What Is Sorafenib?

It is a new type of multi-targeted oral medicine for treating tumors. Its primary development goal is to treat gastrointestinal stromal tumors and metastatic kidney cells that are not responsive or intolerable to standard therapies. Can selectively target the receptors of certain proteins, which are thought to play a molecular switch-like role in tumor growth. Its above-mentioned indications have obtained the "Fast Track" approval status granted by the FDA in the United States.

Chinese name: Sorafeni
Foreign name: sorafenib ^[1]

CAS number: 284461-73-0
Molecular formula: C21H16ClF3N4O3
Molecular weight: 464.82500

Sorafenib compounds

Sorafenib Basic Information

Chinese name: Sorafenib

Chinese alias: Raf inhibitor;

English name: sorafenib

English alias: Nexavar; NEXAVAR; BAY-43-900; Sorafenib; SORAFENIB TOLSYLATE; Sorafenib Free Base; Bay 43-9006; Forafenib; 4- (4- (3- (4-Chloro-3- (trifluoromethyl) phenyl) ureido ) phenoxy) -N-methylpicolinamide;

CAS number: 284461-73-0

MDL number: MFCD06411450

Molecular formula: C ₂₁ H ₁₆ ClF ₃ N ₄ O ₃

Structural formula:

Molecular weight: 464.82500

Exact mass: 464.08600

PSA: 92.35000

LogP: 6.08660

Sorafenib physical and chemical properties

Appearance and properties: white to off-white solid

Density: 1.454 g / cm ³

Melting point: 202-204 ° C

Boiling point: 523.3ºC at 760 mmHg

Flash point: 270.3ºC

Vapor pressure: 4.76E-11mmHg at 25 ° C

Sorafenib safety information

WGK Germany: 2

Danger category code: R36 / 37/38

Safety instructions: S26; S37 / 39

RTECS number: HM1650000

Dangerous goods sign: Xi ^[2]

Sorafenib molecular structure data

1. Molar refractive index: 113.10

2. Molar volume (m / mol): 319.4

3. Isometric Zhang Rongrong (90.2K): 856.9

4. Surface tension (dyne / cm): 51.7

5. Dielectric constant (F / m):

6. Dipole distance (D):

7. Polarizability (10cm): 44.83

Sorafenib Computational Chemistry Data

1. Hydrophobic parameter calculation reference value (XlogP): 4.1

2.Number of hydrogen-bonded donors: 3

3.Number of hydrogen bond acceptors: 7

4.Number of rotatable chemical bonds: 5

5.Number of tautomers: 6

6. Topological molecular polar surface area 92.4

7.Number of heavy atoms: 32

8.Surface charge: 0

9.Complexity: 646

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 0

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

15. Number of covalent bond units: 1 ^[3]

Sorafenib uses

It is a new type of multi-targeted oral medicine for treating tumors. It is used to treat hepatocellular carcinoma that cannot be operated on or distantly metastasized.

Sorafenib Compound Related Drug Description

[Common name] Sorafenib Tosylate

[Commodity name] Dogemei

[English name] Sorafenib tosylate Tablets

[Chinese Pinyin] Jia Ben Huang Suan Suo La Fei Ni Pian

Sorafenib Ingredients:

Chemical name: 4- (4-3- [4-chloro-3- (trifluoromethyl) phenyl] ureidophenoxy) -N2-methylpyridine-2-carboxamide-4-toluenesulfonate

Molecular formula: C21H16CIF3N4O3 · C7H8O3S

Molecular weight: 637.0

Sorafenib category:

Chemical Drugs and Biological Products >> Tumor Drugs >> Antitumor Drugs >> Small Molecule Targeted Therapy Drugs ^[4]

Overview of Sorafenib

Sorafenib tosylate is a new type of multi-targeted anti-tumor drug, which was successfully developed by Bayer Pharmaceuticals, Germany, and can simultaneously act on tumor cells and tumor blood vessels. It has dual antitumor effects: it can directly inhibit tumor cell proliferation by blocking the cell signaling pathway mediated by RAF / MEK / ERK, and it can also inhibit VEGFR and platelet-derived growth factor (PDGF) receptor Block tumor neovascularization and indirectly inhibit tumor cell growth. ^[5]

Extensive antitumor activity has been shown in preclinical animal tests. In the phase III randomized clinical study of advanced renal cancer in the United States and Europe, 903 patients with advanced renal cancer who failed a single systemic treatment (biological immunity or chemotherapy) were randomly divided into two groups, one group received tosylate Lafenib (Sorafenib), another group received placebo. At the time of the interim analysis, 222 deaths had occurred, and the results showed that the objective effective rates of the two groups were 10% and 2%, respectively, and tumors remained stable in 74% and 53% of the patients, respectively.

