Clinical Pharmacology

Mechanism of Action1,2

Regorafenib is a kinase inhibitor that targets pathways involved in tumour Angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, REG, RAF-1, BRAF, BRAFV600E), and the tumour microenvironment (PDGFR, FGFR). In preclinical studies, regorafenib (or its major metabolites M-2 and M-5) had potent, broad-spectrum anti-tumour activity, which included colorectal and gastrointestinal stromal tumour models. Regorafenib also demonstrated anti-metastatic effects in vivo.


Metastatic colorectal cancer previously treated with, or ineligible for, fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy.

Unresectable or metastatic gastrointestinal stromal tumour (GIST) previously treated with imatinib and sunitinib.

Recommended dosage

160 mg orally, once daily for the first 21 days of each 28-day cycle.1,2



Systemic exposure to regorafenib at steady-state increases in proportion to dose up to 60 mg, and is less than dose-proportional (i.e. non-linear) at higher doses. Regorafenib plasma concentrations increase by approximately 2-fold due to accumulation at steady-state. Mean plasma concentrations at steady state exhibit a peak-to-trough ratio of less than 2. The metabolites M-2 and M-5 exhibit non-linear accumulation, but have steady-state plasma concentrations comparable to that of the parent compound.

Absorption and Distribution,1,2

Peak regorafenib plasma levels are reached 3-4 hours after a single oral dose of 160 mg. The mean bioavailability of 60 mg or 100 mg tablets relative to an oral solution is 69-83%.

Regorafenib undergoes enterohepatic circulation, with multiple plasma concentration peaks occurring over the 24-hour dosing interval. Regorafenib is highly bound to human plasma proteins (99.5%), as are the metabolites M-2 and M-5 (99.8% and 99.95%, respectively).

Metabolism and Elimination1,2

Regorafenib is metabolised primarily in the liver by CYP3A4-mediated oxidative metabolism, as well as by glucuronidation mediated by UGT1A9.

Following oral administration, the mean elimination half-lives for regorafenib and M-2 were 20-30 hours in different studies, with M-5 having a longer half-life (approximately 60 hours, range, 40-100 hours).

Approximately 90% of a radioactive oral solution was recovered within 12 days after administration, with 71% of the dose excreted in faeces and around 19% as glucuronides in urine.

Drug Interactions

Please consult the section on drug-drug interactions with regorafenib


  1. European Medicines Agency. Regorafenib (STIVARGA). Summary of Product Characteristics. 2015.
  2. Food and Drug Administration. Regorafenib (STIVARGA) Prescribing information. 2015.

The Summary of Product Characteristics should be reviewed before prescribing any medication.

Last update: 01 July 2015