Protein kinase inhibitors.
Sorafenib is a multikinase inhibitor which has demonstrated both anti-proliferative and anti-angiogenic properties in vitro and in vivo.
Mechanism of Action and Pharmacodynamic effects:
Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation in vitro.
Sorafenib inhibits tumor growth 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.
The clinical safety and efficacy of Nexavar have been studied in patients with hepatocellular carcinoma (HCC) and in patients with advanced renal cell carcinoma (RCC).
Hepatocellular Carcinoma: Study 3 (study 100554) was a Phase III, international, multi centre, randomized, double blind, placebo controlled study in 602 patients with hepatocellular carcinoma. Demographics and baseline disease characteristics were comparable between the Nexavar and the placebo group with regard to ECOG status (status 0: 54% vs. 54%; status 1: 38% vs. 39%; status 2: 8% vs. 7%), TNM stage (stage 1: <1% vs. <1%; stage II: 10.4% vs. 8.3%; stage III: 37.8% vs. 43.6%; stage IV: 50.8% vs. 46.9%), and BCLC stage (stage B: 18.1% vs. 16.8%; stage C: 81.6% vs. 83.2%; stage D: <1% vs. 0%).
The study was stopped after a planned interim analysis of OS had crossed the prespecified efficacy boundary. This OS analysis showed a statistically significant advantage for Nexavar over placebo for OS (HR: 0.69, P = 0.00058, See Table 1). In the prespecified stratification factors (ECOG status, presence or absence of macroscopic vascular invasion and/or extrahepatic tumor spread) the hazard ratio consistently favoured Nexavar over placebo. The descriptive subgroup analysis suggested a potentially less pronounced treatment effect for the subgroups of patients below 65 years of age and those with metastatic disease. There are limited data from this study in patients with Child Pugh B liver impairment and only one patient with Child Pugh C had been included. (See Table 1.)
Click on icon to see table/diagram/image
Renal Cell Carcinoma: The safety and efficacy of Nexavar in the treatment of advanced renal cell carcinoma (RCC) were investigated in two clinical studies: Study 1 was a Phase III, international, multi-centre, randomized, double blind, placebo-controlled study in 903 patients. Primary study endpoints included overall survival and progression-free survival (PFS). Tumor response rate was a secondary endpoint.
Patients were randomized to Nexavar 400 mg twice daily (N=451) or to placebo (N=452). Baseline demographics and patient characteristics were well balanced for both treatment groups. Approximately half of the patients had an ECOG performance Status of 0, and half of the patients were in the low MSKCC (Memorial Sloan Kettering Cancer Center) prognostic group.
In a planned interim analysis of survival based on 220 deaths, there was an estimated 39% improvement in overall survival for patients receiving Nexavar vs. placebo. The estimated hazard ratio (risk of death With Nexavar compared to placebo) was 0.72 (95% CI, 0.55-0.95; p=0.018. The threshold for statistical significance of the interim analysis was p<0.0005).
The PFS analysis included 769 patients randomised to Nexavar 400 mg twice daily (N=384) or to placebo (N=385). PFS was evaluated by blinded independent radiological review using RECIST criteria. The median PFS was double for patients randomized to Nexavar (167 days) compared to placebo patients (84 days) (HR=0.44; 95% CI: 0.35-0.55; p<0.000001).
The effect on PFS was also explored across different patient subsets. The subsets included age above or below 65 years, ECOG PS 0 or 1, MSKCC prognostic risk category 1, whether the prior therapy was for progressive metastatic disease or for an earlier disease setting, and time from diagnosis of less than or greater than 1.5 years. The effect of Nexavar on PFS was consistent across these subsets, including patients with no prior IL-2 or interferon therapy (n=137; 65 patients receiving Nexavar and 72 placebo), for whom the median PFS was 172 days on Nexavar compared to 85 days on placebo.
Best overall tumor response was determined by investigator radiological review according to RECIST criteria. In the Nexavar group 1 patient (0.2%) had a complete response, 43 patients (9.5%) had a partial response, and 333 patients (73.8%) had stable disease. In the placebo group O patients (0%) had complete response, 8 patients (1.8%) had partial response, and 239 patients (52.9%) had stable disease.
