ソラフェニブ

PFAS -> PFAS identified in REACH Regulation EC No. 1272/2008

PFAS -> Suspected persistent, mobile, toxic (PMT) PFAS or PFAS-like compounds

Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agents

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

< 0.01 g/L

1.71e-03 g/L

Breast Feeding; Lactation; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Tyrosine Kinase Inhibitors;

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

187-226

205.6 °C

Danger

H351 (40%): Suspected of causing cancer [Warning Carcinogenicity]

P203, P260, P263, P264, P270, P273, P280, P318, P319, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 5 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including sorafenib tosylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sorafenib tosylate/

Drug Name: Nexavar; FDA Application No.: (NDA) 021923; Active Ingredient: Sorafenib tosylate; Company: Bayer Healthcare; Original Approval or Tentative Approval Date: December 20, 2005; Chemical Type: 1 New molecular entity (NME); Review Classification: Priority review drug, orphan drug. /Sorafenib tosylate/

Accidental release measures: After Inhalation: cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves. Measures for cleaning/collecting: absorb solutions with finely- powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material /in accordance with prevailing country, federal, state and local regulations/. /Sorafenib tosylate/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Sorafenib does not appear to affect the metabolism of warfarin (a CYP2C9 substrate) in vivo; mean changes from baseline in prothrombin time (PT)/international normalized ratio (INR) did not appear to be greater in patients receiving sorafenib as compared with placebo. However, infrequent bleeding events or elevations in INR have been reported in some patients receiving concomitant therapy with warfarin and sorafenib.

Potential pharmacokinetic interaction with doxorubicin and irinotecan (increased area under the serum concentration-time curve (AUC) of doxorubicin and of irinotecan and its active metabolite SN-38). The clinical importance of these findings is not known. Caution is advised.

In vitro studies indicate that sorafenib inhibits glucuronidation by the uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and 1A9 pathways; potential pharmacokinetic interaction (increased systemic exposure to UGT 1A1 or 1A9 substrates). Caution is advised when sorafenib is used concomitantly with drugs predominantly metabolized by the UGT 1A1 pathway (e.g., irinotecan, whose active metabolite SN-38 is metabolized by UGT 1A1).

In vitro studies using human hepatic microsomes indicate that sorafenib inhibits CYP isoenzymes 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4; however, sorafenib does not appear to alter exposure to dextromethorphan (a CYP2D6 substrate), midazolam (a CYP3A4 substrate), or omeprazole (a CYP2C19 substrate). The manufacturer states that it is unlikely that sorafenib will alter the metabolism of substrates of CYP isoenzymes 2C19, 2D6, or 3A4 in vivo or induce CYP isoenzymes 1A2 or 3A4. However, sorafenib may increase systemic exposure to CYP2B6 or CYP2C8 substrates; caution is advised when substrates of CYP2B6 or CYP2C8 are used concomitantly with sorafenib.

For more Interactions (Complete) data for Sorafenib (6 total), please visit the HSDB record page.

In large clinical trials of sorafenib, elevations in serum aminotransferase levels were common, occurring in up to half of patients, but values greater than 5 times the upper limit of normal (ULN) occurred in only 1% to 3% of treated subjects. In addition, there have been several single case reports of clinically apparent liver injury arising during sorafenib therapy which was often severe and occasionally fatal. The onset of acute liver injury ranged from a few days to 8 weeks of starting sorafenib, and the pattern of injury was typically hepatocellular with marked elevations in serum aminotransferase levels. Immunoallergic and autoimmune features were absent. Recovery was usually rapid once sorafenib was stopped, but some cases were associated with progressive liver injury and hepatic failure. Most of the reports of severe liver injury occurred in patients being treated for hepatocellular carcinoma who also had cirrhosis or in patients receiving other potentially hepatotoxic drugs31.

The mean relative bioavailability is 38-49% for the tablet form, when compared to an oral solution. Sorafenib reached peak plasma levels in 3 hours following oral administration. With a high-fat meal, bioavailability is reduced by 29% compared to administration in the fasted state.

Sorafenib interacts with multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-&szlig;). Several of these kinases are thought to be involved in angiogenesis, thus sorafenib reduces blood flow to the tumor. Sorafenib is unique in targeting the Raf/Mek/Erk pathway. By inhibiting these kinases, genetic transcription involving cell proliferation and angiogenesis is inhibited.

The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic events. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals.