The progression-free survival of the Sorafenib group was twice as long as that of the placebo group (5.8 vs. 2.8 months, with a hazard ratio of 0.51), and Sorafenib significantly improved the quality of life of patients compared with placebo. The survival time of the Sorafinib group was longer than that of the placebo group, with a hazard ratio of 0.72. However, this difference has not reached statistical significance. Because this is only the result of an interim analysis, the final comparison of survival time cannot be made until the final analysis of the trial.

Sorafenib treatment is well tolerated and the main adverse reactions are controlled diarrhea, rash, fatigue, hand-foot syndrome, hypertension, hair loss, nausea / vomiting, and loss of appetite.

In December 2005, it was approved by the US Food and Drug Administration (FDA) as a first-line drug for the treatment of advanced kidney cancer.

In October 2007, the European Medicines Agency's (EMEA) approved sorafenib (Dogemet) for the treatment of hepatocellular carcinoma.

In November 2007, the US Food and Drug Administration approved Dorgemet for the treatment of unresectable hepatocellular carcinoma.

In August 2009, China s State Food and Drug Administration approved Bayer Pharmaceuticals sorafenib tosylate (trade name: Dorgeme) officially entered the Chinese liver cancer treatment market for the treatment of inoperable advanced liver cancer patients . ^[5]

Sorafenib pharmacological effects

Sorafenib is a multiple kinase inhibitor

In vitro tests have shown that it can inhibit tumor cell proliferation and anti-angiogenesis. Sorafenib inhibits CRAF, BRAF, V600EBRAF, c-Kit, FLT-3, and CRAF, VEGFR-2, VEGFR-3, and PDGFR- in tumor target sites. RAF kinases are serine / threonine kinases, while c-Kit, FLT-3, VEGFR-2, VEGFR-3, and PDGFR- are tyrosine kinases, which act on tumor cell signaling pathways, angiogenesis, and apoptosis . In vivo tests have shown that in various human tumor suppressive nude mouse models, such as human hepatocellular tumors and renal cell tumors, tumor growth and angiogenesis can be inhibited.

Sorafenib Toxicology Study

The preclinical safety of sorafenib was evaluated in mice, rats, dogs and rabbits.

Repeated dose toxicity tests showed mild to moderate changes (degeneration and regeneration) in different organs.

Effects on bone and teeth can be observed in juvenile and developmental dogs after multiple doses, including when sorafenib dose reaches 600 mg / m body surface area (equivalent to 1.2 times the clinically recommended dose of 500 mg / m2 body surface area). The epiphyseal plate was irregularly thickened, and bone marrow cells decreased (200 mg / m / day) and changes in dentin composition (600 mg / m / day) near the growth plate. No similar situation was found in adult dogs. Mutagenicity: In vitro chromosome aberration tests were performed on mammalian cells (Chinese hamster ovary). Sorafenib is genotoxic when metabolically activated. The in vitro cytogenetic test (Ames test) of an intermediate during the production process is positive, and the limit in the drug is controlled below 0.15%. Ames test and micronucleus test in mice show that sorafenib is not genotoxic (the content of this intermediate in the test drug is 0.34%). Carcinogenicity: No sorafenib carcinogenicity test.

