Pharmacology Update
Dasatinib Tablets (Sprycel®)
By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.
An orally active kinase inhibitor is available for patients with chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia who are intolerant or resistant to prior therapy with imatinib. Dasatinib, in contrast to imatinib, binds to numerous kinase domains (multi-targeted). It is marketed by Bristol-Myers Squibb as Sprycel.
Indications
Dasatinib is approved for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic, myeloid leukemia and Philadelphia chromosome-positive acute lymphobastic leukemia (Ph+ ALL) who are intolerant or resistant to prior therapy with imatinib.1
Dosage
The recommended initial dose is 70 mg twice daily (morning and evening). The tablet may be taken with or without food and should be taken whole, not crushed or cut.1
Dose adjustments are required for neutropenia, thrombocytopenia, and other adverse reactions.
Dasatinib is available as 20 mg, 50 mg, and 70 mg.
Potential Advantages
Dasatinib has been shown to produce hematologic and cytogenetic response in patients intolerant to or resistant to imatinib.1, 2, 3, 4 It is more active against the wild-type BCR-ABL, but also active against most of the imatinib-resistant BCR-ABL mutants.5
Potential Disadvantages
Myelosuppression is the primary adverse reaction. The frequency of grade 3 or 4 neutropenia ranged from 49% in patients with chronic-phase disease; 74% with accelerated phase disease, 83% myeloid blast phase, and 81% with lymphoid blast phase and Philadelphia positive acute lymphoblastic leukemia.1 The frequencies of thrombocytopenia are roughly similar. Other serious adverse reactions include bleeding events, fluid retention, and QT prolongation. Dasatinib is an inhibitor of CYP3A4 and may increase plasma levels of drug metabolized by this pathway.
Comments
CML is the result of translocation of parts of two chromosomes (Philadelphia chromosomes) leading to a fused BCR-ABL protein that leads to abnormal cell growth. This abnormal protein is a tyrosine kinase. Dasatinib is a multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases. It is more active against the wild-type BCR-ABL as well as all but one the imatinib-resistant BCR-ABL mutants tested.5 It has been shown to be effective in CML resistant to imatinib or in patients intolerant of imatinib. Major hematologic responses (complete hematologic response and no evidence of leukemia) ranged from 31% to 59% and cytogenetic response [complete (0% Ph + cells) and partial (> 0% -35%) responses] from 30% to 58%.1 The median duration of major hematologic response was 3.7 months in lymphoid blast CML and 4.8 months in Ph+ ALL. Major toxicities are myelosuppression and bleeding events (e.g., CNS and GI). Most bleeding events are associated with thrombocytopenia. Myelosuppression is generally reversible and managed by reducing or withdrawal of the drug. Other common adverse reactions include diarrhea, headache, skin rash, fatigue, and nausea. The wholesale cost of a 30-day supply of dasatinib (70 mg twice daily) is $4205.
Clinical Implications
CML is most common in the middle-aged and elderly with an annual incidence of 1 to 2 per 100,000 individuals. There are three phases of the disease; chronic, accelerated, and blast phases. The majority of patients (85%) are diagnosed in the chronic phase. While imatinib is considered first line therapy, resistance is becoming more problematic at the later stages of the disease due to mutations of BCR-ABL. Dasatinib is an important addition to the treatment CML.
References
1. Sprycel Product Information. Bristol-Myer Squibb Company. July 2006.
2. Talpaz M et al. N Engl J Med. 2006;354:2531-2541.
3. Cortes J, et al. Blood. 2006;Dec 21; Epub.
4. Hochhaus A et al. Blood.>2006;Nov 30; Epub.
5. Tokarski JS, et al. Cancer Res. 2006;66(11):5790-5797.
An orally active kinase inhibitor is available for patients with chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia who are intolerant or resistant to prior therapy with imatinib.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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