title: Population pharmacokinetics and exploratory pharmacodynamics of ifosfamide according to continuous or short infusion schedules: an n = 1 randomized study.
abstract: BACKGROUND
  * The optimal infusion duration for ifosfamide remains to be determined. * No differences according to time of infusion have been identified in traditional pharmacokinetic endpoints, such as area under the curve. * The impact on pharmacodynamics has never been modelled or correlated with pharmacokinetics.
  
  
  CONCLUSIONS
  * The pharmacokinetics and pharmacodynamics of ifosfamide and its main metabolites can both be modelled with no influence of infusion duration. * Pharmacodynamic modelling (renal and haematological toxicity) allows further simulations of new schedules with favourable toxicity profiles.
  
  
  OBJECTIVE
  To model the pharmacokinetics and pharmacodynamics of ifosfamide and its key metabolites. The pharmacodynamic parameters included were renal toxicity and myelosuppression measured using urinary beta(2)-microglobulin (BMG) and absolute neutrophil count (ANC), respectively.
  
  
  METHODS
  Seventeen patients were enrolled into an n = 1 randomized trial during two consecutive cycles of ifosfamide 9 g m(-2) during each cycle given by a 3 h or 72 h infusion. Data were analyzed using NONMEM.
  
  
  RESULTS
  Ifosfamide and metabolite concentration-time profiles were described by a one-compartment open-model with auto-induction of clearance. BMG and ANC time-courses were related to ifosfamide concentration via indirect response models.
  
  
  CONCLUSIONS
  This modelling allowed the simulation of weekly schedules of flat doses with favourable myelotoxic profiles.
authors.affiliation: Department of Medical Oncology, René Huguenin Cancer Centre, 35, rue Dailly, 92210 Saint-Cloud, France. e.brain@stcloud-huguenin.org
authors.forename: Etienne G C
authors.initials: EG
authors.lastname: Brain
authors.forename: Kevan
authors.initials: K
authors.lastname: Rezai
authors.forename: François
authors.initials: F
authors.lastname: Lokiec
authors.forename: Maya
authors.initials: M
authors.lastname: Gutierrez
authors.forename: Saïk
authors.initials: S
authors.lastname: Urien
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000188:drug therapy*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide