Patient-Specific Pharmacokinetics and Dasatinib Nephrotoxicity

Author:

Adegbite Benjamin O.12ORCID,Abramson Matthew H.1ORCID,Gutgarts Victoria3,Musteata Florin M.4ORCID,Chauhan Kinsuk1ORCID,Muwonge Alecia N.1ORCID,Meliambro Kristin A.1,Salvatore Steven P.5ORCID,El Ghaity-Beckley Sebastian6ORCID,Kremyanskaya Marina6ORCID,Marcellino Bridget6,Mascarenhas John O.6ORCID,Campbell Kirk N.1ORCID,Chan Lili1ORCID,Coca Steven G.1,Berman Ellin M.7,Jaimes Edgar A.3,Azeloglu Evren U.18ORCID

Affiliation:

1. Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York

2. Internal Medicine, Mount Sinai Morningside/West, New York, New York

3. Renal Service, Memorial Sloan Kettering Cancer Center, New York, New York

4. Department of Pharmaceutical Sciences, Albany College of Pharmacy & Health Sciences, Albany, New York

5. Clinical Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York

6. Division of Hematology/Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York

7. Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York

8. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York

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. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_09_08_CJN0000000000000219.mp3

Funder

National Institutes of Health

U.S. Department of Defense

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Transplantation,Nephrology,Critical Care and Intensive Care Medicine,Epidemiology

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