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Drug Metabolism & Disposition

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Augmented clearance of nivolumab is associated with renal functions in chronic renal disease model rats

Kazuaki Taguchi, Yukitaka Hayashi, Mayu Ohuchi, Hotaka Yamada, Shigehiro Yagishita, Yuki Enoki, Kazuaki Matsumoto and Akinobu Hamada
Drug Metabolism and Disposition August 4, 2021, DMD-AR-2021-000520; DOI: https://doi.org/10.1124/dmd.121.000520
Kazuaki Taguchi
1Keio University, Japan
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Yukitaka Hayashi
2Faculty of Pharmacy, Keio University of Pharmacy, Japan
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Mayu Ohuchi
3Division of Molecular Pharmacology, National Cancer Center Research Institute., Japan
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Hotaka Yamada
2Faculty of Pharmacy, Keio University of Pharmacy, Japan
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Shigehiro Yagishita
3Division of Molecular Pharmacology, National Cancer Center Research Institute., Japan
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Yuki Enoki
2Faculty of Pharmacy, Keio University of Pharmacy, Japan
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Kazuaki Matsumoto
2Faculty of Pharmacy, Keio University of Pharmacy, Japan
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Akinobu Hamada
3Division of Molecular Pharmacology, National Cancer Center Research Institute., Japan
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  • For correspondence: akhamad@ncc.go.jp
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Abstract

The clinically approved dose of nivolumab is 240 mg Q2W. 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 due to 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.

Significance Statement We demonstrated that nivolumab was rapidly eliminated from the circulation in chronic kidney disease model rats compared to sham rats with an increased urinary nivolumab excretion. Moreover, nivolumab clearance was significantly correlated with the baseline levels of certain laboratory parameters reflecting renal functions. These results indicate the potential applicability of baseline renal function as a prognostic index to qualitatively estimate nivolumab clearance prior to nivolumab treatment under conditions with renal impairment.

  • chronic renal failure
  • clearance
  • pharmacokinetic
  • renal excretion
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 50 (6)
Drug Metabolism and Disposition
Vol. 50, Issue 6
1 Jun 2022
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Accelerated blood clearance of nivolumab in renal impairment

Kazuaki Taguchi, Yukitaka Hayashi, Mayu Ohuchi, Hotaka Yamada, Shigehiro Yagishita, Yuki Enoki, Kazuaki Matsumoto and Akinobu Hamada
Drug Metabolism and Disposition August 4, 2021, DMD-AR-2021-000520; DOI: https://doi.org/10.1124/dmd.121.000520

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OtherArticle

Accelerated blood clearance of nivolumab in renal impairment

Kazuaki Taguchi, Yukitaka Hayashi, Mayu Ohuchi, Hotaka Yamada, Shigehiro Yagishita, Yuki Enoki, Kazuaki Matsumoto and Akinobu Hamada
Drug Metabolism and Disposition August 4, 2021, DMD-AR-2021-000520; DOI: https://doi.org/10.1124/dmd.121.000520
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