Reproductive toxicity: No specific animal fertility test. Repeated drug toxicity tests have observed changes in the reproductive organs of animals, so damage to male and female fertility can be foreseen. Typical changes include degeneration and blockage of rat testis, epididymis, prostate, and seminal vesicles. These effects were more pronounced when the daily dose of sorafenib reached 150 mg / m body surface area (equivalent to 0.3 times the clinically recommended dose of 500 mg / m body surface area). When the dose reached 30 mg / m / day, corpus luteum central necrosis and follicular developmental stagnation were observed in the ovaries of female rats. For test dogs, when the dose reached 600 mg / m / day, the seminiferous tubules deteriorated; when the dose reached 1200 mg / m / day, the semen decreased. Sorafenib in rats and rabbits appears to be embryotoxic and teratogenic, including weight loss in the mother and fetus, increased chance of miscarriage, and increased appearance and visceral deformities. Adverse effects on the fetus were observed at oral doses of 6 mg / m / day and 36 mg / m / day in rats and rabbits, respectively.

Sorafenib pharmacokinetics

Compared with oral solutions, the average relative bioavailability of taking sorafenib tablets is 38% -49%.

Sorafenib has a clear half-life of approximately 25-48 hours. Compared with single-dose administration, 2.5-7 times accumulation can be achieved after 7 days of repeated administration.

Seven days after the administration, the plasma concentration of sorafenib reached a steady state, and the peak-to-valley ratio of the average plasma concentration was less than 2.

Absorption distribution

Sorafenib reached the highest plasma concentration about 3 hours after oral administration. The medium-fat diet is similar to the bioavailability in the fasted state. With high-quality diets, bioavailability of sorafenib was reduced by 29% compared to fasting.

When the oral preparation exceeds 0.4 g twice daily, the increase in Cmax and AUC is not linear.

In vitro, the binding rate of sorafenib to human plasma proteins was 99.5%.

Metabolism and clearance

Sorafenib is mainly metabolized by CYP3A4 in the liver, in addition to glucuronidation by UGT1A9. Sorafenib conjugates can be broken down by glucuronidases of the digestive tract bacteria, which allows the non-binding components of sorafenib to be reabsorbed. The combination of neomycin and sorafenib can interfere with this process, reducing the average bioavailability of sorafenib by 54%.
When the plasma concentration reaches steady state, sorafenib accounts for about 70% -85% of all blood analytes in the plasma. Sorafenib has eight known metabolites, five of which were detected in plasma. The main circulating metabolite of sorafenib in plasma is pyridine-N-oxide. In vitro tests show that the substance is similar to sorafenib in that it contains approximately 9% -16% of blood analytes in steady-state plasma.

After oral administration of 100 mg of sorafenib (solution), 96% of the drug was eliminated within 14 days, of which 77% was excreted in the feces and 19% was excreted in the urine as glycosylated metabolites. 51% of the original drug was excreted with feces, and no original drug was found in urine. Enzyme Inhibition Test Human liver microsomal tests show that sorafenib competitively inhibits CYP2C19, CYP2D6 and CYP3A4. When midazolam, dextromethorphan, and omeprazole (the substrates of cytochromes CYP3A4, CYP2D6, and CYP2C19, respectively) are used in combination, subsequent administration of this product for 4 weeks does not change the in vivo exposure of these drugs. These indicate that this product is neither an inhibitor nor an inducer of these cytochrome P450 isoenzymes. In vitro data indicate that sorafenib inhibits glucosinolate metabolism through the UTG1A1 and UTG1A9 pathways. When this product is combined with irinotecan (its active metabolite SN-38 can be further metabolized through the UTG1A1 pathway), the AUC of SN-38 can increase by 67% -120%. When these drugs are used in combination with sorafenib, they may increase the exposure concentrations of the metabolic substrates of UTG1A1 and UTG1A9. In vitro experiments show that sorafenib inhibits CYP2B6 and CYP2C8 with Ki values of 6 and 1-2 M, respectively. The combination of paclitaxel and paclitaxel results in an increase, rather than a decrease, in the in vivo exposure of 6-hydroxypaclitaxel (the active metabolite of paclitaxel metabolized by CYP2C8). These data indicate that this product may not be an in vivo inhibitor of CYP2C8. Systemic exposure to CYP2B6 and CYP2C8 increased when administered with sorafenib. Human liver microsomal tests show that sorafenib competitively inhibits CYP2C9 with a Ki value of 7-8 M. Patients (sorafenib and placebo) were combined with warfarin to evaluate the potential effect of sorafenib on CYP2C9 substrates. The average change in PT-INR from baseline in the sorafenib group was not higher than Placebo group. This result indicates that sorafenib is not an in vivo inhibitor of CYP2C9. CYP3A4 inhibitor ketoconazole is a strong inhibitor of CYP3A4. Healthy male volunteers use ketoconazole once a day, 400 mg each time for 7 consecutive days, while taking a single oral dose of sorafenib 50 mg daily, sorafenib The mean plasma concentration did not change. So it is unlikely that sorafenib and CYP3A4 inhibitors have a clinical pharmacokinetic interaction.

