Binefaros Mechanism of Action

Pharmacotherapeutic group: Antineoplastic agent, Protein kinase inhibitor.
Pharmacology: Pharmacodynamics: Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib inhibits tumor growth of a broad spectrum of human tumor xenografts in athymic mice accompanied by a reduction of tumor angiogenesis. Sorafenib inhibits the activity of targets present in the tumor cell (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumor vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-β). RAF kinases are serine/threonine kinases, whereas c-KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-β are receptor tyrosine kinases.
Pharmacokinetics: Absorption and distribution: After administration of sorafenib tablets, the mean relative bioavailability is 38-49% when compared to an oral solution. The absolute bioavailability is not known. Following oral administration sorafenib reaches peak plasma concentrations in approximately 3 hours. When given with a high-fat meal sorafenib absorption was reduced by 30% compared to administration in the fasted state.
Mean C_max and AUC increased less than proportionally beyond doses of 400 mg administered twice daily. In vitro binding of sorafenib to human plasma proteins is 99.5%.
Multiple dosing of sorafenib for 7 days resulted in a 2.5- to 7-fold accumulation compared to single-dose administration. Steady-state plasma sorafenib concentrations are achieved within 7 days, with a peak-to-trough ratio of mean concentrations of less than 2.
The steady-state concentrations of sorafenib administered at 400 mg twice daily were evaluated in DTC, RCC, and HCC patients. The highest mean concentration was observed in DTC patients (approximately twice that observed in patients with RCC and HCC), though variability was high for all tumor types. The reason for the increased concentration in DTC patients is unknown.
Biotransformation and elimination: The elimination half-life of sorafenib is approximately 25-48 hours. Sorafenib is metabolized primarily in the liver and undergoes oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib conjugates may be cleaved in the gastrointestinal tract by bacterial glucuronidase activity, allowing the reabsorption of unconjugated active substances. Coadministration of neomycin has been shown to interfere with this process, decreasing the mean bioavailability of sorafenib by 54%.
Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady state.
Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in feces but not in urine, indicating that biliary excretion of unchanged active substance might contribute to the elimination of sorafenib.
Pharmacokinetics in Special Populations: Analyses of demographic data suggest that there is no relationship between pharmacokinetics and age (up to 65 years), gender, or body weight.
Pediatric population: No studies have been conducted to investigate the pharmacokinetics of sorafenib in pediatric patients.
Race: There are no clinically relevant differences in pharmacokinetics between Caucasian and Asian subjects.
Renal impairment: In four Phase I clinical trials, steady-state exposure to sorafenib was similar in patients with mild or moderate renal impairment compared to the exposures in patients with normal renal function. In a clinical pharmacology study (single dose of 400 mg sorafenib), no relationship was observed between sorafenib exposure and renal function in subjects with normal renal function, mild, moderate, or severe renal impairment. No data is available on patients requiring dialysis.
Hepatic impairment: In hepatocellular carcinoma (HCC) patients with Child-Pugh A or B (mild to moderate) hepatic impairment, exposure values were comparable and within the range observed in patients without hepatic impairment. The pharmacokinetics (PK) of sorafenib in Child-Pugh A and B non-HCC patients were similar to the PK in healthy volunteers. There are no data for patients with Child-Pugh C (severe) hepatic impairment. Sorafenib is mainly eliminated via the liver, and exposure might be increased in this patient population.