The mechanism of action and therapeutic effect of axitinib/axitinib

Axitinib/Axitinib is a targeted drug specifically for advanced renal cell carcinoma (RCC). It is widely used in patients who have not yet received systemic treatment or have poor results in other treatment options. Its efficacy mainly comes from its unique pharmacological mechanism. By effectively inhibiting the activity of growth factor receptors, it controls the proliferation of cancer cells and inhibits angiogenesis, and has a good control effect on tumor growth and metastasis.

Axitinib can specifically inhibit a variety of receptors related to tumor growth, especially vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3. These receptors play critical roles in pathological angiogenesis and tumor progression. Multiple in vitro and animal experimental studies have shown that axitinib can effectively inhibit the proliferation and survival of endothelial cells triggered by VEGF. In tumor xenograft mouse models, axitinib showed significant inhibitory effects on tumor growth and effectively prevented VEGFR-2 phosphorylation.

In terms of pharmacokinetics, the effective plasma half-life of axitinib is relatively short, typically 2.5 to 6.1 hours. The drug is rapidly absorbed after oral administration, typically reaching maximum plasma concentration (Cmax) within 4 hours, and its mean absolute bioavailability is 58%. For patients with advanced renal cell carcinoma, in a 5 mg twice daily dosing regimen, the geometric mean Cmax of the drug was 27.8 ng/mL, and the area under the plasma concentration-time curve (AUC24) was 265 ng·h/mL. In addition, the binding rate of axitinib to human plasma proteins in the body exceeds 99%, mainly to albumin, and also to α1-acid glycoprotein to a certain extent.

The metabolism of axitinib mainly occurs in the liver and is mainly dependent on cytochromeP450 (CYP) 3A4/5. It also involves CYP1A2, CYP2C19 and uridine diphosphate glucuronosyltransferase (UGT) 1A1. Its main metabolites, M12 and M7, are considered to lack pharmacological activity. The excretion of axitinib is primarily via the liver and gallbladder, with relatively small amounts excreted in the urine. Studies have shown that mild hepatic impairment does not significantly affect axitinib plasma concentrations, but patients with moderate hepatic impairment may have a double AUC (from time to infinity) after taking a 5 mg dose.

Regarding drug interactions, when axitinib is used with potentiolWhen CYP3A4/5 inhibitors (such as ketoconazole) are used together, their Cmax and AUC may increase by 1.5-fold and 2-fold respectively; while when used together with strong CYP3A4/5 inducers (such as rifampicin), their Cmax and AUC may decrease by 71% and 79%. It is worth noting that at normal clinical doses, axitinib does not significantly inhibit multiple CYP enzymes, including CYP3A4/5, CYP1A2, CYP2C8, etc., so no significant interactions with other drugs metabolized by these enzymes are expected.

Reference materials:https://pubmed.ncbi.nlm.nih.gov/23677771/