regorafenib

Action and Spectrum

Actions and Spectrum: 

Actions: 

• Inhibition of angiogenesis: regorafenib inhibits the vascular endothelial growth factor receptor (VEGFR) 1-3, platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), which are involved in angiogenesis. It reduces blood supply to tumors, leading to cell death. 
• Inhibition of tumor cell proliferation: regorafenib inhibits the receptor tyrosine kinases (RTKs) KIT and RET, which are involved in the growth and proliferation of cancer cells. It leads to a reduction in tumor cell growth and division. 
• Induction of tumor cell death: regorafenib induces apoptosis (cell death) in cancer cells by inhibiting the RTKs BRAF and RAF-1, which are involved in the MAPK/ERK signaling pathway. This leads to the activation of caspases and the cleavage of poly (ADP-ribose) polymerase (PARP), ultimately resulting in cancer cell death. 

Spectrum: 

• Colorectal cancer: regorafenib is indicated for the treatment of metastatic colorectal cancer (mCRC) that has progressed after standard therapies. 
• Gastrointestinal stromal tumors: regorafenib is indicated for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST) that have progressed after imatinib and sunitinib therapy. 
• Hepatocellular carcinoma: regorafenib is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 

Drug Interaction

Adverse Reaction

Frequency defined:  

>10% 

HFSR/PPES  

Pain  

Hypertension  

Proteinuria  

Increased AST  

Hypophosphatemia  

Asthenia  

Diarrhea  

Mucositis  

Dysphonia  

Increased ALT  

Hyperbilirubinemia  

Infection  

Decreased appetite  

Rash  

Lymphopenia  

Alopecia  

Fever  

HFSR/PPES 

Hypokalemia  

Nausea  

Hypophosphatemia 

Hypothyroidism  

Vomiting  

Hypocalcemia  

Headache  

Neutropenia  

Weight loss  

Increased lipase  

Muscle spasms  

Thrombocytopenia  

Hemorrhage  

1-10% 

Lymphopenia 

Pain  

Diarrhea 

Rash 

Infection 

Asthenia/fatigue 

Hemorrhage 

Increased AST/ALT 

Hyperbilirubinemia 

Proteinuria 

Hypokalemia 

Neutropenia 

Mucositis 

Nausea 

Hypocalcemia 

Thrombocytopenia 

Black Box Warning

Black-Box Warning: 

Hepatotoxicity: 

Fatal hepatotoxicity is observed in the clinical trials 

Monitor the hepatic functionality before and during the treatment 

Interrupt/reduce or discontinue the dosing in case of severe hepatocellular necrosis 

Contraindication / Caution

Contraindication/Caution: 

Contraindications: 

• Hypersensitivity or allergy to regorafenib or any of its components 
• Pregnancy or breastfeeding 

Cautions: 

• Liver impairment or liver disease 
• Kidney impairment or kidney disease 
• History of bleeding disorders or taking anticoagulant medications 
• Cardiac disease, including heart failure or myocardial infarction (heart attack) 
• Hypertension (high blood pressure) 
• Gastrointestinal perforation (a hole in the stomach or intestine) 
• Wound healing complications 
• History of radiation therapy 
• Concurrent use of other medications, especially those that may increase the risk of bleeding, including nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or warfarin 
• Use with caution in elderly patients, as they may be more susceptible to side effects 

Pregnancy / Lactation

Pregnancy consideration: The drug is toxic and unsafe for pregnant women and the developing fetus.  

Breastfeeding warnings: No data on the excretion of regorafenib in breast milk is available. Because of possible serious effects, women are advised to breastfeed two weeks after the last dose of regorafenib. 

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no affirmation of risk to the fetus found in animal reproduction studies, and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for a product in humans; Pregnant women must take care of the potential risks. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms. However, despite potential dangers may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits. The drug is not for pregnant women. 
• Category N: No data is available for the drug under this category. 

Pharmacology

Pharmacology: 

regorafenib is an oral multi-kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) for treating metastatic colorectal cancer and advanced gastrointestinal stromal tumors (GISTs) that are resistant to imatinib and sunitinib. 

regorafenib works by inhibiting multiple kinases, including vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), and fibroblast growth factor receptors (FGFRs). By blocking these signaling pathways, regorafenib inhibits angiogenesis and tumor growth. 

Pharmacodynamics: 

The pharmacodynamics of regorafenib involves its effects on various molecular targets, signaling pathways, and cellular processes. regorafenib is a multi-kinase inhibitor that targets multiple kinases, including vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptors (FGFRs), and RET, KIT, RAF, and BRAF kinases. 

Pharmacokinetics: 

Absorption 

The bioavailability is 69-83% (in the case of low-fat meals) 

The peak plasma concentration is achieved in 4 hours 

Peak Plasma Concentration is 2.5 mcg/mL (for a single dose) and 3.9 mcg/mL (for steady-state) 

The area under the curve is 70.4 mcg•h/mL (for single dose) and 58.3 mcg•h/mL (for steady state) 

Distribution 

Protein Bound is 99.5% (for regorafenib) and 99.8% (for M-2 active metabolite), and 99.95% (for M-5 active metabolite) 

Metabolism 

The drug is metabolized by UGT1A9 and CYP3A4  

Elimination and Excretion 

The half-life is 28 hours (for regorafenib) and 25 hours (for M-2 active metabolite) and 51 hours (for M-5 active metabolite) 

The drug is excreted 71% in feces and 9% in urine (within 12 days of single dose) 

Adminstartion

Administration: 

regorafenib is available in tablet form for oral administration. The recommended dose of regorafenib is usually 160 mg once daily for three weeks, followed by a one-week break before starting a new cycle. The tablets should be taken simultaneously every day, with or without food. It is essential to take regorafenib precisely as prescribed by a healthcare provider.

The tablets should be swallowed whole with water and not crushed, chewed, or broken. If a dose of regorafenib is missed, it should be taken as soon as possible on the same day, and the next dose should be taken at the regularly scheduled time. However, if a dose is missed for an entire day, it should be skipped, and the next dose should be taken at the regularly scheduled time. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: regorafenib (Rx) 

Pronounced: re-goe-RAF-e-nib 

Why do we use regorafenib? 

regorafenib is used to treat several types of cancer, including colorectal cancer, gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma (HCC). It is used when cancer has progressed or has not responded to other treatments. 

It is also an important treatment option for advanced or metastatic cancers that have not responded to other therapies. It has been shown to improve overall and progression-free survival in patients with these types of cancers.