REGORAFENIB

Clinical safety rating: avoid

Contraindicated (not allowed)

How it works

Regorafenib is a multikinase inhibitor that targets various angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic kinases (KIT, RET, RAF). It inhibits tumor angiogenesis, growth, and metastasis.

What the body does with it

Metabolism	Primarily metabolized by CYP3A4 and UGT1A9.
Excretion	Primarily fecal (approximately 71% of the radiolabeled dose) with renal excretion accounting for 19% (mostly as metabolites). Unchanged regorafenib is minimal in urine.
Half-life	Terminal half-life is 14–28 hours (mean approximately 20 hours), supporting twice-daily dosing with a 3-weeks-on/1-week-off schedule to allow washout and reduce toxicity accumulation.
Protein binding	Highly bound to plasma proteins (>99.5%), primarily to serum albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Large apparent volume of distribution (approximately 43–100 L), indicating extensive tissue distribution and sequestration, likely due to high lipophilicity and protein binding.
Bioavailability	Oral bioavailability is approximately 60–90% (absolute bioavailability not determined in humans due to lack of IV formulation; estimates from animal models and mass balance studies).
Onset of Action	For oral administration: clinical response (e.g., disease stabilization) typically observed after 2–8 weeks of continuous dosing; antiangiogenic effects may begin within days of starting therapy.
Duration of Action	Duration of pharmacodynamic effect (e.g., VEGF inhibition) persists for approximately 2–3 days after the last dose, correlating with the half-life. Clinical benefit (e.g., progression-free survival) requires sustained dosing cycles.

Classification & Brands

Dosing & administration

160 mg orally once daily on days 1-21 of a 28-day cycle until disease progression or unacceptable toxicity.

Dosage form	TABLET
Renal impairment	No dose adjustment required for mild to moderate renal impairment (CrCl >=30 mL/min). Not studied in severe renal impairment (CrCl <30 mL/min).
Liver impairment	Child-Pugh A: No dose adjustment. Child-Pugh B: Reduce initial dose to 80 mg once daily. Child-Pugh C: Not recommended.
Pediatric use	Safety and effectiveness not established in pediatric patients.
Geriatric use	No specific dose adjustment recommended; monitor for increased toxicity in patients >65 years.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause severe hepatotoxicity and hemorrhage.

Breastfeeding	No human data on regorafenib excretion in breast milk. M/P ratio unknown. Based on molecular weight and high protein binding, excretion is likely low but potential for infant harm exists. Discontinue breastfeeding during treatment and for at least 2 weeks after last dose.
Teratogenic Risk	Regorafenib is embryotoxic and teratogenic in animal studies. First trimester: High risk of major congenital malformations based on animal data and its antiangiogenic mechanism. Second and third trimesters: Risk of fetal growth restriction, oligohydramnios, and fetal renal impairment due to VEGF inhibition. Avoid in pregnancy unless no alternative.

Warnings & precautions

■ FDA Black Box Warning

Severe and sometimes fatal hepatotoxicity has occurred. Monitor liver function tests before and during treatment. Interrupt and reduce dose as appropriate.

Side Effect Profile

Common Effects	GIST
Serious Effects

Absolute Contraindications

["Hypersensitivity to regorafenib or any excipient"]

Clinical Precautions

Precautions

["Hepatotoxicity: Severe and fatal liver injury; monitor LFTs.","Hemorrhage: Serious bleeding events; monitor for bleeding.","Cardiac ischemia/infarction: Increased incidence; monitor for cardiac symptoms.","Gastrointestinal perforation or fistula: Discontinue if occurs.","Dermatological toxicity: Hand-foot skin reaction and severe rash; manage with dose modification.","Hypertension: Monitor blood pressure; treat as needed.","Wound healing complications: Withhold for at least 2 weeks before elective surgery.","Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue if diagnosed."]

Clinical Tips & Counseling

Drug interactions

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