title: A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients.
abstract: OBJECTIVE
  This study investigated the pharmacokinetics of cyclophosphamide (CP) and its main metabolite 4-hydroxycyclophosphamide (4-OH-CP) in patients with breast cancer undergoing high dose chemotherapy prior to autologous stem cell transplantation. An enzyme turn-over model was also developed to study the time course of cyclophosphamide induction.
  
  
  METHODS
  Fourteen patients received a combination of CP (6 g m-2 ), thiotepum (500 mg m-2 ) and carboplatin (800 mg m-2 ) as a 96 h infusion. Plasma concentrations of CP and 4-OH-CP were determined with h.p.l.c. and a pharmacokinetic and enzyme turn-over model applied to data using NONMEM.
  
  
  RESULTS
  CP plasma concentrations were described by a two-compartment model with a noninducible and an inducible pathway, the latter forming 4-OH-CP. In the final enzyme model, CP affects the amount of enzymes by increasing the enzyme production rate. CP concentrations decreased during the infusion with no subsequent change in 4-OH-CP concentrations. CP inducible and noninducible clearance were estimated to 1.76 l h-1 (90% C.I. 0.92-2.58) and 1.14 l h-1 (0.31-1.85), respectively. The induction resulted in an approximately doubled CP clearance through the inducible pathway at the end of treatment. The model predicted the enzyme turn-over half-life to be 24 h.
  
  
  CONCLUSIONS
  The presented mechanism-based enzyme induction model where the pharmacokinetics of the inducer and the enzyme pool counterbalance each other successfully described CP autoinduction. It is reasonable to believe that CP affects its own elimination by increasing the enzyme production rate and thereby increasing the amount of enzyme by which CP is eliminated.
authors.affiliation: Department of Hematology, Huddinge University Hospital, Huddinge; Department of Medical Laboratory Science and Technology, Division of Clinical Pharmacology, Huddinge University Hospital, Huddinge; Karolinska Pharmacy, Sweden. hassan@algonet.se
authors.forename: M
authors.initials: M
authors.lastname: Hassan
authors.forename: U S
authors.initials: US
authors.lastname: Svensson
authors.forename: P
authors.initials: P
authors.lastname: Ljungman
authors.forename: B
authors.initials: B
authors.lastname: Björkstrand
authors.forename: H
authors.initials: H
authors.lastname: Olsson
authors.forename: M
authors.initials: M
authors.lastname: Bielenstein
authors.forename: M
authors.initials: M
authors.lastname: Abdel-Rehim
authors.forename: C
authors.initials: C
authors.lastname: Nilsson
authors.forename: M
authors.initials: M
authors.lastname: Johansson
authors.forename: M O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000097:blood / Q000378:metabolism*; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D018906:Antineoplastic Agents, Alkylating; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide