NEXAVAR, a multikinase inhibitor targeting several serine/threonine and receptor tyrosine kinases, is the tosylate salt of sorafenib.

Sorafenib tosylate has the chemical name 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl] ureido}phenoxy)-N ²-methylpyridine-2-carboxamide 4-methylbenzenesulfonate and its structural formula is:

Sorafenib tosylate is a white to yellowish or brownish solid with a molecular formula of C₂₁H₁₆ClF₃N₄O₃ x C₇H₈O₃S and a molecular weight of 637.0 g/mole. Sorafenib tosylate is practically insoluble in aqueous media, slightly soluble in ethanol and soluble in PEG 400.

Each red, round NEXAVAR film-coated tablet contains sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib and the following inactive ingredients:

croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl sulphate, magnesium stearate, polyethylene glycol, titanium dioxide and ferric oxide red.

Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib inhibited tumor growth of the murine renal cell carcinoma, RENCA, and several other human tumor xenografts in athymic mice. A reduction in tumor angiogenesis was seen in some tumor xenograft models. Sorafenib was shown to interact with multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT- 3, VEGFR- 2, VEGFR- 3, and PDGFR- β). Several of these kinases are thought to be involved in angiogenesis.

After administration of NEXAVAR tablets, the mean relative bioavailability is 38-49% when compared to an oral solution. The mean elimination half-life of sorafenib is approximately 25-48 hours. Multiple dosing of NEXAVAR 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.

Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a moderate-fat meal, bioavailability was similar to that in the fasted state. With a high-fat meal, sorafenib bioavailability was reduced by 29% compared to administration in the fasted state. It is recommended that NEXAVAR be administered without food (at least 1 hour before or 2 hours after eating) (see DOSAGE AND ADMINISTRATION section).

Mean C_max and AUC increased less than proportionally beyond doses of 400 mg administered orally twice daily.

In vitro binding of sorafenib to human plasma proteins is 99.5%.

Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9.

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.

Analyses of demographic data suggest that no dose adjustments are necessary for age or gender.

Limited pharmacokinetic data on sorafenib 400 mg twice daily in a study in Japanese patients (n=6) showed a 45% lower systemic exposure (mean steady-state AUC) as compared to pooled Phase 1 pharmacokinetic data in Caucasian patients (n=25). The clinical significance of this finding is not known (see PRECAUTIONS – General - Race).

There are no pharmacokinetic data in pediatric patients.

Sorafenib is cleared primarily by the liver.

In patients with mild (Child-Pugh A, n=14) or moderate (Child-Pugh B, n=8) hepatic impairment, exposure values were within the range observed in patients without hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment (See PRECAUTIONS – Patients with Hepatic Impairment section).

In a study of drug disposition after a single oral dose of radiolabeled sorafenib to healthy subjects, 19% of the administered dose of sorafenib was excreted in urine.

In four Phase 1 clinical trials, sorafenib was eva luated in patients with normal renal function (n=71) and in patients with mild renal impairment (CrCl >50–80 mL/min, n=24) or moderate renal impairment (CrCl 30–50 mL/min, n=4). No relationship was observed between renal function and steady-state sorafenib AUC at doses of 400 mg twice daily. The pharmacokinetics of sorafenib have not been studied in patients with severe renal impairment (CrCl <30 ml/min) or in patients undergoing dialysis (see PRECAUTIONS – Patients with Renal Impairment section).

CYP3A4 inhibitors:In vitro data indicate that sorafenib is metabolized by CYP3A4 and UGT1A9 pathways. Ketoconazole (400 mg), a potent inhibitor of CYP3A4, administered once daily for 7 days did not alter the mean AUC of a single oral 50 mg dose of sorafenib in healthy volunteers. Therefore, sorafenib metabolism is unlikely to be altered by CYP3A4 inhibitors.

CYP isoform-selective substrates: Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C19, CYP2D6, and CYP3A4 as indicated by K_i values of 17 μM, 22 μM, and 29 μM, respectively. Administration of NEXAVAR 400 mg twice daily for 28 days did not alter the exposure of concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), and omeprazole (CYP2C19 substrate). This indicates that sorafenib is unlikely to alter the metabolism of substrates of these enzymes in vivo.

CYP2C9 substrates: Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C9 with a K_i value of 7-8 μM. The possible effect of sorafenib on the metabolism of the CYP2C9 substrate warfarin was assessed indirectly by measuring PT-INR. The mean changes from baseline in PT-INR were not higher in NEXAVAR patients compared to placebo patients, suggesting that sorafenib did not inhibit warfarin metabolism in vivo (see PRECAUTIONS –Warfarin Co-administration section).

CYP3A4 inducers: There is no clinical information on the effect of CYP3A4 inducers on the pharmacokinetics of sorafenib. Substances that are inducers of CYP3A4 activity (e.g. rifampin, St. John's wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) are expected to increase metabolism of sorafenib and thus decrease sorafenib concentrations.

Combination with other antineoplastic agents: In clinical studies, NEXAVAR has been administered with a variety of other antineoplastic agents at their commonly used dosing regimens, including gemcitabine, oxaliplatin, doxorubicin, and irinotecan. Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin. Concomitant treatment with NEXAVAR resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT1A1 pathway, there was a 67-120% increase in the AUC of SN-38 and a 26-42% increase in the AUC of irinotecan. The clinical significance of these findings is unknown (see PRECAUTIONS – Drug Interactions section).

In vitro studies of enzyme inhibition: Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with K_i values of 6 and 1-2 μM, respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 is expected to increase when co-administered with NEXAVAR.

Sorafenib inhibits glucuronidation by the UGT1A1 (K_i value: 1 μM) and UGT1A9 pathways (K_i value: 2 μM). Systemic exposure to substrates of UGT1A1 and UGT1A9 may increase when co-administered with NEXAVAR.

In vitro studies of CYP enzyme induction: CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 or CYP3A4.