indication

For the potential treatment of various leukemias, including chronic myeloid leukemia (CML).

pharmacology

Nilotinib is a transduction inhibitor that targets BCR-ABL, c-kit and PDGF, for the potential treatment of various leukemias, including chronic myeloid leukemia (CML).

mechanism of action

Chronic myelogenous leukaemia (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 leukaemia, and FIP1-like-1-PDGFRalpha, which causes hypereosinophilic syndrome, suggests potential use of AMN107 for myeloproliferative diseases characterised 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 tumours (Weisberg et al, 2005; von Bubnoff et al, 2005; Gleixner et al, 2006).

absorption

Orally available

half life

15 hours

drug interactions

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Nilotinib prescribing information recommends avoiding concurrent use of nilotinib with strong inhibitors of CYP3A4.

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Tacrolimus: May cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.

Tamoxifen: Nilotinib may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Nilotinib, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Nilotinib is initiated, discontinued, or dose changed.

Telithromycin: Telithromycin may reduce clearance of Nilotinib. Concomitant therapy should be avoided.

Thiothixene: May cause additive QTc-prolonging effects. Concomitant therapy should be avoided.

Topotecan: The p-glycoprotein inhibitor, Nilotinib, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.

Toremifene: May cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.

Tramadol: Nilotinib may decrease the effect of Tramadol by decreasing active metabolite production.

Trastuzumab: Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.

Tretinoin: The moderate CYP2C8 inhibitor, Nilotinib, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Nilotinib is initiated, discontinued to dose changed.

Trimipramine: May cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.

Voriconazole: Voriconazole may increase the serum concentration of nilotinib by inhibiting its metabolism by CYP3A4. Additive QTc prolongation may also occur. Concomitant therapy should be avoided.

Vorinostat: Additive QTc prolongation may occur. Concomitant therapy should be avoided.

Ziprasidone: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Zuclopenthixol: Additive QTc-prolonging effects increases risk of cardiac arrhythmias. Concomitant therapy should be avoided.