PHARMACOKINETICS OF HIGH-DOSE CYCLOPHOSPHAMIDE FOR BONE-MARROW TRANSPLANTATION

Background. Despite the fact that high-dose cyclophosphamide (CP) is currently used for both cancer treatment and bone marrow transplantation, its pharmacokinetics is not well defined. Methods. Serum and urine concentrations of CP were determined in 19 patients who received 2 or more high doses of CP before bone marrow transplantation. Results. Urinary recovery ranged between 1% and 32% and was essentially the same after the first and the second CP dose. In contrast, the pattern of disappearance from the serum of the two doses of CP was substantially different. The serum half-life of the first dose varied over a wide range (4.4 to 25.0 h, mean 8.7 +/- 4.6 h), while the half-life of the second dose was always shorter (1.7 to 6.0 h, mean 3.6 +/- 0.9 h). Accordingly, the CP area under the curve (AUC) of the first dose was much more variable and was always much higher than the CP AUC of the second dose. Therefore, prior administration of CP resulted in a very significant increase of CP metabolism. Conclusions. These differences can be relevant to the outcome of treatment, and suggest that the metabolism of CP can be manipulated and can be made more homogeneous, either by giving a priming dose of CP (leading to a lower CP AUC, to a faster conversion into activated metabolites and to the exposure of host cells to a higher concentration of the metabolites for a shorter time) or by giving the drug as a continuous infusion over a longer time, to obtain the opposite results.