Nilotinib is an orally bioavailable aminopyrimidine-derivative Bcr-Abl tyrosine kinase inhibitor with antineoplastic activity. Designed to overcome imatinib resistance, nilotinib binds to and stabilizes the inactive conformation of the kinase domain of the Abl protein of the Bcr-Abl fusion protein, resulting in the inhibition of the Bcr-Abl-mediated proliferation of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) cells. This agent also inhibits the receptor tyrosine kinases platelet-derived growth factor receptor (PDGF-R) and c-kit, a receptor tyrosine kinase mutated and constitutively activated in most gastrointestinal stromal tumors (GISTs). With a binding mode that is energetically more favorable than that of imatinib, nilotinib has been shown to have an approximately 20-fold increased potency in kinase and proliferation assays compared to imatinib.

Mechanism of action of Nilotinib

Chronic myelogenous leukemia (CML) is caused by the BCR-ABL oncogene. Nilotinib inhibits the tyrosine kinase activity of the BCR-ABL protein. Nilotinib fits into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib, over-riding resistance caused by mutations. The ability of AMN107 to inhibit TEL-platelet-derived growth factor receptor-beta (TEL-PDGFRbeta), which causes chronic myelomonocytic leukemia, and FIP1-like-1-PDGFRalpha, which causes hypereosinophilic syndrome, suggests the potential use of AMN107 for myeloproliferative diseases characterized by these kinase fusions (Stover et al, 2005; Weisberg et al, 2005). AMN107 also inhibits the c-Kit receptor kinase, including the D816V-mutated variant of KIT, at pharmacologically achievable concentrations, supporting potential utility in the treatment of mastocytosis, and gastrointestinal stromal tumors.

or

Nilotinib, an inhibitor of Bcr-Abl tyrosine kinase, is an antineoplastic agent. Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of hematopoietic cells carrying the Philadelphia chromosome (Ph), resulting from a reciprocal translocation of the long arms of chromosomes 9 and 22. A novel fusion gene is formed, Bcr-Abl, which encodes a constitutively active, cytoplasmic form of protein tyrosine kinase. The unregulated activity of the Abl tyrosine kinase in Bcr-Abl is the cause of CML. Nilotinib is an orally active aminopyrimidine-derivative tyrosine kinase inhibitor that functions through competitive inhibition at the ATP-binding site of Bcr-Abl, leading to the inhibition of tyrosine phosphorylation of proteins that are involved in the intracellular signal transduction that Bcr-Abl mediates.

Indications of Nilotinib

• Chronic Myelogenous Leukemia
• Chronic Phase Chronic Myeloid Leukemia
• Refractory Gastrointestinal stromal tumor
• Refractory, accelerated phase Chronic myeloid leukemia
• Treatment for Philadelphia chromosome(Ph+)-positive chronic myelogenous leukemia.
• Adult and pediatric patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in the chronic phase,
• adult patients with chronic phase and accelerated phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib. Efficacy data in patients with CML in blast crisis are,
• Pediatric patients with chronic phase Philadelphia chromosome-positive CML with resistance or intolerance to prior therapy including imatinib.

Contra-Indications of Nilotinib

• Diabetes
• High cholesterol
• Low amount of magnesium in the blood
• Low amount of phosphate in the blood
• Low amount of calcium in the blood
• Low amount of sodium in the blood
• The high amount of potassium in the blood
• Low amount of potassium in the blood
• Anemia
• Decreased Blood Platelets
• Decreased Neutrophils a Type of White Blood Cell
• High blood pressure
• Very Rapid Heartbeat – Torsades de Pointes
• prolonged QT interval on EKG
• Abnormal EKG with QT changes from Birth
• Hardening of the arteries due to plaque buildup
• Liver problems
• High Amount of Bilirubin in the Blood
• High Blood Sugar
• Abnormal liver function tests
• Pregnancy
• A mother who is producing milk and breastfeeding
• Relapse of Hepatitis B Infection Symptoms
• Pancreatitis
• past history of complete removal of the stomach
• Reduced UGT1A1 Enzyme Activity due to *28 Polymorphism
• High Blood Levels of the Lipase Enzyme
• High Blood Levels of the Amylase Enzyme

