CONDITIONING REGIMEN-DEPENDENT DISPOSITION OF CYCLOPHOSPHAMIDE AND HYDROXYCYCLOPHOSPHAMIDE IN HUMAN MARROW TRANSPLANTATION PATIENTS

The pharmacokinetics of cyclophosphamide (CY) and 4-hydroxycyclophosph amide (HCY) were studied in 14 patients being prepared for bone marrow transplantation with either busulfan (BU)/CY(n = 7) or CY/total-body irradiation (TBI) (n = 7) to determine whether exposure to CY and its proximate toxic metabolite HCY is modulated by other agents used in th e preparative regimen. Patients and Methods: HCY wets assayed by a new method that stabilized the metabolite at bedside, In BU/CY patients ( who also received phenytoin), CY clearance was 112% greater (P = .0014 ), half-life 54% less (P = .0027), peak HCY concentration in plasma/CY dose 113% greater (P = .0006), and the ratio of area under the plasma concentration-time curves (AUCs) of HCY to CY 166% greater (P = .0116 ) than in CY/TBI patients, The ratio of the AUC of HCY/CY dose was 48% greater in BU/CY patients than in CY/TBI patients when one CY/TBI pat ient with an apparent impaired ability to eliminate HCY was excluded f rom analysis. In CY/TBI patients, there was an inverse correlation bet ween the AUC of HCY and that of CY (R(2) = .740, P = .028), Also, the ratio of the AUC of HCY/CY dose was correlated with the average concen tration of BU at steady-state ((C) over bar(ss,Bu)) (R(2) = .646, P = .029). Variability in CY and HCY pharmacokinetics among the 14 patient s overall was pronounced, with the highest variability (15-fold) obser ved in the ratio of the AUC of HCY to that of CY, Conclusion: Prior ad ministration of BU and/or phenytoin significantly alters exposure to C Y and HCY, Interpatient variability in HCY exposure at a given CY dose is substantial. (C) 1996 by American Society of Clinical Oncology.