CYP enzyme inducers did not change the activity of CYP1A2 and CYP3A4 after treatment of cultured human hepatocytes with sorafenib. This suggests that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4. The continuous and simultaneous administration of sorafenib and rifampicin in clinical practice resulted in a 37% average reduction in the AUC value of sorafenib. Other CYP3A4 enzyme activation inducers (such as Hypericum hypericum, commonly known as St. John's wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase the metabolism of sorafenib, thus reducing the concentration of sorafenib .

Pharmacokinetics of Sorafenib in Specific Populations

Elderly (over 65), gender: Demographic data show that there is no need to adjust the dose according to the age or sex of the patient.

Pediatric patients: There are no pharmacokinetic data for pediatric patients.

Patients with liver damage: Sorafenib is mainly cleared by the liver.

Drug exposure in patients with mild (Child-PughA, N = 14) or moderate (Child-PughB, N = 8) liver damage was consistent with that in patients without liver damage. Exposure is within the range of variation in patients without liver damage. The pharmacokinetics of Sorafenib in patients with severe hepatic impairment (Child-PughC) have not yet been studied.

Patients with renal impairment: In a clinical pharmacological study, in patients with normal renal function, patients with mild renal impairment (CrCL50-80ml / min), patients with moderate renal impairment (CrCL30-50ml / min), and no dialysis required In patients with severe renal impairment (CrCL <30ml / min) (n = 8 / group), the pharmacokinetics of sorafenib (single dose of 400mg) were evaluated. Sorafenib's pharmacokinetics were not affected by impaired renal function. No dose adjustment is necessary for patients with mild, moderate or severe renal impairment who do not require dialysis.

Race: The results of the pharmacokinetic analysis of trial 11559 showed that the plasma concentration-time curve of sorafenib was slower in absorption, the elimination phase was longer, and the curve in drug time was relatively flat. There are significant individual differences in the pharmacokinetic parameters of sorafenib and its metabolites. In this study, the Cmax and AUC (0-12h) of Taiwanese and mainlanders who went to sorafenib were similar to those of the Japanese, and there was a large overlap in the data ranges measured between these groups.

The pharmacokinetic analysis of trial 11849 (24 cases) was similar to the results of previous studies. The steady-state plasma concentration was reached on the 7th day of treatment and was relatively stable during the treatment period. The drug metabolism data is consistent with the Japanese study (Experiment 10875), sorafenib Cmax, ss and AUCss were 3-4mg / L and 30 · mgh / L, respectively. The relative amount of each metabolite is also consistent with the results of Japan and Caucasians. The pharmacokinetics of sorafenib in Chinese patients are similar to those in other study populations. Trial 12162 was a pharmacokinetic study in healthy volunteers whose main purpose was to compare the exposure of sorafenib in Caucasians and Asians. Under control conditions, healthy, age-appropriate subjects are administered under fasting conditions without concomitant combination medications that may cause pharmacokinetic interference. Japanese and Chinese subjects were selected for the trial on behalf of the Asian race. The study included 40 Japanese, 38 Chinese and 40 Caucasians. Research data show that sorafenib exposure is 30% lower in Asian subjects than in Caucasian subjects. Compared with Caucasian subjects, the geometric mean of the AUC of sorafenib in the plasma of Japanese subjects was 25% lower, and that of Chinese subjects was 35% lower. The difference between Japanese subjects and Caucasian subjects observed in this study (25%) was lower than previously reported values (45%). There was no significant difference between the average Cmax of Japanese subjects and Caucasian subjects, and the average Cmax of Chinese subjects was 16% lower than that of Caucasian subjects. The differences in pharmacokinetics observed during single-dose pharmacokinetic comparisons and steady-state pharmacokinetic comparisons were consistent with population pharmacokinetic evaluations. Data from seven single-drug Phase I clinical studies in cancer patients and supporting data from healthy subjects were used to establish a population pharmacokinetic model of sorafenib. In the main analysis data set, Caucasian subjects accounted for the majority (64.7%, n = 191), followed by Asians (21.4%). The results of a population pharmacokinetic analysis (focusing on racial differences) showed that Japanese patients had a 28.9% lower exposure than Caucasian patients. However, the drug-time curves of Asians and Caucasians simulated according to the finally established model overlap, suggesting that the pharmacokinetic differences between the two races may not be clinically significant.

