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 me tabolized to both cytotoxic and inactive compounds. We have previously show n that following dose escalation from conventional-dose (CD) to high-dose ( HD) levels; the fraction of the dose cleared by bioactivation is significan tly decreased (66% versus 48.5%) in favor of inactivating elimination pathw ays when the HD is given as a single I-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. Parients and methods: Plasma concentrations of CP (measured by high-performance liquid chromatography, HPLC) and urinary concentrations o f CP and its major metabolites (quantified by [P-31]-nuclear magnetic reson ance spectroscopy; [P-31]-NMR spectroscopy), were determined in four patien ts 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). Resul ts: (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 f or dl versus d2) The latter was translated into an increase in formation CL of both active (+16.3 ml/min) and inactive metabolites (+ 17.6 ml/min) and reflects autoinduction of metabolism. As compared with CD-CP, no statistic ally significant de crease was observed in the relative contribution of bio activation CL to overall CL during both days of HD (63% versus 57%/53%). R ecovery of intact CP in 24-h urine corresponded to 24%, 29%, 32% of the dos e (P < 0.05 for d(1) versus d(2) of HD). Conclusions: Following dose escala tion of CP, dividing the high dose over 2 days instead of one single infusi on 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.