Dasatinib Tablets (Sprycel)
Manufacturer: Bristol-Myers Squibb Company, Princeton, NJ
Indication: Dasatinib is indicated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast-phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy, including imatinib mesylate (Gleevec, Novartis). The effectiveness of dasatinib is based on hematological and cytogenetic response rates. There have been no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
Dasatinib is also indicated for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy.
Drug Class: Dasatinib is an inhibitor of multiple tyrosine kinases. Its chemical name is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2- methyl-4-pyrimidinyl] amino]-5-thiazolecarboxamide, monohydrate.
Uniqueness of Product: At nanomolar concentrations, dasatinib inhibits the following kinases: breakpoint cluster region-Abelson (Bcr-Abl): Src family (Src, Lck, Yes, Fyn); C-kit; EphA2; and platelet-derived growth factor receptor, beta polypeptide (PDGFR-p). 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-sensitive and imatinib-resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and ALL cell lines overexpressing Bcr-Abl. Under the conditions of the assays, dasatinib overcame 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.
Pregnancy (Category D). Dasatinib may cause fetal harm in pregnant women. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, fetal toxicity was observed in rats and rabbits and fetal death was observed in rats. kamagra soft tablets
The lowest doses of dasatinib (in rats, 2.5 mg/kg per day or 15 mg/m2 per day; in rabbits, 0.5 mg/kg per day or 6 mg/m2 per day) resulted in embryo-fetal toxicities. These doses produced maternal area-under-the-curve (AUC) concentrations of 105 ng • hour/ml (0.3-fold the human AUC in females at the recommended dose of 70 mg twice daily) and 44 ng • hour/ml (0.1-fold the human AUC) in rats and rabbits, respectively.
Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and micro-hepatia.
Dasatinib is not recommended for women who are pregnant or who are contemplating pregnancy. If dasatinib is used during pregnancy or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.
The potential effects of dasatinib on sperm counts, function, and fertility have not been studied. Sexually active men and women taking dasatinib should use adequate contraception.
Myelosuppression. Treatment with dasatinib is associated with severe grade 3 or 4 thrombocytopenia, neutropenia, and anemia, according to National Cancer Institute Common Toxicity Criteria (NCI CTC). The occurrence of these events is more frequent in patients with advanced CML or Ph+ ALL than in those with chronic-phase CML.
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Complete blood counts should be performed weekly for the first two months and then monthly thereafter or as clinically indicated. Myelosuppression was generally reversible and usually managed when the drug was withheld temporarily or when the dose was reduced.
Bleeding-Related Events. In addition to causing thrombo-cytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. Severe CNS hemorrhages, including fatalities, occurred in 1% of patients receiving dasatinib. Severe gastrointestinal (GI) hemorrhage occurred in 7% of patients, and treatment and transfusions generally had to be interrupted. Other cases of severe hemorrhage occurred in 4% of patients. Most bleeding events were associated with severe thrombocytopenia.
Patients were excluded from participating in dasatinib clinical studies if they took medications that inhibited platelet function or anticoagulants. Caution should be exercised if patients are required to take these types of medications.
Fluid Retention. Dasatinib was associated with fluid retention, which was severe in 9% of patients; pleural effusion was reported in 5% of patients, and pericardial effusion was reported in 1%. Severe ascites, generalized edema, and severe pulmonary edema were each reported in 1% of patients.
Patients who develop symptoms suggestive of pleural effusion, such as dyspnea or dry cough, should be evaluated by chest x-ray. Patients with severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention was typically managed by supportive care measures such as diuretics and short courses of steroids.
QT Prolongation. In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (the QT interval). In single-arm clinical studies in patients with
leukemia who were treated with dasatinib, the mean corrected QT (QTc) interval changes from baseline using Fridericia’s method (QTcF) were 3 to 6 milliseconds (msec); the upper 95% confidence intervals for all mean changes from baseline were less than 8 msec. In nine patients, QTc prolongation was reported as an adverse event. Three patients (fewer than 1%) experienced a QTcF greater than 500 msec.
Dasatinib should be administered with caution to patients who have or who may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medications or other medicinal products that lead to QT prolongation, and cumulative high-dose anthra-cycline therapy. Hypokalemia or hypomagnesemia should be corrected before dasatinib administration.
Dosage and Administration: The recommended dosage of dasatinib is 140 mg/day, administered orally in two divided doses (70 mg twice daily): one dose in the morning and one dose in the evening, with or without a meal. Tablets should not be crushed or cut; they should be swallowed whole.
In clinical studies, treatment with dasatinib was continued until disease progression or until it was no longer tolerated by the patient. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated.
Commentary: Dasatinib offers a new treatment option for patients with CML or Ph+ ALL who are resistant or intolerant to prior therapy, including imatinib. Known mechanisms of imatinib resistance include mutations in the protein sequence of the Bcr-Abl tyrosine kinase, multidrug resistance gene over-expression, and the activation of alternate signaling pathways involving the Src family kinases.
For many patients with CML, the risk of developing resistance increases with the number of years of previous treatment and severity of disease. Patients with advanced Ph+ ALL generally develop resistance more rapidly (in about two months) than patients with CML (in 10 months), including those in the blast phase.
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Dasatinib is the first approved oral tyrosine kinase inhibitor predicted to bind to multiple conformations of the Abl kinase based on modeling studies. At nanomolar concentrations, dasatinib inhibits Bcr-Abl, Src family, C-kit, EphA2, and PDGFR-p. By targeting these kinases, dasatinib inhibits the overproduction of leukemia cells in the bone marrow of patients with CML and Ph+ ALL, and it enables normal production of red blood cells, white blood cells, and blood platelets to resume.
Imatinib has rightfully been heralded as a breakthrough drug. Dasatinib is an excellent example, though, of how cancer researchers are learning from the successes and failures of targeted therapies like imatinib to make important advances in the development of next-generation targeted agents. Dasatinib has a 325-fold stronger affinity for its gene target, Bcr-Abl, than imatinib does, and it appears to be effective against 18 of the 19 identified mutated forms of Bcr-Abl—the very mutations that drive imatinib resistance.