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The pharmacokinetics and safety of ABT-751, a novel, orally bioavailable sulfonamide antimitotic agent: results of a phase 1 study.

AbstractPURPOSE:
Microtubules play a critical role in many cellular functions, including cell division and mitosis. ABT-751 is a novel sulfonamide antimitotic that binds to the colchicine site on beta-tubulin that leads to a block in the cell cycle at the G2M phase, resulting in cellular apoptosis. ABT-751 was investigated in this phase 1 trial designed to assess its maximum tolerated dose (MTD), dose-limiting toxicity (DLT), tolerability, and pharmacokinetics.
EXPERIMENTAL DESIGN:
ABT-751 was administered on a daily (q.d.) or twice daily (b.i.d.) oral schedule for 7 days every 3 weeks to 39 patients with refractory solid tumors. Toxicity was monitored weekly. Plasma and urine ABT-751 and metabolite pharmacokinetics were determined.
RESULTS:
The MTD for the q.d. schedule was 250 mg/d. DLTs during cycle 1 were abdominal pain, constipation, and fatigue. The MTD on the b.i.d. schedule was 150 mg. Cycle 1 of therapy with the 175 mg b.i.d. schedule was tolerated without DLT. However, six of seven patients reported grade 3 toxicity (ileus, constipation, abdominal pain, or fatigue), which occurred in cycle 2 or 3. ABT-751 was absorbed after oral administration with an overall mean T(max) of about 2 hours. The pharmacokinetics of ABT-751 were dose-proportional and time-independent. There was minimal accumulation of ABT-751 after multiple q.d. and b.i.d. doses. Efficacious concentrations, as determined from preclinical models (0.5-1.5 microg/mL), were achieved in all subjects. ABT-751 metabolism occurred primarily by glucuronidation and sulfation. No complete or partial tumor responses were noted, but one patient had a minor response, and four patients had stable disease lasting at least 6 months.
CONCLUSIONS:
The MTD and recommended phase 2 doses for ABT-751 were 250 mg q.d. and 150 mg b.i.d. on a 7-day schedule given every 3 weeks, due to subsequent cycle toxicities at 175 mg b.i.d. dosing. Toxicities were abdominal pain, constipation, and neuropathy.
AuthorsKenneth R Hande, Anne Hagey, Jordan Berlin, Yingna Cai, Kysa Meek, Hiro Kobayashi, A Craig Lockhart, Diane Medina, Jeffrey Sosman, Gary B Gordon, Mace L Rothenberg
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 9 Pg. 2834-40 (May 01 2006) ISSN: 1078-0432 [Print] United States
PMID16675578 (Publication Type: Clinical Trial, Phase I, Journal Article)
Chemical References
  • ABT751
  • Sulfonamides
Topics
  • Administration, Oral
  • Adult
  • Aged
  • Biological Availability
  • Cell Division (drug effects)
  • Drug Administration Schedule
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasms (blood, urine)
  • Safety
  • Sulfonamides (pharmacokinetics, therapeutic use, toxicity)

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