Dasatinib

Introduction Overview

Generic Name

dasatinib

Brand Name

Sprycel

Dosage Form

Oral tablets

Drug Class

BCR-ABL tyrosine kinase inhibitors

Pharmacokinetics

Absorption:
Dasatinib is administered orally and exhibits variable bioavailability with peak plasma concentrations typically reached within 0.5 to 3 hours after dosing. Food intake does not significantly affect the extent of absorption, allowing administration with or without food. However, coadministration with antacids within two hours before or after dosing should be avoided as they can reduce dasatinib absorption due to increased gastric pH. Dasatinib displays moderate to high intestinal permeability and solubility in gastric fluid, facilitating effective absorption from the gastrointestinal tract.

Distribution:
Following absorption, dasatinib is extensively distributed throughout the body. It has a large volume of distribution (~2500 L) indicating extensive tissue binding. Dasatinib is approximately 96% bound to plasma proteins, primarily albumin and alpha-1 acid glycoprotein. The drug penetrates various tissues, including leukemic cells in bone marrow. Dasatinib can cross cellular membranes and exert its action intracellularly. Due to its tissue distribution, caution is advised in patients with organ dysfunction affecting tissue binding.

Metabolism:
Dasatinib undergoes extensive hepatic metabolism primarily via the cytochrome P450 enzyme CYP3A4, with minor contributions from other CYP enzymes like CYP2C8 and CYP2D6. Its major metabolites have significantly lower pharmacologic activity. In vitro and clinical studies have demonstrated that strong CYP3A4 inhibitors increase dasatinib exposure whereas CYP3A4 inducers reduce drug plasma levels. Therefore, concomitant use with CYP3A4-modulating drugs requires careful monitoring and potentially dose adjustment.

Elimination:
The elimination half-life of dasatinib is approximately 3 to 5 hours, necessitating once or twice daily dosing depending on indication. Excretion occurs primarily through feces (85%), with minimal renal clearance (<5%) of unchanged drug, indicating hepatic and biliary excretion pathways predominate. The relatively short half-life and extensive metabolism require consistent dosing to maintain therapeutic concentrations. Patients with hepatic impairment may require dose modification due to reduced metabolism and clearance potential.

Dosage Forms

Available Dosage Forms:
Sprycel is available as oral tablets designed for once-daily administration. The commercially available strengths include 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg tablets, facilitating individualized dosing based on disease phase and patient tolerance.

Dosages for Adults and Adolescents:
- For Chronic Phase Philadelphia chromosome-positive (Ph+) Chronic Myelogenous Leukemia (CML): The usual dose is 100 mg orally once daily until disease progression or intolerance.
- For Accelerated Phase, Myeloid or Lymphoid Blast Phase Ph+ CML, and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL): The recommended dose is 140 mg orally once daily until disease progression or intolerance.
Dose adjustments should be grounded on therapeutic response and adverse effects, aiming to use the lowest effective dose to reduce toxicity risks.

Specific Patient Populations:
- Pediatric Use: Dasatinib (Sprycel) is approved for use in children with Ph+ CML and Ph+ ALL. Pediatric dosing is weight-based and should be individually determined by a healthcare provider.
- Hepatic Impairment: Dose modification may be necessary in patients with moderate to severe hepatic dysfunction due to altered metabolism.
- Renal Impairment: No dose adjustment is generally required as renal clearance is minimal; however, close monitoring is recommended.
- Pregnancy and Lactation: Not recommended as dasatinib may cause fetal harm. Effective contraception is required for both males and females during treatment and for at least 30 days after. Breastfeeding is contraindicated during therapy and for two weeks after cessation.

Mechanism Of Action

Sprycel (dasatinib) is a potent, orally bioavailable inhibitor of the BCR-ABL fusion protein tyrosine kinase, which is the abnormal enzyme product of the Philadelphia chromosome present in certain leukemias. BCR-ABL kinase constitutively activates several cell signaling pathways responsible for uncontrolled proliferation and reduced apoptosis of leukemic cells.

At the molecular level, dasatinib binds to the ATP-binding site of BCR-ABL, inhibiting its kinase activity. This inhibition prevents phosphorylation of substrates involved in downstream signaling cascades such as the Ras/MAPK, PI3K/AKT, and STAT pathways, leading to cell cycle arrest and apoptosis of malignant cells.

Beyond BCR-ABL, dasatinib exhibits multi-targeted activity, inhibiting other kinases including SRC family kinases, c-KIT, PDGFR, and ephrin receptor kinases. This broader kinase inhibition contributes to its efficacy in resistant leukemias and may also affect angiogenesis and tumor microenvironment modulation.

Clinically, dasatinib has demonstrated activity in patients with imatinib-resistant or -intolerant chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. The ability to bind both active and inactive conformations of BCR-ABL kinase accounts for its superior potency and efficacy compared to first-generation inhibitors. Clinical trials have shown significant cytogenetic and molecular response rates, providing improved progression-free and overall survival.

Pharmacological Actions

Selective inhibition of BCR-ABL tyrosine kinase activity leading to apoptosis of leukemic cells.
Inhibition of SRC family kinases, contributing to anti-leukemic effects and possible modulation of cell adhesion and migration.
Blocking of c-KIT and PDGFR kinases which are involved in cell proliferation and survival.
Interference with multiple signaling pathways downstream of BCR-ABL resulting in decreased cell proliferation.
Induction of cell cycle arrest in leukemic cells.
Suppression of tumor progression in Philadelphia chromosome-positive chronic myelogenous leukemia and acute lymphoblastic leukemia.
Activity against mutated forms of BCR-ABL that confer resistance to other tyrosine kinase inhibitors.
Oral administration allows direct and targeted therapy with systemic effects.
Modulation of the tumor microenvironment through inhibition of kinases involved in angiogenesis.
Potential immunomodulatory effects due to impact on various kinase pathways.
Rapid onset of kinase inhibition following oral dosing.

Therapeutic Or Clinical Uses

Treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in chronic phase in adults and children.
Management of accelerated phase, myeloid or lymphoid blast phase Ph+ CML.
Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults and pediatric patients.
Use in patients with resistance or intolerance to prior therapy including imatinib.
Off-label use in certain other malignancies expressing BCR-ABL or related kinases.
Targeted therapy option for leukemias with specific genetic mutations involving BCR-ABL fusion gene.
Part of combination chemotherapy regimens in Ph+ ALL for improving outcomes.
Maintenance therapy to prevent disease progression in Ph+ CML.
Therapy to inhibit tumor growth and spread by targeting tyrosine kinases involved in malignancy.
Potential to provide improved survival and remission rates in resistant or relapsed leukemias.

Side Or Adverse Effects

Myelosuppression including neutropenia, thrombocytopenia, and anemia leading to increased infection and bleeding risk.
Pulmonary arterial hypertension (PAH), a rare but serious and potentially fatal condition.
Pleural effusions causing respiratory symptoms and chest discomfort.
Gastrointestinal disturbances such as nausea, diarrhea, vomiting, and abdominal pain.
Headache and musculoskeletal pain including muscle and joint aches.
Dermatologic reactions including skin rash and pruritus.
Hepatotoxicity manifested as elevated liver enzymes, jaundice, and rare cases of liver failure.
Bleeding complications including bruising, nosebleeds, gastrointestinal bleeding, and hematuria.
Fatigue and weakness impacting patient quality of life.
Fluid retention causing edema and rapid weight gain.
QT prolongation and potential for cardiac arrhythmias in patients with predisposing conditions.
Rare hypersensitivity reactions including anaphylaxis and severe skin reactions.
Tumor lysis syndrome signs such as electrolyte abnormalities and renal dysfunction.
Hypokalemia and hypomagnesemia may be observed, necessitating electrolyte monitoring.
Potential for growth suppression in pediatric patients during prolonged treatment.

Precautions

Monitor complete blood counts frequently to detect myelosuppression and adjust dose accordingly.
Assess for signs of pulmonary arterial hypertension and investigate promptly if symptoms develop.
Avoid concomitant use of medications that increase bleeding risk without close monitoring.
Avoid grapefruit and grapefruit juice as they increase dasatinib plasma concentrations.
Do not take antacids within two hours before or after dosing to prevent reduction in dasatinib absorption.
Use effective contraception during therapy and for at least 30 days after discontinuation due to teratogenic risk.
Closely monitor hepatic function and modify dose or discontinue if hepatotoxicity occurs.
Patients should be counseled about the risk of infections due to immunosuppression.
Handle broken tablets with caution; avoid exposure of drug to skin, eyes, or mucous membranes.
Pregnant or breastfeeding women should avoid dasatinib due to potential fetal/neonatal harm.
In patients with known pulmonary or cardiac disease, proceed with caution due to risk of PAH and fluid retention.
Evaluate electrolyte levels periodically and correct abnormalities to minimize arrhythmia risk.
Avoid exposure to individuals with active infections and maintain good hygiene to reduce infection risk.
Patients need to report any signs of bleeding, infection, or unusual bruising promptly.
Dose modifications may be required based on tolerability and adverse effect profile.