Due to the high individual differences in pharmacokinetics between patients and the high overlap between AUC and Cmax values in Asians and Caucasians, taking into account similar effectiveness and safety data for Asian and Caucasian renal cell carcinoma patients, Small apparent differences in systemic exposure to sorafenib may not be clinically significant. ^[4]

Sorafenib indication

1.Treatment of liver tumor cells that cannot be surgically or distantly metastasized

2.Treatment of inoperable kidney tumor cells

3. Treatment of patients with locally relapsed or metastatic, progressively differentiated thyroid that is no longer effective for radioiodine treatment ^[4]

Sorafenib dosage

Recommended dosage: It is recommended to take sorafenib 0.4 g (2x0.2 g) each time, twice daily, on an empty stomach or with a low-fat, medium-fat diet.

How to take: Take orally and swallow with a glass of warm water. ^[4]

Sorafenib Taboo

Patients with severe allergic symptoms to sorafenib or inactive ingredients of the drug are contraindicated. ^[4]

Sorafenib adverse reactions

Common adverse events caused by sorafenib include rash, diarrhea, elevated blood pressure, and redness, pain, swelling, or blisters in the palms or soles of the feet ^[6] . In clinical trials, the most common treatment-related adverse events were diarrhea, rash / desquamation, fatigue, skin reaction to hands and feet, hair loss, nausea, vomiting, pruritus, hypertension, and loss of appetite. Among patients treated with sorafenib, the number of grade 3 and 4 adverse events accounted for 31% and 7% of the total number of adverse events, respectively, compared with 22% and 6% of patients in the placebo control group, respectively.

[Some suggestions for improving hand, foot and skin reactions]:

1. When wearing soft-soled shoes or tennis shoes, you should wear cotton socks or cushions to prevent foot pressure;

2. Should not stand for a long time;

3. Dissolve magnesium sulfate in warm water and soak the affected area of the skin;

4. Use urea-containing ointment or lotion on the feet, 2 times a day or apply a thick layer, wear cotton socks to stay overnight;

5. If necessary, you can use the spot removal spray;

6. If the skin on the foot continues to thicken or cocoon, you can ask the therapist to prevent further aggravation; use a moisturizing ointment immediately after the foot treatment;

7. Apply aloe vera juice to affected area

Sorafenib precautions

This product must be taken under the guidance of a doctor with experience in use.

Data on randomized controlled clinical studies comparing sorafenib with interventional treatments such as TACE in patients with advanced hepatocellular carcinoma are currently lacking. Therefore, the advantages of this product over interventional treatments are not clear, nor can it be clearly used for patients who have previously received interventional treatment Is Sorafenib beneficial? It is recommended that doctors comprehensively consider the patient's specific conditions and choose the appropriate treatment.

Pregnancy: Women of childbearing age should pay attention to contraception during treatment. Women of childbearing age should be informed of the possible harm the drug may cause to the fetus, including severe deformities (teratogenicity), developmental disorders and fetal death (embryo toxicity). Sorafenib should be avoided during pregnancy. It should only be used in pregnant women if the benefits of treatment outweigh the potential harm to the fetus.

Sorafenib has been found to have teratogenicity and embryo-fetal toxicity (including increased risk of miscarriage and developmental disorders) in animal experiments, and these harmful effects appear at significantly lower clinical doses. Based on the mechanism of sorafenib inhibition of multiple kinases and animal experimental results, it is speculated that sorafenib may be harmful to the fetus by pregnant women.

Breastfeeding women should stop breastfeeding during treatment with sorafenib.

