title: Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response.
abstract: BACKGROUND
  Cyclophosphamide, which forms the nucleus for virtually all preparative regimens for autologous bone marrow transplantation (ABMT), is an alkylating agent of which cytotoxicity is not directly caused by the parent compound but by its biologically active metabolites. Its nonmyelosuppressive toxicity in the ABMT setting is cardiomyopathy. We attempted to determine any correlation between plasma levels of total cyclophosphamide and the subsequent development of cardiac dysfunction.
  
  
  METHODS
  Analyses of plasma levels and the derivation of plasma concentration-time curves (area under the curve [AUC]) were performed in 19 women with metastatic breast carcinoma, who received a continuous 96-hour infusion of cyclophosphamide, thiotepa, and carboplatin (CTCb) with ABMT. The assay for total cyclophosphamide measures the inactive parent compound; reliable assays of the active metabolites of cyclophosphamide are not yet available.
  
  
  RESULTS
  Six of 19 women developed moderate, but transient, congestive heart failure (CHF) as assessed by clinical and radiologic criteria. These patients had a significantly lower AUC of total cyclophosphamide (median, 2,888 mumol/L/h) than patients who did not develop CHF (median, 6,121 mumol/L/h) (P less than .002). Median duration of tumor response in these patients was also more durable; at least 22 months in patients with lower AUCs versus a median of 5.25 months in those with higher AUCs (P = .008).
  
  
  CONCLUSIONS
  These pharmacokinetic data support the premise that enhancement of cyclophosphamide activation may lead to both greater tumor cytotoxicity and increased but reversible end-organ toxicity. Early analysis of pharmacokinetic data may allow modulation of cyclophosphamide administration in an attempt to enhance therapeutic efficacy.
authors.affiliation: Department of Medicine, Dana-Farber Cancer Institute, Beth Israel Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: L J
authors.initials: LJ
authors.lastname: Ayash
authors.forename: J E
authors.initials: JE
authors.lastname: Wright
authors.forename: O
authors.initials: O
authors.lastname: Tretyakov
authors.forename: R
authors.initials: R
authors.lastname: Gonin
authors.forename: A
authors.initials: A
authors.lastname: Elias
authors.forename: C
authors.initials: C
authors.lastname: Wheeler
authors.forename: J P
authors.initials: JP
authors.lastname: Eder
authors.forename: A
authors.initials: A
authors.lastname: Rosowsky
authors.forename: K
authors.initials: K
authors.lastname: Antman
authors.forename: E
authors.initials: E
authors.lastname: Frei
mesh_terms: D000328:Adult; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy; D003520:Cyclophosphamide / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006333:Heart Failure / Q000139:chemically induced*; D006801:Humans; D008875:Middle Aged
chemical_list: D003520:Cyclophosphamide