title: Metabolism-based cyclophosphamide dosing for hematopoietic cell transplant.
abstract: When cyclophosphamide (120 mg/kg) is used for hematopoietic cell transplant, the increased area under the curve of carboxyethylphosphoramide mustard (AUC(CEPM)) is related to liver toxicity and death. We determined the feasibility of dose-adjusting cyclophosphamide to a preset metabolic endpoint (AUC(CEPM), 325 +/- 25 micromol/L.h). In 20 patients blood sampling was done over a 16-hour period after administration of 45 mg/kg cyclophosphamide; AUC(CEPM) from 0 to 16 hours was calculated by noncompartmental analysis. The expected AUC(CEPM) 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 AUC(CEPM) for the time from 0 to 48 hours was 296 micromol/L.h (95% confidence interval, 275-317 micromol/L.h). A retrospective analysis indicated that AUC(CEPM) 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.
authors.affiliation: Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
authors.forename: George B
authors.initials: GB
authors.lastname: McDonald
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
authors.forename: Ami
authors.initials: A
authors.lastname: Batchelder
authors.forename: Scott
authors.initials: S
authors.lastname: Cole
authors.forename: Brian
authors.initials: B
authors.lastname: Phillips
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Ren
authors.forename: Paolo
authors.initials: P
authors.lastname: Vicini
authors.forename: Robert
authors.initials: R
authors.lastname: Witherspoon
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Kalhorn
authors.forename: John T
authors.initials: JT
authors.lastname: Slattery
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001499:Bayes Theorem; D001792:Blood Platelets / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects; D010752:Phosphoramide Mustards / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D010752:Phosphoramide Mustards; C445000:carboxyethylphosphoramide mustard; D003520:Cyclophosphamide