Pharmacokinetics of cyclophosphamide and its metabolites in paediatric patients receiving high-dose myeloablative therapy.

INTRODUCTION: In order to better understand the impact of high-dose on the pharmacokinetics and metabolism of cyclophosphamide, a pharmacological study was performed in children with malignant mesenchymal tumours with metastatic disease.
METHODS: Patients received four courses of chemotherapy including two courses of cyclophosphamide. Plasma concentrations of cyclophosphamide and the metabolites 4-ketocyclophosphamide, dechloroethylcyclophosphamide and carboxyphosphamide were determined on days 1, 2 and 3 of each course. A population pharmacokinetic model for cyclophosphamide was developed using non-linear mixed effects modelling and metabolite AUC values were compared between days and courses.
RESULTS: Data were available on 21 cyclophosphamide courses from 15 patients. A one compartment model, incorporating a term in surface area for both CL and V, best described cyclophosphamide pharmacokinetics. Typical CL and V on day 1 of treatment for a patient with a SA of 1.4m(2) were 4.3 L/h and 28.5L, respectively. On days 2 and 3 CL increased by 88% (95% CI, 72-105%) and 125% (95% CI, 108-145%) over day 1 levels; V increased by 14% (95% CI, 5-23%) on days 2 and 3. V tended to be larger for males than similarly sized females but no effect of age was found upon CL or V. Significant increases in metabolite AUCs were observed on days 2 and 3 compared to day 1 and a significant increase in CXCP AUC from course 1 to course 3.
CONCLUSION: Administration of high-dose cyclophosphamide over several days results in an increase in metabolism, possibly by induction of the activation pathway. This induction is effectively reversed following a four week period between cyclophosphamide doses. The degree of intersubject variation in cyclophosphamide elimination is largely accounted for by body surface area and is less than previously reported.