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Clinical Trial
. 2007 Aug;25(4):327-34.
doi: 10.1007/s10637-007-9041-z. Epub 2007 Mar 9.

Human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry

J H Beumer  1 , R C Garner, M B Cohen, S Galbraith, G F Duncan, T Griffin, J H Beijnen, J H M Schellens
Affiliations
Clinical Trial

Human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry

J H Beumer et al. Invest New Drugs. 2007 Aug.

Abstract

Ixabepilone (BMS-247550) is a semi-synthetic, microtubule stabilizing epothilone B analogue which is more potent than taxanes and has displayed activity in taxane-resistant patients. The human plasma pharmacokinetics of ixabepilone have been described. However, the excretory pathways and contribution of metabolism to ixabepilone elimination have not been determined. To investigate the elimination pathways of ixabepilone we initiated a mass balance study in cancer patients. Due to autoradiolysis, ixabepilone proved to be very unstable when labeled with conventional [14C]-levels (100 microCi in a typical human radio-tracer study). This necessitated the use of much lower levels of [14C]-labeling and an ultra-sensitive detection method, Accelerator Mass Spectrometry (AMS). Eight patients with advanced cancer (3 males, 5 females; median age 54.5 y; performance status 0-2) received an intravenous dose of 70 mg, 80 nCi of [14C]ixabepilone over 3 h. Plasma, urine and faeces were collected up to 7 days after administration and total radioactivity (TRA) was determined using AMS. Ixabepilone in plasma and urine was quantitated using a validated LC-MS/MS method. Mean recovery of ixabepilone-derived radioactivity was 77.3% of dose. Fecal excretion was 52.2% and urinary excretion was 25.1%. Only a minor part of TRA is accounted for by unchanged ixabepilone in both plasma and urine, which indicates that metabolism is a major elimination mechanism for this drug. Future studies should focus on structural elucidation of ixabepilone metabolites and characterization of their activities.

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Figures

Fig. 1
Fig. 1
Chemical structures of epothilone B and its lactam analogue ixabepilone
Fig. 2
Fig. 2
Mean (±SD) plasma concentration-time curves of [14C]ixabepilone derived radioactivity (filled square) and unchanged [14C]ixabepilone (open square) for eight patients
Fig. 3
Fig. 3
Mean (+SD) [14C]ixabepilone to total radioactivity ratio in plasma over time for patients 1–7 (filled square) and patient 8 (open square)
Fig. 4
Fig. 4
Mean urinary (open square, −SD), faecal (open circle, +SD) and total (filled square, +SD) cumulative excretion (168 h) of [14C]ixabepilone derived radioactivity for eight patients
Fig. 5
Fig. 5
Mean (±SD) cumulative urinary excretion of [14C]ixabepilone derived radioactivity (filled square) and unchanged [14C]ixabepilone (open square) for eight patients
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