Axitinib: Uses, Dosage, Side Effects and Interactions

Axitinib is a targeted oral medication that has transformed the landscape of cancer therapy, particularly for certain advanced cancers. As a potent and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs), axitinib stands out for its ability to halt the growth of blood vessels that feed tumors. In this comprehensive guide, we explore the uses, dosage, potential side effects, and important interactions of axitinib, providing patients and healthcare providers with a clear, evidence-based resource.

Uses of Axitinib

Axitinib’s medical applications are rooted in its unique mechanism of action as a tyrosine kinase inhibitor. This section explores the conditions where axitinib is most effective and the scientific rationale for its use.

Indication	Description	Key Mechanism	Sources
Renal Cell Carcinoma	First- and second-line treatment for advanced/metastatic RCC	Inhibits VEGFR-1, -2, -3	1,4,6,7,8,9,11,12,14
Thyroid Cancer	Advanced, radioiodine-resistant thyroid cancers	Anti-angiogenesis	2
Drug-Resistant Leukemia	BCR-ABL1(T315I) mutant chronic myeloid leukemia	Inhibits mutant ABL1	16
Solid Tumors (Experimental)	Investigational use in other solid tumors	Anti-angiogenesis, Wnt/β-catenin inhibition	1,3,19

Table 1: Clinical and Research Uses of Axitinib

Advanced Renal Cell Carcinoma (RCC)

Axitinib is primarily used for treating advanced or metastatic RCC. It’s approved for use in patients who have failed previous therapies (such as cytokines or other VEGF-targeted treatments) and as a first-line option, often in combination with immune checkpoint inhibitors like pembrolizumab or avelumab 6,7,8,9,11,12,15. Its efficacy in RCC is tied to its ability to block the signals that tumors use to grow blood vessels and evade the immune system 1,4,5.

Advanced Thyroid Cancer

Axitinib has shown compelling efficacy in patients with thyroid cancer that is resistant to radioactive iodine. Clinical trials have demonstrated meaningful response rates and disease stabilization in diverse subtypes of advanced thyroid cancer 2.

Drug-Resistant Leukemia

Recent research has identified axitinib as a potent inhibitor for the T315I mutation in BCR-ABL1, a notorious resistance mutation in chronic myeloid leukemia. This opens new avenues for patients who do not respond to conventional ABL1 kinase inhibitors 16.

Investigational and Experimental Uses

Axitinib is being explored for other solid tumors due to its anti-angiogenic properties and ability to interfere with pathways like Wnt/β-catenin signaling, which are implicated in cancer progression 1,3,19. Its role in enhancing immune responses and reversing tumor-induced immunosuppression is also under study 4,5,19.

Dosage of Axitinib

Getting the dosage right is crucial for maximizing the benefits of axitinib while minimizing risks. Dosage may be individualized based on patient response, tolerability, and the presence of adverse effects.

Dose	Administration	Adjustment Criteria	Sources
5 mg BID	Oral, twice daily	Increase up to 10 mg BID if tolerated, or decrease for toxicity	6,8,10,12,13,14
Combination Use	With checkpoint inhibitors (e.g., pembrolizumab/avelumab)	No initial adjustment; monitor for toxicity	7,9,15
Special Populations	Japanese patients, hepatic/renal impairment	Dose modifications as needed	12,13,14

Table 2: Axitinib Dosing Guidelines

Standard Dose and Titration

• Initial Dose: The typical starting dose is 5 mg taken orally twice daily (BID) 6,8,10,12,13,14.
• Dose Escalation: If tolerated (i.e., no severe side effects, blood pressure controlled), the dose may be increased incrementally to 7 mg and then to a maximum of 10 mg BID 6,10.
• Dose Reduction: For patients experiencing significant side effects—such as hypertension, proteinuria, or fatigue—doses may be reduced in steps below 5 mg BID 6,8,12,14.
• Individualization: Dose adjustments are based on tolerability, blood pressure control, kidney function, and the presence of proteinuria. Pharmacokinetic studies indicate that optimal exposure varies among patients, so clinical judgment is essential 10,12,14.

Combination with Immune Checkpoint Inhibitors

• Axitinib is often combined with pembrolizumab or avelumab for first-line treatment of advanced RCC 7,9,15.
• In these regimens, the axitinib dose remains at 5 mg BID, with close monitoring for overlapping toxicities, particularly gastrointestinal, hepatic, and cardiovascular events 7,9,15.

Special Populations and Considerations

• Japanese Patients: Dose-finding studies in Japanese populations support the standard 5 mg BID dose but highlight a higher risk of hypertension and proteinuria; careful monitoring and dose adjustment are recommended 12,13,14.
• Hepatic/Renal Impairment: Dosage may need to be reduced in patients with impaired kidney or liver function, though specific protocols depend on individual tolerance and lab values 12.

Side Effects of Axitinib

Like all cancer therapies, axitinib is associated with a spectrum of side effects. Understanding the most common and serious adverse events can help patients and clinicians manage them proactively.

