DRUG STUDY AND INFORMATION FORM Generic Name: Nilotinib Trade Name: Tasigna, AMN107 Drug Class: Protein

Tyrosine Kinase Inhibitors Structure/Chemistry: Designed to have increased potency and specificity compared to imatinib. It promotes hydrogen bonding with a glutamate and asparagine residue on the BCR-ABL kinase and overcomes mutations that cause imatinib resistance.

Pharmacodynamics

Mechanism of Action: Binds to a segment of the BCR-ABL tyrosine kinase domain that fixes the enzyme in a closed or nonfunctional state, in which the protein is unable to bind its substrate/phosphate donor, ATP. It also affects the platelet-derived growth factor receptor (PDGFR). Inhibits the kinase more potently than does imatinib. It promotes hydrogen bonding with a glutamate and asparagine residue on the BCR-ABL kinase and overcomes mutations that cause imatinib resistance. Background: A 9:22 translocation results in the fusion of the genes BCR and ABL which yield a constitutively activated protein kinase, BCR-ABL, which may lead to the malignant phenotype. Pharmacologic Effects: Has efficacy in diseases in which the ABL, kit, or PDGFR have dominant roles in driving the proliferation of the tumor.

Drug Resistance or Tolerance: Point mutations in separate segments of the kinase domain where nilotinib contacts the kinase although nilotinib maintains inhibitory activity in the presence of most point mutations that confer resistance to imatinib. Drug-resistant cells typically have mutations in the kinase that lock it in the open configuration where it can bind its substrate. Other mutations affect the phosphate-binding region and the activation loop of the domain with varying degrees of associated resistance. Other mechanisms or resistance besides the kinase mutations exist such as amplifications of the kinase gene (leading to overexpression of the enzyme) and drug efflux by MDR.

Pharmacokinetics

Absorption: Only 30% absorbed after an oral administration. Unlike the other BCR-ABL inhibitors, nilotinibs bioavailability increases significantly in the presence of food. Distribution:

Elimination: t1/2 of 17 hours.

Metabolism: CYP3A4 is the major enzyme responsible for nilotinib metabolism.

Adverse Side Effects/Toxicity: GI distress (diarrhea, nausea, vomiting), fluid retention (may lead to dependent edema or per-iorbital swelling), and hepatotoxicity. May prolong the QT interval and should be used with caution in patients with underlying heart disease or arrhythmias. Myelosuppression occurs infrequently. Drug Interactions: Must be cautious in introducing drugs that interact with nilotinib or CYP3A4 (ketoconazole/inhibitor or rifampin/inducer)

Therapeutic uses: CML (chronic myelogenous leukemia) that is resistant to or intolerant of prior imatinib therapy

Miscellaneous: Nilotinib is also a substrate and an inhibitor for P-glycoprotein.