Dasatinib

Dasatinib is a thiazole carboxamide oral multikinase inhibitor that inhibits BCR-ABL and SRC kinases that is used for the treatment of chronic myeloid leukaemia and BCR-ABL positive acute lymphoblastic leukaemia.

Mechanism of Action

The kinases inhibited by dasatinib include

1. BCR-ABL
2. SRC family (SRC, LCK, YES, FYN)
3. c-KIT
4. Epirin A receptor
5. Platelet derived growth factor β (PDGF-β) receptors

BCR-ABL kinase inhibition
As an inhibitor of BCR-ABL kinase dasatinib is 325 times more potent than imatinib and 16 times more potent than nilotinib. Unlike imatininb and nilotinib dasatinib binds the active and the inactive configurations of the enzyme. It is effective against mutations that have destabilized the inactive configuration. Unlike imatinib chronic inhibition of the kinase in not achieved and does not appear to be necessary for action. Activity of dasatinib appears to be related to the peak levels and the side effects to the nadir. In keeping with this observation, once a day therapy with dasatinib is as effective and less toxic than the same dose administered in two daily doses. Though dasatinib targets cells that are more premature than imatinib, it has no action against the CML stem cell. Dasatinib therapy, like imatinib and nilotinib, is needed lifelong. Dasatinib is ineffective against cells carrying the T315I mutation.

Inhibition of Other Kinases
Dasatinib has immunomodulatory effects. Inhibition of PDGF-β receptors may be responsible for the chylous effusion seen with dasatinib.

Pharmacokinetics

Dasatinib is rapidly absorbed on oral administration and peak levels are achieved in 0.5-3 hours. Absorption is not affected by food. The solubility of dasatinib decreases with increasing pH.  It is highly protein bound (96%). The volume of distribution is large (2505L) indicating extensive extravascular distribution. The concentrations achieved depend on the total dose and schedule. Once a day therapy results in doubling of C_max and halving of C_min. Efficacy of dasatinib is related to the average concentration. The toxicity of dasatinib increases with age and with C_min. These observations suggest that once a day therapy would be efficacious and less toxic and this is borne out in clinical trials (Haematologica. 2010; 95: 232–240). Animal studies show that dasatinib crosses the blood brain barrier and achieves therapeutic concentrations in the CSF. In patients of Ph+ve ALL the CSF levels have ranged from 5-28% of plasma levels and this has correlated with sustained responses in patients with Ph +ve CML in BC or Ph +ve ALL (Blood 2008; 112:1005-12). Dasatinib is metabolized by the liver and the metabolites are eliminated in the feces. There are no active metabolites. Only about 4% of the drug is eliminated in the urine mostly in the form of metabolites. No dose reduction is needed for liver of kidney dysfunction.

Drug Interactions

Four potential processes at that drugs can interact with dasatinib include absorption, protein binding, drug metabolism and effect of the QT interval.

1. Dasatinib and Inhibitors of acid secretion: Famotidine decreases dasatinib exposure by 61%. H-2 antagonists and proton pump inhibitors should not be used with dasatinib. Antacids may be used but an interval of at least 2 hours must separate dasatinib and antacids.
2. Protein Binding: Dasatinib is highly protein bound. Displacement from protein binding has the potential tom increase the dasatininb levels. No such interaction has been identified.
3. Dasatinib Metabolism: Dasatinib is a substrate for and an inhibits CYP3A4 and dasatinib levels may be affected by inhibitors and inducers of CYP3A4.
   1. Inhibitors of CYP3A4: Ketoconazole may increase the exposure to dasatinib. Other drugs that may show a similar effects include iraconazole, voraconazole, verapamil, erythromycin, clarythromycin and cyclosporine.
   2. Inducers of CYP3A4: Rifampicin induces CYP3A4 and reduces exposure to dasatinib by  80%.  Phenobarbital, phenytoin, carbamazepine are expected to have the same effect.
4. Drugs prolonging QT interval: Dasatinib prolongs the QT interval and should be used with caution with other agents that prolong QT.
5. Others: Dasatinib increases the simvastatin by about 20%

Adverse Effects

1. Myelosupression: Myelosupression manifests as neutropenia and /or thrombocytopenia and is more frequent in patients with advanced CML or acute lymphoblastic leukaemia. It is less common when the drug is administered at a dose of 100mg once a day dose than other dosing schedules. It is reversible of withholding the drug.
2. Fluid Retention: Fluid retention is seen in about one-third of the patients. About 4-10% have severe fluid retention. The incidence of pleural effusions is lower when the drug is administered at a dose of 100mg once a day.
3. Cardiopulmonary toxicity: Cardiopulmonary toxicity manifests as congestive cardiac failure, QT prolongation and pulmonary hypertenssion. Pericardial effusions may be seen.
4. Hepatotoxicity: Hepatic toxicity manifests as elevated transaminases.
5. Musculoskeletal system: Musculoskeletal toxicity manifests as arthralgia and myalgia and cramps.
6. Gastrointestinal toxicity: Gastrointestinal toxicity includes nausea, vomiting, dyspepsia, diarrhoea and gastrointestinal bleed.
7. Others:  Fatigue, asthenia and anorexia may be seen. Dasatinib use has been associated with hypocalcaemia and hypophosphataemia

Indication

1. Chronic Myeloid Leukaemia: Dasatinib is indicated for chronic phase, accelerated phase and blast crisis of chronic myeloid leukaemia. It may be used in first line setting or in patients who progress or are intolerant to imatinib. It is not effective in the T515I mutation.
2. Ph +ve Acute Lymphoblastic Leukaemia resistant or intolerant to previous TKI therapy.

Dose

1. Chronic myeloid Leukaemia:
   1. Chronic Phase: 100mg once a day. The dose may be increased to a maximum of 140mg once a day.
   2. Acclerated Phase and Blast Crisis: 140mg once a day. The dose may be increased to a maximum of 180mg once a day.
2. Ph +ve Acute Lymphoblastic Leukaemia: 140mg once a day. The dose may be increased to a maximum of 180mg once a day.

For dose modification for neutropenia and thrombocytopenia refer to sprycel.com.