title: High dose methotrexate treatment in children with acute lymphoblastic leukaemia may be optimised by a weight-based dose calculation.
abstract: BACKGROUND
  The inter-individual variation in exposure to methotrexate is considerable after intravenous high dose methotrexate (HDMTX) administration and both under- and over exposures may have dire consequences. Thus, optimal dose individualisation is of paramount importance.
  
  
  METHODS
  We studied how pharmacokinetic parameters were related to outcome in 340 patients with acute lymphoblastic leukaemia (ALL). A population pharmacokinetic model was developed with data from 1284 HDMTX courses in 304 children evaluating age, height, weight, body surface area (BSA), sex, serum creatinine and serum alanine aminotransferase as potential covariates.
  
  
  RESULTS
  Body weight improved the population pharmacokinetic model significantly more than any of the other patient characteristics, indicating that body weight may be the better way of dose normalisation. In a logistic regression analysis, higher values of clearance as well as volume of distribution were related to increased relapse risk in the standard (SR) and intermediate risk (IR) groups as well as in the entire cohort. A higher weight was strongly associated with worse outcome in the SR and IR groups, (P = 0.0186 and 0.0121, respectively).
  
  
  CONCLUSIONS
  We conclude that dose normalisation of methotrexate according to body weigh may give more predictable pharmacokinetics of methotrexate and may also improve the outcome for children with ALL.
authors.affiliation: Department of Clinical Chemistry and Pharmacology, Lund University Hospital, Lund, Sweden. peter.g.jonsson@gmail.com
authors.forename: Peter
authors.initials: P
authors.lastname: Jönsson
authors.forename: Tor
authors.initials: T
authors.lastname: Skärby
authors.forename: Jesper
authors.initials: J
authors.lastname: Heldrup
authors.forename: Henrik
authors.initials: H
authors.lastname: Schrøder
authors.forename: Peter
authors.initials: P
authors.lastname: Höglund
mesh_terms: D000367:Age Factors; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology; D008954:Models, Biological; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality; D012737:Sex Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate