Pharmacokinetics of Dasatinib

Abstract

Tyrosine kinase inhibitors have recently become an essential tool in management of chronic myeloid leukaemia (CML). Dasatinib, a representative of those drugs, acts by inhibiting key proteins included in CML development, predominantly Bcr-Abl and Src. Its advantage is that it shows activity in many cases where other agents bring no improvement due to resistance. Pharmacokinetics of dasatinib has specific characteristics that may play an important role in achieving sufficient exposure in patients. Therefore, the key pharmacokinetic properties are summarized in this report. For example, dasatinib absorption is significantly influenced by gastric pH and its modulation can be a source of serious interactions, as well as simultaneous administration of drugs affecting cytochrome P450.

Expression Patterns of CD44 and AREG Under Treatment With Selective Tyrosine Kinase Inhibitors in HPV+ and HPV− Squamous Cell Carcinoma

“…Dasatinib and nilotinib have been investigated in hematopoietic malignancies and inhibit plateletderived growth factor-β receptor signaling, ephrin receptor kinases and mast/stem cell growth factor receptor (23). Dasatinib has also been shown to inhibit sarcoma tyrosine kinase (SRC) family kinases, a major means of resistance to anti-HER2 therapy in patients with breast cancer (24)(25)(26).…”

Anti-Senescence Therapy

“…Dasatinib, quercetin, and fisetin are the most well-studied senolytic agents [22]. Dasatinib is a secondgeneration tyrosine kinase inhibitor that is used for the treatment of CML and AML [23]. Quercetin is a polyphenolic flavonoid compound with antioxidant properties, which exerts preventive effects for various diseases, such as osteoporosis, some forms of cancer, tumors, and lung and cardiovascular diseases [24].…”

Therapeutic Drug Monitoring and Individualized Medicine of Dasatinib: Focus on Clinical Pharmacokinetics and Pharmacodynamics

“…Dasatinib is rapidly absorbed following oral administration with time to C max (T max ) ranging from 0.5 to 6 h ( European Medicines Agency, 2006 ). With the emergence of more studies, T max values observed among subjects ranged from 0.28 to 6.3 h ( Horinkova et al, 2019 ). The oral bioavailability was rather low in preclinical studies with values ranging from 45 to 51% ( Luo et al, 2006a ), whereas other studies showed bioavailability from 14 to 34% ( Kamath et al, 2008b ).…”

“…Dasatinib is metabolized in humans, primarily by CYP3A4, and flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites ( Bristol-Myers Squibb, 2017 ). Routes of metabolism include hydroxylation, N-dealkylation, N-oxidation, alcohol oxidation and direct glucuronide or sulphate conjugation ( Horinkova et al, 2019 ). There are five phase I circulating metabolites: M4, M5, M6, M20 and M24, among which M20 and M24 represent 45 and 25% of the AUC 0-24 of dasatinib, respectively.…”