Nilotinib

Nilotinib, sold under the brand name Tasigna among others, is an anti-cancer medication used to treat chronic myelogenous leukemia (CML) which has the Philadelphia chromosome.[2][5] 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.[2][5] It is taken by mouth.[2]

Common side effects may include low platelets, low white blood cells, anemia, rashes, vomiting, diarrhea, and joint pains. Other serious side effects may include QT prolongation, sudden death, pancreatitis, and liver problems. It is not safe for use during pregnancy. Nilotinib is a Bcr-Abl tyrosine kinase inhibitor and works by interfering with signalling within the cancer cell.[2]

Nilotinib was approved for medical use in the United States in 2007.[2][6] It is on the World Health Organization's List of Essential Medicines.[7] It is approved as a generic medication.[8]

Medical uses

Nilotinib is used to treat Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia.[2][9] It is indicated for the treatment of newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase;[2][4] adults with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia resistant to or intolerant to prior therapy that included imatinib;[2][4] and children with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia resistant or intolerant to prior tyrosine-kinase inhibitor therapy.[2][4]

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 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. Nilotinib can also affect the body's electrolyte and glucose 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.[10]

Nilotinib carries a black box warning in the United States for possible heart complications.[2][11] Contraindications include long QT syndrome, hypokalaemia, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/lactose intolerance.[9]

Cautions include:[9]

Dose reduction has been recommended in people with liver problems which involves recommendation of lower starting dose and monitoring of any hepatic function abnormalities.[12]

Hepatitis B virus reactivation may also occur.[13]

• 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

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.[12] Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3.[14]

It is a substrate for CYP3A4 and hence grapefruit juice and other CYP3A4 inhibitors[15] will increase its action and inducers like St. John's wort[16] will decrease it. Patients report that pomegranates and starfruit may also interfere.

Pharmacology

Nilotinib inhibits the kinases BCR-ABL,[17] KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK.[18]

Structurally related to imatinib,[19] it is 10–30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells.[19][20]

History

Nilotinib was developed by Novartis.[6] It was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance.[21][22][23]

Society and culture

Research