title: Variations in schedules of ifosfamide administration: a better understanding of its implications on pharmacokinetics through a randomized cross-over study.
abstract: OBJECTIVE
  The metabolism of ifosfamide is a delicate balance between a minor activation pathway (4-hydroxylation) and a mainly toxification pathway (N-dechloroethylation), and there remains uncertainty as to the optimal intravenous schedule.
  
  
  METHODS
  This study assesses ifosfamide pharmacokinetics (PK) according to two standard schedules. Using a 1:1 randomized trial design, we prospectively evaluated ifosfamide PK on two consecutive cycles of 3 g/m2/day for 3 days (9 g/m2/cycle) given in one of two schedules either by continuous infusion (CI) or short (3 h) infusion. Highly sensitive analytical methods allowed determination of concentrations of ifosfamide and the key metabolites 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide.
  
  
  RESULTS
  Extensive PK analysis was available in 12 patients and showed equivalence between both schedules (3 h versus CI) based on area under the curves (micromol/l x h) for ifosfamide, 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide (9,379 +/- 2,638 versus 8,307 +/- 1,995, 152 +/- 59 versus 161 +/- 77, 1,441 +/- 405 versus 1,388 +/- 393, and 2,808 +/- 508 versus 2,634 +/- 508, respectively, all P > 0.2). The classical auto-induction of metabolism over the 3 days of infusion was confirmed for both schedules.
  
  
  CONCLUSIONS
  This study confirms similar PK for both active and toxic metabolites of ifosfamide in adult cancer patients when 9 g/m2 of ifosfamide is administered over 3 days by CI or daily 3-h infusions.
authors.affiliation: Department of Medical Oncology, René Huguenin Cancer Centre, 35, rue Dailly, 92210 Saint-Cloud, France. e.brain@stcloud-huguenin.org
authors.forename: E G C
authors.initials: EG
authors.lastname: Brain
authors.forename: K
authors.initials: K
authors.lastname: Rezai
authors.forename: S
authors.initials: S
authors.lastname: Weill
authors.forename: M F
authors.initials: MF
authors.lastname: Gauzan
authors.forename: J
authors.initials: J
authors.lastname: Santoni
authors.forename: B
authors.initials: B
authors.lastname: Besse
authors.forename: A
authors.initials: A
authors.lastname: Goupil
authors.forename: F
authors.initials: F
authors.lastname: Turpin
authors.forename: S
authors.initials: S
authors.lastname: Urien
authors.forename: F
authors.initials: F
authors.lastname: Lokiec
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D019540:Area Under Curve; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007069:Ifosfamide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide