Phase I and pharmacokinetic study of amrubicin, a synthetic 9-aminoanthracycline, in patients with refractory or relapsed lung cancer.
Amrubicin is a novel synthetic 9-aminoanthracycline derivative and is converted enzymatically to its C-13 hydroxy metabolite, amrubicinol, whose cytotoxic activity is 10-100 times that of amrubicin. We aimed to determine the maximum tolerated dose (MTD) of amrubicin and to characterize the pharmacokinetics of amrubicin and amrubicinol in previously treated patients with refractory or relapsed lung cancer. The 15 patients were treated with amrubicin intravenously at doses of 30, 35, or 40 mg/m(2) on three consecutive days every 3 weeks for a total of 43 courses. Neutropenia was the major toxicity (grade 4, 67%). The MTD was 40 mg/m(2), with the specific dose-limiting toxicities being grade 4 neutropenia persisting for >4 days, febrile neutropenia, or grade 3 arrhythmia in the three patients treated at this dose. A patient with non-small-cell lung cancer showed a partial response, and ten individuals experienced a stable disease. The area under the plasma concentration versus time curve (AUC) for amrubicin and that for amrubicinol increased with amrubicin dose. The amrubicin AUC was significantly correlated with the amrubicinol AUC. The recommended phase II dose of amrubicin for patients with lung cancer refractory to standard chemotherapy is thus 35 mg/m(2) once a day for three consecutive days every 3 weeks.
Okamoto
Isamu
I
Department of Respiratory Medicine, Graduate School of Medical Science, Kumamoto University, Japan. okamoto@dotd.med.kindai.ac.jp
Hamada
Akinobu
A
Matsunaga
Yusuke
Y
Sasaki
Ji-ichiro
J
Fujii
Shinji
S
Uramoto
Hideshi
H
Yamagata
Haruhiko
H
Mori
Ichiro
I
Kishi
Hiroto
H
Semba
Hiroshi
H
Saito
Hideyuki
H
D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001281:Atrial Fibrillation / Q000139:chemically induced / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004206:Disopyramide / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004417:Dyspnea / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D006207:Half-Life; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced / Q000188:drug therapy; D007262:Infusions, Intravenous; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009503:Neutropenia / Q000139:chemically induced / Q000628:therapy; D017713:Platelet Transfusion; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy; D013256:Steroids / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000139:chemically induced / Q000628:therapy
D018943:Anthracyclines; D000970:Antineoplastic Agents; D013256:Steroids; C116173:amrubicinol; C055866:amrubicin; D004206:Disopyramide