Dasatinib nephrotoxicity correlates with patient-specific pharmacokinetics

Abstract

Introduction: 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 101 chronic myelogenous leukemia patients who were on tyrosine-kinase inhibitor (TKI) therapy for at least 90 days. 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: Patients treated with dasatinib (n= 32) had significantly higher UACR levels (median 28.0 mg/g, IQR 11.5 - 119.5) than patients treated with other TKIs (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 TKIs. 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 a significant chance of developing proteinuria compared to other similar TKIs. Dasatinib plasma concentration significantly correlates with increased risk of developing proteinuria while receiving dasatinib. Screening for renal dysfunction and proteinuria is strongly advised for all dasatinib patients.