title: Pharmacokinetik population of methotrexate in tunisian population with acute lymphoblastic leukemia.
abstract: BACKGROUND
  The use of high dose of MTX in the treatment of the leukemia is actually better controlled by renal preparation, control of plasma concentrations and administration of folinic acid. However, High dose MTX has been proven to cause substantial toxicity and have high intra-and inter-patient variability. Population pharmacokinetic analysis is a useful tool for identification of sources of pharmacokinetic variability during anticancer drug development and can aid the design of alternative dosing regimens to enhance their efficacy and safety.
  
  
  OBJECTIVE
  The aim of our study is to developed and validate a population pharmacokinetics model of our population. We hereby describe the clinical covariates (age, sex and clearance of the creatinine) that influence MTX pharmacokinetic for predicting optimal dose to reduce MTX toxicity.
  
  
  METHODS
  It is a prospective study achieved between January 2005 to January 2012 in the Service of Clinical Pharmacology. Including 273 patients treated for acute lymphocytic leukaemia 2582 plasma concentration was achieved. The data have been analyzed with Nonmem© software (non linear regression to mixed effect).
  
  
  RESULTS
  The age of our patients varied from 2 to 23 years with an average of 13 years. The patients received high dose MTX therapy (1 to 8 g/m2) in 24 hours infusion every 15 days. Three compartiment models describe the pharmacokinetic of MTX. The most important covariables affecting the model were clearance of the creatinine, age and weight. We obtained a good correlation between the predicted and the observed concentrations.
  
  
  CONCLUSIONS
  The development of population pharmacokinetics model of MTX allows us to propose a therapeutic diagram adapted to every patient according to its morphological and pharmacological features while taking in consideration the therapeutic objective.
authors.forename: Nadia
authors.initials: N
authors.lastname: Jebabli
authors.forename: Emna
authors.initials: E
authors.lastname: Gaïes
authors.forename: Hanen
authors.initials: H
authors.lastname: El Jebari
authors.forename: Rim
authors.initials: R
authors.lastname: Charfi
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lakhal
authors.forename: Anis
authors.initials: A
authors.lastname: Klouz
authors.forename: Issam
authors.initials: I
authors.lastname: Salouage
authors.forename: Sameh
authors.initials: S
authors.lastname: Trabelsi