Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma

Cancer Sci. 2008 Jan;99(1):140-4. doi: 10.1111/j.1349-7006.2007.00638.x. Epub 2007 Oct 27.


The purpose of this phase I and II study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in Japanese patients with relapsed or refractory multiple myeloma. This was a dose-escalation study designed to determine the recommended dose for Japanese patients (phase I) and to investigate the antitumor activity and safety (phase II) of bortezomib administered on days 1, 4, 8, and 11 every 21 days. Thirty-four patients were enrolled. A dose-limiting toxicity was febrile neutropenia, which occurred in one of six patients in the highest-dose cohort in phase I and led to the selection of 1.3 mg/m(2) as the recommended dose. Adverse events >or= grade 3 were rare except for hematological toxicities, although there was one fatal case of interstitial lung disease. The overall response rate was 30% (95% confidence interval, 16-49%). Pharmacokinetic evaluation showed a biexponential decline, characterized by a rapid distribution followed by a longer elimination, after dose administration, whereas the area under the concentration-time curve increased proportionately with the dose. Bortezomib was effective in Japanese patients with relapsed or refractory multiple myeloma. A favorable tolerability profile was also seen, although the potential for pulmonary toxicity should be monitored closely. The pharmacokinetic and pharmacodynamic profiles of bortezomib in the present study warrant further investigations, including more relevant administration schedules.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Boronic Acids / adverse effects
  • Boronic Acids / blood
  • Boronic Acids / pharmacokinetics*
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Middle Aged
  • Multiple Myeloma / blood*
  • Multiple Myeloma / drug therapy*
  • Protease Inhibitors / adverse effects
  • Protease Inhibitors / blood
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / therapeutic use
  • Pyrazines / adverse effects
  • Pyrazines / blood
  • Pyrazines / pharmacokinetics*
  • Pyrazines / therapeutic use*


  • Antineoplastic Agents
  • Boronic Acids
  • Protease Inhibitors
  • Pyrazines
  • Bortezomib