Fractionated administration of high-dose cyclophosphamide: influence on dose-dependent changes in pharmacokinetics and metabolism

Purpose : The alkylating agent cyclophosphamide (CP) is a prodrug that is metabolized to both cytotoxic and inactive compounds. We have previously shown that following dose escalation from conventional-dose (CD) to high-dose (HD) levels; the fraction of the dose cleared by bioactivation is significantly decreased (66% versus 48.5%) in favor of inactivating elimination pathways when the HD is given as a single 1-h infusion. Based on the concept of bioactivating enzyme saturation with increasing doses, we investigated the influence of fractionated application of HD-CP on dose-dependent changes in metabolism. Patients and methods : Plasma concentrations of CP (measured by high-performance liquid chromatography, HPLC) and urinary concentrations of CP and its major metabolites (quantified by [ 31 P]-nuclear magnetic resonance spectroscopy; [ 31 P]-NMR spectroscopy), were determined in four patients with high-risk primary breast cancer who received adjuvant chemotherapy including both CD-CP (500 mg/m 2 infused over 1 h) and split HD-CP (50 mg/kg infused over 1 h on each of 2 consecutive days (d): d 1 and d 2 . Results : (Data are given as mean values for CD and d 1 /d 2 of HD, respectively). Systemic clearance (CL) of CP was similar during CD and d 1 of HD, but significantly increased on d 2 of HD (CL: 83 and 78/115 ml/min; P < 0.01 for d 1 versus d 2 ). The latter was translated into an increase in formation CL of both active (+16.4 ml/min) and inactive metabolites (+17.6 ml/min) and reflects autoinduction of metabolism. As compared with CD-CP, no statistically significant decrease was observed in the relative contribution of bioactivation CL to overall CL during both days of HD (63% versus 57%/53%). Recovery of intact CP in 24-h urine corresponded to 24%, 29%, 22% of the dose ( P < 0.05 for d 1 versus d 2 of HD). Conclusions : Following dose escalation of CP, dividing the high dose over 2 days instead of one single infusion may favorably impact the metabolism of CP in terms of bioactivation. In addition, on day 2 of a split regimen, renal elimination of CP is decreased, which implies that more drug is available for metabolism.