Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia.
OBJECTIVE
To develop and a priori validate a methotrexate population pharmacokinetic model in children with acute lymphoblastic leukaemia (ALL), receiving high-dose methotrexate followed by folinic acid rescue, identifying the covariates that could explain part of the pharmacokinetic variability of methotrexate.


METHODS
The study was carried out in 49 children (aged 6 months to 17 years) who received high-dose methotrexate (3 g/m(2) per course) in long-term treatment. In an index group (37 individuals; 1236 methotrexate plasma concentrations), a population pharmacokinetic model was developed using a nonlinear mixed-effects model. The remaining patients' data (12 individuals; 278 methotrexate plasma concentrations) were used for model validation. Age, sex, total bodyweight (TBW), height, body surface area, lowest urine pH during infusion, serum creatinine, ALT, AST, folinic acid dose and length of rescue were analysed as possible covariates. The final predictive performance of the pharmacokinetic model was tested using standardised mean prediction errors.


RESULTS
The final population pharmacokinetic model (two-compartmental) included only age and total bodyweight as influencing clearance (CL) and volume of distribution of central compartment (V(1)). For children aged < or =10 years: CL (L/h) = 0.287 . TBW(0.876); V(1) (L) = 0.465 . TBW, and for children aged >10 years: CL (L/h) = 0.149 . TBW; V(1) (L) = 0.437 . TBW. From the base to the final model, the inter-individual variabilities for CL and V(1) were significantly reduced in both age groups (30-50%). The coefficients of variation of the pharmacokinetic parameters were <30%, while residual and inter-occasional coefficients maintained values close to 40%. Validation of the proposed model revealed the suitability of the model.


CONCLUSIONS
A methotrexate population pharmacokinetic model has been developed for ALL children. The proposed model could be used in Bayesian algorithms with a limited sampling strategy to estimate the systemic exposure of individual patients to methotrexate and adapt both folinic acid rescue and methotrexate dosing accordingly.
Aumente
Dolores
D
Department of Pharmacy, Reina Sofía University Hospital, Córdoba, Spain.
Buelga
Dolores Santos
DS
Lukas
John C
JC
Gomez
Pedro
P
Torres
Antonio
A
García
Maria José
MJ
D000293:Adolescent; D000367:Age Factors; D000410:Alanine Transaminase / Q000097:blood; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000097:blood; D001499:Bayes Theorem; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008954:Models, Biological; D009010:Monte Carlo Method; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D016896:Treatment Outcome; D014803:Vitamin B Complex / Q000008:administration & dosage
D000964:Antimetabolites, Antineoplastic; D014803:Vitamin B Complex; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002955:Leucovorin; D008727:Methotrexate