NONLINEAR PHARMACOKINETICS OF CYCLOPHOSPHAMIDE IN PATIENTS WITH METASTATIC BREAST-CANCER RECEIVING HIGH-DOSE CHEMOTHERAPY FOLLOWED BY AUTOLOGOUS BONE-MARROW TRANSPLANTATION

The pharmacokinetics of cyclophosphamide has been evaluated in 15 pati ents with metastatic breast cancer undergoing high-dose chemotherapy w ith alkylating agents followed by autologous bone marrow transplantati on. Each patient received two courses of chemotherapy: 4 g/m(2) of cyc lophosphamide by 90-min infusion prior to peripheral blood progenitor cell collection (the first course) and 6 g/m(2) of cyclophosphamide wi th 800 mg/m(2) of thiotepa by 96-h constant infusion before marrow and stem cell reinjection (the second course). In the first course, plasm a cyclophosphamide concentration-time data of 9 of 15 patients were fi t by a one-compartment model with Michaelis-Menten saturable eliminati on in parallel with first-order renal elimination. The mean (SD) V-max and K-m values were 1.47 (0.89) mu M/min and 575 (347) mu M, respecti vely. The first course data of the remaining six patients were fit usi ng first-order elimination only. In the second drug course, plasma cyc lophosphamide disposition curves of 13 of 15 patients demonstrated a d ecline in concentration following attainment of an initial steady stat e. The plasma cyclophosphamide disposition data of these patients were fit by a one-compartment pharmacokinetic model, in which the decline of plasma cyclophosphamide concentration after reaching the initial st eady state was modeled as being due to an increase in the clearance ra te of cyclophosphamide. The mean (SD) initial and final clearance rate s were 51 (16) ml/min and 106 (48) ml/min, respectively. Michaelis-Men ten elimination was not apparent in the second course because the plas ma concentration of cyclophosphamide was much lower. The mean renal cl earance rate was 17 ml/min in the first course and 16 ml/min in the se cond course. Urinary excretion of cyclophosphamide accounted for 17% a nd 23% of the total dose administered in the first and the second cour se, respectively. No change in cyclophosphamide clearance rate was app arent in a patient who was taking phenytoin, but a change was present in a patient who was taking phenobarbital. A drug interaction between cyclophosphamide and thiotepa may explain the smaller initial clearanc e rate for cyclophosphamide during the second drug course.