Journal of Clinical Oncology, Vol 15, 1885-1896, Copyright © 1997 by American Society of Clinical Oncology
Dose escalation of cyclophosphamide in patients with breast cancer: consequences for pharmacokinetics and metabolism
D Busse, FW Busch, F Bohnenstengel, M Eichelbaum, P Fischer, J Opalinska, K Schumacher, E Schweizer and HK Kroemer
Dr. Margarete Fischer-Bosch-Institut fur Klinische Pharmakologie, Stuttgart, Germany.
PURPOSE: 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. PATIENTS AND 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. CONCLUSION: 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.
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