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. 2023 Sep 1;18(9):1175-1185.
doi: 10.2215/CJN.0000000000000219. Epub 2023 Jun 29.

Patient-Specific Pharmacokinetics and Dasatinib Nephrotoxicity

Benjamin O Adegbite  1   2 , Matthew H Abramson  1 , Victoria Gutgarts  3 , Florin M Musteata  4 , Kinsuk Chauhan  1 , Alecia N Muwonge  1 , Kristin A Meliambro  1 , Steven P Salvatore  5 , Sebastian El Ghaity-Beckley  6 , Marina Kremyanskaya  6 , Bridget Marcellino  6 , John O Mascarenhas  6 , Kirk N Campbell  1 , Lili Chan  1 , Steven G Coca  1 , Ellin M Berman  7 , Edgar A Jaimes  3 , Evren U Azeloglu  1   8
Affiliations

Patient-Specific Pharmacokinetics and Dasatinib Nephrotoxicity

Benjamin O Adegbite et al. Clin J Am Soc Nephrol. .

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.

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Conflict of interest statement

M.H. Abramson reports employment with Icahn School of Medicine at Mount Sinai. B.O. Adegbite reports employment with Mount Sinai. E.U. Azeloglu reports employment with Icahn School of Medicine at Mount Sinai, consultancy for Ikena Oncology, ownership interest in Novartis, research funding from Aurinia Pharmaceuticals and Renalytix AI, patents or royalties from Mount Sinai Health System, and role on Kidney International Editorial Board. K.N. Campbell reports employment with Icahn School of Medicine at Mount Sinai; consultancy for Calliditas, Chinook, Sanofi, and Travere; research funding from Aurinia; and Board memberships (unpaid) for National Kidney Foundation and Nephcure Foundation. L. Chan reports employment with Icahn School of Medicine at Mount Sinai, consultancy for CSL Vifor Pharma, INC, research funding from NIH, and honoraria from Fresenius. K. Chauhan reports employment with Icahn School of Medicine at Mount Sinai. S.G. Coca reports employment with Icahn School of Medicine at Mount Sinai—Mount Sinai owns part of Renalytix; consultancy for 3ive, Axon, Bayer, Boehringer-Ingelheim, Nuwellis, Renalytix, Reprieve Cardiovascular, Takeda, and Vifor; ownership interest in pulseData and Renalytix; research funding from ProKidney, Renal Research Institute, Renalytix, and XORTX; patents or royalties from Renalytix; and role as an Associate Editor for Kidney360 and role on the Editorial Boards of CJASN, JASN, and Kidney International. S. El Ghaity-Beckley reports employment with Mount Sinai Health System. V. Gutgarts reports employment with Memorial Sloan Kettering Cancer Center. E.A. Jaimes reports employment with Memorial Sloan Kettering Cancer Center and honoraria from Natera and UpToDate. M. Kremyanskaya reports consultancy for AbbVie, CTI, Incyte, Morphosys, and Protagonist and honoraria from AbbVie, CTI, Incyte, Morphosys, and Protagonist. B. Marcellino reports employment with Mount Sinai Health System. J.O. Mascarenhas reports employment with Icahn School of Medicine at Mount Sinai; consultancy for Abbvie, BMS, Celgene, CTI Bio, Geron, GSK, Incyte, Kartos, Karyopharm, MorphoSys, Novartis, Pfizer, and Roche; research funding from Abbvie, BMS, CTI Bio, Geron, Incyte, Kartos, Novartis, and PharmaEssentia; honoraria from Abbvie, BMS, Celgene, CTI Bio, Geron, GSK, Incyte, Kartos, Karyopharm, MorphoSys, Novartis, Pfizer, and Roche; and advisory or leadership roles for BMS, CTI Bio, Geron, and Incyte. K.A. Meliambro reports employment with Icahn School of Medicine at Mount Sinai. F.M. Musteata reports employment with Regeneron. S.P. Salvatore reports ownership interest in AAPL, CCNE, COIN, DIS, DKNG, Fundrise, IBM, KD, LCID, MJ, RIVN, and VZ. All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Boxplot for UACR values for dasatinib and nondasatinib participants. Chronic myeloid leukemia participants on dasatinib for at least 90 days (n=32) had significantly higher UACR levels (median 28.0 µg/mg; IQR, 11.5–119.5) than participants treated with other tyrosine-kinase inhibitors (imatinib, nilotinib, bosutinib, and ponatinib) for at least 90 days (n=50; median 15.0 µg/mg; IQR, 8.0–35.0; P = 0.03). Our case study participant had a UACR of 702. IQR, interquartile range; UACR, urine albumin-creatinine ratio.
Figure 2
Figure 2
Percentages of participants with albuminuria among dasatinib and nondasatinib patients. Half of all dasatinib-treated participants in this study exhibited albuminuria, compared with 30% for non–dasatinib-treated participants with chronic myelogenous leukemia. 9.4% of dasatinib participants had severe albuminuria (>300 mg/g), whereas none of the participants in the nondasatinib group. Figure 2 can be viewed in color online at www.cjasn.org.
Figure 3
Figure 3
Level of UACR over treatment duration for dasatinib and nondasatinib participants and level of UACR over normalized dosage for both dasatinib and nondasatinib participants. (A) The adjusted estimates of log-transformed UACR for patients being treated with dasatinib compared with nondasatinib in interaction with time were insignificant. Estimate (SEM) 0.01 (0.01), P value = 0.3. (B) However, when assessing the association with dosage, there was borderline significance (SEM=0.4, P value = 0.048). Overall, both relationships show a trend of increased UACR as a function of treatment time or dosage in dasatinib participants. CI, confidence interval.
Figure 4
Figure 4
Dasatinib plasma concentration and its correlation to UACR. A significant and positive correlation was observed between dasatinib plasma concentration and UACR (R=0.54, P value = 0.03). Figure 4 can be viewed in color online at www.cjasn.org.
Figure 5
Figure 5
Histopathological case study findings. Glomerulus from dasatinib-treated biopsy participant showing segmental capillary wall double contour formation (arrows) in both (A) Jones silver staining, ×40, as well as (B) periodic acid–Schiff staining, ×40. Scale bars represent 50 μm. There was further global foot process effacement along with glomerular basement membrane duplication and multilayering along with focal entrapment of hyaline material but no deposits. Focal intracapillary mononuclear inflammatory cells can be seen. (C) Transmission electron microscopy, ×6000. (D) Transmission electron microscopy, ×6000. Scale bars represent 2 μm.
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