Sign Out
Pharmacology: Mechanism of Action: Dasatinib inhibits the activity of the BCR-ABL kinase and SRC family kinases (LYN, HCK), along with a number of other kinases including c-KIT, ephrin (EPH) receptor kinases, and PDGFβ receptor. Dasatinib is a potent inhibitor of the BCR-ABL and SRC family kinases with potency at sub-nanomolar concentrations. It binds not only to the inactive but also to the active conformation of the enzyme.
Pharmacodynamics: In vitro, dasatinib is active in leukemic cell lines representing variants of imatinib sensitive and resistant disease. These nonclinical studies show that dasatinib can overcome imatinib resistance resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations (14/15 mutations with exception of T315I), activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene, MDR1, overexpression.
In vivo, in separate experiments using murine models of CML, dasatinib prevented the progression of chronic CML to blast phase and prolonged the survival of mice bearing patient-derived CML cell lines.
Electrocardiogram: In five Phase II clinical studies in patients with leukemia, repeated baseline and on-treatment ECGs were obtained at pre-specified time points and read centrally for 865 patients receiving dasatinib 70 mg BID. QT interval was corrected for heart rate by Fridericia's method. At all post-dose time points on day 8, the mean changes from baseline in QTcF interval were 4 to 6 msec, with associated upper 95% confidence intervals <7 msec. Of the 2182 patients who received dasatinib in clinical trials, 21 patients (<1%) experienced a QTcF >500 msec. (See Precautions.)
Pharmacokinetics: The pharmacokinetics of dasatinib were evaluated in 229 healthy subjects and in 84 patients with leukemia.
Absorption: Dasatinib is rapidly absorbed in patients following oral administration. Peak concentrations were observed between 0.25 to 6 hours. The overall mean terminal half-life of dasatinib is approximately 3 to 5 hours.
Distribution: In patients, dasatinib has a large apparent volume of distribution (2505 L) suggesting that the drug is extensively distributed in the extravascular space.
Metabolism: Dasatinib is extensively metabolized in humans. In a study of 8 healthy subjects administered 100 mg of [14C]-labeled dasatinib, unchanged dasatinib represented 29% of circulating radioactivity in plasma. Plasma concentration and measured in vitro activity indicate that metabolites of dasatinib are unlikely to play a major role in the observed pharmacology of the drug. CYP3A4 is a major enzyme responsible for the metabolism of dasatinib.
Excretion: Elimination is predominantly in the feces, mostly as metabolites. Following a single oral dose of [14C]-labeled dasatinib, approximately 89% of the dose was eliminated within 10 days, with 4% and 85% of the administered radioactivity recovered in the urine and feces, respectively. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and feces, respectively, with the remainder of the dose being metabolites.
Special Populations and Conditions: Pediatrics: No clinical studies were conducted with dasatinib in pediatric populations.
Hepatic Insufficiency: The effect of hepatic impairment on the single-dose pharmacokinetics of dasatinib was assessed in 8 moderately hepatic impaired subjects who received a 50-mg dose and 5 severely hepatic impaired subjects who received a 20-mg dose compared to matched healthy subjects who received a 70-mg dose of dasatinib. The mean Cmax and AUC of dasatinib adjusted for the 70-mg dose was decreased by 47% and 8%, respectively, in moderate hepatic impairment compared to subjects with normal hepatic function. In severe hepatic impaired subjects, the mean Cmax and AUC adjusted for the 70-mg dose was decreased by 43% and 28%, respectively, compared to subjects with normal hepatic function. Hepatic impairment did not result in clinically meaningful change in dasatinib exposure at the doses studied. However no pharmacokinetic information is available from patients with hepatic impairment treated with a 70 to 100 mg dose of dasatinib. Due to limitations of this clinical study, caution is recommended in patients with hepatic impairment (see Precautions and Dosage & Administration).
Renal Insufficiency: No clinical studies were conducted with dasatinib in patients with decreased renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney. (See Precautions.)
Drug-Drug Interactions: See Interactions.
Drug-Food Interactions: Data from a study of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 minutes following consumption of a high-fat meal indicated a 14% increase in the mean AUC of dasatinib. Consumption of a low-fat meal 30 minutes prior to dasatinib resulted in a 21% increase in the mean AUC of dasatinib. The observed food effects do not represent clinically relevant changes in exposure.
