Modulation of thalidomide pharmacokinetics by cyclophosphamide or 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice: the role of tumour necrosis factor

Purpose There is considerable current interest in the use of thalidomide as a single agent or in combination with drugs such as cyclophosphamide in the treatment of multiple myeloma and other cancers. Our previous work has shown that thalidomide potentiates the antitumour activity of both cyclophosphamide and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) against murine Colon 38 tumours. In both of these cases, thalidomide extends the half-life (t_1/2) of the other drug. We wished to determine whether cyclophosphamide and DMXAA altered the t_1/2 of thalidomide. Since both thalidomide and DMXAA modulate tumour necrosis factor (TNF), we also wished to determine the role of TNF in this interaction.Methods Mice with Colon 38 tumours were treated with cyclophosphamide (220 mg/kg) and/or thalidomide (20 mg/kg) or DMXAA (25 mg/kg) and thalidomide (100 mg/kg), combinations that have previously demonstrated synergistic activity. Plasma and tumour tissue drug concentrations were analysed by high-performance liquid chromatography. To determine the role of TNF, similar experiments were performed using mice defective in the TNF gene (TNF^–/–) or the TNF receptor-1 gene (TNFR1^–/–).Results Coadministration of cyclophosphamide increased the thalidomide t_1/2 by 3.9- and 3.6-fold, respectively, in plasma and tumour tissue, with a corresponding increase in the concentration-time curve (AUC). The corresponding values following coadministration of DMXAA were 3.0- and 4.6-fold, respectively. Coadministration of cyclophosphamide had similar effects on thalidomide t_1/2 in C57Bl/6, TNF^–/– and TNFR1^–/– mice, while coadministration of DMXAA did not alter the t_1/2 or AUC in TNF^–/– and TNFR1^–/– mice.Conclusions Both cyclophosphamide and DMXAA have a pharmacokinetic interaction with thalidomide, increasing t_1/2 and AUC. TNF mediates the effect of DMXAA on thalidomide pharmacokinetics but not that of cyclophosphamide.This work was supported by the Auckland Medical Research Foundation, the Marsden Fund and the Auckland Cancer Society. Francisco Chung is a recipient of an Asian Development Bank Scholarship.