Purpose: Cyclophosphamide has a steep dose-response curve making it a good candidate for dose intensification. The purpose of this pharmacological study performed in children with metastatic soft tissue sarcoma was to better understand the impact of high-dose on the pharmacokinetics and metabolism of cyclophosphamide.
Method: Patients received four courses of chemotherapy including two courses of high-dose cyclophosphamide. Plasma concentrations of cyclophosphamide and the metabolites 4-ketocyclophosphamide (KetoCP), dechloroethylcyclophosphamide (DCCP) and carboxyphosphamide (CXCP) were determined on days 1, 2 and 3 of each course. A population pharmacokinetic model for cyclophosphamide was developed using nonlinear mixed effects modelling and metabolite AUC values 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 Clearance(CL) and Volume of distribution(V), best described cyclophosphamide pharmacokinetics. Typical CL and V on day 1 of treatment for a patient with a Surface area of 1.4m2 were 4.3 L/hr and 28.5 L 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.