Side Effect	Frequency/Severity	Management Strategies	Sources
Hypertension	Very common, can be severe	Antihypertensives, dose adjustment	2,6,8,11,12,13,14,15
Fatigue	Common, sometimes severe	Thyroid monitoring, hormone replacement	8,11,13,14,15
Proteinuria	Common, can require discontinuation	Urine monitoring, dose reduction	12,13,14
Diarrhea	Common	Supportive care, dose reduction	6,8,11,15
Hand-Foot Syndrome	Common	Skin care, dose adjustment	8,12,14
Nausea, Anorexia	Common	Dietary management	11,13,14
Hepatic Toxicity	Occasional, may be severe	Monitor liver enzymes, adjust therapy	7,9,15
Rare: Cardiac, Immune, Endocrine	Rare but serious events possible	Specialist consultation	7,9,15

Table 3: Common and Serious Side Effects of Axitinib

Common Side Effects

• Hypertension: This is the most frequent and potentially severe side effect, requiring regular blood pressure monitoring and sometimes antihypertensive medication 2,6,8,11,12,13,14,15.
• Fatigue and Thyroid Dysfunction: Fatigue is common and often linked to hypothyroidism. Routine thyroid function tests are recommended, and thyroid hormone replacement can mitigate symptoms 8,11,13,14,15.
• Proteinuria: Axitinib can cause protein loss in the urine, sometimes leading to dose reductions or discontinuation. Baseline and ongoing urine protein monitoring are important 12,13,14.
• Gastrointestinal Effects: Diarrhea, nausea, and decreased appetite are frequent but usually manageable with supportive measures or dose changes 6,8,11,13,14,15.
• Dermatologic Effects: Hand-foot syndrome (palmar-plantar erythrodysesthesia) is common and may require topical therapies or dose adjustment 8,12,14.

Less Common and Serious Adverse Events

• Hepatic Toxicity: Elevated liver enzymes and rare severe hepatic events have been reported, especially in combination regimens. Liver function should be checked routinely 7,9,15.
• Cardiovascular and Immune-Related Effects: When used with immune checkpoint inhibitors, distinguishing between axitinib-related and immune-mediated side effects (such as myocarditis) is essential for appropriate management 7,9,15.
• Other Effects: Hoarseness, dyspnea, and rare cases of cardiac events or immune-related sequelae have been described 11,15.

Monitoring and Management

• Most side effects are manageable with dose adjustments, supportive medications, or temporary treatment interruption 6,8,11,12,14,15.
• Preventive monitoring—especially of blood pressure, renal and thyroid function—is critical for minimizing risks and optimizing therapy 12,13,14.

Interactions of Axitinib

Axitinib’s effectiveness and safety can be influenced by its interactions with other drugs and biological systems. Knowing these interactions is vital for minimizing complications.

Interaction Type	Description	Clinical Significance	Sources
Drug-Drug	Potential with P-gp/BCRP inhibitors; protein binding	May alter axitinib plasma levels	17,18
Immunotherapy	Combined with checkpoint inhibitors	Increased efficacy, overlapping toxicity	7,9,15
Food	High-fat meals may alter absorption	Generally advised to take without food	13
Transporters	Weak substrate for P-gp; minimal BCRP	Low risk for interactions, but possible in GI tract	18
Serum Proteins	Binds to human serum albumin (HSA)	May affect distribution and displacement	17

Table 4: Axitinib Drug and Biological Interactions

Drug-Drug Interactions

• Transporter Interactions: Axitinib is a weak substrate for the P-glycoprotein (P-gp) efflux transporter and minimally interacts with breast cancer resistance protein (BCRP). While systemic interactions are unlikely at clinical doses, there is a potential for interactions in the gastrointestinal tract if co-administered with strong P-gp or BCRP inhibitors 18.
• Protein Binding: Axitinib binds moderately strongly to human serum albumin (HSA), which could affect the free (active) concentration of the drug, especially if other highly protein-bound drugs are administered concurrently 17.
• Cytochrome P450 (CYP) Enzymes: Although not detailed in these sources, axitinib is metabolized mainly by CYP3A4. Co-administration with strong CYP3A4 inhibitors or inducers may alter axitinib levels, requiring dose adjustments.

Interactions with Immune Checkpoint Inhibitors

• Enhanced Efficacy and Toxicity: When combined with immune checkpoint inhibitors (pembrolizumab, avelumab), axitinib can enhance anti-tumor immunity, but also increases the risk of side effects such as diarrhea, hepatic toxicity, and fatigue. Careful monitoring and specialized management protocols are required to distinguish and treat overlapping toxicities 7,9,15.

Food and Absorption

• Food Effect: While detailed food effects are not highlighted in these sources, axitinib absorption can be altered by high-fat meals. It is generally recommended to take axitinib consistently with respect to meals 13.

Biological and Experimental Interactions

• Albumin Binding: Axitinib’s binding to serum albumin could theoretically affect its efficacy or side effect profile if patient albumin levels are abnormal or if other protein-bound drugs are used 17.
• Blood-Brain Barrier: Axitinib is largely excluded from the brain, suggesting low risk of central nervous system side effects due to efflux transport at the blood-brain barrier 18.

Conclusion

Axitinib is a powerful targeted therapy with established roles in advanced renal cell carcinoma, radioiodine-resistant thyroid cancer, and investigational uses in other cancers. Its effectiveness is grounded in robust anti-angiogenic and immunomodulatory mechanisms, with dosing tailored to individual tolerance. While side effects are common—especially hypertension, fatigue, and proteinuria—most are manageable with vigilant monitoring and supportive care. Understanding potential drug and biological interactions is crucial, particularly when axitinib is combined with immune checkpoint inhibitors. As research advances, axitinib’s roles and optimal use strategies will continue to evolve, offering new hope for patients with challenging cancers.

Key Points:

• Axitinib is mainly used for advanced RCC, thyroid cancer, and drug-resistant leukemia 1,2,6,8,11,12,16.
• Standard starting dose is 5 mg BID, with adjustments based on tolerance and side effects 6,8,10,12,13,14.
• Common side effects include hypertension, fatigue, proteinuria, diarrhea, and hand-foot syndrome; most are manageable 2,6,8,11,12,13,14,15.
• Drug interactions are generally limited, but care is needed with P-gp/BCRP inhibitors and when combining with immune checkpoint inhibitors 7,9,15,17,18.
• Ongoing research is expanding axitinib’s therapeutic potential and refining its integration into cancer care 1,3,16,19.