Validation of the pharmacodynamics of BMS-247550, an analogue of epothilone B, during a phase I clinical study

Hayley M. McDaid, Sridhar Mani, Heng Jia Shen, Franco Muggia, Daryl Sonnichsen, Susan Band Horwitz

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Abstract

The primary aims of this study were to evaluate the time course and dose response of microtubule bundle formation in peripheral blood mononuclear cells (PBMCs) and to correlate these data with BMS-247550 pharmacokinetics. The data presented here were obtained from 17 patients enrolled in a Phase I trial who received five dose levels of BMS-247550 (7.4-59.2 mg/m2), given as a 1-h infusion once every 3 weeks. Plasma drug exposure or area under the curve (AUC), and tubulin bundle formation in PBMCs were assessed in cycles 1 and 2. Similar analyses were also performed on tumor biopsies from one eligible patient. PBMCs exhibited dramatic microtubule bundle formation 1 h after infusion that declined by 24 h, showing a positive correlation with AUC(0-24) for cycles 1 and 2. A similar pattern of tubulin bundle formation also was observed in a smaller proportion of breast tumor cells from one patient who exhibited a partial response to BMS-247550. This patient's tumor expressed multidrug resistance (MDR1) and MDR-associated protein (MRP1), and in addition poly(ADP-ribose) polymerase cleavage, a marker of cell death, was observed within 23 h after drug infusion. This patient was also heterozygous for a novel polymorphism at the extreme COOH terminus of β-tubulin (Gly 437 Gly/Ser), although the relevance of the polymorphism to the response is unknown. In summary, microtubule bundle formation in PBMCs occurs within 1 h of treatment with BMS-247550 and is related to plasma AUC. Similar bundle formation was seen in one tumor sample, despite expression of MDR1 and MRP1. Cell death occurred 23 h after peak microtubule bundle formation in these tumor cells. These findings validate in vitro pharmacodynamic observations.

Original languageEnglish (US)
Pages (from-to)2035-2043
Number of pages9
JournalClinical Cancer Research
Volume8
Issue number7
StatePublished - 2002

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Microtubules
Blood Cells
Tubulin
Area Under Curve
Neoplasms
Cell Death
Poly(ADP-ribose) Polymerases
Multiple Drug Resistance
Pharmaceutical Preparations
Pharmacokinetics
ixabepilone
Clinical Studies
epothilone B
Breast Neoplasms
Biopsy
Proteins
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Validation of the pharmacodynamics of BMS-247550, an analogue of epothilone B, during a phase I clinical study. / McDaid, Hayley M.; Mani, Sridhar; Shen, Heng Jia; Muggia, Franco; Sonnichsen, Daryl; Band Horwitz, Susan.

In: Clinical Cancer Research, Vol. 8, No. 7, 2002, p. 2035-2043.

Research output: Contribution to journalArticle

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