Dasatinib

Dasatinib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.

The FDA approved Dasatinib for treating adults with newly diagnosed and advanced chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL).

After ingesting a high-fat meal, dasatinib absorption increases by 14% following a 100 mg single dose. The drug shows a large volume of distribution (2505 L) and high plasma protein binding (96% for Dasatinib, 93% for the active metabolite), undergoing extensive hepatic metabolism through the CYP3A4 isoenzyme. Elimination primarily occurs through faeces (85%), with additional urinary excretion (4%), including 0.1% as an unchanged drug.

The most common side effects of Dasatinib include nausea, vomiting, abdominal pain and rash.

Dasatinib is available as an oral tablet.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Dasatinib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.

A tyrosine kinase inhibitor with multiple targets is Dasatinib. At nanomolar concentrations, it inhibits BCR-ABL, c-KIT, EPHA2, PDGFRβ, and the SRC family (SRC, LCK, YES, FYN). In patients with CML, the tyrosine kinase activity of BCR-ABL is deregulated, resulting to the proliferation, growth and survival of cancerous hematopoietic cells. Compared to imatinib, Dasatinib has a greater affinity for both the active and inactive conformations of the ABL kinase domain. Dasatinib inhibits cell growth in cell lines overexpressing BCR-ABL in acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML). Moreover, Dasatinib exhibits activity in vitro against leukemic cell lines that are either imatinib-sensitive or --resistant.

Dasatinib is available as an oral tablet.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once daily, with or without food.

Dasatinib is indicated for the treatment of the following conditions:

Orally: Administer Dasatinib orally once daily at approximately the same time. Swallow tablets whole with a glass of water; do not open, break, or chew them. If a dose is missed, take it as soon as possible on the same day and resume the regular schedule the following day. Do not take additional capsules or tablets to compensate for a missed dose. Pregnant personnel should avoid exposure to crushed or broken tablets.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Dasatinib is available as an oral tablet.

Newly diagnosed: 100 mg PO every day (morning or evening); if the response is insufficient, may increase to 140 mg every day

Advanced CML: 140 mg PO qDay; if the response is inadequate, may raise to 180 mg qDay

180 mg PO qDay may be increased from 140 mg PO qDay in the event of insufficient response.

During Dasatinib treatment, avoid grapefruit or its juice to prevent potential drug metabolism issues. A diet high in protein, healthy fats, whole grains, vitamins, and minerals should be given priority to those suffering from chronic illnesses, such as cancer. Incorporate leafy greens, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, broccoli, cauliflower, and cabbage into your diet, along with beans and herbs. Avoid smoking and alcohol consumption. Refrain from fast and fried food, processed meats, refined carbs, and added sugars.

The dietary restriction should be individualized as per patient requirements.

The adverse reactions related to Dasatinib can be categorized as:

Cardiac conditions: Atrial fibrillation/flutter

Thrombosis and embolism (including deep vein thrombosis and pulmonary embolism) are examples of vascular disorders.

Pulmonary arterial hypertension and interstitial lung disease are signs of respiratory, thoracic, and mediastinal disorders.

Dermatologic reactions: erythema multiforme, Stevens-Johnson syndrome

Reactivation of the hepatitis B virus: Infection.

Disorders of the kidneys and urinary system: Nephrotic syndrome

Disorders of the blood and lymphatic system: Thrombotic microangiopathy

Disorders of the hepatobiliary system: Hepatotoxicity

The clinically relevant drug interactions of Dasatinib are briefly summarized here.

Alfentanil, cisapride, ciclosporin, fentanyl, pimozide, quinidine, simvastatin, sirolimus, tacrolimus, and ergot alkaloids are examples of medications whose concurrent use may raise their serum levels. NSAIDs, anticoagulants, and antiplatelet medications increase the risk of thrombocytopenia and bleeding.

Possibly Fatal: Antacid administration should be done two hours apart from dasatinib administration as it may lower plasma levels. May increase plasma levels w/ CYP3A4 inhibitors (e.g. atazanavir, clarithromycin, erythromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole). When combined with CYP3A4 inducers (such as carbamazepine, dexamethasone, phenytoin, phenobarbital, or rifampicin), plasma levels may be reduced.

