Dasatinib is indicated for the treatment of adults with: Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
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 could 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.
Absorption: The maximum plasma concentrations (Cmax) of Dasatinib are observed between 0.5 hours and 6 hours (Tmax) following oral administration. Food Effect: A high-fat meal increased the mean AUC of Dasatinib following a single dose of 100 mg by 14%. The total calorie content of the high-fat meal was 985 kcal. The calories derived from fat, carbohydrates, and protein were 52%, 34%, and 14% for the high-fat meal.
Distribution: The apparent volume of distribution is 2505 (CV% 93%). Binding of Dasatinib to human plasma proteins in vitro was approximately 96% and of its active metabolite was 93%, with no concentration dependence over the range of 100 ng/ml to 500 ng/ml. Dasatinib is a P-gp substrate in vitro.
Elemination: The mean terminal half-life of Dasatinib is 3 hours to 5 hours. The mean apparent oral clearance is 363.8 l/hr (CV% 81.3%).
Metabolism: Dasatinib is metabolized in humans, primarily by CYP3A4. CYP3A4 is 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. The exposure of the active metabolite, which is equipotent to Dasatinib, represents approximately 5% of the AUC of Dasatinib. The active metabolite of Dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also has several other inactive oxidative metabolites.
Excretion: Elimination is primarily via the feces. Following a single radiolabeled dose of oral Dasatinib, 4% of the administered radioactivity was recovered in the urine and 85% in the feces within 10 days. Unchanged Dasatinib accounted for 0.1% of the administered dose in the urine and 19% of the administered dose in the feces with the remainder of the dose being metabolites.
The recommended starting dosage of Dasatinib for: Chronic phase CML is 100 mg administered orally once daily. 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. In clinical studies, treatment with Dasatinib was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic response (including complete cytogenetic response [CCyR]) or major molecular response (MMR) is not known.
Strong CYP3A4 Inhibitors: The coadministration with strong CYP3A inhibitors may increase Dasatinib concentrations. Increased Dasatinib concentrations may increase the risk of toxicity. Concomitant use of strong CYP3A4 inhibitors should be avoided. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, Dasatinib dose reduction should be considered.
Strong CYP3A4 Inducers: The coadministration of Dasatinib with strong CYP3A inducers may decrease Dasatinib concentrations. Decreased Dasatinib concentrations may reduce efficacy. Alternative drugs with less enzyme induction potential should be considered. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, Dasatinib dose increase should be considered.
Gastric Acid Reducing Agents: The coadministration of Dasatinib with a gastric acid reducing agent may decrease the concentrations of Dasatinib. Decreased Dasatinib concentrations may reduce efficacy. H2 antagonists or proton pump inhibitors should not be administered with Dasatinib. The use of antacids in place of H2 antagonists or proton pump inhibitors should be considered. The antacid at least 2 hours prior to or 2 hours after the dose of Dasatinib should be administered. Simultaneous administration of Dasatinib with antacids should be avoided.
Concomitant use with CYP3A4 inhibitors (e.g. atazanavir, clarithromycin, erythromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole or grapefruit juice); CYP3A4 inducers (e.g. carbamazepine, dexamethasone, phenytoin, phenobarbital, rifampicin or St John's wort); antacid. Pregnancy. Patients with predisposing factors for QT prolongation (e.g. congenital long QT syndrome, hypokalaemia, hypomagnesaemia, on antiarrhythmic therapy, or receiving cumulative high doses of anthracyclines). Hepatic impairment. Lactation.
Reversible myelosuppression, neutropenia, anaemia, thrombocytopenia, fluid retention, pulmonary arterial HTN, QT prolongation, cardiac failure, arrhythmias, HTN, musculoskeletal pain, GI disturbances, headache, chills, fatigue, asthenia, myalgia, chest pain, arthralgia, pyrexia, mucositis, flushing, colitis, electrolyte disturbances, appetite and wt disturbances, rash, dermatitis, hyperhidrosis, pruritus, acne.
Pregnancy category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
Experience with overdose of Dasatinib in clinical studies is limited to isolated cases. The highest overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding. Since Dasatinib is associated with severe myelosuppression, patients should be monitored who ingest more than the recommended dosage closely for myelosuppression and give appropriate supportive treatment.
Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.
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