Metabolism-based cyclophosphamide dosing for hematopoietic cell transplant

When cyclophosphamide (120 mg/kg) is used for hematopoietic cell transplant, the increased area under the curve of carboxyethylphosphoramide mustard (AUCCEPM) is related to liver toxicity and death. We determined the feasibility of dose-adjusting cyclophosphamide to a preset metabolic endpoint (AUCCEPM, 325 ± 25 μmol/L · h). In 20 patients blood sampling was done over a 16-hour period after administration of 45 mg/kg cyclophosphamide; AUCCEPM from 0 to 16 hours was calculated by noncompartmental analysis. The expected AUCCEPM for 0 to 48 hours was estimated, and the second cyclophosphamide dose was determined. The mean second cyclophosphamide dose was 42 mg/kg, and the mean total cyclophosphamide dose was 86 mg/kg (range, 54–120 mg/kg). The mean AUCCEPM for the time from 0 to 48 hours was 296 μmol/L · h (95% confidence interval, 275–317 μmol/L · h). A retrospective analysis indicated that AUCCEPM could be more accurately predicted by use of a population pharmacokinetic model. We conclude that metabolism-based dosing of cyclophosphamide is feasible and that a lower cyclophosphamide dose does not affect engraftment. Clinical Pharmacology & Therapeutics (2005) 78, 298–308; doi: 10.1016/j.clpt.2005.05.005