Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone

Sridhar Mani, Hayley M. McDaid, A. Grossman, F. Muggia, Sanjay Goel, T. Griffin, D. Colevas, Susan Band Horwitz, M. J. Egorin

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)190-195
Number of pages6
JournalAnnals of Oncology
Volume18
Issue number1
DOIs
StatePublished - Jan 2007

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Microtubules
Blood Cells
Neoplasms
Neutropenia
Pharmacokinetics
Pharmaceutical Preparations
Drug Evaluation
epothilone B
ixabepilone
Cell Count

Keywords

  • Neuropathy
  • Neutropenia
  • Pharmacodynamics
  • Tubulin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone. / Mani, Sridhar; McDaid, Hayley M.; Grossman, A.; Muggia, F.; Goel, Sanjay; Griffin, T.; Colevas, D.; Band Horwitz, Susan; Egorin, M. J.

In: Annals of Oncology, Vol. 18, No. 1, 01.2007, p. 190-195.

Research output: Contribution to journalArticle

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