Introduction
Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML). The main targets of Dasatinib, are BCRABL, SRC, Ephrins and GFR.
Uses
Dasatinib is a tyrosine kinase inhibitor used for the treatment of lymphoblastic or chronic myeloid leukemia with resistance or intolerance to prior therapy.
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.
Associated Conditions
Pharmacodynamics
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.
Volume of Distribution
- 2505 L
Protein Binding
96%
Route of Elimination
Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. Elimination is primarily via the feces.
Half Life
The overall mean terminal half-life of dasatinib is 3-5 hours.
Toxicity
Acute overdose in animals was associated with cardiotoxicity.
Food Interactions
- Avoid grapefruit products. Grapefruit may reduce the CYP3A4 metabolism of dasatinib, increasing its serum levels.
- Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of dasatinib.
- Take with or without food. High fat meals may increase the AUC of dasatinib by to 14%.
Dosage
Dosage of Dasatinib In Pediatric Patients: With CML, or Ph+ ALL: The recommended starting dosage for pediatrics is based on body weight as shown in below chart. The recommended dose should be administered orally once daily with or without food. The dose should be recalculated every 3 months based on changes in body weight, or more often if necessary.
- Body Weight (kg): 10 to less than 20: Daily Dose 40 mg
- Body Weight (kg): 20 to less than 30: Daily Dose 60 mg
- Body Weight (kg): 30 to less than 45: Daily Dose 70 mg
- Body Weight (kg): At least 45: Daily Dose 100 mg
