TY - JOUR
T1 - Augmented Clearance of Nivolumab Is Associated with Renal Functions in Chronic Renal Disease Model Rats
AU - Taguchi, Kazuaki
AU - Hayashi, Yukitaka
AU - Ohuchi, Mayu
AU - Yamada, Hotaka
AU - Yagishita, Shigehiro
AU - Enoki, Yuki
AU - Matsumoto, Kazuaki
AU - Hamada, Akinobu
N1 - Funding Information:
This work was supported in part by the “Research on Regulatory Science of Pharmaceuticals and Medical Devices” fund from the Japan Agency for Medical Research and Development (AMED). No author has an actual or perceived conflict of interest with the contents of this article. 1K.T., Y.H., and M.O. contributed equally to this work. dx.doi.org/10.1124/dmd.121.000520. S This article has supplemental material available at dmd.aspetjournals.org.
Publisher Copyright:
Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - The clinically approved dose of nivolumab is 240 mg every 2 weeks. However, previous studies have shown that baseline nivolumab clearance (CL) is associated with treatment outcomes in patients with solid cancers, thus motivating researchers to identify prognostic factors and indices influencing nivolumab CL. This study used chronic kidney disease model rats to investigate whether chronic renal impairment affected nivolumab CL and explored the surrogate markers associated with nivolumab CL. We observed that the total CL for nivolumab (CLtot) was approximately 1.42 times higher in chronic kidney disease model rats than that in sham rats with an increased urinary excretion. Additionally, CLtot showed positive correlation with renal CL for nivolumab (CLR) but not with extrarenal CL. Furthermore, the baseline levels of creatinine, blood urea nitrogen, creatinine CL, and urinary albumin/creatine ratio based on laboratory data were also significantly correlated with CLR. Our findings suggest that nivolumab CL increases as renal function deteriorates because of an increased excretion of nivolumab in the urine; additionally, laboratory data reflecting renal function may be a feasible index to qualitatively estimate nivolumab CL prior to nivolumab treatment under conditions of renal impairment.
AB - The clinically approved dose of nivolumab is 240 mg every 2 weeks. However, previous studies have shown that baseline nivolumab clearance (CL) is associated with treatment outcomes in patients with solid cancers, thus motivating researchers to identify prognostic factors and indices influencing nivolumab CL. This study used chronic kidney disease model rats to investigate whether chronic renal impairment affected nivolumab CL and explored the surrogate markers associated with nivolumab CL. We observed that the total CL for nivolumab (CLtot) was approximately 1.42 times higher in chronic kidney disease model rats than that in sham rats with an increased urinary excretion. Additionally, CLtot showed positive correlation with renal CL for nivolumab (CLR) but not with extrarenal CL. Furthermore, the baseline levels of creatinine, blood urea nitrogen, creatinine CL, and urinary albumin/creatine ratio based on laboratory data were also significantly correlated with CLR. Our findings suggest that nivolumab CL increases as renal function deteriorates because of an increased excretion of nivolumab in the urine; additionally, laboratory data reflecting renal function may be a feasible index to qualitatively estimate nivolumab CL prior to nivolumab treatment under conditions of renal impairment.
UR - http://www.scopus.com/inward/record.url?scp=85133100947&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85133100947&partnerID=8YFLogxK
U2 - 10.1124/dmd.121.000520
DO - 10.1124/dmd.121.000520
M3 - Article
C2 - 34348939
AN - SCOPUS:85133100947
SN - 0090-9556
VL - 50
SP - 822
EP - 826
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 6
ER -
