Plasma and cerebrospinal fluid pharmacokinetics of intravenously administered ABT-751 in non-human primates

Steve Y. Cho, Elizabeth Fox, Cynthia McCully, Joy Bauch, Kennan Marsh, Frank M. Balis

Research output: Contribution to journalArticle

Abstract

Purpose: ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine binding site on β-tubulin and inhibits microtubule polymerization. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of ABT-751, after a short intravenous infusion, were evaluated in a non-human primate (Macaca mulatta) model that is highly predictive of the CSF penetration of drugs in humans. Materials and methods: Plasma and CSF samples were collected over 24 h after 7.5 mg/kg (150 mg/m2) ABT-751 infused over 0.25-0.70 h, and ABT-751 concentrations in plasma and CSF were quantified using a validated HPLC-MS/MS assay. Pharmacokinetic parameters in plasma and CSF were derived using non-compartmental methods. Results and conclusion: Plasma disappearance was bi-exponential with a terminal half-life of 13 h. The mean ± SD clearance was 100 ± 18 ml/min m2, the mean ± SD volume of distribution at steady state was 1.3 ± 0.5 l/kg, and the mean ± SD mean residence time was 4.6 ± 1.8 h. The mean ± SD peak ABT-751 concentration in CSF was 0.26 ± 0.08 μM, and the mean ± SD CSF half-life of 1.3 ± 0.3 h. CSF penetration was limited (mean ± SD AUCCSF:AUCplasma, 1.1 ± 0.3%) relative to total (protein-bound + free) plasma drug concentrations, but the CSF concentrations approximated the estimated free drug concentrations in plasma.

Original languageEnglish (US)
Pages (from-to)563-567
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume60
Issue number4
DOIs
StatePublished - Sep 1 2007

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Keywords

  • ABT-751
  • Cerebrospinal fluid
  • Microtubule
  • Non-human primate
  • Pharmacokinetics
  • Tubulin

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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