Skin toxicity: Hand and foot skin reactions and rashes are the most common adverse reactions when taking sorafenib. Rash and hand, foot, and skin reactions are usually NCI CTCAE grades 1 to 2 and occur more than 6 weeks after starting sorafenib. Treatment of skin toxic reactions includes topical application to reduce symptoms, temporary discontinuation or / and dose adjustment of sorafenib. Sorafenib is permanently discontinued in patients with severe skin toxicity or persistent reactions.

Hypertension: The incidence of hypertension will increase in patients taking sorafenib. High blood pressure is usually mild to moderate, and it appears in the early stages after starting medication, which can be controlled with conventional antihypertensive drugs. Blood pressure should be monitored regularly and treated according to standard treatment protocols if necessary. Patients with severe or persistent hypertension or hypertensive crisis after application of antihypertensive drugs need to consider the permanent discontinuation of sorafenib.

Bleeding: Sorafenib treatment may increase the chance of bleeding. Severe bleeding is uncommon. Once the bleeding needs treatment, it is recommended to consider permanently discontinuing sorafenib.

Warfarin: Some patients taking both sorafenib and warfarin have occasional blood or elevated INR. Patients taking warfarin should regularly monitor changes in prothrombin time, INR value, and pay attention to signs of clinical bleeding.

Wound healing complications: The effects of taking sorafenib on wound healing have not been formally studied. Patients who need major surgery are advised to suspend sorafenib. Patients have limited clinical experience when to apply sorafenib after surgery. Therefore, patients should be considered clinically to ensure wound healing before deciding to take it again.

Myocardial ischemia and / or myocardial infarction: In trial 11213, treatment-related myocardial ischemia / myocardial infarction occurred more frequently in the sorafenib group (2.9%) than in the placebo group (0.4%). In trial 100554, the incidence of treatment-related ischemia / myocardial infarction was 2.7% in the sorafenib group and 1.3% in the placebo group. Patients with unstable coronary heart disease and patients with recent myocardial infarction were not included in these two trials. Patients with myocardial ischemia and / or myocardial infarction should consider temporarily or permanently discontinuing sorafenib.

QT interval prolongation: Sorafenib has been reported to extend the QT / QTc interval and increase the risk of ventricular arrhythmias. In a clinical pharmacological study, baseline (pre-treatment) and post-treatment QT / QTc measurements were performed on 31 patients. After a 28-day treatment cycle, QTcB was prolonged by 4 ± 19msec and QTcF was prolonged by 9 ± 18msec compared to the placebo-treated baseline at the time when the highest concentration of sorafenib was in vivo. During the electrocardiogram (ECG) monitoring after treatment, none of the patients had QTcB or QTcF greater than 500 msec. Therefore, patients with or who may develop QTc interval prolongation (eg, patients with congenital QT prolongation syndrome, patients treated with a high cumulative dose of anthracycline antibiotics, take antiarrhythmic drugs or other drugs that cause QT prolongation, Patients with electrolyte disorders such as hypokalemia, hypocalcemia, or hypomagnesemia) should be treated with caution with sorafenib. When sorafenib is used in these patients, regular monitoring of the electrocardiogram and electrolytes (magnesium, potassium, calcium) during treatment should be considered.

Gastrointestinal perforation: Gastrointestinal perforation is rare. Gastrointestinal perforation was reported in less than 1% of patients taking sorafenib. In some cases, gastrointestinal perforation has nothing to do with intra-abdominal tumors. Treatment of this product should be stopped.

Liver damage: There are no studies of patients taking Sorafenib in patients with severe liver damage (Child-Pugh Class C). Because sorafenib is primarily eliminated by the liver, its exposure to patients with severely impaired liver function will increase.

Drug-drug interaction:

UTG1A1 pathway: Caution is required when combining sorafenib with drugs metabolized / cleared by UTG1A1 (such as irinotecan) (see [Drug Interactions]).

Docetaxel: Previous studies have shown that when docetaxel (75mg / m or 100mg / m) is used in combination with sorafenib (0.2g or 0.4g twice daily) (sorafenib in Docetaxel is discontinued for three days), which can increase the AUC of docetaxel by 36% -80%. Caution is advised when using this product in combination with docetaxel (see [Drug Interactions]).