Food interactions: Avoid St John's wort as it may decrease dasatinib levels. Avoid grapefruit juice as it could raise dasatinib levels.

The common side effects of Dasatinib include:

Myelosuppression (Thrombocytopenia, Neutropenia, Anemia)

Bleeding Events (CNS, Gastrointestinal Hemorrhages)

Fluid Retention (Ascites, Edema, Effusions)

QT Prolongation

Congestive Heart Failure

Infections

Headache

Gastrointestinal Disturbances (Nausea, Diarrhea, Abdominal Pain, Vomiting)

Musculoskeletal Pain

Rash

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

Pregnant women who receive Dasatinib may experience fetal harm based on the limited human data that is available. Adverse pharmacologic effects, such as hydrops fetal, fetal leukopenia, and fetal thrombocytopenia, have been linked to maternal exposure to Dasatinib.

Rat studies on animal reproduction have shown widespread the fetal period, mortality during organogenesis and in neonates; skeletal abnormalities have been noted in a small percentage of surviving rat and rabbit conceptuses; these results have been obtained at dasatinib plasma concentrations lower than those in humans receiving therapeutic doses of Dasatinib.

Inform a pregnant woman of the possible danger to the unborn child.

Dasatinib transplacental transfer has been documented.

Advise men who have female partners who are also capable of reproducing to use effective contraception both during and for 30 days following their last dose of treatment.

Animal research suggests that Dasatinib may harm the reproductive tissues of both men and women.

There is no data on Dasatinib's presence in human milk, the medication's effects on breastfed children, or the medication's impact on milk production.

Dasatinib, however, is found in nursing rats' milk.

The safety and efficacy of Dasatinib in the pediatric patients have not been extensively studied. Limited data are available, and caution is advised when considering its use in this population.

When the diagnosis is confirmed, start therapy no later than day 15 of induction chemotherapy and continue for two years.

Initial dosage recommendation based on body weight

Under 10 kg: Not recommended.

10 to <20 kg: 40 mg orally qDay; 20 to <30 kg: 60 mg orally qDay; 30 to <45 kg: 70 mg orally qDay; 45 to ≥45 kg: 100 mg PO qDay

Initial dosage recommendation based on body weight

Under 10 kg: Not recommended.

10 to <20 kg: 40 mg orally qDay

20 to <30 kg: 60 mg orally qDay

30 to <45 kg: 70 mg orally qDay

≥45 kg: 100 mg orally qDay

There are currently no clinical studies with Dasatinib in patients with impaired renal

function. Less than 4% of Dasatinib and its metabolites are excreted via the kidney.

Mild (Child-Pugh A): No dosage modification is required.

Moderate (Child-Pugh B): Mean Cmax is reduced by 47%, and mean AUC is decreased by 8% compared to patients with normal liver function.

Severe (Child-Pugh C): Mean Cmax is reduced by 43%, and mean AUC is decreased by 28% compared to patients with normal liver function.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Dasatinib.

Overconsumption of Dasatinib could result in significant platelet count reduction and myelosuppression.

In the event of a Dasatinib overdose, there is no specific antidote. Promptly discontinue the medication and initiate supportive care with close monitoring of hepatic function, electrolytes, and cardiac status. Activated charcoal may be administered to lower further absorption if ingestion is recent. Consider appropriate interventions for adverse effects, such as antiemetics or hematopoietic growth factors for myelosuppression. Due to Dasatinib's extensive protein binding, hemodialysis is unlikely to be beneficial. Supportive measures, including transfusions and antimicrobial therapy for infections, should be considered based on clinical presentation.

In clinical trials, 1% of patients receiving Dasatinib experienced a QTcF more significant than 500 ms, and less than 1% experienced QTc prolongation as an adverse reaction. Myelosuppression, cardiovascular toxicity, bleeding-related events, fluid retention, pulmonary arterial hypertension, severe dermatologic reactions, tumour lysis syndrome, and hepatotoxicity are further side effects linked to dasatinib use. It may also cause embryo-fetal toxicity and may lead to adverse reactions associated with bone growth and development in the pediatric patients.