/HUMAN EXPOSURE STUDIES/ Fatal adverse events (FAEs) have been reported with sorafenib, a vascular endothelial growth factor receptor kinase inhibitor (VEGFR TKI). /The authors/ performed an up-to-date and detailed meta-analysis to determine the overall risk of FAEs associated with sorafenib. Databases, including PubMed, Embase and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies. Eligible studies included randomized controlled trials evaluating sorafenib effects in patients with all malignancies. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated for FAEs. In addition, subgroup analyses were performed according to tumor type and therapy regimen. 13 trials recruiting 5,546 patients were included in our analysis. The overall incidence of FAEs with sorafenib was 1.99% (95%CI, 0.98-4.02%). Patients treated with sorafenib had a significantly increased risk of FAEs compared with patients treated with control medication, with an RR of 1.77 (95%CI 1.25-2.52, P=0.001). Risk varied with tumor type, but appeared independent of therapy regimen. A significantly increased risk of FAEs was observed in patients with lung cancer (RR 2.26; 95% CI 1.03-4.99; P= 0.043) and renal cancer (RR 1.84; 95% CI 1.15-2.94; P= 0.011). The most common causes of FAEs were hemorrhage (8.6%) and thrombus or embolism (4.9%). It is important for health care practitioners to be aware of the risks of FAEs associated with sorafenib, especially in patients with renal and lung cancer.

/CASE REPORTS/ Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFbeta and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort. ... /The authors/ report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial.

/CASE REPORTS/ Hepatocellular carcinoma (HCC) is a critical global health issue and the third most common cause of cancer-related deaths worldwide. The majority of patients who present HCC are already at an advanced stage and their tumors are unresectable. Sorafenib is a multi-kinase inhibitor of the vascular endothelial growth factor pathway and was recently introduced as a therapy for advanced HCC. Furthermore, studies have shown that oral sorafenib has beneficial effects on survival. However, many patients experience diverse side effects, and some of these are severe. ... /The authors/ report the case of a HCC patient that developed a liver abscess while being treated with sorafenib.

/OTHER TOXICITY INFORMATION/ Possible increased risk of bleeding. In clinical studies, bleeding (regardless of causality) was reported in 15.3 or 8.2% of patients receiving sorafenib or placebo, respectively. The incidences of grade 3 and 4 bleeding were 2 and 0%, respectively, in patients receiving sorafenib compared with 1.3 and 0.2%, respectively, in patients receiving placebo. Fatal hemorrhage occurred in one patient in each treatment group. Permanent discontinuance of sorafenib should be considered if any bleeding episode requires medical intervention.

/OTHER TOXICITY INFORMATION/ Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and International Normalized Ratio (INR) may also occur. The incidence of severe drug-induced liver injury, defined as elevated transaminase levels above 20 times the upper limit of normal or transaminase elevations with significant clinical sequelae (for example, elevated INR, ascites, fatal, or transplantation), was two of 3,357 patients (0.06%) in a global monotherapy database. Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation, such as viral hepatitis or progressing underlying malignancy, discontinue Nexavar.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

sorafenib

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Acute Exposure/ The toxicity of single doses of sorafenib has been investigated via the oral route in mice, rats and dogs. The highest single oral sorafenib dose of 1460 mg/kg was tolerated in mice and rats without any sign of toxicity. In Beagle dogs, vomiting was observed after a single oral dose of 120 mg/kg solution, and 1000 mg/kg powder (1370 mg/kg of the tosylate salt) After administration of two times 24 hours i.p doses of 125-500 mg/kg of sorafenib in mice, apathy, roughened fur, hard abdomen, spasm, periodically stretching of body and difficulty in breathing were observed but mortality was not induced. At 500 mg/kg one male died. At the 1000 mg/kg dose, all males and one female died.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a 4-week study in dogs with initial twice-daily administration of 10, 30, or 60 mg/kg, both 30 mg/kg bid and 60 mg/kg bid of sorafenib induced emesis, bloody diarrhea and reduced body weight gain. Dosing was therefore reduced to once daily after one week of treatment. After the administration of 30 mg/kg of sorafenib, once-daily for 3 or 12 months in dogs, effects on the GI tract (bloody diarrhoea) and on the skin (hair loss, inflammation) were observed. At histopathology, degenerative and regenerative processes were seen dose-dependently in multiple tissues including kidneys, lymphoreticular / hematopoetic system, GI tract, adrenals, teeth and bone. Marked morphological changes were observed in the liver and skin. The morphological no-effect-level after 3 or 12 months treatment was below 10 mg/kg/day.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a 6 month toxicity study, 20 male and 20 female Wistar rats were treated daily orally by gavage at 0 -2.5 mg/kg dose of sorafenib. The lowest dose causing significant toxicity (LOAEL) was 1 mg/kg/day. A NOAEL was not established for females.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ A group of 10 male and 10 female Wistar rats were treated orally for 4 weeks at 0 -125 mg/kg dose of sorafenib. Mortalities prior to the end of 4 weeks treatment included 3 males and 9 females at 25 mg/kg, 3 males and 1 female at 125 mg/kg. Dose-dependent clinical signs of toxicity were noted at 5 mg/kg and above. In the clinico-chemical investigations, increases were seen in AST, ALT (beginning at 1 mg/kg), GLDH and LDH (at 25 and 125 mg/kg), cholesterol and bilirubin (beginning at 5 mg/kg). An increase was seen in alkaline phosphatase (ALP) at 5 mg/kg with decreases at 25 and 125 mg/kg. In urine, increases were seen in protein, urine creatinine (in females only), NAG, and LDH, particularly at 25 and 125 mg/kg. Histopathological evaluation revealed treatment-related findings in the majority of animals treated at 25 or 125 mg/kg. Overall, the changes were classified as degenerative in the adrenal glands, liver, stomach, duodenum, pancreas, kidneys, heart, and ovaries. Regenerative changes were observed in the liver (bile duct proliferation), pancreas, duodenum and kidneys. Necrosis was observed in the spleen, lymph nodes, and thymus. Effects in male reproductive organs included retardation in testes, epididymides, prostate and seminal vesicles. Most of the findings could be shown to be reversible. However, bile duct proliferation, liver fibrosis, effects on lymphoreticular system were still visible at the end of the 1-month recovery period. A NOAEL was not established.

