Plasma concentration of amrubicinol in gamma phase in patients treated for 3 days with amrubicin and hematological toxicities

Abstract

e14606 Background: Amrubicinol (AMR-OH) is an active metabolite of amrubicin (AMR), a novel synthetic 9-amino-anthracycline derivative. The time-concentration profile of AMR-OH exhibits a continuous long plateau slope in 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 performed a PK/PD study of AMR in patients with lung cancer treated with AMR alone or the combination of AMR + cisplatin (CDDP). Methods: AMR was given at a dose of 30 or 40 mg/m2 on days 1 to 3. Plasma samples were collected at pretreatment, 24 hours after the 1st injection (day 2), and 24 hours after the 3rd injection (day 4). Plasma concentrations of AMR, AMR-OH, and CDDP were determined by HPLC and AAS. Percent change in neutrophil count (dANC) and the plasma concentration of AMR-OH were evaluated using a sigmoid Emax model. Results: A total of 35 patients with a median age of 65 years (range 40–78), including 10 with small cell lung cancer (SCLC), 23 with non-small cell lung cancer (NSCLC), 1 with thymic cancer, and 1 with neuroblastoma were enrolled. A total of 107 plasma samples were available for study. Mean concentrations of AMR on day 2, AMR on day 4, AMR-OH on day 2, and AMR-OH on day 4 were 8.52ng/mL+4.63, 16.55ng/mL+11.92, 7.28 ng/mL+3.56 SD, and 13.35ng/mL+5.56 (mean ± SD), with significant increase from day 2 to day 4 for both AMR (p<0.0001) and AMR-OH (p<0.0001). Significant relationships were observed between AMR-OH on day 4 and the toxicity grades of leukopenia, neutropenia, and anemia (p=.018, p=.012, and p=.025). Thrombocytopenia grade exhibited a tendency toward relationship with AMR-OH on day 4 (p = .081). No relationships were observed between drug concentrations and responses. 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 with co-administration with CDDP using a sigmoid Emax model. Conclusions: The plasma concentration of AMR-OH on day 4 was correlated with hematological toxicities in patients treated with AMR. Assessment of plasma concentration of AMR-OH at one time point might enable prediction of hematological toxicities. No significant financial relationships to disclose.