Open AccessPhase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma
Author(s) -
Ogawa Yoshiaki,
Tobinai Kensei,
Ogura Michinori,
Ando Kiyoshi,
Tsuchiya Takahide,
Kobayashi Yukio,
Watanabe Takashi,
Maruyama Dai,
Morishima Yasuo,
Kagami Yoshitoyo,
Taji Hirofumi,
Minami Hironobu,
Itoh Kuniaki,
Nakata Masanobu,
Hotta Tomomitsu
Publication year - 2008
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2007.00638.x
Subject(s) - bortezomib , medicine , pharmacokinetics , multiple myeloma , tolerability , pharmacodynamics , neutropenia , pharmacology , adverse effect , toxicity , refractory (planetary science) , proteasome inhibitor , lung cancer , gastroenterology , oncology , physics , astrobiology
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 ≥ 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. ( Cancer Sci 2008; 99: 140–144)