For more Non-Human Toxicity Excerpts (Complete) data for Sorafenib (8 total), please visit the HSDB record page.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including sorafenib tosylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sorafenib tosylate/

Drug Name: Nexavar; FDA Application No.: (NDA) 021923; Active Ingredient: Sorafenib tosylate; Company: Bayer Healthcare; Original Approval or Tentative Approval Date: December 20, 2005; Chemical Type: 1 New molecular entity (NME); Review Classification: Priority review drug, orphan drug. /Sorafenib tosylate/

L01XE05

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Sorafenib decreases tumour cell proliferation _in vitro_. It attenuated tumour growth of human tumour xenografts in immunocompromised mice, reduced tumour angiogenesis, and increased tumour apoptosis in models of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma. Some studies suggest that sorafenib induces apoptosis in several tumour cell lines, although this effect is inconsistent across cell lines. Antiviral effects of sorafenib have been documented, as it was shown to inhibit hepatitis C viral replication _in vitro_.

Kinases are involved in tumour cell signalling, proliferation, angiogenesis, and apoptosis. Sorafenib inhibits multiple intracellular serine/threonine kinases in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. Intracellular Raf serine/threonine kinase isoforms inhibited by sorafenib include Raf-1 (or C-Raf), wild-type B-Raf, and mutant B-Raf. Sorafenib inhibits cell surface tyrosine kinase receptors such as KIT, FMS-like tyrosine kinase 3 (FLT-3), RET, RET/PTC, vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor-β (PDGFR-β). Sorafenib is thought to exhibit a dual mechanism of action: it blocks tumour proliferation and growth by inhibiting the RAF/MEK/extracellular signal-regulated kinase (ERK) pathway on tumour cells, and reduces tumour angiogenesis by inhibiting VEGFR and PDGFR signalling in tumour vasculature.

Sorafenib is U.S. Food and Drug Administration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, /the researchers/ report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH2-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis.

Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype. Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 umol/L; K(i) = 11.7 umol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure. This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.

Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib was shown to inhibit multiple intracellular (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT- 3, RET, RET/PTC, VEGFR-1, VEGFR- 2, VEGFR- 3, and PDGFR-beta). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis and apoptosis. Sorafenib inhibited tumor growth of hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and differentiated thyroid carcinoma (DTC) human tumor xenografts in immunocompromised mice. Reductions in tumor angiogenesis were seen in models of HCC and RCC upon sorafenib treatment, and increases in tumor apoptosis were observed in models of HCC, RCC, and DTC.

The mean elimination half-life of sorafenib was approximately 25 to 48 hours.

After intravenous administration of (14)C-sorafenib tosylate to mice, rats, and dogs the elimination of the radioactivity from plasma occurred with similar terminal half-lives of 6.8, 8.8, and 7.3 hours, respectively. The terminal half-lives of radioactivity after oral administration were 6.1 hours in mice and 5.8 hours in dogs. In rats, terminal half-live after oral administration was longer (11.2 hr) than after intravenous administration. In rats, the elimination of the unchanged compound was slower (half life: 9.3 hr) than in the mice (half life: 6.5 hr) and dogs (half life:4.3 hr).

The mean elimination half-life of sorafenib was approximately 25 to 48 hours.

