Patient-Specific Pharmacokinetics and Dasatinib Nephrotoxicity.
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Issue Date
2023-09
Authors
Adegbite, Benjamin O
Abramson, Matthew H
Gutgarts, Victoria
Musteata, Florin Marcel
Chauhan, Kinsuk
Muwonge, Alecia N
Meliambro, Kristin A
Salvatore, Steven P
El Ghaity-Beckley, Sebastian
Kremyanskaya, Marina
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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 examined glomerular injury through urine albumin-creatinine ratio (UACR) in 82 patients with chronic myelogenous leukemia 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 assayed plasma dasatinib pharmacokinetics using tandem mass spectroscopy and further described 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; interquartile range, 11.5-119.5) than participants treated with other tyrosine-kinase inhibitors ( n =50; median 15.0 mg/g; interquartile range, 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) and duration of treatment ( P = 0.003). There were no associations with elevated BP or other confounding factors. In the case study, kidney biopsy revealed global glomerular damage with diffuse foot process effacement that recovered on termination of dasatinib treatment.
Conclusions: Exposure to dasatinib was associated with a significant chance of developing proteinuria compared with other similar tyrosine-kinase inhibitors. Dasatinib plasma concentration significantly correlated with higher risk of developing proteinuria while receiving dasatinib.
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Citation
Adegbite BO, Abramson MH, Gutgarts V, Musteata FM, Chauhan K, Muwonge AN, Meliambro KA, Salvatore SP, El Ghaity-Beckley S, Kremyanskaya M, Marcellino B, Mascarenhas JO, Campbell KN, Chan L, Coca SG, Berman EM, Jaimes EA, Azeloglu EU. Patient-Specific Pharmacokinetics and Dasatinib Nephrotoxicity. Clin J Am Soc Nephrol. 2023 Sep 1;18(9):1175-1185. doi: 10.2215/CJN.0000000000000219. Epub 2023 Jun 29. PMID: 37382967.
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R01 DK118222/DK/NIDDK NIH HHS/United States , R01GM123330/NH/NIH HHS/United States , R01DK129299/NH/NIH HHS/United States , R01DK1182222/NH/NIH HHS/United States , K23 DK124645/DK/NIDDK NIH HHS/United States