title: High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy.
abstract: We investigated whether the occurrence of veno-occlusive disease of the liver (VOD) may be associated with individual variations in the pharmacokinetics of high-dose cyclophosphamide. Patients received single or multiple courses of cyclophosphamide (1000 or 1500 mg m-2 day-1), thiotepa (80 or 120 mg m-2 day-1) and carboplatin (265-400 mg m-2 day-1) (CTC) for 4 consecutive days. The area under the plasma concentration-time curves (AUCs) were calculated for cyclophosphamide and its activated metabolites 4-hydroxycyclophosphamide and phosphoramide mustard based on multiple blood samples. Possible relationships between the AUCs and the occurrence of VOD were studied. A total of 59 patients (115 courses) were included. Four patients experienced VOD after a second CTC course. The first-course AUC of 4-hydroxycyclophosphamide (P=0.003) but not of phosphoramide mustard (P=0.101) appeared to be predictive of the occurrence of VOD after multiple courses. High exposures to bioactivated cyclophosphamide may lead to increased organ toxicity.
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. apmil@slz.nl
authors.forename: M E
authors.initials: ME
authors.lastname: de Jonge
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: S
authors.initials: S
authors.lastname: Rodenhuis
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy; D016190:Carboplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005260:Female; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced*; D006801:Humans; D007262:Infusions, Intravenous; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy; D013852:Thiotepa / Q000008:administration & dosage
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D013852:Thiotepa; D016190:Carboplatin