In this article, we will discuss Crizotinib (Mechanism of Action). So, let’s get started.
Mechanism of Action
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor
(HGFR, c-Met), and Recepteur d’Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene’s expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met.
Pharmacokinetics
Absorption
Following oral single-dose administration, crizotinib was absorbed with median time to achieve peak concentration of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8. Steady state systemic exposure (Cmin and AUC)
appeared to increase in a greater than dose proportional manner over the dose range of 200-300 mg twice daily. The mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%) following the administration of a single 250 mg oral dose. A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14%. Crizotinib can be administered with or without food.