Nexavar demonstrated no overall deterioration in kidney-cancer specific symptoms (FKSI-10) or health-related quality of life compared to placebo. At 18 and 24 weeks of treatment, more patients receiving Nexavar reported improvement in total FKSI-10 score (55 and 44%, respectively) and the physical well-being (FACT-G PWB) score (57 and 47%, respectively) versus placebo (FKSI-10, 33 and 21% and FACT-G PWB 37 and 21%, respectively).
Study 2 was a Phase II randomized discontinuation trial in patients with metastatic malignancies, including RCC. The primary endpoint of the study was the percentage of randomized patients (N=65) remaining progression-free at 24 weeks. Progression-free survival was significantly longer in the Nexavar group (163 days) than in the placebo group (41 days) (p=0.0001, HR=0.29). The progression-free rate was significantly higher in patients randomized to Nexavar (50%) than in the placebo patients (18%) (p=0.0077).
After administration of sorafenib tablets, the mean relative bioavailability is 38-49% when compared to an oral solution.
The elimination half-life of sorafenib is approximately 25-48 hours. Multiple dosing of sorafenib for 7 days results 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.
Absorption and Distribution:
Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a moderate-fat meal, bioavailability is similar to that in the fasted state, with a high-fat meal, sorafenib bioavailability is reduced by 29% compared to administration in the fasted state. It is recommended that sorafenib be administered without food (at least 1 hour before or 2 hours after eating).
and AUC increase less than proportionally beyond doses of 400 mg administered orally twice daily.
binding of sorafenib to human plasma proteins is 99.5%.
Metabolism and Elimination:
Sorafenib is metabolized primarily in the liver undergoing oxidative metabolism mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib conjugates may be cleaved in the GI tract by bacterial glucuronidase activity, allowing reabsorption of unconjugated drug. Co-administration of neomycin interferes 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 and 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.
Studies on enzyme inhibition:
Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C19, CYP2D6, and CYP3A4. Sorafenib may increase the blood level of drugs that are substrates of these enzymes.
data show that Sorafenib inhibits glucuronidation by the UGT1A1 and UGT1A9 pathways. Systemic exposure to substrates of UGT1A1 and UGT1A9 may be increased when co-administered with sorafenib.
Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with Ki
values of 6 and 1-2 μM, respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 may increase when co-administered with sorafenib.
Concomitant administration of sorafenib with cyclophosphamide resulted in a small decrease in cyclophosphamide exposure, but no decrease in the systemic exposure of 4-OH cyclophosphamide, the active metabolite of cyclophosphamide that is formed primarily by CYP2B6. These data suggest that sorafenib may not be an in vivo inhibitor of CYP2B6.
Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C9 with a Ki
value of 7-8 μM. The possible effect of sorafenib on a CYP2C9 substrate was assessed in patients receiving sorafenib or placebo in combination with warfarin. The mean changes from baseline in PT-INR were not higher in sorafenib patients compared to placebo patients, suggesting that sorafenib may not be an in vivo
inhibitor of CYP2C9.
Effect of CYP3A4 inhibitors:
Ketoconazole (400 mg), a potent inhibitor of CYP3A4, administered once daily for 7 days to healthy male volunteers did not alter the mean AUC of a single 50 mg dose of sorafenib.
Effect of CYP inducers:
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 and CYP3A4.
Combination with other anti-neoplastic agents:
In clinical studies, sorafenib has been administered together with a variety of other anti-neoplastic agents at their commonly used dosing regimens, including gemcitabine, cisplatin, oxaliplatin, paclitaxel. carboplatin, capecitabine, doxorubicin, irinotecan, and docetaxel, and cyclophosphamide. Sorafenib had no clinically relevant effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin, or cyclophosphamide.
Administration of paclitaxel (225 mg/m2
) and carboplatin (AUC = 6) with sorafenib (≤400 mg twice daily) administered with a 3-day break in sorafenib dosing around administration of paclitaxel/carboplatin, resulted in no significant effect on the pharmacokinetics of paclitaxel.
Co-administration of paclitaxel (225 mg/m2
, once every 3 weeks) and carboplatin (AUC=6) with sorafenib (400 mg twice daily, without a break in sorafenib dosing) resulted in a 35% increase in sorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in 6-OH paclitaxel exposure. The pharmacokinetics of carboplatin were unaffected.
These data indicate no need for dose adjustments when paclitaxel and carboplatin are co-administered with sorafenib with a 3-day break in sorafenib dosing. The clinical significance of the small increases in sorafenib and paclitaxel exposure, upon co-administration of sorafenib without a break in dosing, is unknown.
