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Investigational New Drugs

, Volume 25, Issue 3, pp 227–235 | Cite as

Phase I dose-finding and pharmacokinetic trial of orally administered indibulin (D-24851) to patients with solid tumors

  • I. E. L. M. KuppensEmail author
  • P. O. Witteveen
  • M. Schot
  • V. M. Schuessler
  • A. Daehling
  • J. H. Beijnen
  • E. E. Voest
  • J. H. M. Schellens
Phase I Studies

Summary

Indibulin is a synthetic small molecule which antitumor activity is based upon destabilization of microtubules. The primary study objectives were to determine the impact of fasted and fed condition on pharmacokinetic parameters, as well as the maximum tolerated dose of the oral drinking solution of indibulin administered once daily for 14 days every 3 weeks in patients with solid tumors. In the pilot food effect part, patients received a single dose of 20 mg indibulin on day-8 and -4, fasted or fed, in a randomized crossover design. In the dose-escalation part, patients received a single dose of indibulin on day-4. Three dose levels were evaluated: 20, 40 and 80 mg. After a washout period, patients received indibulin once daily for 14 days every 3 weeks (multiple dose part). Blood samples were collected in the pilot food effect- and in the dose escalation study. A total of 14 patients entered, of which 6 completed the food effect study. The ratio of indibulin (fed/fasted) in the food effect study for AUC0-72 was estimated as 1.24 (P=0.082, 95%CI 0.96–1.41) and C max ratio was 0.89 (P=0.54, 95%CI 0.55–1.44). Interpatient variability was high. Higher peak plasma concentrations were reached under fasting conditions which was undesired regarding tolerability. Therefore the dose escalation study was continued under fed conditions. Dose limiting toxicities, nausea and vomiting, appeared to be related to the increased volume of the solvent lactic acid. This study is continued, evaluating indibulin administered as capsules on the recommended dose level of 60 mg daily for 14 days.

Keywords

Indibulin D-24851 Oral Phase I Food effect Dose-escalation 

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Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • I. E. L. M. Kuppens
    • 1
    • 6
    Email author
  • P. O. Witteveen
    • 2
  • M. Schot
    • 1
  • V. M. Schuessler
    • 3
  • A. Daehling
    • 3
  • J. H. Beijnen
    • 4
    • 5
  • E. E. Voest
    • 2
  • J. H. M. Schellens
    • 4
    • 5
  1. 1.Department of Medical OncologyThe Netherlands Cancer Institute, Antoni van Leeuwenhoek HospitalCX AmsterdamThe Netherlands
  2. 2.Department of Medical OncologyUniversity Medical Center UtrechtCX UtrechtThe Netherlands
  3. 3.Baxter Deutschland GmbHClinical DevelopmentHeidelbergGermany
  4. 4.Department of Pharmacy & PharmacologySlotervaart Hospital/The Netherlands Cancer InstituteEC AmsterdamThe Netherlands
  5. 5.Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical SciencesUniversity UtrechtUtrechtThe Netherlands
  6. 6.Department of Clinical Pharmacy and ToxicologyUniversity Hospital MaastrichtAZ, MaastrichtThe Netherlands

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