Therapeutic drug monitoring of regorafenib and its metabolite M5 can predict treatment efficacy and the occurrence of skin toxicities



Regorafenib is a multiple tyrosine kinase inhibitor, and the use of this drug is approved for the treatment of cancers that are resistant to chemotherapy, which include advanced colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma. However, the drug causes adverse events, including skin toxicities that require dose modification in approximately 75% of cases. At present, the blood concentration of regorafenib is not assessed in clinical settings; thus, we recently developed a method that can assess the blood concentration of the drug using high-performance liquid chromatography.


We measured the trough blood concentrations (Ctrough) of regorafenib and its metabolites (M2 and M5) in 14 and 4 patients with advanced colorectal cancer and gastrointestinal stromal tumor, respectively, using high-performance liquid chromatography. Then, the correlation between the Ctrough and therapeutic outcomes of regorafenib was analyzed.


In patients who were receiving regorafenib 40–160 mg/day, the Ctrough values of regorafenib, M2, and M5 were 318–9467, 34–3594, and 38–3796 ng/mL, respectively. The difference in the values was significant. Although the specific factors influencing this difference were not elucidated, the Ctrough of regorafenib was extremely lower in some patients, even though the drug was administered at a standard dose, which may explain the lower response rate. Moreover, the Ctrough value of M5 was significantly correlated to the incidence of skin toxicities, which is the most frequent cause of dose modification.


The use of regorafenib may not be suitable in patients with a low Ctrough value. To prevent skin toxicities, the Ctrough value of M5 should be monitored.

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We thank Enago ( for their critical English editing.

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Correspondence to Hiroyuki Shibata.

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Taguchi, D., Inoue, M., Fukuda, K. et al. Therapeutic drug monitoring of regorafenib and its metabolite M5 can predict treatment efficacy and the occurrence of skin toxicities. Int J Clin Oncol 25, 531–540 (2020).

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  • Colorectal cancer
  • Gastrointestinal stromal tumor
  • C trough
  • Regorafenib
  • Therapeutic drug monitoring