Co-administration of capecitabine (750-1050 mg/m2
, Days 1-14 every 21 days) and sorafenib (200 or 400 mg twice daily, continuous uninterrupted administration) resulted in no significant change in sorafenib exposure, but a 15-50% increase in capecitabine exposure and a 0-52% increase in 5-FU exposure. The clinical significance of these small to modest increases in capecitabine and 5-FU exposure upon co-administered with sorafenib is unknown.
Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT 1A1 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).
Docetaxel (75 or 100 mg/m2
administered once every 21 days) when co-administered with sorafenib (200 mg twice daily or 400 mg twice daily administered on Day 2 through 19 of a 21-day cycle), with a 3-day break in dosing, around administration of docetaxel, resulted in a 36-80% increase in docetaxel AUC and a 16-32% increase in docetaxel Cmax. Caution is recommended when sorafenib is co-administered with docetaxel. (See Precautions).
Combination with antibiotics:
Neomycin: Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate GI flora microbes with the enterohepatic recycling of sorafenib (see previously mentioned), resulting in decreased sorafenib exposure. In healthy volunteers treated with a 5-day regimen of neomycin the average bioavailability of sorafenib decreased by 54%. The clinical significance of these findings for is unknown. Effects of other antibiotics have not been studied, but will likely depend on their ability to decrease glucuronidase activity.
Combination with proton pump Inhibitors:
Omeprazole: Co-administration of omeprazole has no impact on the pharmacokinetics of sorafenib. No dose adjustment for sorafenib is necessary.
Pharmacokinetics in Special Populations:
Elderly (above 65 years) and gender: Analyses Of demographic data suggest that no dose adjustments are necessary for age or gender.
Pediatric patients: There are no pharmacokinetic data in pediatric patients.
Hepatic impairment: Sorafenib is cleared primarily by the liver.
In HCC patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, exposure values were within the range observed in patients without hepatic impairment. The pharmacokinetics (PK) of sorafenib in Child-Pugh A and Child-Pugh B non-HCC patients were similar to the PK in healthy volunteers. The pharmacokinetics of sorafenib has not been studied in patients with severe (Child-Pugh C) hepatic impairment. (See Precautions).
Sorafenib is mainly eliminated via the liver, and exposure might be increased in this patient population.
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 of 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 in patients requiring dialysis.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility:
The preclinical safety profile of sorafenib was assessed in mice, rats, dogs and rabbits.
Repeat-dose toxicity studies revealed changes (degenerations and regenerations) in various organs at exposures below the anticipated clinical exposure (based on AUC comparisons).
After repeated dosing to young and growing dogs effects on bone and teeth were observed at exposures below the clinical exposure. Changes consisted in irregular thickening of the femoral growth plate at a daily sorafenib dose of 600 mg/m2
body surface area (equivalent to 1.2 times the recommended clinical dose of 500 mg/m2
on a body surface area basis), hypocellularity of the bone marrow next to the altered growth plate at 200 mg/m2
/day, and alterations of the dentin composition at 600 mg/m2
/day. Similar effects were not induced in adult dogs.
Positive genotoxic effects were obtained for sorafenib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. One intermediate in the manufacturing process, which is also present in the final drug substance (<0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test). Sorafenib was not genotoxic in the Ames test (the material contained the intermediate at 0.34%), and in an in vivo mouse micronucleus assay.
Carcinogenicity studies have not been performed with sorafenib.
No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility. An adverse effect on male and female fertility can however be expected because repeat-dose studies in animals have shown changes in male and female reproductive organs at exposure below the anticipated clinical exposure (based on AUC). Typical changes consisted of signs of degeneration and retardation in testes, epididymides, prostate, and seminal vesicles of rats. Female rats showed central necrosis of the corpora lutea and arrested follicular development in the ovaries. Dogs showed tubular degeneration in the testes and oligospermia. Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits at exposures below the clinical exposure. Observed effects included decreases in maternal and fetal body weights, an increased number of fetal resorptions and an increased number of external and visceral malformations. Adverse fetal outcomes were observed at an oral dose of 6 mg/m2
/day in rats and 36 mg/m2
/day in rabbits (see Precautions and Use in Pregnancy & Lactation).