title: Dose escalation of cyclophosphamide in patients with breast cancer: consequences for pharmacokinetics and metabolism.
abstract: OBJECTIVE
  The alkylating anticancer agent cyclophosphamide (CP) is a prodrug that undergoes a complex metabolism in humans producing both active and inactive metabolites. In parallel, unchanged CP is excreted via the kidneys. The aim of this study was to investigate the influence of dose escalation on CP pharmacokinetics and relative contribution of activating and inactivating elimination pathways.
  
  
  METHODS
  Pharmacokinetics of CP were assessed in 12 patients with high-risk primary breast cancer who received an adjuvant chemotherapy regimen that included four courses of conventional-dose CP (500 mg/m2 over 1 hour every 3 weeks) followed by one final course of high-dose CP (100 mg/kg over 1 hour). Plasma concentrations of CP were analyzed by high-performance liquid chromatography (HPLC), 24-hour urinary concentrations of CP, and its inactive metabolites (carboxyphosphamide, dechloroethylcyclophosphamide [dechlorethylCP], ketocyclophosphamide [ketoCP]) were determined by 31-phosphorus-nuclear magnetic resonance (31P-NMR)-spectroscopy.
  
  
  RESULTS
  There was no difference in dose-corrected area under the concentration-time curve (AUC) (216 v 223 [mumol.h/[mL.g]), elimination half-life (4.8 v 4.8 hours), systemic clearance (79 v 77 mL/min) and volume of distribution (0.49 v 0.45 L/kg) of CP between conventional- and high-dose therapy, respectively. However, during high-dose chemotherapy, we observed a significant increase in the renal clearance of CP (15 v 23 mL/min; P < .01) and in the formation clearance of carboxyphosphamide (7 v 12 mL/min; P < .05) and dechloroethylCP (3.2 v 4.2 mL/min; P < .05), whereas metabolic clearance to ketoCP remained unchanged (1.3 v 1.2 mL/min). Consequently, metabolic clearance to the remaining (reactive) metabolites decreased from 52 to 38 mL/min (P < .001). The relative contribution of the different elimination pathways to overall clearance of CP demonstrated wide interindividual variability.
  
  
  CONCLUSIONS
  Overall pharmacokinetics of CP are apparently not affected during eightfold dose escalation. However, there is a shift in the relative contribution of different clearances to systemic CP clearance in favor of inactivating elimination pathways, thereby indicating saturation of bioactivating enzymes during dose escalation. Besides individual enzyme capacity, hydration and concomitant medication with dexamethasone modulated CP disposition.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Busse
authors.forename: F W
authors.initials: FW
authors.lastname: Busch
authors.forename: F
authors.initials: F
authors.lastname: Bohnenstengel
authors.forename: M
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: P
authors.initials: P
authors.lastname: Fischer
authors.forename: J
authors.initials: J
authors.lastname: Opalinska
authors.forename: K
authors.initials: K
authors.lastname: Schumacher
authors.forename: E
authors.initials: E
authors.lastname: Schweizer
authors.forename: H K
authors.initials: HK
authors.lastname: Kroemer
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D006801:Humans; D008875:Middle Aged
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide