1. ¹Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands
2. ²Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

Correspondence: Dr ME de Jonge, E-mail: apmil@slz.nl

Received 18 January 2006; Revised 15 March 2006; Accepted 15 March 2006; Published online 18 April 2006.

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.