Pharmacokinetics and Pharmacodynamics of Nilotinib in Gastrointestinal Stromal Tumors

Nilotinib is a second-generation, oral tyrosine kinase inhibitor that provides specific inhibition of KIT, platelet-derived growth factor receptors (PDGFRs) alpha and beta, as well as breakpoint cluster region Abelson. Studies in healthy volunteers and patients with chronic myelogenous leukemia or gastrointestinal stromal tumors (GIST) have shown that the pharmacokinetics (PK) of nilotinib are similar to those of imatinib and well suited to twice-daily administration of a 400-mg dose. These studies show that the maximum plasma concentration of nilotinib is reached 3 to 4 hours after oral administration, with an elimination half-life of 17 hours through metabolism via oxidation and hydroxylation. Bioavailability of nilotinib is increased if administered with a high-fat meal or with cytochrome P450 3A4 inhibitors, but consumption of high-fat meals to allow lower doses of nilotinib is not recommended. Proton pump inhibitors have not been shown to have a clinically significant impact on nilotinib PK. Several studies have demonstrated preliminary evidence that nilotinib provides clinical benefit and can be safely administered to imatinib-resistant GIST patients.