Dasatinib-50

Mechanism of Action

Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modelling 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 leukaemia (CML) and acute lymphoblastic leukaemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, Dasatinib was able to overcome imatinib resistance resulting from BCRABL kinase domain mutations, activation of alternate signalling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.

PharmacoKinetics

Absorption: Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib exhibits dose-proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg to 240 mg/day. The overall mean terminal half-life of dasatinib is 3–5 hours.

Data from a trial of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 minutes following consumption of a high-fat meal resulted in a 14% increase in the mean AUC of dasatinib. The observed food effects were not clinically relevant.

Distribution: In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting that the drug is extensively distributed in the extravascular space. Binding of dasatinib and its active metabolite to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence over the range of 100–500 ng/mL.

Metabolism: Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was 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 dasatinib AUC. This indicates that the active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also had several other inactive oxidative metabolites.

Dasatinib is a weak time-dependent inhibitor of CYP3A4. At clinically relevant concentrations, dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib is not an inducer of human CYP enzymes.

Elimination: Elimination is primarily via the faeces. Following a single oral dose of dasatinib, approximately 4% and 85% of the administered radioactivity was recovered in the urine and faeces, respectively, within 10 days. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and faeces, respectively, with the remainder of the dose being metabolites..

Adverse Reactions

Common side effects of Dasatinib in newly diagnosed chronic phase CML patients include myelosuppression, fluid retention, diarrhoea, headache, musculoskeletal pain, and rash. Occasionally, it may cause increased heartbeat and low or high blood pressure. Patients should contact their doctor if they face any side effects due to treatment.

Drug Interactions

Drugs such as CYP3A4 Inhibitors and CYP3A4 Inducers, Antacids and H2 Antagonists/Proton Pump Inhibitors, may alter available levels of Dasatinib and efficacy, thus requiring Dosage adjustment. If needed, antacid should be administered at least 2 hours prior to or 2 hours after Dasatinib dose, and Antacids in place of H2 antagonists or proton pump inhibitors are advised.

Precautions

1. Not recommended for use during pregnancy. It may cause harm to an unborn baby.

2. Dasatinib may cause severe thrombocytopenia, neutropenia, and/or anaemia which requires dose interruption or reduction. Patients are advised to monitor complete blood counts regularly and seek medical advice.

Dosage

Chronic phase CML: 100 mg once daily.

Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL: 140 mg once daily

To be administered orally, with or without a meal. Tablets should not be crushed or cut.

(*As advised by the doctor).

Storage

Do not store above 30°C.
Store in the original package in order to protect from moisture.
Keep all medications away from children and pets.

Overdose

Patients who ingest more than the recommended dosage should be closely monitored for myelosuppression and given appropriate supportive treatment.