Sorafenib undergoes oxidative metabolism by CYP3A4 in the liver, as well as glucuronidation by UGT1A9 in the liver and kidneys. At steady-state, sorafenib accounts for 70-85% of the circulating analytes in plasma. About eight metabolites of sorafenib have been identified, of which five were detected in plasma. The main circulating metabolite was the pyridine N-oxide form, which comprises approximately 9–16% of the total circulating dose at steady-state: the pharmacological activity of this metabolite was comparable to the parent drug.

Sorafenib undergoes oxidative metabolism by hepatic CYP3A4, as well as glucuronidation by UGT1A9. Inducers of CYP3A4 activity can decrease the systemic exposure of sorafenib. Sorafenib accounted for approximately 70-85% of the circulating analytes in plasma at steady-state. Eight metabolites of sorafenib have been identified, of which 5 have been detected in plasma. The main circulating metabolite of sorafenib, the pyridine N-oxide that comprises approximately 9-16% of circulating analytes at steady-state, showed in vitro potency similar to that of sorafenib.

Sorafenib has known human metabolites that include A-D-GlucuronideDISCONTINUED and Sorafenib.

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 <i>in vitro</i> potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state. Route of Elimination: 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. Half Life: 25-48 hours

9ZOQ3TZI87

SORAFENIB

Established Pharmacologic Class [EPC] - Kinase Inhibitor

Mechanisms of Action [MoA] - Protein Kinase Inhibitors

Sorafenib is a Kinase Inhibitor. The mechanism of action of sorafenib is as a Protein Kinase Inhibitor.

SORAFENIB

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Agents that inhibit PROTEIN KINASES.

The administration of multiple doses for seven days resulted in a 2.5- to 7-fold accumulation compared to a single dose. Steady-state concentrations were achieved within seven days, with a peak-to-trough ratio of mean concentrations of less than 2. Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. The Tmax is approximately three hours. The mean relative bioavailability was 38–49% following the administration of oral sorafenib tablets. A high-fat meal reduced bioavailability by 29%.

Following oral administration of a 100 mg dose of sorafenib, about 96% of the dose was recovered within 14 days, with 77% of the dose being excreted in feces and 19% of the dose being excreted in urine as glucuronidated metabolites. Unchanged sorafenib accounted for 51% of the dose excreted in feces.

Sorafenib is widely distributed to tissues, indicating that it is lipophilic.

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.

After administration of Nexavar tablets, the mean relative bioavailability was 38-49% when compared to an oral solution. Following oral administration, sorafenib reached peak plasma levels in approximately 3 hours. With a moderate-fat meal (30% fat; 700 calories), bioavailability was similar to that in the fasted state. With a high-fat meal (50% fat; 900 calories), bioavailability was reduced by 29% compared to that in the fasted state. It is recommended that Nexavar be administered without food. Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. In vitro binding of sorafenib to human plasma proteins was 99.5%.

The absorption and the basic pharmacokinetics following a single dose of sorafenib tosylate were evaluated in female CD-1 mice, male Wistar rats, and female Beagle dogs. For the determination of the absorption of sorafenib in rats, bile duct-cannulated rats (n=5/group) were used. Twenty-four hours after surgery (14)C-sorafenib tosylate was administered orally or intravenously to the rats at a dose of 5 mg/kg sorafenib. The absorption of sorafenib was almost complete in female CD-1 mice (78.6%) and male Wistar rats (79.2%). In Beagle dogs the absorption (67.6 %, calculated from AUC norm values after intravenous and oral administration) and the absolute bioavailability (59.9 %) were lower than in rodents. Maximum plasma concentrations of radioactivity between 1.5 hr and 2 hr after oral administration were observed in all species. After intravenous administration of (14)C-sorafenib tosylate to mice, rats, and dogs the elimination of the radioactivity from plasma occurred with similar terminal half-lives of 6.8, 8.8, and 7.3 hours, respectively. The terminal half-lives of radioactivity after oral administration were 6.1 hours in mice and 5.8 hours in dogs. In rats, terminal half-live after oral administration was longer (11.2 hr) than after intravenous administration. In rats, the elimination of the unchanged compound was slower (half life: 9.3 hr) than in the mice (half life: 6.5 hr) and dogs (half life:4.3 hr). The total plasma clearance in rats was 0.044 L/(hr/kg) corresponding to a blood clearance of 0.049 L/(hr/kg). In mice and dogs the total plasma clearance was 0.13 and 0.15 lL/(hr/kg) respectively. The volume of distribution at steady state ranged from 0.65 l/kg to 0.74 l/kg, depending on the species.

Antineoplastic Agents; Protein Kinase Inhibitors

THERAPEUTIC CATEGORY: Antineoplastic

MEDICATION

Use (kg; approx.) in Germany (2009): >250

Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma.