Sunitinib
Encyclopedia
Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase
(RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma
(RCC) and imatinib
-resistant gastrointestinal stromal tumor
(GIST) on January 26, 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications.
These include all receptors
for platelet-derived growth factor
(PDGF-Rs) and vascular endothelial growth factor
receptors (VEGFRs), which play a role in both tumor angiogenesis
and tumor cell proliferation. The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularization and cancer cell death, and ultimately tumor shrinkage.
Sunitinib also inhibits KIT (CD117
), the RTK that (when improperly activated by mutation) drives the majority of gastrointestinal stromal cell tumors. It has been recommended as a second-line therapy for patients whose tumors develop mutations in KIT that make them resistant to imatinib
, or who become intolerant to the drug.
In addition, sunitinib inhibits other RTKs. These include:
The fact that sunitinib targets many different receptors, leads to many of its side effects such as the classic hand-foot syndrome, stomatitis
, and other dermatologic
toxicities.
was the first cancer agent proven effective for metastatic GIST and represented a major development in the treatment of this rare but challenging disease. However, approximately 20% of patients do not respond to imatinib (early or primary resistance), and among those who do respond initially, 50% develop secondary imatinib resistance and disease progression within 2 years. Prior to sunitinib, patients had no therapeutic option once they became resistant to imatinib.
Sunitinib offers patients with imatinib-resistant GIST a new treatment option to stop further disease progression and, in some cases, even reverse it. This was shown in a large, Phase III clinical trial in which patients who failed imatinib therapy (due to primary resistance, secondary resistance, or intolerance) were treated in a randomized and blinded fashion with either sunitinib or placebo.
The study was unblinded early, at the very first interim analysis, due to the clearly emerging benefit of sunitinib. At that time, patients receiving placebo were offered to switch over to sunitinib. In the primary endpoint
of this study, median time to tumor progression (TTP) was more than 4-fold longer with sunitinib (27 weeks) compared with placebo (6 weeks, P<.0001). These are based on the assessments of an independent radiology lab assessment. The benefit of sunitinib remained statistically significant when stratified for a multitude of prespecified baseline factors.
Among the secondary endpoints
, the difference in progression-free survival (PFS) was similar to that in TTP (24 weeks vs 6 weeks, P<.0001). 7% of sunitinib patients had significant tumor shrinkage (objective response) compared with 0% of placebo patients (P=.006). Another 58% of sunitinib patients had disease stabilization vs. 48% of patients receiving placebo. The median time to response with sunitinib was 10.4 weeks.
Sunitinib reduced the relative risk of disease progression or death by 67%, and the risk of death alone by 51%. The difference in survival benefit may be diluted by the fact that placebo patients crossed over to sunitinib upon disease progression, and most of these patients subsequently responded to sunitinib.
Sunitinib was relatively well tolerated. 83% of sunitinib patients experienced a treatment-related adverse event of any severity, as did 59% of patients who received placebo. Serious adverse events were reported in 20% of sunitinib patients and 5% of placebo patients. Adverse events were generally moderate and easily managed by dose reduction, dose interruption, or other treatment. 9% of sunitinib patients and 8% of placebo patients discontinued therapy due to an adverse event.
Fatigue is the adverse event most commonly associated with sunitinib therapy. In this study, 34% of sunitinib patients reported any grade of fatigue, compared with 22% for placebo. The incidence of grade 3 (severe) fatigue was similar between the two groups, and there was no grade 4 fatigue reported.
which is associated with Neurofibromatosis
.
patients with 'progressive neuroendocrine cancerous tumors located in the pancreas that cannot be removed by surgery or that have spread to other parts of the body (metastatic)'.
(Nexavar), temsirolimus
(Torisel), interleukin-2 (Proleukin), everolimus
(Affinitor), and bevacizumab
(Avastin).
RCC is generally resistant to chemotherapy or radiation. Prior to RTKs, metastatic disease could only be treated with the cytokines interferon alpha (IFNα) or Interleukin 2
(IL-2). However, these agents demonstrated low rates of efficacy (5%-20%).
In a phase 3 study, median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), hazard ratio 0.42. In the secondary endpoints, 28% of had significant tumor shrinkage with sunitinib compared to 5% with IFNα. Patients receiving sunitinib had a better quality of life than IFNα.
At ASCO 2008, Dr Robert Figlin presented updated data from the final study analysis, including overall survival. The primary endpoint of median progression-free survival (PFS) remained superior with sunitinib: 11 months versus 5 months for IFNα, P<.000001. Objective response rate also remained superior: 39-47% for sunitinib versus 8-12% with IFNα, P<.000001.
Sunitinib was associated with somewhat longer overall survival, although this was not statistically significant.
This was the largest comparative trial in RCC to date, and sunitinib is the first agent to demonstrate an overall survival longer than 2 years in these patients.
Hypertension was found to be a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. Patients with mRCC and sunitinib-induced hypertension had better outcomes than those without treatment-induced HTN (objective response rate: 54.8% vs 8.7%; median PFS: 12.5 months, 95% confidence interval [CI] = 10.9 to 13.7 vs 2.5 months, 95% CI = 2.3 to 3.8 months; and OS: 30.9 months, 95% CI = 27.9 to 33.7 vs 7.2 months, 95% CI = 5.6 to 10.7 months; P < .001 for all).
activities of KIT, PDGFR, VEGFR2 and other tyrosine kinases that are involved in the development of tumours.
a biotechnology company which pioneered protein kinase inhibitors. It was the third in a series of compounds including SU5416 (Semaxanib
) and SU6668. The concept was of a ATP analogue that would compete with ATP
for binding to the catalytic site of receptor tyrosine kinase
s. This concept led to the invention of many small-molecule tyrosine kinase inhibitors including Gleevec, Sutent, Tarceva and many other cancer drugs.
The most common adverse events associated with sunitinib therapy are fatigue, diarrhea, nausea, anorexia, hypertension, a yellow skin discoloration, hand-foot skin reaction, and stomatitis. In the placebo-controlled Phase III GIST study, adverse events which occurred more often with sunitinib than placebo included diarrhea, anorexia, skin discoloration, mucositis/stomatitis, asthenia, altered taste, and constipation.
Dose reductions were required in 50% of the patients studied in RCC in order to manage the significant toxicities of this agent.
Serious (grade 3 or 4) adverse events occur in ≤10% of patients and include hypertension, fatigue, asthenia, diarrhea, and chemotherapy-induced acral erythema. Lab abnormalities associated with sunitinib therapy include lipase, amylase, neutrophils, lymphocytes, and platelets. Hypothyroidism and reversible erythrocytosis have also been associated with sunitinib.
Most adverse events can be managed through supportive care, dose interruption, or dose reduction.
The efficacy of the dose reduced sub-group has never been published.
sunitinib when they are taken together.
as Sutent, and is subject to patent
s and market exclusivity as a new chemical entity until February 15, 2021. Sutent has been cited in financial news as a potential revenue source to replace royalties lost from Lipitor following the expiration of the latter drug's patent expiration in November 2011. Sutent is one of the most expensive drugs widely marketed. Doctors and editorials have criticized the high cost, for a drug that doesn't cure cancer but only prolongs life.
" for Medicare
part D
coverage. Patients have to spend thousands of dollars out of pocket to get through the donut hole. If this is done at the end of a calendar year, it has to be paid again at the beginning of the next calendar year which may be burdensome financially.
refused (late 2008) to recommend sunitinib for late stage renal cancer (kidney cancer) due to the high cost per QALY, estimated by NICE at £72,000/QALY and by Pfizer at £29,000/QALY.
This was overturned in Feb 2009 after pricing changes and public responses.
for this chemical from commercially available precursors is disclosed in US patent 6573293, together with nuclear magnetic resonance
and mass spectrometry
data to assist in characterizing intermediates. It proceeds in the following conceptual steps:
5-fluoroisatin
is reacted with hydrazine
hydrate, a highly reactive base
which bonds to the compound by opening the indole
ring. The resulting compound is then reacted with 12 N HCl
, a strong acid
which effectively strips away the hydrazine and recloses the ring. The net effect is a net reduction at the 3-position of the indole ring, with two hydrogens replacing the ketone
.
3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester is a somewhat uncommon precursor, sometimes sold as a "Sunitinib intermediate", citing the U.S. research exemption to patent law. This compound is decarboxylated in the presence of strong acid, losing the t-BOC unit. The compound is then subjected to a formylation reaction
(the Vilsmeier-Haack reaction
), which uses dimethylformamide
in the presence of phosphorus oxychloride to attach a formyl group to the site on the arene
ring which was opened by the previous reaction. The product is then extracted by phase separation.
The product of the preceding reaction is now modified at the other carboxylic acid
group on the pyrrole ring by refluxing the ester
in water with strong base
(potassium hydroxide
). This hydrolysis
releases a free carboxylic acid which is then modified by a 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDCI) in the presence of hydroxybenzotriazole
(HOBT). (See carbodiimide
for further information) The primary amine of diethylethylenediamine reacts with this over the course of a 20-hour reaction to produce 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide.
The final step, not shown, is to mix the final products from the first and third figures above in ethanol
and pyrrolidine
at 78 C for three hours, producing sunitinib. (See Aldol condensation
)
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
(RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
(RCC) and imatinib
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
-resistant gastrointestinal stromal tumor
Gastrointestinal stromal tumor
A gastrointestinal stromal tumor is one of the most common mesenchymal tumors of the gastrointestinal tract...
(GIST) on January 26, 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications.
Mechanism of action
Sunitinib inhibits cellular signaling by targeting multiple receptor tyrosine kinases (RTKs).These include all receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
for platelet-derived growth factor
Platelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...
(PDGF-Rs) and vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
receptors (VEGFRs), which play a role in both tumor angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
and tumor cell proliferation. The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularization and cancer cell death, and ultimately tumor shrinkage.
Sunitinib also inhibits KIT (CD117
CD117
Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...
), the RTK that (when improperly activated by mutation) drives the majority of gastrointestinal stromal cell tumors. It has been recommended as a second-line therapy for patients whose tumors develop mutations in KIT that make them resistant to imatinib
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
, or who become intolerant to the drug.
In addition, sunitinib inhibits other RTKs. These include:
- RETRET proto-oncogeneThe RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
- CSF-1RGranulocyte colony-stimulating factorGranulocyte colony-stimulating factor is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 ....
- flt3CD135Cluster of differentiation antigen 135 also known as Fms-like tyrosine kinase 3 or receptor-type tyrosine-protein kinase FLT3 is a protein that in humans is encoded by the FLT3 gene...
The fact that sunitinib targets many different receptors, leads to many of its side effects such as the classic hand-foot syndrome, stomatitis
Stomatitis
Stomatitis is an inflammation of the mucous lining of any of the structures in the mouth, which may involve the cheeks, gums, tongue, lips, throat, and roof or floor of the mouth...
, and other dermatologic
Dermatology
Dermatology is the branch of medicine dealing with the skin and its diseases, a unique specialty with both medical and surgical aspects. A dermatologist takes care of diseases, in the widest sense, and some cosmetic problems of the skin, scalp, hair, and nails....
toxicities.
Gastrointestinal stromal tumor
Like RCC, GIST does not generally respond to standard chemotherapy or radiation. ImatinibImatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
was the first cancer agent proven effective for metastatic GIST and represented a major development in the treatment of this rare but challenging disease. However, approximately 20% of patients do not respond to imatinib (early or primary resistance), and among those who do respond initially, 50% develop secondary imatinib resistance and disease progression within 2 years. Prior to sunitinib, patients had no therapeutic option once they became resistant to imatinib.
Sunitinib offers patients with imatinib-resistant GIST a new treatment option to stop further disease progression and, in some cases, even reverse it. This was shown in a large, Phase III clinical trial in which patients who failed imatinib therapy (due to primary resistance, secondary resistance, or intolerance) were treated in a randomized and blinded fashion with either sunitinib or placebo.
The study was unblinded early, at the very first interim analysis, due to the clearly emerging benefit of sunitinib. At that time, patients receiving placebo were offered to switch over to sunitinib. In the primary endpoint
End point of clinical trials
An endpoint is something which is measured in a clinical trial or study. Measuring the selected endpoints is the goal of a trial. The response rate and survival are examples of the endpoints....
of this study, median time to tumor progression (TTP) was more than 4-fold longer with sunitinib (27 weeks) compared with placebo (6 weeks, P<.0001). These are based on the assessments of an independent radiology lab assessment. The benefit of sunitinib remained statistically significant when stratified for a multitude of prespecified baseline factors.
Among the secondary endpoints
End point of clinical trials
An endpoint is something which is measured in a clinical trial or study. Measuring the selected endpoints is the goal of a trial. The response rate and survival are examples of the endpoints....
, the difference in progression-free survival (PFS) was similar to that in TTP (24 weeks vs 6 weeks, P<.0001). 7% of sunitinib patients had significant tumor shrinkage (objective response) compared with 0% of placebo patients (P=.006). Another 58% of sunitinib patients had disease stabilization vs. 48% of patients receiving placebo. The median time to response with sunitinib was 10.4 weeks.
Sunitinib reduced the relative risk of disease progression or death by 67%, and the risk of death alone by 51%. The difference in survival benefit may be diluted by the fact that placebo patients crossed over to sunitinib upon disease progression, and most of these patients subsequently responded to sunitinib.
Sunitinib was relatively well tolerated. 83% of sunitinib patients experienced a treatment-related adverse event of any severity, as did 59% of patients who received placebo. Serious adverse events were reported in 20% of sunitinib patients and 5% of placebo patients. Adverse events were generally moderate and easily managed by dose reduction, dose interruption, or other treatment. 9% of sunitinib patients and 8% of placebo patients discontinued therapy due to an adverse event.
Fatigue is the adverse event most commonly associated with sunitinib therapy. In this study, 34% of sunitinib patients reported any grade of fatigue, compared with 22% for placebo. The incidence of grade 3 (severe) fatigue was similar between the two groups, and there was no grade 4 fatigue reported.
Meningioma
Sunitinib is being studied for treatment of meningiomaMeningioma
The word meningioma was first used by Harvey Cushing in 1922 to describe a tumor originating from the meninges, the membranous layers surrounding the CNS ....
which is associated with Neurofibromatosis
Neurofibromatosis
Neurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...
.
Pancreatic neuroendocrine tumors
In Nov 2010 Sutent gained approval from the European Commission for the treatment of 'unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults'. In May 2011, the USFDA approved Sunitininb for treatingpatients with 'progressive neuroendocrine cancerous tumors located in the pancreas that cannot be removed by surgery or that have spread to other parts of the body (metastatic)'.
Renal cell carcinoma
Sunitinib is approved for treatment of metastatic RCC. Other therapeutic options in this setting are sorafenibSorafenib
Sorafenib , is a drug approved for the treatment of primary kidney cancer and advanced primary liver cancer ....
(Nexavar), temsirolimus
Temsirolimus
Temsirolimus is an intravenous drug for the treatment of renal cell carcinoma , developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration in late May 2007, and was also approved by the European Medicines Agency on November 2007...
(Torisel), interleukin-2 (Proleukin), everolimus
Everolimus
Everolimus is the 40-O- derivative of sirolimus and works similarly to sirolimus as an mTOR inhibitor....
(Affinitor), and bevacizumab
Bevacizumab
Bevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas....
(Avastin).
RCC is generally resistant to chemotherapy or radiation. Prior to RTKs, metastatic disease could only be treated with the cytokines interferon alpha (IFNα) or Interleukin 2
Interleukin 2
Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
(IL-2). However, these agents demonstrated low rates of efficacy (5%-20%).
In a phase 3 study, median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), hazard ratio 0.42. In the secondary endpoints, 28% of had significant tumor shrinkage with sunitinib compared to 5% with IFNα. Patients receiving sunitinib had a better quality of life than IFNα.
At ASCO 2008, Dr Robert Figlin presented updated data from the final study analysis, including overall survival. The primary endpoint of median progression-free survival (PFS) remained superior with sunitinib: 11 months versus 5 months for IFNα, P<.000001. Objective response rate also remained superior: 39-47% for sunitinib versus 8-12% with IFNα, P<.000001.
Sunitinib was associated with somewhat longer overall survival, although this was not statistically significant.
- Median OS was 26 months with sunitinib vs 22 months for IFNα regardless of stratification (P-value ranges from .051 to .0132, depending on statistical analysis).
- The first analysis includes 25 patients initially randomized to IFNα who crossed over to sunitinib therapy, which may have confounded the results; in an exploratory analysis that excluded these patients, the difference becomes more robust: 26 vs 20 months, P=.0081.
- Patients in the study were allowed to receive other therapies once they had progressed on their study treatment. For a “pure” analysis of the difference between the two agents, an analysis was done using only patients who did not receive any post-study treatment. This analysis demonstrated the greatest advantage for sunitinib: 28 months vs 14 months for IFNα, P=.0033. The number of patients in this analysis was small and this does not reflect actual clinical practice and is therefore not meaningful.
- Also worth noting in this presentation was the fact that the updated percentage of patients that had to discontinue sunitinib due to adverse events was 19%. This is a clinically meaningful number.
This was the largest comparative trial in RCC to date, and sunitinib is the first agent to demonstrate an overall survival longer than 2 years in these patients.
Hypertension was found to be a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. Patients with mRCC and sunitinib-induced hypertension had better outcomes than those without treatment-induced HTN (objective response rate: 54.8% vs 8.7%; median PFS: 12.5 months, 95% confidence interval [CI] = 10.9 to 13.7 vs 2.5 months, 95% CI = 2.3 to 3.8 months; and OS: 30.9 months, 95% CI = 27.9 to 33.7 vs 7.2 months, 95% CI = 5.6 to 10.7 months; P < .001 for all).
Other solid tumors
The efficacy of sunitinib is currently being evaluated in a broad range of solid tumors, including breast, lung, thyroid and colorectal cancers. Early studies have shown single-agent efficacy in a number of different areas. Sunitinib blocks the tyrosine kinaseTyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
activities of KIT, PDGFR, VEGFR2 and other tyrosine kinases that are involved in the development of tumours.
- A Phase II study in previously-treated patients with metastatic breast cancer found that sunitinib “has significant single agent activity”
- A Phase II study of refractory non-small-cell lung cancer found that “Sunitinib has provocative single-agent activity in previously treated pts with recurrent and advanced NSCLC, with the level of activity similar to currently approved agents.”
- In a Phase II study of patients with nonresectable neuroendocrine tumors (NET), 91% of patients responded to sunitinib (9% partial response + 82% stable disease)
Unsuccessful trials
Between April 2009 and May 2011 Pfizer has reported unsuccessful late-stage trials in breast cancer, metastatic colorectal cancer, advanced non-small-cell lung cancer, and castration-resistant prostate cancer.History
The drug was discovered at SUGENSUGEN
SUGEN was a drug discovery company focused on development of protein kinase inhibitors. It was founded in 1991, and shut down in 2003, after pioneering protein kinases as therapeutic targets and developing the successful cancer therapy sunitinib .-Early history and focus:Sugen was founded in 1991...
a biotechnology company which pioneered protein kinase inhibitors. It was the third in a series of compounds including SU5416 (Semaxanib
Semaxanib
Semaxanib is a tyrosine-kinase inhibitor drug designed by SUGEN as a cancer therapeutic. It is an experimental stage drug, not licensed for use on human patients outside of clinical trials....
) and SU6668. The concept was of a ATP analogue that would compete with ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
for binding to the catalytic site of receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
s. This concept led to the invention of many small-molecule tyrosine kinase inhibitors including Gleevec, Sutent, Tarceva and many other cancer drugs.
Side effects
Sunitinib has been generally well tolerated. Adverse events were considered somewhat manageable and the incidence of serious adverse events low.The most common adverse events associated with sunitinib therapy are fatigue, diarrhea, nausea, anorexia, hypertension, a yellow skin discoloration, hand-foot skin reaction, and stomatitis. In the placebo-controlled Phase III GIST study, adverse events which occurred more often with sunitinib than placebo included diarrhea, anorexia, skin discoloration, mucositis/stomatitis, asthenia, altered taste, and constipation.
Dose reductions were required in 50% of the patients studied in RCC in order to manage the significant toxicities of this agent.
Serious (grade 3 or 4) adverse events occur in ≤10% of patients and include hypertension, fatigue, asthenia, diarrhea, and chemotherapy-induced acral erythema. Lab abnormalities associated with sunitinib therapy include lipase, amylase, neutrophils, lymphocytes, and platelets. Hypothyroidism and reversible erythrocytosis have also been associated with sunitinib.
Most adverse events can be managed through supportive care, dose interruption, or dose reduction.
The efficacy of the dose reduced sub-group has never been published.
Interactions
Epigallocatechin-3-gallate, a major constituent of green tea, may reduce the bioavaialbiltyBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
sunitinib when they are taken together.
Costs
Sunitinib is marketed by PfizerPfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
as Sutent, and is subject to patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
s and market exclusivity as a new chemical entity until February 15, 2021. Sutent has been cited in financial news as a potential revenue source to replace royalties lost from Lipitor following the expiration of the latter drug's patent expiration in November 2011. Sutent is one of the most expensive drugs widely marketed. Doctors and editorials have criticized the high cost, for a drug that doesn't cure cancer but only prolongs life.
US
In the U.S., insurance companies have refused to pay for all or part of the costs of Sutent. Because Sutent is an oral therapy, the "co-pay" associated with this therapy can be very substantial. If a patient's secondary insurance does not cover this, the cost burden to the patient can be extreme. Particularly challenging is the "donut holeDonut Hole (Medicare)
The Medicare Part D coverage gap — informally known as the Medicare donut hole — is the difference of the initial coverage limit and the catastrophic coverage threshold, as described in the Medicare Part D prescription drug program administered by the United States federal government...
" for Medicare
Medicare (United States)
Medicare is a social insurance program administered by the United States government, providing health insurance coverage to people who are aged 65 and over; to those who are under 65 and are permanently physically disabled or who have a congenital physical disability; or to those who meet other...
part D
Medicare Part D
Medicare Part D is a federal program to subsidize the costs of prescription drugs for Medicare beneficiaries in the United States. It was enacted as part of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 and went into effect on January 1, 2006.- Eligibility and...
coverage. Patients have to spend thousands of dollars out of pocket to get through the donut hole. If this is done at the end of a calendar year, it has to be paid again at the beginning of the next calendar year which may be burdensome financially.
UK
In the UK NICENICE
NICE may refer to:* National Independent Cadres and Elites in Iraq* National Institute for Coordinated Experiments, a fictional organisation in C.S...
refused (late 2008) to recommend sunitinib for late stage renal cancer (kidney cancer) due to the high cost per QALY, estimated by NICE at £72,000/QALY and by Pfizer at £29,000/QALY.
This was overturned in Feb 2009 after pricing changes and public responses.
Synthesis
The organic synthesisOrganic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
for this chemical from commercially available precursors is disclosed in US patent 6573293, together with nuclear magnetic resonance
Nuclear magnetic resonance
Nuclear magnetic resonance is a physical phenomenon in which magnetic nuclei in a magnetic field absorb and re-emit electromagnetic radiation...
and mass spectrometry
Mass spectrometry
Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...
data to assist in characterizing intermediates. It proceeds in the following conceptual steps:
5-fluoroisatin
Isatin
Isatin or 1H-indole-2,3-dione is an indole derivative. The compound was first obtained by Erdman and Laurent in 1841 as a product from the oxidation of indigo dye by nitric acid and chromic acids...
is reacted with hydrazine
Hydrazine
Hydrazine is an inorganic compound with the formula N2H4. It is a colourless flammable liquid with an ammonia-like odor. Hydrazine is highly toxic and dangerously unstable unless handled in solution. Approximately 260,000 tons are manufactured annually...
hydrate, a highly reactive base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
which bonds to the compound by opening the indole
Indole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...
ring. The resulting compound is then reacted with 12 N HCl
HCL
HCL or HCl can stand for:* Hairy cell leukemia, an uncommon and slowly progressing B cell leukemia* Hardware compatibility list...
, a strong acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
which effectively strips away the hydrazine and recloses the ring. The net effect is a net reduction at the 3-position of the indole ring, with two hydrogens replacing the ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
.
3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester is a somewhat uncommon precursor, sometimes sold as a "Sunitinib intermediate", citing the U.S. research exemption to patent law. This compound is decarboxylated in the presence of strong acid, losing the t-BOC unit. The compound is then subjected to a formylation reaction
Formylation reaction
A formylation reaction in organic chemistry is the catch-all name for any organic reaction in which an organic compound is functionalized with a formyl group .Aromatic formylation reactions via electrophilic aromatic substitution include:...
(the Vilsmeier-Haack reaction
Vilsmeier-Haack reaction
The Vilsmeier–Haack reaction is the chemical reaction of a substituted amide with phosphorus oxychloride and an electron-rich arene to produce an aryl aldehyde or ketone . The reaction is named after Anton Vilsmeier and Albrecht Haack...
), which uses dimethylformamide
Dimethylformamide
Dimethylformamide is an organic compound with the formula 2NCH. Commonly abbreviated as DMF , this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions...
in the presence of phosphorus oxychloride to attach a formyl group to the site on the arene
Arene
Arene or Arênê or Arène may refer to:*an aromatic hydrocarbon*Arene , a genus of marine snails in the family Areneidae*Arene , the wife of Aphareus and mother of Idas and Lynceus in Greek mythology...
ring which was opened by the previous reaction. The product is then extracted by phase separation.
The product of the preceding reaction is now modified at the other carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
group on the pyrrole ring by refluxing the ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
in water with strong base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
(potassium hydroxide
Potassium hydroxide
Potassium hydroxide is an inorganic compound with the formula KOH, commonly called caustic potash.Along with sodium hydroxide , this colorless solid is a prototypical strong base. It has many industrial and niche applications. Most applications exploit its reactivity toward acids and its corrosive...
). This hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
releases a free carboxylic acid which is then modified by a 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
EDC is a water soluble carbodiimide usually obtained as the hydrochloride. It is typically employed in the 4.0-6.0 pH range. It is generally used as a carboxyl activating agent for the coupling of primary amines to yield amide bonds...
(EDCI) in the presence of hydroxybenzotriazole
Hydroxybenzotriazole
Hydroxybenzotriazole is an organic compound that is a derivative of benzotriazole. It is mainly used to suppress racemization and improve the efficiency of peptide synthesis. It is a white crystalline powder...
(HOBT). (See carbodiimide
Carbodiimide
A carbodiimide or a methanediimine is a functional group consisting of the formula RN=C=NR. Carbodiimides hydrolyze to form ureas, which makes them uncommon in nature.-Carbodiimide formation:...
for further information) The primary amine of diethylethylenediamine reacts with this over the course of a 20-hour reaction to produce 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide.
The final step, not shown, is to mix the final products from the first and third figures above in ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
and pyrrolidine
Pyrrolidine
Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula C4H9N. It is a cyclic secondary amine with a five-membered heterocycle containing four carbon atoms and one nitrogen atom...
at 78 C for three hours, producing sunitinib. (See Aldol condensation
Aldol condensation
An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by a dehydration to give a conjugated enone....
)
External links
- Sutent.com — Manufacturer's site
- The Life Raft Group-The Life Raft Group (LRG) is an organization that provides support, information and assistance to patients and families with a rare cancer called Gastrointestinal Stromal Tumor (GIST).
- GIST Support International — An international organization for the support of GIST patients, families, and friends. Includes detailed information from some of the foremost experts on GIST, links to research, treatment options, and GIST registry.
- Kidney Cancer Association — An organization that educates physicians and patients about kidney cancer; funds, promotes, and collaborates on research projects; and advocates at the federal and state levels on behalf of patient interests.
- http://mpablog.typepad.com/david_foster Cancer veteran's blog with two years experience with Sutent, Nexavar and chemo.
- Cancer Management Handbook: Principles of Oncologic Pharmacotherapy