Patient-Specific Pharmacokinetics and Dasatinib Nephrotoxicity.

Overview

abstract

BACKGROUND: Dasatinib has been associated with nephrotoxicity. We sought to examine the incidence of proteinuria on dasatinib and determine potential risk factors that may increase dasatinib-associated glomerular injury. METHODS: We examine glomerular injury via urine albumin-to-creatinine ratio (UACR) in 82 chronic myelogenous leukemia patients who were on tyrosine-kinase inhibitor therapy for at least 90 days. T-tests were used to compare mean differences in UACR while regression analysis was used to assess the effects of drug parameters on proteinuria development while on dasatinib. We assay plasma dasatinib pharmacokinetics using tandem mass spectroscopy, and further describe a case study of a patient who experienced nephrotic-range proteinuria while on dasatinib. RESULTS: Participants treated with dasatinib (n = 32) had significantly higher UACR levels (median 28.0 mg/g, IQR 11.5 - 119.5) than participants treated with other tyrosine kinase inhibitors (n = 50; median 15.0 mg/g, IQR 8.0 - 35.0; p < 0.001). In total, 10% of dasatinib users exhibited severely increased albuminuria (UACR > 300 mg/g) versus zero in other tyrosine kinase inhibitors. Average steady state concentrations of dasatinib were positively correlated with UACR (ρ = 0.54, p = 0.03) as well as duration of treatment ( p =0.003). There were no associations with elevated blood pressure or other confounding factors. In the case study, kidney biopsy revealed global glomerular damage with diffuse foot process effacement that recovered upon termination of dasatinib treatment. CONCLUSIONS: Exposure to dasatinib is associated with a significant chance of developing proteinuria compared to other similar tyrosine kinase inhibitors.