Annals of Oncology Advance Access originally published online on October 3, 2006
Annals of Oncology 2007 18(1):190-195; doi:10.1093/annonc/mdl315
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© 2006 European Society for Medical Oncology
phase I and pharmacokinetics |
Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone
1 The Albert Einstein Comprehensive Cancer Center
2 Department of Molecular Genetics
3 Department of Molecular Pharmacology, Albert Einstein College of Medicine
4 Comprehensive Cancer Center of NYU School of Medicine, New York University, New York
5 Bristol-Myers Squibb, Wallingford
6 Cancer Therapy Evaluation Program of the National Cancer Institute, Bethesda
7 University of Pittsburgh Cancer Institute, Pittsburgh, USA
* Correspondence to: Dr S. Mani, Department of Oncology, Weiler Hospital, Room 2S-49, 1825 Eastchester Road, Bronx, NY 10461, USA. Tel: +1-718-904-2529; Fax: +1-718-904-2892; E-mail: smani{at}montefiore.org
Background: We previously demonstrated that peak microtubule bundle formation (MBF) in peripheral blood mononuclear cells (PBMCs) occurs at the end of drug infusion and correlates with drug pharmacokinetics (PK). In the current study, a new expanded evaluation of drug target effect was undertaken.
Patients and methods: Patients with advanced solid malignancies were treated with ixabepilone 40 mg/m2 administered as a 1-h i.v. infusion every 3 weeks. Blood, plasma, and tumor tissue sampling was carried out to characterize pharmacodynamics and PK.
Results: Forty-seven patients were treated with 141 cycles of ixabepilone. In both PBMCs (n = 27) and tumor cells (n = 9), peak MBF occurred at the end of infusion; however, at 24–72 h after drug infusion, the number of cells with MBF was significantly greater in tumor cells, relative to PBMCs. A Hill model (EC50 = 109.65 ng/ml; r2 = 0.94) was fitted, which demonstrated a relationship between percentage of PBMCs with MBF and plasma ixabepilone concentration. The percentage of PBMCs with MBF at the end of infusion also correlated with severity of neutropenia (P = 0.050).
Conclusions: Plasma ixabepilone concentration and severity of neutropenia correlate with the level of MBF in PBMCs. Therefore, this technically straightforward assay should be considered as a complement to the clinical development of novel microtubule-binding agents.
Key words: neuropathy, neutropenia, pharmacodynamics, tubulin
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