indication

For the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia with resistance or intolerance to prior therapy. Also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy.

pharmacology

Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinase inhibitor

mechanism of action

Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase. In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.

toxicity

Acute overdose in animals was associated with cardiotoxicity.

biotransformation

Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4

half life

The overall mean terminal half-life of dasatinib is 3-5 hours.

route of elimination

Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. Elimination is primarily via the feces.

drug interactions

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

Omeprazole: Omeprazole may decrease the serum level of dasatinib.

Pantoprazole: Pantoprazole may decrease the serum level of dasatinib.

Phenobarbital: Phenobarbital may decrease the serum level and efficacy of dasatinib.

Phenytoin: Phenytoin may decrease the serum level and efficacy of dasatinib.

Rabeprazole: Rabeprazole may decrease the serum level of dasatinib.

Ranitidine: Ranitidine may decrease the serum level of dasatinib.

Rifampin: Rifampin may decrease the serum level and efficacy of dasatinib.

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Telithromycin: Telithromycin may reduce clearance of Dasatinib. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Dasatinib if Telithromycin is initiated, discontinued or dose changed.

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Trimipramine: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Voriconazole: Additive QTc prolongation may occur. Voriconazole, a strong CYP3A4 inhibitor, may also increase the serum concentration of dasatinib by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dasatinib if voriconazole is initiated, discontinued or dose changed.

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).