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, Akinobu Hamada

Research output: Contribution to journalArticlepeer-review

Abstract

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. SIGNIFICANCE STATEMENT: This study demonstrated that nivolumab was rapidly eliminated from the circulation in chronic kidney disease model rats compared with 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.

Original languageEnglish
Pages (from-to)822-826
Number of pages5
JournalDrug metabolism and disposition: the biological fate of chemicals
Volume50
Issue number6
DOIs
Publication statusPublished - 2022 Jun 1

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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