Abstract
PurposeTo investigate the exposure-toxicity relationship of bosutinib and to identify the target trough plasma concentration (C0).MethodsThe 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).ResultsNine 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 was 63.7 ng/mL and 63.0 ng/mL in the SD and DE groups, respectively. Liver dysfunction (all grades) and diarrhea (> grade 2) were prevalent in quartile 4 of C0 (> 91.0 ng/mL), as calculated by the total C0 distribution.ConclusionsThe 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.
Highlights
Bosutinib is a second-generation tyrosine kinase inhibitor (TKI) for the Src and Abelson (Abl) kinases, which was originally developed for the treatment of patientsMita et al Exp Hematol Oncol (2018) 7:9 molecular response (MMR) was significantly higher, and the median times to achieve major molecular response (MMR) was significantly shorter, in patients taking bosutinib than in those taking imatinib [4, 5]
These results show that therapeutic drug monitoring (TDM) may be necessary for bosutinib
After beginning the 500 mg/day treatment, dosage was adjusted based on the adverse events (AEs) grade, 2 patients discontinued bosutinib therapy due to grade 3 elevation of lipase levels and grade 3 pancytopenia
Summary
Bosutinib is a second-generation tyrosine kinase inhibitor (TKI) for the Src and Abelson (Abl) kinases, which was originally developed for the treatment of patientsMita et al Exp Hematol Oncol (2018) 7:9 molecular response (MMR) was significantly higher, and the median times to achieve MMR was significantly shorter, in patients taking bosutinib than in those taking imatinib [4, 5]. In TKI therapy for CML patients, therapeutic drug monitoring (TDM) is a new strategy for optimizing dosage to achieve faster and deeper responses, such as an MMR [6]. This strategy could increase efficacy and/or decrease toxicity from TKI therapy, it is important to confirm the proposed target plasma concentrations, especially in medications with narrow therapeutic windows. Patients with a higher bosutinib C0 tended to have an elevated risk of bosutinibinduced diarrhea [8], which is the most frequent adverse event due to bosutinib [1,2,3,4,5, 7,8,9,10] These results show that TDM may be necessary for bosutinib. The dose reduction of bosutinib is typically a result of AEs, which was shown to occur in about 39% of patients assessed for at least 1 year during a phase III trial [4]
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