Dosages of Nilotinib

• Strengths: 150 mg ;200 mg

Chronic Myelogenous Leukemia

• Philadelphia Chromosome Positive Chronic Myeloid Leukemia (Ph+ CML)

Newly Diagnosed in Chronic Phase (Ph+ CML-CP)

• 300 mg orally twice a day, approximately 12 hours apart

Resistant or Intolerant in Chronic Phase and Accelerated Phase (Ph+ CML-CP and Ph+ CML-AP)

• 400 mg orally twice a day, approximately 12 hours apart

Side Effects of Nilotinib

The most common

• chest pain
• certainly hair loss
• a headache
• joint painPain
• dizziness
• nausea and vomiting
• Severe stomach ache
• epigastric pain,
• diarrhea,
• anorexia,
• flatulence,
• a headache,
• dizziness,
• fainting, fast or pounding heartbeats.

More common

• Fast or irregular heartbeat
• appetite loss
• changes in nails
• constipation
• fatigue
• fever
• Back pain
• dizziness
• a headache
• increased cough
• Acid or sour stomach
• decreased appetite
• Agitation
• chest congestion
• chest pain
• cold sweats
• confusion
• decreased sexual ability or desire
• stomach or abdominal cramps, gas, or pain
• trouble sleeping

Less common

• bleeding gums
• blood in the urine or stools
• chest pain
• diarrhea
• Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
• difficulty in moving
• muscle stiffness
• redness of the face, neck, arms and occasionally, upper chest
• lack or loss of strength
• muscle spasm
• difficult or labored breathing
• dry mouth
• headache
• irritability
• lack or loss of strength
• loose stools
• loss of interest or pleasure
• muscle stiffness
• night sweats
• passing gas
• stomach discomfort, upset, or pain
• swollen joints
• trouble concentrating
• increased blood pressure

Drug Interactions of Nilotinib

Nilotinib may interact with following drugs, supplements & may change the efficacy of the drug

• alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
• anticancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
• “azole” antifungal medications (e.g.,  fluconazole, itraconazole, ketoconazole)
• beta-blockers (e.g., atenolol, propranolol, metoprolol)
• barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
• benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
• calcium channel blockers (e.g., nifedipine, diltiazem, verapamil, amlodipine, )
• carbamazepine
• chloroquine
• corticosteroids (e.g., dexamethasone, prednisone, methylprednisolone)
• cyclosporine
• dantrolene
• “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
• HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
• losartan
• macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
• metronidazole
• mirtazapine
• montelukast
• ondansetron
• carbamazepine
• phenytoin
• progestins (e.g., dienogest, levonorgestrel, medroxyprogesterone, norethindrone)
• proton pump inhibitors (PPIs; e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
• selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine,paroxetine, sertraline)
• sildenafil
• “statin” anticholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
• tadalafil
• tetracycline
• theophylline
• tocilizumab
• tolterodine
• tramadol
• other selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, sertraline)
• 5-HT3 antagonists (e.g., granisetron, ondansetron)
• tamsulosin
• tapentadol
• thiazide diuretics (e.g., hydrochlorothiazide, indapamide)
• tramadol
• tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine, 
• other tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
• tetracycline
• tocilizumab
• vemurafenib
• trimethoprim
• vaccines
• warfarin

Pregnancy & Lactation of Nilotinib

 FDA Pregnancy Category D 

Pregnancy

This medication may cause harm to an unborn fetus and should not be used during pregnancy. If you or your partner become pregnant while taking this medication, contact your doctor immediately. Both men and women of childbearing age who are taking nilotinib should use an effective method of birth control (e.g., birth control pill, condoms) during treatment and for at least 4 weeks after finishing treatment.

Lactation

It is not known if nilotinib passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.

References