Individual optimal dose of amrubicin to prevent severe neutropenia in Japanese patients with lung cancer.

This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic and pharmacodynamic modeling incorporating gene polymorphisms of metabolizing enzymes and transporters. Fifty patients with lung cancer, who were given 35-40 mg/m2 amrubicin on days 1-3 every 3-4 weeks, were enrolled. Mechanism-based modeling described relationships between the pharmacokinetics of amrubicin and absolute neutrophil counts. A population pharmacokinetic and pharmacodynamic model was developed for amrubicin and amrubicinol (active metabolite), connected by a delay compartment. The final model incorporated body surface area as a covariate of amrubicin and amrubicinol clearance and distribution volume. SLC28A3 single nucleotide polymorphism (rs7853758) was also incorporated as a constant covariate of the delay compartment of amrubicinol. Performance status was considered a covariate of pharmacokinetic (amrubicinol clearance) and pharmacodynamic (mean maturation time) parameters. Twenty-nine patients with grade 4 neutropenia showed higher amrubicinol area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72 , P = .01) and shorter overall survival periods than other patients did (P = .01). Using the final population pharmacokinetic and pharmacodynamic model, median optimal dose to prevent grade 4 neutropenia aggravation was estimated at 22 (range, 8-40) mg/m2 for these 29 patients. We clarified correlations between area under the plasma concentration-time curve from 0 to 72 hours of amrubicinol and severity of neutropenia and survival of patients given amrubicin after platinum chemotherapy. This analysis revealed important amrubicin pharmacokinetic-pharmacodynamic covariates and provided useful information to predict patients who would require prophylactic granulocyte colony stimulating factor.

Simultaneous optimization of limited sampling points for pharmacokinetic analysis of amrubicin and amrubicinol in cancer patients.

AIM: Limited sampling points for both amrubicin (AMR) and its active metabolite amrubicinol (AMR-OH) were simultaneously optimized using Akaike's information criterion (AIC) calculated by pharmacokinetic modeling. METHODS: In this pharmacokinetic study, 40 mg/m(2) of AMR was administered as a 5-min infusion on three consecutive days to 21 Japanese lung cancer patients. Blood samples were taken at 0, 0.08, 0.25, 0.5, 1, 2, 4, 8 and 24 h after drug infusion, and AMR and AMR-OH concentrations in plasma were quantitated using a high-performance liquid chromatography. The pharmacokinetic profile of AMR was characterized using a three-compartment model and that of AMR-OH using a one-compartment model following a first-order absorption process. These pharmacokinetic profiles were then integrated into one pharmacokinetic model for simultaneous fitting of AMR and AMR-OH. After fitting to the pharmacokinetic model, 65 combinations of four sampling points from the concentration profiles were evaluated for their AICs. Stepwise regression analysis was applied to select the sampling points for AMR and AMR-OH to predict the area under the concentration-time curves (AUCs) at best. RESULTS: Of the three combinations that yielded favorable AIC values, 0.25, 2, 4 and 8 h yielded the best AUC prediction for both AMR (R(2) = 0.977) and AMR-OH (R(2) = 0.886). The prediction error for AUC was less than 15%. CONCLUSION: The optimal limited sampling points of AMR and AMR-OH after AMR infusion were found to be 0.25, 2, 4 and 8 h, enabling less frequent blood sampling in further expanded pharmacokinetic studies for both AMR and AMR-OH.

Review of the management of relapsed small-cell lung cancer with amrubicin hydrochloride.

Lung cancer is the leading cause of cancer death, and approximately 15% of all lung cancer patients have small-cell lung cancer (SCLC). Although second-line chemotherapy can produce tumor regression, the prognosis is poor. Amrubicin hydrochloride (AMR) is a synthetic anthracycline anticancer agent and a potent topoisomerase II inhibitor. Here, we discuss the features of SCLC, the chemistry, pharmacokinetics, and pharmacodynamics of AMR, the results of in vitro and in vivo studies, and the efficacy and safety of AMR monotherapy and combination therapy in clinical trials. With its predictable and manageable toxicities, AMR is one of the most attractive agents for the treatment of chemotherapy-sensitive and -refractory relapsed SCLC. Numerous studies are ongoing to define the applicability of AMR therapy for patients with SCLC. These clinical trials, including phase III studies, will clarify the status of AMR in the treatment of SCLC.

Efficacy and safety of amrubicin hydrochloride for treatment of relapsed small cell lung cancer.

Long-term survival is quite uncommon in refractory small cell lung cancer (SCLC) patients, with less than 25% of patients with limited-stage disease and 1%-2% of patients with extensive-stage disease remaining alive at five years. Recent clinical studies have demonstrated the promising efficacy of amrubicin for patients with relapsed SCLC. This review presents the results of clinical studies showing the efficacy and safety of amrubicin for the treatment of relapsed SCLC. Amrubicin is a synthetic anthracycline agent with a similar structure to doxorubicin, in which the hydroxyl group at position 9 in amrubicin is replaced by an amino group to enhance efficacy. It is converted to an active metabolite, amrubicinol, which is 5-54 times more active than amrubicin. Amrubicin and amrubicinol are inhibitors of DNA topoisomerase II, exerting their cytotoxic effects by stabilizing a topoisomerase II-mediated cleavable complex. The toxicity of amrubicin is similar to that of doxorubicin, although amrubicin shows almost no cardiotoxicity. In the relevant trials, amrubicin was administered intravenously at a dose of 35-40 mg/m(2) on days 1-3 every three weeks. The response rate was 34%-52% and median survival times were 8.1-12.0 months. Common hematologic toxicities included neutropenia, leucopenia, anemia, thrombocytopenia, and febrile neutropenia. Nonhematologic adverse events included Grade 3-4 anorexia, asthenia, hyponatremia, and nausea. The results of the studies which demonstrated the efficacy of monotherapy for relapsed SCLC involved mainly Japanese patients. Therefore, it is necessary to conduct more clinical studies in non-Japanese patients to confirm the efficacy of amrubicin.