DOSE-ESCALATION OF CYCLOPHOSPHAMIDE IN PATIENTS WITH BREAST-CANCER - CONSEQUENCES FOR PHARMACOKINETICS AND METABOLISM

Purpose: The alkylating anticancer agent cyclophosphamide (CP) is a pr odrug that undergoes a complex metabolism in humans producing both act ive and inactive metabolites. In parallel, unchanged CP is excreted vi a 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. Patients and Method s: Pharmocokinetics of CP were assessed in 12 patients with high-risk primary breast cancer who received an adjuvant chemotherapy regimen th at included four courses of conventional-dose CP (500 mg/m(2) over 1 h our every 3 weeks) followed by one final course of high-dose CP (100 m g/kg over 1 hour). plasma concentrations of CP were analyzed by high-p erformance liquid chromatography (HPLC), 24-hour urinary concentration s of CP, and its inactive metabolites (carboxyphosphamide, dechloroeth ylcyclophosphamide [dechloroethylCP], ketocyclophosphamide [ketoCP]) w ere determined by 31-phosphorus-nuclear magnetic resonance (P-31-NMR)- spectroscopy. Results: There was no difference in dose-corrected area under the concentration-time curve (AUG) (216 v 223[mu mol . 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 betwee n conventional- and high-dose therapy, respectively. However, during h igh-dose chemotherapy, we observed a significant increase in the renal clearance of CP (15 v 23 mL/min; P <.01) and in the formation clearan ce of corboxyphosphamide (7 v 12 ml/min; P <.05) and dechloroethylCP ( 3.2 v 4.2 ml/min; P <.05), whereas metabolic clearance to ketoCP remai ned 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 pathw ays to overall clearance of CP demonstrated wide interindividual varia bility. Conclusion: Overall pharmacokinetics of CP are apparently not affected during eightfold dose escalation. However, there is a shift i n the relative contribution of different clearances to systemic CP cle arance in favor of inactivating elimination pathways, thereby indicati ng saturation of bioactivating enzymes during dose escalation. Besides individual enzyme capacity, hydration and concomitant medication with dexamethasone modulated CP disposition. (C) 1997 by American Society of Clinical Oncology.