Regorafenib

BRAND NAMES

Primary brand name

Stivarga: This is the most widely recognized brand name for regorafenib and is approved by the FDA. 

Other brand names

Regonat: A brand name found in some markets, manufactured by companies like Natco Pharma.

Nublexa: Another brand name for the medication.

Regdual: A brand name available from Intas Pharmaceuticals.

Regonix: A brand name used in countries like Bangladesh.

Resihance: Also listed as a brand name for regorafenib.

Rezitix: Also listed as a brand name for regorafenib. 

MECHANISM OF ACTION

Regorafenib is a multikinase inhibitor that targets and blocks several tyrosine kinases involved in key processes such as angiogenesis (formation of new blood vessels), oncogenesis (tumor growth), and the maintenance of the tumor microenvironment. By inhibiting kinases including VEGFR, KIT, and RET, regorafenib suppresses tumor cell proliferation, angiogenesis, and metastatic spread, thereby limiting cancer progression.

PHARMACOKINETICS

Absorption

Regorafenib is well absorbed orally, with an absolute bioavailability of about 69–83% when taken by mouth. Its absorption is influenced by food; taking it with a low-fat meal increases bioavailability, whereas a high-fat meal can significantly alter its pharmacokinetics. The time to reach peak plasma concentration (Tmax) is typically around 3 to 4 hours after oral administration. Because of its variable absorption with food, it is generally recommended to take regorafenib after a low-fat meal to ensure consistent drug levels.

Distribution

Regorafenib has a volume of distribution of 88 L, indicating that it is widely distributed throughout body tissues rather than confined to the bloodstream. Additionally, the drug is highly protein-bound, with approximately 99.5% binding to plasma proteins.

Metabolism 

Regorafenib is primarily metabolized in the liver via the cytochrome P450 enzyme CYP3A4 and through glucuronidation by UGT1A9. Its metabolism produces two major active metabolites, M-2 (N-oxide) and M-5 (N-oxide/N-desmethyl), which contribute significantly to its pharmacologic activity. The drug undergoes extensive hepatic processing, and these metabolites have similar kinase inhibitory profiles to the parent compound, prolonging the overall therapeutic effect of regorafenib.

Excretion

Regorafenib is primarily excreted in the feces (about 71%), with a smaller amount eliminated in the urine (about 19%). 

PHARMACODYNAMICS

Regorafenib’s pharmacodynamic effects stem from its role as a multikinase inhibitor, targeting multiple receptors and intracellular kinases involved in angiogenesis, tumor growth, and the tumor microenvironment. By blocking these pathways, regorafenib produces anti-angiogenic and anti-proliferative effects, limiting tumor cell proliferation, survival, and the formation of new blood vessels. Its primary targets include VEGFR, TIE2, KIT, RET, PDGFR, and RAF, among others.

DOSAGE AND ADMINISTRATION

Recommended Dose:

• The standard adult dose is 160 mg orally once daily for 3 weeks followed by 1 week off (28-day cycle).

Administration:

• Take whole tablets with a low-fat meal (no more than 30% of calories from fat) to improve absorption and reduce variability.

• Swallow tablets whole, without crushing or chewing.

• Maintain a consistent schedule to ensure steady drug levels.

Dose Adjustments:

• Dose modifications may be required for toxicity, hepatic impairment, or adverse events such as hand-foot skin reaction, hypertension, or diarrhea.

• Interrupt or reduce the dose according to clinical guidelines if severe adverse effects occur.

DRUG INTERACTIONS

Regorafenib has multiple drug interactions, some of which can be significant. Medications such as apalutamide, efavirenz, itraconazole, and ketoconazole may reduce regorafenib levels, while drugs like alpelisib, ceritinib, and fexinidazole can increase its effects or plasma concentrations. Patients are also advised to avoid grapefruit and St. John’s wort during treatment. It is essential to consult a healthcare provider before starting or discontinuing any medication while taking regorafenib.

FOOD INTERACTIONS

Regorafenib’s absorption is affected by dietary fat content. Taking the drug with a high-fat meal can significantly increase its bioavailability, potentially raising the risk of adverse effects, while a fasted state or low-fat meal leads to more predictable absorption. To ensure consistent drug levels and reduce variability, it is recommended to take regorafenib with a low-fat meal (≤30% of calories from fat) and to avoid sudden changes in diet during treatment.

CONTRAINDICATIONS

Regorafenib is contraindicated in individuals with a known hypersensitivity to the drug or any of its ingredients. Furthermore, due to its mechanism of action and evidence from animal studies, it should not be used during pregnancy or breastfeeding, as it may cause fetal harm and adverse effects in nursing infants.

SIDE EFFECTS

• Asthenia/Fatigue (weakness)

• Hand-foot skin reaction (HFSR) (redness, pain, blistering, or peeling on palms and soles)

• Diarrhea

• Decreased appetite and food intake

• Hypertension (high blood pressure)

• Infection

• Mucositis/Stomatitis (mouth sores or inflammation)

• Weight loss

• Pain (including gastrointestinal and abdominal pain)

• Dysphonia (changes in voice volume or quality) 

OVERDOSE

• Dermatological events.

• Gastrointestinal issues.

• Cardiovascular issues.

• Liver damage.

• Bleeding.

• Neurological symptoms.

TOXICITY

Regorafenib has a narrow therapeutic window, and its toxicity mainly arises from its multikinase inhibitory effects. Common adverse effects include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain, as well as hepatic toxicity with elevated liver enzymes and, in rare cases, liver failure. Patients may also experience dermatologic reactions like hand-foot skin reaction, rash, and hair loss, along with cardiovascular effects such as hypertension and, rarely, cardiac ischemia or thromboembolic events. Mild hematologic abnormalities like anemia or thrombocytopenia can occur. Severe or life-threatening toxicity is uncommon but may develop in cases of overdose or in patients with hepatic impairment, making careful monitoring of liver function, blood pressure, and overall clinical status essential during therapy.