title: Dosing algorithm to target a predefined AUC in patients with primary central nervous system lymphoma receiving high dose methotrexate.
abstract: OBJECTIVE
  There is no consensus regarding optimal dosing of high dose methotrexate (HDMTX) in patients with primary CNS lymphoma. Our aim was to develop a convenient dosing algorithm to target AUC(MTX) in the range between 1000 and 1100 µmol l(-1) h.
  
  
  METHODS
  A population covariate model from a pooled dataset of 131 patients receiving HDMTX was used to simulate concentration-time curves of 10,000 patients and test the efficacy of a dosing algorithm based on 24 h MTX plasma concentrations to target the prespecified AUC(MTX) . These data simulations included interindividual, interoccasion and residual unidentified variability. Patients received a total of four simulated cycles of HDMTX and adjusted MTX dosages were given for cycles two to four.
  
  
  RESULTS
  The dosing algorithm proposes MTX dose adaptations ranging from +75% in patients with MTX C(24) < 0.5 µmol l(-1) up to -35% in patients with MTX C(24) > 12 µmol l(-1). The proposed dosing algorithm resulted in a marked improvement of the proportion of patients within the AUC(MTX) target between 1000 and 1100 µmol l(-1) h (11% with standard MTX dose, 35% with the adjusted dose) and a marked reduction of the interindividual variability of MTX exposure.
  
  
  CONCLUSIONS
  A simple and practical dosing algorithm for HDMTX has been developed based on MTX 24 h plasma concentrations, and its potential efficacy in improving the proportion of patients within a prespecified target AUC(MTX) and reducing the interindividual variability of MTX exposure has been shown by data simulations. The clinical benefit of this dosing algorithm should be assessed in patients with primary central nervous system lymphoma (PCNSL).
authors.affiliation: Department of Oncology and Hematology, Cantonal Hospital, Rorschacherstrasse 95, 9007 St Gallen, Switzerland. markus.joerger@kssg.ch
authors.forename: Markus
authors.initials: M
authors.lastname: Joerger
authors.forename: Andrés J M
authors.initials: AJ
authors.lastname: Ferreri
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Thomas
authors.initials: T
authors.lastname: Cerny
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000465:Algorithms; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001499:Bayes Theorem; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate