Correlation of plasma concentration and adverse effects of bosutinib: standard dose or dose-escalation regimens of bosutinib treatment for patients with chronic myeloid leukemia

摘要

To investigate the exposure-toxicity relationship of bosutinib and to identify the target trough plasma concentration (C0). The toxicity and C0 of bosutinib in Japanese chronic myeloid leukemia (CML) patients were monitored every 2?weeks for the first 3?months of treatment, and subsequently once a month during the 6?months after beginning 500?mg/day of standard dose (SD group, n?=?10) or beginning 100?mg/day and increased by 100?mg every 2?weeks of dose escalation (DE group, n?=?15). Nine of 10 patients (90%) in the SD group were not able to continue bosutinib therapy without interruption due to adverse events, compared to 2 patients (13.5%) in the DE group. The total duration of treatment interruption was 35 and 14?days in the SD and DE groups, respectively. The median time until liver dysfunction or diarrhea was day 28 and day 1 in the SD group, and day 53.5 and day 19 in the DE group, respectively. The cumulative dose of bosutinib was comparable between the SD and DE groups (51,700 vs. 53,550?mg, respectively). At 6?months, the median C0?grade 2) were prevalent in quartile 4 of C0?91.0?ng/mL), as calculated by the total C0 distribution. The DE regimen was better suited to avoid treatment interruption. The daily dose of bosutinib might be adjusted based on target C0 to avoid adverse events by therapeutic drug monitoring in general practice.