Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers

Cancer Chemother Pharmacol. 2021 Jun;87(6):767-777. doi: 10.1007/s00280-021-04237-x. Epub 2021 Feb 26.


Purpose: The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (Ctrough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer.

Methods: The Ctrough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5.

Results: We analyzed 43 patients who received regorafenib 40-120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the Ctrough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 Ctrough levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 Ctrough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035).

Conclusion: This study showed that the Ctrough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the Ctrough of M5 was significantly correlated with hypertension and severe rash.

Keywords: Adverse events; Pharmacokinetics; Polymorphisms; Regorafenib.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics*
  • Adult
  • Aged
  • Aged, 80 and over
  • Colorectal Neoplasms / blood
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Phenylurea Compounds / adverse effects
  • Phenylurea Compounds / blood*
  • Phenylurea Compounds / pharmacokinetics
  • Phenylurea Compounds / therapeutic use
  • Polymorphism, Genetic / genetics*
  • Prospective Studies
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / blood
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridines / adverse effects
  • Pyridines / blood*
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Neoplasm Proteins
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • regorafenib