Sunitinib

Sunitinib is the backbone of an antitumor drug sold under the brand name Sutent by the pharmaceutical company Pfizer, Inc. (USA) and intended for oral administration. Dosage form - gelatin capsules; Sunitinib malate acts as an active substance ^[6] .

Mechanism of Action

The main target of sunitinib are platelet growth factor α- and β-receptors ( PDGFR ) ^[4] . In addition, it inhibits:

• vascular endothelial growth factor receptors ( VEGFR-1 , VEGFR-2 and VEGFR-3 );
• stem cell receptors ( KIT );
• receptors for Fms-like tyrosine kinase-3 ( FLT-3 );
• colony stimulating factor receptors ( CSF-1R );
• receptors for neurotrophic glial factor ( RET ).

Pharmacokinetics

Sunitinib is used orally in the form of malate , in gelatin capsules, regardless of food intake ^[7] . After taking the drug, the maximum concentration of sunitinib in blood plasma is reached approximately 6-12 hours after administration; food intake does not affect the bioavailability of sunitinib. Equilibrium concentrations of sunitinib and its main metabolite in blood plasma are reached 10-14 days after the start of the drug. The connection of sunitinib and its metabolite with plasma proteins is 95 and 90%, respectively ^[8] .

Sunitinib metabolism occurs mainly in the liver - due to oxidation mediated by the CYP3A4 isoenzyme , resulting in the formation of the main active metabolite (which is further metabolized by the same CYP3A4 isoenzyme ). The activity of the main metabolite is similar to the activity of sunitinib itself. The fraction of the active metabolite circulating in plasma is 23–37% of the area under the concentration-time curve ^[9] .

Sunitinib has a half-life of 40-60 hours, its main active metabolite is 80-110 hours; it is excreted mainly with feces (60%) ^{[9] [7]} .

Indications

Sunitinib is indicated at ^[10] :

• widespread and (or) metastatic renal cell carcinoma (including in the absence of the effect of cytokine therapy);
• gastrointestinal stromal tumors in the absence of the effect of imatinib therapy;
• unresectable or metastatic neuroendocrine tumors of the pancreas ^[11] .

Side Effects

The following is a list (incomplete) of the main adverse events identified with sunitib ^[12] . Depending on their nature and severity, the attending physician makes a decision: to continue treatment with this drug using a standard or reduced dosage (and using, if necessary, local symptomatic therapy); on the suspension of the drug for 7 or more days; on discontinuation of sunitinib therapy.

Contraindications

The main contraindication is hypersensitivity to sunitinib. The drug should not be used by pregnant women, since the drug is potentially dangerous for the fetus, having teratogenic effects and embryotoxicity (in animal experiments, the ability of sunitinib to cause malformations was revealed). The efficacy and safety of the drug for children and nursing mothers have not been established. Caution should be exercised in patients with arterial hypertension , skin diseases, a history of bleeding, heart disease, and renal or hepatic insufficiency ^[9] .

Drug Interactions

It is recommended to avoid concomitant use of the drug with potential inhibitors of the CYP3A4 isoenzyme ( ketoconazole , ritonavir , itraconazole , erythromycin , clarithromycin , grapefruit juice), which can increase the concentration of sunitinib in blood plasma ; if this cannot be done, a reduction in the daily dose may be required. It is also recommended to avoid concomitant use with potential inducers of the CYP3A4 isoenzyme ( rifampicin , dexamethasone , phenytoin , carbamazepine , phenobarbital , St. John's wort perforated ), which can lower the concentration of sunitinib in blood plasma ; if this cannot be done, a phased increase in the daily dose may be required with careful monitoring of its tolerability ^[13] .

Sunitinib has proven itself - along with sorafenib - as one of the most promising targeted therapies for renal cell carcinoma . The effectiveness of this drug was studied, in particular, in two phase II studies, respectively, in 63 and 105 patients with metastatic kidney cancer who had not received a positive effect from cytokine therapy before. The frequency of partial regressions in these studies was 40–43%, and stabilization for more than 3 months was 22–27%. In phase III studies, it was shown that the use of sunitinib led to a longer, disease-free survival of patients than interferon-alpha therapy ^[14] .

Sunitinib toxicity is considered to be moderate; at the same time, the question of the prevention and effective treatment of toxic manifestations during therapy with this drug is very acute, because (unlike routine therapy with cytostatic drugs , which is carried out in limited periods of time), treatment with sunitinib (and other tyrosine kinase inhibitors) is continuous and prolonged and sometimes lasts several years. Under these conditions, it is very important for the doctor to know the side effects of using sunitinib, the methods of their prevention and treatment, the possibilities of changing the dose and the regimen of the drug, which minimizes the need for forced interruptions of targeted therapy (fraught with rapid progression of the disease) ^[15] .

• Alekseev B. Ya., Shegay P.V. Targeted therapy of advanced kidney cancer // Oncourology. - 2007. - No. 4 . - S. 6-11 .
• Alekseev B. Ya., Kalpinsky A. S. Targeted therapy of common kidney cancer Sutent®: side effects and their correction // Oncourology. - 2008. - No. 3 . - S. 31-38 . Archived July 20, 2012.
• Oncourology. Pharmacotherapy without errors / Ed. I. G. Rusakova, V. I. Borisova. - M .: E-noto, 2014 .-- 544 p. - ISBN 978-5-906023-07-0 .

• Sunitinib (neopr.) . From the drug database . Clifar . Archived on September 2, 2013.
• Sutent Patient Handbook Pfizer, Inc. (2012). Archived on September 2, 2013.
• Sutent (neopr.) . Description of the drug . Reference "Vidal". Archived on September 2, 2013.