"SORAFENIB"

Course Title: Human Physiology and Anatomy-IV

Course Code: 2209

Submitted By :
Joyosree Sarker Submitted To :
Id: 181025 Md Nazmul Hasan Zilani
2nd Year; 2nd Semester Lecturer
Session: 2018-19
Department of Pharmacy
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Jashore University of Science and Technology

01 02 03 04
Dosage and Molecular
Introduction Pharmacology
Administration Mechanism

CONTENTS
05
Drug
Interactions

09 08 07 06
Adverse Contra-
Precautions Indications
Effects indications
 Introduction :
Sorafenib, a Kinase Inhibitor ; is the tosylate salt of
sorafenib drug approved for the treatment of primary kidney
cancer (advanced renal cell carcinoma), advanced primary liver
cancer (hepatocellular carcinoma), FLT3-ITD positive AML and
radioactive iodine resistant advanced thyroid carcinoma.
✓ It is a chemotherapy drug that works by slowing or stopping the
growth of cancer cells.

Brand Name: Nexavar

Figure: Sorafenib 3
(C21H16ClF3N4O3)
Dosage and Administration :

Dosage Administration
* The recommended dose * For oral use.
of Nexavar in adults is 400 mg * It is recommended that
sorafenib (two tablets of 200 sorafenib should be administered
mg) twice daily (equivalent to a without food or with a low or
total daily dose of 800 moderate fat meal. If the patient
mg).Treatment should continue intends to have a high-fat meal,
as long as clinical benefit is sorafenib tablets should be taken
observed or until unacceptable at least 1 hour before or 2 hours
toxicity occurs. after the meal. The tablets should
be swallowed with a glass of
water.

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Pharmacology of Sorafenib:
Pharmacokinetics
Absorption:
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.

Distribution:
In vitro binding of sorafenib to human plasma proteins was 99.5%.

Metabolism:
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. 5
 Excretion:
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.

Pharmacodynamics
The effect of NEXAVAR 400 mg after taking twice daily, No large
changes in QTc interval were observed. After one 28-day treatment
cycle, the largest mean QTc interval change of 8.5 ms (upper
bound of two-sided 90% confidence interval, 13.3 ms) was
observed at 6 hours post-dose on day 1 of cycle 2.

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Molecular Mechanism of Sorafenib:
Sorafenib is a type of biological therapy called a protein tyrosine
kinase inhibitor (TKI) .Tyrosine kinase is a protein which acts as a
chemical messenger (an enzyme).

Sorafenib blocks a number of protein kinases and is called a multi

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, 7

VEGFR-2, VEGFR-3, and

PDGFR-B).
Several of these kinases are
thought to be involved in
tumer cell signaling,
angiogenesis and apoptosis.

Sorafenib inhibited tumor growth of human hepatocellular

carcinoma( HCC), renal cell carcinoma RCC), and Differentiated
thyroid carcinoma (DTC).

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.

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 Basically, Sorafenib works on tumer cells
and tumer vessels in two ways :

By Blocking tumor cell signals By Reducing the formation of

so that cancer cells can not new blood vessels that provide
grow and divide oxygen and nutrients needed
for cancer cells to keep growing

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 Drug Interactions of Sorafenib:

Continuous co-administration of sorafenib and rifampicin

CYP3A4 resulted in an average 37% reduction of sorafenib AUC.Other
Inducers inducers of CYP3A4 activity may also increase metabolism of
sorafenib and thus decrease sorafenib concentrations.

Ketoconazole, a strong inhibitor of CYP3A4 and P-

CYP3A4 glycoprotein, administered at a dose of 400 mg once daily for 7
Inhibitors days did not alter the mean AUC of a single oral dose of
NEXAVAR 50 mg in healthy volunteers.

Effect of NEXAVAR 400 mg twice daily for 28 days did not increase the
sorafenib systemic exposure of concomitantly administered midazolam
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on other (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate),
drugs and omeprazole (CYP2C19 substrate)
 UGT1A1 Sorafenib inhibits glucuronidation by the UGT1A1 and
and UGT1A9 pathways. Systemic exposure to substrates of
UGT1A9 UGT1A1 and UGT1A9, such as acetaminophen, may therefore
increase when co-administered with sorafenib.
Substrates

Neomycin administered as an oral dose of 1 g three times

daily for 5 days decreased the mean AUC of sorafenib by 54%
Neomycin in healthy volunteers administered a single oral dose of
NEXAVAR 400 mg.

The aqueous solubility of sorafenib is pH dependent, with

Drugs That higher pH resulting in lower solubility. Omeprazole, a proton
Increase pump inhibitor, administered at a dose of 40 mg once daily for
Gastric pH 5 days, did not result in a clinically meaningful change in
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sorafenib single dose exposure.
Indications of Sorafenib:

Kidney cancer:
For treatment of locally advanced/metastatic
1 clear cell Renal Cell Carcinoma (RCC) in
patients who have failed or are intolerant of
prior systemic therapy.

Liver cancer:
For the treatment of patients with
unresectable Hepato Cellular Carcinoma
(HCC). Combination of sorafenib
and DEB-TACE in patients with
2
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unresectable HCC is well tolerated and safe.
 Thyroid cancer:
For the treatment of patients with locally

3 recurrent or metastatic, progressive,

Differentiated thyroid carcinoma (DTC)
that is refractory to radioactive iodine
treatment.

Desmoid tumors:
Clinical trial is under way testing the
effectiveness of Sorafenib to treat
desmoid tumors (also known
4
as aggressive fibromatosis).

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Contraindications of Sorafenib:

• NEXAVAR is contraindicated in patients with known

severe hypersensitivity to sorafenib or any other component
of NEXAVAR.

• NEXAVAR in combination with carboplatin and

paclitaxel is contraindicated in patients with squamous cell
lung cancer .

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 Cardiac
ischemia,infarc-
Hand-foot skin
tion, Congestive
reaction, rash, heart failure Hemorrhage,
Stevens-Johnson Hyper-tension,
syndrome, and Hypophos-
toxic epidermal
necrolysis
Adverse Phataemia

Gastrointestinal
Effects of QT Interval
perforation, Sorafenib Prolongation,
Nausea, Drug-Induced
diarrhea,fatigue, hepatitis ,
weight loss, Leucopenia,
Impairment of TSH
abdominal pain Anaemia,
suppression in DTC
Hypocalcaemia,
Hypokalaemia, 15

Depression, kidney
failure
 Precautions of Sorafenib:
★ Hemorrhage:
Discontinue sorafenib if Drug-Induced
needed.
★ Gastrointestinal
1 2 Hepatitis: Discontinue
sorafenib for unexplained
Perforation: transaminase elevations.
Discontinue Sorafenib

★Embryofetal Hypertension:
toxicity: Advise woman
of potential risk to fetus. 3 4 Monitor blood pressure
weekly during 1st 6
★Cardiac
ischemia/infarction: weeks of therapy and
Temporary/permanent periodically there
discontinuation after.

★ Dermatologic
toxicities:
5 6 QT prolongation:
Monitor electro-
Interrupt/decrease dose. cardiograms and 16
★ Impairment of electrolytes in patients at
TSH suppression in increased risk for
DTC ventricular arrhythmias
Reference:
• https://en.m.wikipedia.org/wiki/Sorafenib

• https://www.rxlist.com/nexavar-drug.htm#interactions

• https://www.webmd.com/drugs/2/drug-94784/sorafenib-
oral/details

• https://reference.medscape.com/drug/nexavar-sorafenib-342260

• https://medlineplus.gov/druginfo/meds/a607051.html

• https://go.drugbank.com/drugs/DB00398

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