title: Pharmacokinetics of cyclophosphamide and its metabolites in paediatric patients receiving high-dose myeloablative therapy.
abstract: BACKGROUND
  In order to better understand the impact of high-dose on the pharmacokinetics and metabolism of cyclophosphamide, a pharmacological study was performed in children with malignant mesenchymal tumours with metastatic disease.
  
  
  METHODS
  Patients received four courses of chemotherapy including two courses of cyclophosphamide. Plasma concentrations of cyclophosphamide and the metabolites 4-ketocyclophosphamide, dechloroethylcyclophosphamide and carboxyphosphamide were determined on days 1, 2 and 3 of each course. A population pharmacokinetic model for cyclophosphamide was developed using non-linear mixed effects modelling and metabolite AUC values were compared between days and courses.
  
  
  RESULTS
  Data were available on 21 cyclophosphamide courses from 15 patients. A one compartment model, incorporating a term in surface area for both CL and V, best described cyclophosphamide pharmacokinetics. Typical CL and V on day 1 of treatment for a patient with a SA of 1.4m(2) were 4.3 L/h and 28.5L, respectively. On days 2 and 3 CL increased by 88% (95% CI, 72-105%) and 125% (95% CI, 108-145%) over day 1 levels; V increased by 14% (95% CI, 5-23%) on days 2 and 3. V tended to be larger for males than similarly sized females but no effect of age was found upon CL or V. Significant increases in metabolite AUCs were observed on days 2 and 3 compared to day 1 and a significant increase in CXCP AUC from course 1 to course 3.
  
  
  CONCLUSIONS
  Administration of high-dose cyclophosphamide over several days results in an increase in metabolism, possibly by induction of the activation pathway. This induction is effectively reversed following a four week period between cyclophosphamide doses. The degree of intersubject variation in cyclophosphamide elimination is largely accounted for by body surface area and is less than previously reported.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Girish
authors.initials: G
authors.lastname: Chinnaswamy
authors.forename: Julie
authors.initials: J
authors.lastname: Errington
authors.forename: Annabel
authors.initials: A
authors.lastname: Foot
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Veal
authors.forename: Michael
authors.initials: M
authors.lastname: Cole
mesh_terms: D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008637:Mesenchymoma / Q000188:drug therapy*; D010752:Phosphoramide Mustards / Q000097:blood; D012208:Rhabdomyosarcoma / Q000188:drug therapy; D012509:Sarcoma / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D010752:Phosphoramide Mustards; C064445:dechloroethylcyclophosphamide; D003520:Cyclophosphamide; C000028:carboxyphosphamide; C008226:4-ketocyclophosphamide