title: Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma.
abstract: 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.
authors.affiliation: Department of Hematology and Oncology, Tokai University School of Medicine, 143, Shimokasuya, Isehara, Kanagawa, 259-1193, Japan. yoshioga@is.icc.u-tokai.ac.jp
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Kensei
authors.initials: K
authors.lastname: Tobinai
authors.forename: Michinori
authors.initials: M
authors.lastname: Ogura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.forename: Takahide
authors.initials: T
authors.lastname: Tsuchiya
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Dai
authors.initials: D
authors.lastname: Maruyama
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
authors.forename: Yoshitoyo
authors.initials: Y
authors.lastname: Kagami
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Taji
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Itoh
authors.forename: Masanobu
authors.initials: M
authors.lastname: Nakata
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Hotta
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D001897:Boronic Acids / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood* / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011719:Pyrazines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib