Nilotinib, sold under the brand name Tasigna marketed worldwide by

Novartis Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-lo ...

, is a medication used to treat

chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumul ...

(CML) which has the

Philadelphia chromosome The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...

. It may be used both in initial cases of chronic phase CML as well as in accelerated and chronic phase CML that has not responded to imatinib. It is taken by mouth. Common side effects may include low platelets,

low white blood cells Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of in ...

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

, rashes, vomiting,

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

, and joint pains. Other serious side effects may include

QT prolongation Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, ...

, sudden death,

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic p ...

, and liver problems. It is not safe for use during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

. Nilotinib is a

Bcr-Abl tyrosine kinase inhibitor Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadelp ...

and works by interfering with signalling within the cancer cell. Nilotinib was approved for medical use in the United States in 2007. It is on the World Health Organization's List of Essential Medicines.

Medical uses

Nilotinib is used to treat

(Ph+)-positive

chronic myelogenous leukaemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulat ...

Adverse effects

Nilotinib has a number of adverse effects including headache, fatigue, gastrointestinal problems such as nausea, vomiting, diarrhea and constipation, muscle and joint pain,

rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...

and other skin conditions, flu-like symptoms, and reduced blood cell count. Less typical side effects are those of the cardiovascular system, such as high blood pressure, various types of arrhythmia, and prolonged

QT interval The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken ...

. Nilotinib can also affect the body's

electrolyte An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon ...

and

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

balance. Though lung-related adverse effects are rare when compared with imatinib and dasatinib, there is a case report of acute respiratory failure from diffuse alveolar hemorrhage in a people taking nilotinib. Nilotinib carries a

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that i ...

in the United States for possible heart complications. Contraindications include

long QT syndrome Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, ...

hypokalaemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abnorm ...

, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/ lactose intolerance. Cautions include: * Myelosuppression * Tumour lysis syndrome * Liver impairment * History of pancreatitis * Check serum lipase periodically in order to detect pancreatitis * Total gastrectomy * Avoid pregnancy or impregnating women Dose reduction has been recommended in people with liver problems which involves recommendation of lower starting dose and monitoring of any hepatic function abnormalities. Hepatitis B virus reactivation may also occur.

Interactions

Nilotinib has been reported as a substrate for OATP1B1 and OATP1B3. Interaction of nilotinib with OATP1B1 and OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions. Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3. It is a substrate for

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...

and hence grapefruit juice and other

inhibitors will increase its action and inducers like St. John's wort will decrease it. Patients report that pomegranates and starfruit may also interfere. Food should not be eaten two hours before or one hour afterwards because it unpredictably increases its bioavailability, approximately doubling it.

Pharmacology

Nilotinib inhibits the kinases

BCR-ABL The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...

KIT Kit may refer to: Places *Kitt, Indiana, US, formerly Kit * Kit, Iran, a village in Mazandaran Province * Kit Hill, Cornwall, England People * Kit (given name), a list of people and fictional characters * Kit (surname) Animals * Young animal ...

, LCK,

EPHA3 EPH receptor A3 (ephrin type-A receptor 3) is a protein that in humans is encoded by the ''EPHA3'' gene. Function This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been ...

, EPHA8, DDR1, DDR2, PDGFRB,

MAPK11 Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the ''MAPK11'' gene. Function The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...

and

ZAK Zak may refer to: People * Zak (surname), a surname of Russian origin * Żak, a Polish surname * Žák, a Czech surname * Zak (given name) Fictional characters * Zak Adama, in the ''Battlestar Galactica'' franchise * Zak Dingle, in UK TV ''Emmer ...

. Structurally related to imatinib, It is 10–30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells.

History

Nilotinib was developed by

. It was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance. It was approved for medical use by the FDA in October 2007, EMA in September 2009, MHRA in November 2007, and TGA in January 2008.

Research

Parkinson's disease

There is weak evidence that nilotinib may be beneficial with

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...

(PD), with a small clinical trial suggesting it might halt progression and improve symptoms. However, there were significant side effects including

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...

liver function test Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin ti ...

s abnormalities, hallucinations and

heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...

, and the benefit in PD disappeared at follow up after drug discontinuation, raising question as to whether it was truly a disease modifying therapy. Nilotinib is currently undergoing phase II studies for treatment of Parkinson's. Scientists and medical professionals have advised caution with over-optimistic interpretation of its effects in Parkinson's due to the significant

media hype Media circus is a colloquial metaphor, or idiom, describing a news event for which the level of media coverage—measured by such factors as the number of reporters at the scene and the amount of material broadcast or published—is perceived to ...

surrounding the small and early clinical trial. Dystonia and cognitive impairment have also been reported as side effects.

Other

Novartis announced on April 11, 2011, that it was discontinuing a phase III trial of nilotinib as the first-line treatment of gastrointestinal stromal tumor (GIST) based on the recommendation of an independent data monitoring committee. Interim results showed Tasigna is unlikely to demonstrate superiority compared to Novartis's Gleevec (imatinib)*, the current standard of care in this setting. Low dose nilotinib is also being investigated for use in

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

, as well as for ALS,

dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

and

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...

References

External links

* {{Portal bar , Medicine Orphan drugs Non-receptor tyrosine kinase inhibitors Imidazoles CYP2D6 inhibitors Novartis brands Trifluoromethyl compounds Benzanilides Aminopyrimidines 3-Pyridyl compounds Wikipedia medicine articles ready to translate