Plasma concentration of amrubicinol in plateau phase in patients treated for 3 days with amrubicin is correlated with hematological toxicities.
Amrubicinol (AMR-OH) is an active metabolite of amrubicin (AMR), a novel synthetic 9-aminoanthracycline derivative. The time-concentration profile of AMR-OH exhibits a continuous long plateau slope in the terminal phase. To determine the relationships between the steady-state plasma concentration of AMR-OH and treatment effects and toxicities associated with AMR therapy, we carried out a pharmacokinetic/pharmacodynamic study in patients treated with AMR alone or the combination of AMR+cisplatin (CDDP). AMR was given at a dose of 30 or 40 mg/m(2) on days 1-3. Plasma samples were collected 24 h after the third injection (day 4). Plasma concentrations of AMR-OH or total CDDP were determined by a high-performance liquid chromatography or an atomic absorption spectrometry. Percent change in neutrophil count (dANC) and the plasma concentration of AMR-OH were evaluated using a sigmoid E(max) model. A total of 35 patients were enrolled. Significant relationships were observed between AMR-OH on day 4 and the toxicity grades of leukopenia, neutropenia, and anemia (P=0.018, P=0.012, and P=0.025, respectively). Thrombocytopenia grade exhibited a tendency toward relationship with AMR-OH on day 4 (P=0.081). The plasma concentration of AMR-OH on day 4 was positively correlated with dANC in the group of all patients, as well as in patients treated with AMR alone and in patients coadministered with CDDP. In conclusion, the plasma concentration of AMR-OH on day 4 was correlated with hematological toxicities in patients treated with AMR. The assessment of plasma concentration of AMR-OH at one timepoint might enable the prediction of hematological toxicities.
Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Otemae Hospital, Osaka, Japan. kimutats@med.osaka-cu.ac.jp
Tatsuo
T
Kimura
Shinzoh
S
Kudoh
Shigeki
S
Mitsuoka
Naruo
N
Yoshimura
Hidenori
H
Tanaka
Kazuhisa
K
Asai
Shigenori
S
Kyoh
Yoshihiro
Y
Tochino
Kanako
K
Umekawa
Kazuto
K
Hirata
D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy*; D018288:Carcinoma, Small Cell / Q000097:blood / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced*; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome
D018943:Anthracyclines; D000970:Antineoplastic Agents; C116173:amrubicinol; C055866:amrubicin