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 modeling 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 leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.
The pharmacokinetics of dasatinib have been evaluated in 229 healthy subjects and in 137 patients with leukemia.
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 35 hours.
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 resulted in a 14% increase in the mean AUC of dasatinib. The observed food effects were not clinically relevant.
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 100500 ng/mL.
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. In human liver microsomes, dasatinib was a weak time-dependent inhibitor of CYP3A4.
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.
Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled dasatinib, approximately 4% and 85% of the administered radioactivity was recovered in the urine and feces, respectively, within 10 days. 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.
Pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age and gender on the pharmacokinetics of SPRYCEL.
The pharmacokinetics of SPRYCEL have not been evaluated in pediatric patients.
No clinical studies were conducted with SPRYCEL in patients with impaired hepatic function. (See PRECAUTIONS.)
No clinical studies were conducted with SPRYCEL in patients with decreased renal function. Less than 4% of SPRYCEL and its metabolites are excreted via the kidney. (See PRECAUTIONS.)
SPRYCEL is not an inducer of human CYP enzymes. SPRYCEL is a time-dependent inhibitor of CYP3A4 and may decrease the metabolic clearance of drugs that are primarily metabolized by CYP3A4. (See PRECAUTIONS.) At clinically relevant concentrations, dasatinib does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.
Drugs that may increase dasatinib plasma concentrations
CYP3A4 Inhibitors: In a study of 18 patients with solid tumors, 20-mg dasatinib QD coadministered with 200 mg of ketoconazole BID increased the dasatinib Cmax and AUC by four- and five-fold, respectively. Substances that inhibit CYP3A4 activity (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) may decrease metabolism and increase concentrations of dasatinib (see PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION: Dose Modification).
Drugs that may decrease dasatinib plasma concentrations
CYP3A4 Inducers: Data from a study of 20 healthy subjects indicate that when a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampicin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively (see PRECAUTIONS: Drug Interactions).
Antacids: Nonclinical data indicate that dasatinib has pH dependent solubility. In a study of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed. (See PRECAUTIONS: Drug Interactions.)
Famotidine: In a study of 24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. (See PRECAUTIONS: Drug Interactions.)
Drugs that may have their plasma concentrations altered by dasatinib
CYP3A4 Substrates: Single dose data from a study of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of SPRYCEL. (See PRECAUTIONS: Drug Interactions.)