title: Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality.
abstract: The pharmacokinetics of cyclophosphamide (CY) and its metabolites hydroxycyclophosphamide and carboxyethylphosphoramide mustard were determined in 75 patients receiving targeted oral busulfan followed by i.v. CY ((T)BU/CY) and in 147 patients receiving i.v. CY followed by total body irradiation (CY/TBI) in preparation for hematopoietic cell transplantation (HCT). In the (T)BU/CY patients only, the association of the pharmacokinetic data with liver toxicity, relapse, and survival was evaluated. CY was infused at 60 mg/kg/day over 1 or 2 hours on 2 consecutive days; the majority of patients had BU levels targeted to a steady state plasma concentration (Css) of 800-900 ng/mL. Systemic exposure (i.e., area under the concentration-time curve [AUC]) of CY, hydroxycyclophosphamide, and carboxyethylphosphoramide mustard was measured. Liver toxicity was assessed as the development of hepatic sinusoidal obstruction syndrome (SOS). CY metabolism was highly variable and age dependent. (T)BU/CY-treated patients had lower AUC(CY) (P < .0001), higher AUC(HCY) (P < .0001), and higher AUC(CEPM) (P = .15) than CY/TBI-conditioned patients. Among patients receiving (T)BU/CY, 17 (23%) developed SOS, and there were no statistically significant associations between the AUC of CY or its metabolites and SOS, nonrelapse mortality, relapse, or survival (all P >.15). In conclusion, CY exhibits conditioning-regimen dependent pharmacokinetics and pharmacodynamics, suggesting that lowering CY doses is unlikely to improve outcomes to (T)BU/CY. Alternative strategies, such as administering i.v. busulfan or CY before BU, should be explored.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98195, USA. jmccune@u.washington.edu <jmccune@u.washington.edu>
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
authors.forename: Ami
authors.initials: A
authors.lastname: Batchelder
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
authors.forename: Ted
authors.initials: T
authors.lastname: Gooley
authors.forename: Scott
authors.initials: S
authors.lastname: Cole
authors.forename: Brian
authors.initials: B
authors.lastname: Phillips
authors.forename: H Gary
authors.initials: HG
authors.lastname: Schoch
authors.forename: George B
authors.initials: GB
authors.lastname: McDonald
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D002066:Busulfan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D056486:Chemical and Drug Induced Liver Injury; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018572:Disease-Free Survival; D005260:Female; D019337:Hematologic Neoplasms / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008107:Liver Diseases / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D013577:Syndrome; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D003520:Cyclophosphamide; D002066:Busulfan