Neomycin: When used in combination with neomycin, it can lead to decreased bioavailability of sorafenib (see [Drug Interactions]).

Impact on driving and machine operation: There is currently no research on the effect of sorafenib on driving and machine operation. There is no evidence that sorafenib affects driving and machine operation. ^[4]

Sorafenib medications for pregnant and lactating women:

Sorafenib pregnancy

There are no sufficient clinical data on sorafenib in pregnant women. Animal experiments show that the drug has reproductive toxicity including teratogenicity. Sorafenib and its metabolites can pass through the placental barrier in rats, and it is speculated that sorafenib can inhibit fetal angiogenesis. Women of childbearing age should pay attention to contraception during treatment. If sorafenib is used during pregnancy, the patient should be informed of the possible harm the drug may cause to the fetus, including severe deformities (teratogenicity), developmental disorders and fetal death (embryo toxicity). Avoid sorafenib during pregnancy. It should only be used in pregnant women when the benefits of treatment outweigh the potential harm to the fetus.

Sorafenib women of childbearing age

Animal experiments show that sorafenib is teratogenic and embryotoxic. Adequate contraception should be taken during treatment and at least 2 weeks after the end of treatment.

Sorafenib breastfeeding

It is not known whether sorafenib can enter human milk. Animal experiments have shown that sorafenib and / or its metabolic routines can enter milk. Because many drugs are secreted from breast milk and the effects of sorafenib on infants have not been studied, women should stop breastfeeding during the treatment of this drug.

Sorafenib fertility

Animal experiments have shown that sorafenib can impair fertility in both men and women.

Sorafenib for children:

There are no data on the safety and efficacy of sorafenib in pediatric patients.

Sorafenib medication for the elderly:

There is no need to adjust the dose according to the age of the patient (over 65 years). ^[4]

Sorafenib drug interactions:

CYP3A4 inducer: There is no clinical data on the effect of CYP3A4 inducer on the metabolism of sorafenib. CYP3A4 inducers (such as rifampicin, St. John's wort (or St. John's wort, commonly known as St. John's wort), phenytoin, carbamazepine, phenobarbital, and dexamethasone) may accelerate sorafenib metabolism and therefore Rafinib drug concentration.

CYP3A4 inhibitor: Ketoconazole is a strong inhibitor of CYP3A4. Healthy male volunteers use ketoconazole once a day for 7 consecutive days while taking a single dose of sorafenib 50 mg daily. Unchanged. Therefore, CYP3A4 inhibitors are unlikely to affect the metabolism of sorafenib.
CYP2C9 substrate: Warfarin is a substrate for CYP2C9. The effects of sorafenib on warfarin were evaluated by comparing patients taking sorafenib with placebo. The mean PT-INR of patients treated with sorafenib and warfarin did not change compared to the placebo group. However, patients should be monitored regularly for INR when using warfarin.

CYP isoenzyme-selective substrates: Midazolam, dextromethorphan, and omeprazole are substrates for cytochromes CYP3A4, CYP2D6, and CYP2C19, respectively. Sorafenib in combination with the three drugs mentioned above does not change their exposure. This indicates that sorafenib is neither an inhibitor nor an inducer for the isoenzyme of cytochrome P450. In a clinical trial, the combination of paclitaxel with paclitaxel resulted in an increase, rather than a decrease, of 6-hydroxypaclitaxel (the active metabolite of paclitaxel metabolized by CYP2C8) in vivo. These data indicate that this product may not be an in vivo inhibitor of CYP2C8.
Interaction with other anti-tumor drugs: In clinical trials, sorafenib was combined with other conventional doses of anti-tumor drugs, including gemcitabine, oxaliplatin, paclitaxel, carboplatin, capecitabine, and archiex Vegetarian, irinotecan and docetaxel. Sorafenib does not affect the drug metabolism of gemcitabine and oxaliplatin.

