Pharmacodynamics of high-dose methotrexate in pediatric patients.
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/m(2) 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 micro mol/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 micro mol/L in the MTX concentration 24 hours after the end of the infusion (Cp(24h)) 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 Cp(24h) (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. Cp(24h) >3.5 micro mol/L was confirmed as an indicator of high risk of toxicity.
Pharmacy Department, University Hospital of Navarra, Pamplona, Spain. iaquerreta@unav.es
Irene
I
Aquerreta
Azucena
A
Aldaz
Joaquín
J
Giráldez
Luis
L
Sierrasesúmaga
D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D005260:Female; D016231:Fluorescence Polarization Immunoassay; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D009369:Neoplasms / Q000188:drug therapy; D011237:Predictive Value of Tests
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate