amrubicinol and Carcinoma--Non-Small-Cell-Lung

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.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Drug Administration Schedule; Female; Hematologic Diseases; Humans; Leukopenia; Lung Neoplasms; Male; Middle Aged; Neutropenia; Treatment Outcome

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.

Topics: Aged; Anthracyclines; Antineoplastic Agents; Area Under Curve; Atrial Fibrillation; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Chromatography, High Pressure Liquid; Disopyramide; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyspnea; Female; Half-Life; Humans; Hypoxia; Infusions, Intravenous; Leukopenia; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Platelet Transfusion; Pneumonia; Steroids; Thrombocytopenia

Amrubicin, a synthetic 9-aminoanthracycline agent, was recently approved in Japan for treatment of small-cell lung cancer and non-small-cell lung cancer. Amrubicin is converted enzymatically to the C-13 hydroxy metabolite amrubicinol, which is active and possesses a cytotoxicity 10 to 100 times that of the parent drug. The purpose of this study was to characterize the pharmacokinetics of amrubicin and its active metabolite amrubicinol. Amrubicin was administered on days 1-3 in 16 patients with advanced lung cancer. The pharmacokinetics analysis of amrubicin and amrubicinol was performed by high-performance liquid chromatography. When 45 mg/m amrubicin was administered in a bolus injection once every 24 hours for 3 consecutive days, the areas under the curves (0 to 72 hours) for amrubicin and amrubicinol were 13,490 and 2585 ng . h/mL, respectively. The apparent total clearance (CLapp) of amrubicin was 15.4 L/h. The area-under-the-curve ratio of amrubicinol to amrubicin was 15.1 +/- 4.6% (mean +/- SD) at doses ranging from 30 to 45 mg/m. Interindividual variability in the enzymatic conversion of amrubicin to amrubicinol was small. In contrast, a large interindividual variability in the CLapp of amrubicin was observed (CV = 49.8%). The areas under the curves of amrubicin and amrubicinol seemed to be associated with the severity of hematologic toxicities. There is a possibility that monitoring of the plasma concentrations of amrubicin and amrubicinol may provide an efficient tool for establishing the optimal dosage of amrubicin in each patient.

Topics: Aged; Anthracyclines; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Chromatography, High Pressure Liquid; Female; Humans; Leukopenia; Lung Neoplasms; Male; Middle Aged; Thrombocytopenia

The pharmacokinetic (PK)-pharmacodynamic (PD) relationship of amrubicin and its active metabolite, amrubicinol, has only been evaluated using trough levels of these agents since the full PK profiles not yet been clarified so far. This study was performed to analyze the full PK profiles of amrubicin and amrubicinol and to evaluate their toxicity-PK relationships in Japanese patients.. Amrubicin (35-40 mg/m(2)) was administered to 21 lung cancer patients on days 1-3 every 3-4 weeks. Fourteen blood samples were obtained per patient over the course of 3 administration days. The plasma concentrations of amrubicin and amrubicinol were quantitated by HPLC, and the relationships between PK parameters of these compounds and hematological toxicities were evaluated.. The overall PK profiles of amrubicin and amrubicinol were well characterized using a 3-compartment model and a 1-compartment model with a first-order metabolic process, respectively. The major toxicities were hematological. The clearance of amrubicinol was significantly correlated with grade 4 neutropenia (P = 0.01). The percentage decreases in the neutrophil count, hemoglobin level and platelet count were well correlated with the amrubicinol AUC.. The pharmacokinetic profiles of amrubicin and amrubicinol were clarified, and the subsequent PK-PD analyses indicate that the clearance of amrubicinol is the major determinant of neutropenia.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Carcinoma, Non-Small-Cell Lung; Female; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Small Cell Lung Carcinoma

Amrubicin is a promising agent in the treatment of lung cancer, but predictive biomarkers have not yet been described. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme known to metabolize amrubicinol, the active metabolite of amrubicin, to an inactive compound. We examined the relationship between NQO1 and amrubicinol cytotoxicity.. Gene and protein expression of NQO1, amrubicinol cytotoxicity, and C609T single-nucleotide polymorphism of NQO1 were evaluated in 29 lung cancer cell lines: 14 small cell lung cancer (SCLC) and 15 non-SCLC (NSCLC). The involvement of NQO1 in amrubicinol cytotoxicity was evaluated by small interfering RNA against NQO1.. A significant inverse relationship between both gene and protein expression of NQO1 and amrubicinol cytotoxicity was found in all cell lines. Treatment with NQO1 small interfering RNA increased amrubicinol cytotoxicity and decreased NQO1 expression in both NSCLC and SCLC cells. Furthermore, cell lines genotyped homozygous for the 609T allele showed significantly lower NQO1 protein expression and higher sensitivity for amrubicinol than those with the other genotypes in both NSCLC and SCLC cells.. NQO1 expression is one of the major determinants for amrubicinol cytotoxicity, and C609T single-nucleotide polymorphism of NQO1 could be a predictive biomarker for response to amrubicin treatment.

Topics: Adenocarcinoma; Anthracyclines; Biomarkers, Tumor; Blotting, Western; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; DNA, Neoplasm; Genotype; Humans; Lung Neoplasms; NAD(P)H Dehydrogenase (Quinone); Polymorphism, Single Nucleotide; Real-Time Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Small Cell Lung Carcinoma; Tumor Cells, Cultured

Amrubicin, a completely synthetic 9-aminoanthracycline derivative, is an active agent in the treatment of untreated extensive disease-small-cell lung cancer and advanced non-small-cell lung cancer. Amrubicin administered intravenously at 25 mg/kg substantially prevented the growth of five of six human lung cancer xenografts established in athymic nude mice, confirming that amrubicin as a single agent was active in human lung tumors. To survey which antitumor agent available for clinical use produces a synergistic interaction with amrubicin, we examined the effects in combinations with amrubicinol, an active metabolite of amrubicin, of several chemotherapeutic agents in vitro using five human cancer cell lines using the combination index (CI) method of Chou and Talalay. Synergistic effects were obtained on the simultaneous use of amrubicinol with cisplatin, irinotecan, gefitinib and trastuzumab, with CI values after 3 days of exposure being <1. Additive effect was observed with the combination containing vinorelbine with CI values indistinguishable from 1, while the combination of amrubicinol with gemcitabine was antagonistic. All combinations tested in vivo were well tolerated. The combinations of cisplatin, irinotecan, vinorelbine, trastuzumab, tegafur/uracil, and to a lesser extent, gemcitabine with amrubicin caused significant growth inhibition of human tumor xenografts without pronouncedly enhancing body weight loss, compared with treatment using amrubicin alone at the maximum tolerated dose. Growth inhibition of tumors by gefitinib was not antagonized by amrubicin. These results suggest that amrubicin appears to be a possible candidate for combined use with cisplatin, irinotecan, vinorelbine, gemcitabine, tegafur/uracil or trastuzumab.

Topics: Animals; Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Line, Tumor; Cisplatin; Deoxycytidine; Drug Synergism; Female; Gefitinib; Gemcitabine; Humans; In Vitro Techniques; Irinotecan; Lung Neoplasms; Mice; Mice, Nude; Quinazolines; Random Allocation; Stomach Neoplasms; Tegafur; Trastuzumab; Uracil; Vinblastine; Vinorelbine; Xenograft Model Antitumor Assays