Warnings

Potential for severe myelosuppression causing life-threatening infections or bleeding.
Risk of pulmonary arterial hypertension, which can be irreversible and fatal if not recognized early.
Serious bleeding events especially when combined with anticoagulants or antiplatelet agents.
Hepatotoxicity that may lead to severe liver injury and failure requiring treatment discontinuation.
Possible cardiac effects including QT prolongation and arrhythmias.
Severe hypersensitivity reactions including anaphylaxis or Stevens-Johnson syndrome.
Tumor lysis syndrome with rapid tumor cell breakdown after initiation of therapy.
May impair fertility and cause fetal harm; contraindicated in pregnancy.
Risk of fluid retention and pleural effusions necessitating clinical monitoring.
Potential for pulmonary complications such as dyspnea and pleuritis.
Risk of growth retardation in pediatric patients receiving prolonged therapy.
Drug handling precautions to prevent exposure to broken or crushed tablets especially among pregnant women.
Avoid sudden discontinuation to prevent disease relapse.
Serious diarrhea and gastrointestinal adverse events can lead to dehydration and electrolyte imbalance.
Use with caution in patients with pre-existing heart, lung, or liver disease.

Contraindication

Known hypersensitivity to dasatinib or any component of Sprycel formulation.
Pregnancy, due to the high risk of fetal harm and teratogenicity.
Severe uncontrolled bleeding disorders where increased bleeding risk is unacceptable.
Severe hepatic impairment where metabolism of dasatinib is compromised.
Patients unable to swallow tablets when alternative formulations or administration methods are unavailable.
Concomitant use with strong CYP3A4 inducers that cannot be managed or avoided.
Patients with active, severe infections until adequately treated due to immunosuppression risk.
Known long QT syndrome or significant baseline cardiac arrhythmias without cardiac management.
Patients with prior history of severe pulmonary arterial hypertension without specialist evaluation.
Contraindicated in patients unwilling or unable to comply with pregnancy prevention requirements.
Known lactose intolerance if the tablet formulation contains lactose as an excipient.
Patients with severe hypersensitivity reactions to other tyrosine kinase inhibitors unless benefits outweigh risks.
Use in breastfeeding mothers due to unknown transfer and potential harm to the infant.
Concomitant use with medications or supplements increasing risk of enhanced QT interval prolongation.

Drug Interactions

Concomitant use with CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) can increase dasatinib levels and toxicity.
CYP3A4 inducers (e.g., rifampin, carbamazepine) can reduce dasatinib plasma concentration, decreasing efficacy.
Avoid grapefruit and grapefruit juice as they inhibit CYP3A4 and increase dasatinib exposure.
Concurrent use with antacids or proton pump inhibitors may reduce dasatinib absorption and effectiveness.
Increased bleeding risk when combined with anticoagulants (e.g., warfarin) or antiplatelet agents.
Potential pharmacodynamic interactions with other QT-prolonging drugs increasing arrhythmia risk.
Co-administration with drugs that lower potassium or magnesium may exacerbate cardiotoxic effects.
Dasatinib may affect metabolism of other drugs metabolized by CYP3A4 leading to altered plasma levels.
Use with caution when combined with strong CYP2C8 or CYP2D6 substrates due to minor metabolic overlap.
Increased risk of toxicity with other myelosuppressive agents due to additive bone marrow suppression.
Careful monitoring required when used with immunosuppressants due to additive immunosuppressive effects.
Potential interaction with herbal supplements such as St. John's Wort that induce CYP3A4 reducing efficacy.
Interactions with P-glycoprotein substrates or inhibitors can affect dasatinib pharmacokinetics.
Coadministration with certain antiepileptics (e.g., phenytoin) may reduce dasatinib levels.
Close monitoring required when combined with other oral anticancer agents.

Preparations Of The Drug

Sprycel is formulated as oral tablets available in strengths of 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg.
Tablets are film-coated to facilitate swallowing and protect stability.
Each tablet contains dasatinib active ingredient along with excipients including lactose monohydrate.
Tablets should be swallowed whole and not crushed or chewed to prevent inadvertent exposure.
Storage instructions recommend keeping tablets at room temperature away from moisture and heat.
Packaging includes blister packs or bottles with child-resistant caps for safety.
Special handling precautions include avoiding contact of broken tablets with skin or mucous membranes.
Bulk powder or intravenous formulations are not licensed; therapy is restricted to oral solid dosage forms.
Generic formulations of dasatinib are available with equivalent dosing and bioequivalence assured.
Medication guides and patient information leaflets accompany packaging for safe administration.