Paclitaxel (225mg / m2) and carboplatin (AUC = 6) are used with this product (twice daily, 400mg each time) (this product is discontinued for 3 days before and after using paclitaxel / carboplatin). The pharmacokinetics of paclitaxel has a significant effect. Paclitaxel (225mg / m2, once every 3 weeks) and carboplatin (AUC = 6) combined with this product (0.4g, twice daily, without interruption of administration of this product) resulted in sorafenib exposure in vivo 47% increase, paclitaxel increased 29% in vivo, and 6-hydroxypaclitaxel increased 50%. Does not affect the pharmacokinetics of carboplatin. These data show that when paclitaxel and carboplatin are used with this product (3 days before and after paclitaxel / carboplatin is discontinued), no dose adjustment is required; and when combined and this product is not discontinued, The clinical significance of the increased in vivo exposure of this product and paclitaxel is unknown.

Capecitabine ( 750 mg / m21050mg / m2, twice a day, every 21 days as a cycle, administered on the first day to the 14th day) combined with this product (200mg or 400mg, twice a day, continuous administration When the drug was administered, it did not cause a significant change in the in vivo exposure of this product, but the in vivo exposure of capecitabine increased by 15% -50%, and the in vivo exposure of 5-FU increased by 0% -52%. A slight to moderate increase in capecitabine and 5-FU in vivo exposures, and its clinical significance is unknown.

When combined with sorafenib and doxorubicin, the AUC value of doxorubicin in patients can increase by 21%. When sorafenib and irinotecan are combined, because the active metabolite SN-38 of irinotecan is further metabolized by the UTG1A1 enzyme pathway, the combined use of the two causes the AUC of SN-38 to increase by 67% -120%. The AUC value increased by 26% -42%. The clinical significance associated with this is unknown.

Docetaxel (75mg / m2 or 100mg / m2, every 21 days) and sorafenib (in the 21-day treatment cycle, from day 2 to day 19, 0.2 g or 0.4 g is given twice daily Drug) combined application (sorafenib was discontinued for three days while taking docetaxel), can lead to an increase in AUC of docetaxel by 36% -80% and a Cmax increase of 16% -32%. Caution is recommended when using this product in combination with docetaxel.

Neomycin: Neomycin is a non-systemic absorption antibiotic used to eradicate the digestive tract flora. It affects sorafenib exposure by affecting the hepato-enteric circulation of sorafenib (see Clinical Pharmacology, Metabolism and Elimination). decrease. In healthy volunteers, the average bioavailability of sorafenib decreased by 54% after 5 days of neomycin treatment. The clinical significance of this decline is unknown. The effects of other antibiotics have not been studied, and the decline in sorafenib exposure caused by antibiotics is likely to be related to its weakening of glucuronidase activity. ^[4]

Sorafenib overdose:

There is no special treatment for overdose of sorafenib.

The highest dose of sorafenib was 0.8 g twice daily. The main adverse reactions observed at this dose were diarrhea and skin toxicities.

If overdose is suspected, the drug should be discontinued and the patient should be closely observed and corresponding supportive treatment should be given. ^[4]

Sorafenib Risk Bulletin

Sorafeni and osteonecrosis

Osteonecrosis is generally thought to be caused by insufficient local blood supply, so the main hypothesis of ONJ pathophysiology is that the blood vessels of the jawbone are inhibited. A growing body of literature links jaw bones and other osteonecrosis that occur after treatment with new antiangiogenic drugs (tyrosine kinase inhibitors and monoclonal antibodies that target vascular endothelial growth factor). Sorafenib has been listed as an antiangiogenic drug suspected of being associated with ONJ.
The current product information of Dorgemet (sorafenib) in the United States indicates that there has been a case report of ONJ after sorafenib was marketed. As of August 29, 2014, the World Health Organization (WHO) Global Case Safety Report Database System (VigiBase) has a total of 8 ONJ reports suspected of being related to sorafenib. As of July 31, 2014, Health Canada has not received an ONJ report suspected of being related to sorafenib.
Risk factors for ONJ include: radiotherapy, alveolar surgery (including extraction and implants), use of dentures, periodontal disease and other diseases (such as cancer, anemia and diabetes). Drugs that have been reported as risk factors for ONJ include anti-resorption drugs (such as bisphosphonates and denosumab), glucocorticoids, chemotherapy, and anti-angiogenesis drugs.
To reduce the risk of ONJ, it is recommended that patients maintain good oral hygiene. A thorough dental examination and proper oral precautions before treatment begins can effectively reduce the risk of drug-related ONJ. ^[7]