicité
hématologique était influencée significativement par le décompte initial
des leucocytes et par la Cp24h (p inf. à 0.001).
CONCLUSIONS: L’analyse de cette étude sur les hautes doses de MTX a
permis d’élaborer des équations facilement applicables dans notre
pratique quotidienne pour prédire la toxicité du MTX. Une CP24h
supérieure à 3.5 µmol/L est un indicateur imporant de haut risque de
toxicité.
Louise Gagnon

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