Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRB. 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 inhibits 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 multidrug resistance gene overexpression.
Absorption: Maximum plasma concentrations (Cmax) of Dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib exhibits dose-proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg to 240 mg/day. The overall mean terminal half-life of Dasatinib is 3 to 5 hours.
Distribution: In patients, Dasatinib has an apparent volume of distribution of 2505 L, suggesting that the drug is extensively distributed in the extravascular space. Binding of Dasatinib and its active metabolite to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence over the range of 100 to 500 ng/mL.
Metabolism: Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. Flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of Dasatinib metabolites.
Elimination: Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled Dasatinib, approximately 4% and 85% of the administered radioactivity were recovered in the urine and feces, respectively, within 10 days. Unchanged Dasatinib accounted for 0.1% and 19% of the administered dose in urine and feces, respectively, with the remainder of the dose being metabolites.
Dasatinib is a kinase inhibitor indicated for the treatment of:
Newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase.
Adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy, including Imatinib.
Adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
DOSAGE AND ADMINISTRATION
The recommended starting dose of Dasatinib for chronic-phase CML is 100 mg administered orally once daily. The recommended starting dose of Dasatinib for accelerated-phase CML, myeloid or lymphoid blast-phase CML, or Ph+ ALL is 140 mg administered orally once daily.
Tablets should not be crushed or cut; they should be swallowed whole. Dasatinib can be taken with or without a meal, either in the morning or in the evening.
Hypersensitivity to the active substance or any of the excipients.
Myelosuppression: Treatment with Dasatinib is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced-phase CML or Ph+ ALL than in chronic-phase CML.
Bleeding-Related Events: In addition to causing thrombocytopenia in human subjects, Dasatinib caused platelet dysfunction in vitro.
Fluid Retention: Dasatinib is associated with fluid retention. In clinical trials, severe fluid retention was reported in up to 10% of patients.
QT Prolongation: Use Dasatinib with caution in patients who have or may develop prolongation of the QT interval.
Pulmonary Arterial Hypertension: Dasatinib may increase the risk of developing pulmonary arterial hypertension (PAH), which may occur anytime after initiation, including after more than one year of treatment.
Embryo-Fetal Toxicity: Dasatinib can cause fetal harm when administered to a pregnant woman. Adverse fetal and infant outcomes have been reported from women who have taken Dasatinib.
The most common side effects are bloody or black tarry stools, body aches or pain, burning, tingling, numbness, or pain in the hands, arms, feet, or legs, chest pain, constipation, cough or hoarseness, difficulty with breathing, dizziness, ear congestion, fainting, fast, slow, or irregular heartbeat, fever or chills, full or bloated feeling, headache, loss of voice, lower back or side pain, and painful or difficult urination.
US FDA-approved pregnancy category D
Based on limited human data, Dasatinib can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects, including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia, have been reported with maternal exposure to Dasatinib.
No data are available regarding the presence of Dasatinib in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Breastfeeding is not recommended during treatment with Dasatinib and for two weeks after the final dose.
Nursing Mothers: Discontinue drug or nursing, considering the importance of the drug to the mother.
Hepatic Impairment: Use Dasatinib with caution in patients with hepatic impairment.
Children: The safety and effectiveness of Dasatinib monotherapy have been demonstrated in pediatric patients with newly diagnosed chronic-phase Ph+ CML/Ph+ ALL. There are no data available for children under one year of age. Adverse reactions associated with bone growth and development and grade 1 osteopenia were reported.
Adults: While the safety profile of Dasatinib in the geriatric population was similar to that in the younger population, patients aged 65 years and older are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance. They are also more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease, and should be monitored closely.
CYP3A4 Inhibitors: May increase Dasatinib drug levels and should be avoided. If co-administration cannot be avoided, monitor closely and consider reducing the Dasatinib dose.
CYP3A4 Inducers: May decrease Dasatinib drug levels. If co-administration cannot be avoided, consider increasing the Dasatinib dose.
Antacids: May decrease Dasatinib drug levels. Avoid simultaneous administration. If needed, administer the antacid at least two hours prior to or two hours after the dose of Dasatinib.
H2 Antagonists/Proton Pump Inhibitors: May decrease Dasatinib drug levels. Consider antacids in place of H2 antagonists or proton pump inhibitors.
The highest overdose of 280 mg per day for one week was reported in two patients, and both developed severe myelosuppression and bleeding.
Store at a temperature not exceeding 30°C in a dry place. Protect from light and moisture.
Medicine: Keep out of reach of children.
