Abstract
The purpose of this study was to investigate the effects of SLC22A2 808G>T polymorphism and trough concentrations (C0) of bosutinib on serum creatinine in 28 patients taking bosutinib. At 1, 3, 6, 12, 24, and 36 months after administration, analysis of bosutinib C0 and creatinine was performed at the same time of day. Significant correlations were observed between bosutinib C0 and the change rate of serum creatinine or the estimated glomerular filtration rate (eGFR; r = 0.328, P < 0.001 and r = − 0.315, P < 0.001, respectively). These correlations were particularly high in patients having the SLC22A2 808G/G genotype (r = 0.345 and r = − 0.329, respectively); however, in patients having the 808T allele, there were no significant differences. In multivariate analyses, the SLC22A2 808G/G genotype, patient age, bosutinib C0 and second-line or later bosutinib were independent factors influencing the change rate of creatinine. Bosutinib elevated serum creatinine through organic cation transporter 2 (OCT2). We observed a 20% increase in serum creatinine with a median bosutinib C0 of 63.4–73.2 ng/mL. Periodic measurement of serum creatinine after bosutinib therapy is necessary to avoid progression to severe renal dysfunction from simple elevation of creatinine mediated by OCT2 following bosutinib treatment.
Highlights
Bosutinib is a second-generation tyrosine kinase inhibitor (TKI) that acts as a dual inhibitor of Src and ABL kinases[1,2]
In an in vitro study, Omote et al reported that crizotinib and imatinib may increase serum creatinine values by more than 10% based on renal creatinine clearance and the plasma concentrations of these TKIs5
We investigated the relationships between trough plasma concentrations of bosutinib and serum creatinine values and assessed the effects of the SLC22A2 808G>T polymorphism in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) receiving bosutinib therapy
Summary
Bosutinib is a second-generation tyrosine kinase inhibitor (TKI) that acts as a dual inhibitor of Src and ABL kinases[1,2]. In long-term analyses, patients receiving bosutinib therapy have been reported to show declines in renal function, such as an increase from baseline in serum creatinine values and a decrease in the estimated glomerular filtration rate (eGFR)[3]. In an in vitro study, Omote et al reported that crizotinib and imatinib may increase serum creatinine values by more than 10% based on renal creatinine clearance and the plasma concentrations of these TKIs5. To date, no reports have described the relationships between plasma concentrations of bosutinib and serum creatinine values. We investigated the relationships between trough plasma concentrations of bosutinib and serum creatinine values and assessed the effects of the SLC22A2 808G>T polymorphism in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) receiving bosutinib therapy
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